ESC ACCAHA and Malaysian CPG Guidelines on lipids Statins Introduction to non-statins Guideline recommendations for non-statins Clinical trials of non-statin drugs

Non-statin vs placebo

Non-statin vs placebo (on background of statin-based lipid-lowering therapy)

Non-statin + statin vs placebo Non-statins on the horizon Conclusions

25-year-old lady presented at 12 weeks of pregnancy with NSTEMI in Feb 2015She declined termination of pregnancy despite being advised by the feto-maternal specialist

Past historyCoronary Angiogram (Jan 2014) severe ostial LMS and severe RCA stenosisECHO EF 69 Supravalvular AS calcified aortic cusps (AVA 10cm2)Planned for CABG in Feb 2014 but patient defaulted

Premorbid medical history Homozygous Familial Hypercholesterolemia - (Total chol 177 LDL 153)Hypertension

Family history Father - CABG 48yr and sister- PCI RCA 31yr

Tight LMSTight ostial RCA

More emphasise on diet and healthy lifestyle Statin remains the mainstay treatment then combination

therapy with ezetimibe and as a third line the new PCSK9 inhibitors

Focus on ASCVD risk reduction 4 statin benefit groups

Clinical ASCVD

Diabetes aged 40-75 years with LDL-C 70-189 mgdL

LDL-C level gt190mgdl

Estimated 10-year risk of ASCVD of gt75aged 40-75 years with

LDL-C 70-189 mgdL

Stone NJ Robinson J Lichtenstein AH et al 2013 ACCAHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults A Report of the American College of CardiologyAmerican Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 2013

ASCVD atherosclerotic cardiovascular disease LDL-C Low-density lipoprotein cholesterol

Stone NJ et al J Am Coll Cardiol 2013 doi101016jjacc201311002 Available at httpcontentonlinejaccorgarticleaspxarticleid=1770217 Accessed November 13 2013

11

ASCVD Statin Benefit GroupsHeart healthy lifestyle habits are the foundation of ASCVD prevention

ASCVD prevention benefit of statin therapy may be less clear in other groups Consider additional factors influencing ASCVD risk potential ASCVD risk benefits and adverse effects drug-drug interactions and patient preferences for statin treatment

With LDL-C of 70-189 mgdLdagger Estimated using the Pooled Cohort Risk Assessment Equations

Clinical ASCVD

bull High-Intensity statin (age le75 years)

bull Moderate-intensity statin if gt75 years or not a candidate for high-intensity statin

LDL-C ge49 mmolL

bull High-intensity statin

bull Moderate-intensity statin if not a candidate for high-intensity statin

Diabetes age 40-75 years

bull Moderate-intensity statin

bull High-intensity statin if estimated 10 year ASCVD risk ge75

Estimated 10-yr ASCVD risk ge75dagger

age 40-75 years

bull Moderate- to high-intensity statin

Look at1 Family history of premature ASCVD2 LDL-C gt160 mgdl (42mmolL)3 hsCRP ge2 mgdl4 Calcium score ge300 Agatston units or ge75th 5 Sex6 Ethnicity7 Ankle-brachial index lt098 Elevated lifetime risk of ASCVD

Stone NJ Robinson J Lichtenstein AH et al 2013 ACCAHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults A Report of the American College of CardiologyAmerican Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 2013

daggerEvidence from 1 RCT only down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (47)DaggerAlthough simvastatin 80 mg was evaluated in RCTs initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy including rhabdomyolysis

High Moderate and Low-Intensity Statin Therapy (Used in the RCTs reviewed by the Expert Panel)

High-Intensity StatinTherapy

Moderate-Intensity StatinTherapy

Low-Intensity StatinTherapy

Daily dose lowers LDLndashC by approximately ge50

Daily dose lowers LDLndashC by approximately 30 to lt50

Daily dose lowers LDLndashC by lt30

Atorvastatin (40dagger)ndash80 mg Rosuvastatin 20 (40) mg

Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin 20ndash40 mgDagger Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2ndash4 mg

Simvastatin 10 mg Pravastatin 10ndash20 mg Lovastatin 20 mg Fluvastatin 20ndash40 mg Pitavastatin 1 mg

Treat patients aggressively with the right statin dose and intensity for the patients thatrsquos been proven to benefit most from statin treatment

LDL-C targets should NOT be the ONLY determination factor to initiate statin treatment Treat to reduce the CV risk and not just the LDL-C numbers alone

Jones P et al Comparison of the efficacy and safety of rosuvastatin versus atorvastatin simvastatin and pravastatin across doses (STELLAR Trial) Am J Cardiol 200392152-160

The STELLAR study

Rosuvastatin

Atorvastatin

Simvastatin

Pravastatin

X

X

X

ndash60

ndash50

ndash40

ndash30

ndash20

ndash10

0

Dose mg (log scale)10 20 40 80

X

n = 648

n = 473n = 634

n = 485

daggerDagger

Cha

nge

in L

DL-

C fr

om

base

line

() X

Plt002 vs atorvastatin 10 mg simvastatin 10 20 40 mg pravastatin 10 20 40 mgdaggerPlt002 vs atorvastatin 20 40 mg simvastatin 20 40 80 mg pravastatin 20 40 mgDaggerPlt002 vs atorvastatin 40 mg simvastatin 40 80 mg pravastatin 40 mg

dagger

Dagger

Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease the Scandinavian Simvastatin Survival Study (4S) Lancet 19943441383-1389

085

080

000

00

100

095

090

Pro

porti

on a

live

Years since randomisation

Placebo

Simvastatin

64321 5

Log rank P = 0003

Non-statins have been investigated for potential benefit in atherosclerotic cardiovascular disease (ASCVD)

This presentation surveys the clinical evidence to date

bull Cholesterol absorption inhibitors (ezetimibe)

bull Fibrates

bull Omega-3 polyunsaturated fatty acids (PUFAs)

bull Niacin

bull Emerging products

bull PCSK9 inhibitors

bull Cholesterylester transfer protein (CETP) inhibitors

ACCAHA guidelines (2014) do not support routine use of non-statins alone or in combination with statins1

Benefits not acceptable relative to potential adverse effects NICE lipid guidelines (2014) recommend against

non-statins23

No evidence of benefit ESCEAS guidelines (2012) recommend non-statins in limited

situations4

Lipid target not reached with maximally tolerated statin

Statin not tolerated 1 Stone NJ et al J Am Coll Cardiol 2014632889ndash29342 Rabar S et al BMJ 2014349g4356 doi101136bmjg4356

3 National Institute for Health and Care ExcellenceLipid modification July 2014 httpwwwniceorgukGuidanceCG181

4 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash1701

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

FIELD Fenofibrate did not reduce primary outcome (CHD death or nonfatal

MI) in patients with diabetes

FIELD fenofibrate 200 mgd vs placebo in 9795 patients with type 2 diabetesMedian follow-up 5 years

307

11

193

31

11

20

26

112

187

243

113147

00

05

10

15

20

25

30

35

LDL-C HDL-C TGs

Placebo baseline Fenofibrate baseline

Placebo study end Fenofibrate study end

Mea

n lip

id le

vel (

mm

olL

)R

ate

1000

per

son-

year

s

104

44

64 64

142

119117

37

8471

129

150

02468

10121416

Primary outcome CHD mortality Nonfatal MI Stroke All-cause mortality Coronary revascularization

Fenofibrate PlaceboHR 089

95 CI 075 to 105p=016dagger

p=022

p=036

p=018

HR 07695 CI 062 to 094

p=001

HR 07995 CI 068 to 093

p=0003

Keech A et al Lancet 20053661849ndash1861

CHD mortality or nonfatal MIdaggerARR over course of study=07 NNT=143NNT number needed to treat

Keech p7 ndash 1E

Meta-analysis Fibrates may reduce CV events

but not all-cause mortality

151005

090 (082 to 100) p=0048I2=470 p for heterogeneity=0110

087 (081 to 093) plt00001I2=221 p for heterogeneity=0202

081 (075 to 089) plt00001I2=145 p for heterogeneity=0310

100 (093 to 108) p=0918I2=194 p for heterogeneity=0237

Relative risk (95 CI)

5Major CV events

16Coronary event

10Nonfatal coronary events

16All-cause mortality

Number of studies included

Favors placeboFavors fibrateRelative risk (95 CI)

Jun M et al Lancet 20103621563ndash1574Reprinted from The Lancet Volume 362 Jun M et al Effects of fibrates on cardiovascular outcomes

a systematic review and meta-analysis 1563ndash1574 Copyright 2010 with permission from ElsevierMI and stroke

Meta-analysis of 18 placebo-controlled fibrate trials (45 058 patients)

Docosahexenoic acid (DHA)

Eicosapentenoic acid (EPA)

PUFAs Found in fish oil and Mediterranean diet1

Have been used to lower TG1

Omega-3 fatty acids

EPA1

Marketed omega-3 fatty acids include Vascepa (ethyl-EPA)2

Lovaza (mixture of ethyl-esterified EPA DHA and other fish oils)3

1 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash17012 Vascepa Prescribing Information httpwwwdrugscomprovascepahtml

3 Lovaza Prescribing Information httpswwwgsksourcecomgskprmhtdocsdocumentsLOVAZA-PI-PILPDF

Placebo-controlled trials of omega-3 fatty acids

have reported beneficial effects on CV outcomes

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin vs placebo

DART1Men previous MI(n=2033)

Dietary fish intakeMean 2 years

No significant change in total-C over 2 years

All-cause mortality darr29 (plt005)

GISSI-P2 Recent MI (n=11 324)

Omega-3 PUFA1 gd vs control Mean 35 years

LDL-C uarr99 (p=0002) HDL-C uarr88 (p=NS)TGs darr34 (p=0001)

Death nonfatal MI or nonfatal stroke darr10 (p=0048)

GISSI-HF3 Chronic HF(n=6975)

Omega-3 PUFA1 gd vs placebo Median 39 years

TGs darr from 142 to 134 mmolL over 3 years with PUFA (plt00001 vs placebo)

All-cause death darr9 (p=0041)All-cause death or CV hospitalization darr8 (p=0009)

1 Burr ML et al Lancet 19892757ndash7612 GISSI-Prevenzione Investigators Lancet 1999354447ndash455

3 GISSI-HF Investigators Lancet 20083721223ndash1230

Statin use was 5 at study baseline rising to 46 after 42 monthsrsquo follow-upPatients were also randomized to rosuvastatin or placebo no interaction was recorded between PUFA and statin

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Cholesterol absorption inhibitor

Ezetimibe

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

25-year-old lady presented at 12 weeks of pregnancy with NSTEMI in Feb 2015She declined termination of pregnancy despite being advised by the feto-maternal specialist

Past historyCoronary Angiogram (Jan 2014) severe ostial LMS and severe RCA stenosisECHO EF 69 Supravalvular AS calcified aortic cusps (AVA 10cm2)Planned for CABG in Feb 2014 but patient defaulted

Premorbid medical history Homozygous Familial Hypercholesterolemia - (Total chol 177 LDL 153)Hypertension

Family history Father - CABG 48yr and sister- PCI RCA 31yr

Tight LMSTight ostial RCA

More emphasise on diet and healthy lifestyle Statin remains the mainstay treatment then combination

therapy with ezetimibe and as a third line the new PCSK9 inhibitors

Focus on ASCVD risk reduction 4 statin benefit groups

Clinical ASCVD

Diabetes aged 40-75 years with LDL-C 70-189 mgdL

LDL-C level gt190mgdl

Estimated 10-year risk of ASCVD of gt75aged 40-75 years with

LDL-C 70-189 mgdL

Stone NJ Robinson J Lichtenstein AH et al 2013 ACCAHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults A Report of the American College of CardiologyAmerican Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 2013

ASCVD atherosclerotic cardiovascular disease LDL-C Low-density lipoprotein cholesterol

Stone NJ et al J Am Coll Cardiol 2013 doi101016jjacc201311002 Available at httpcontentonlinejaccorgarticleaspxarticleid=1770217 Accessed November 13 2013

11

ASCVD Statin Benefit GroupsHeart healthy lifestyle habits are the foundation of ASCVD prevention

ASCVD prevention benefit of statin therapy may be less clear in other groups Consider additional factors influencing ASCVD risk potential ASCVD risk benefits and adverse effects drug-drug interactions and patient preferences for statin treatment

With LDL-C of 70-189 mgdLdagger Estimated using the Pooled Cohort Risk Assessment Equations

Clinical ASCVD

bull High-Intensity statin (age le75 years)

bull Moderate-intensity statin if gt75 years or not a candidate for high-intensity statin

LDL-C ge49 mmolL

bull High-intensity statin

bull Moderate-intensity statin if not a candidate for high-intensity statin

Diabetes age 40-75 years

bull Moderate-intensity statin

bull High-intensity statin if estimated 10 year ASCVD risk ge75

Estimated 10-yr ASCVD risk ge75dagger

age 40-75 years

bull Moderate- to high-intensity statin

Look at1 Family history of premature ASCVD2 LDL-C gt160 mgdl (42mmolL)3 hsCRP ge2 mgdl4 Calcium score ge300 Agatston units or ge75th 5 Sex6 Ethnicity7 Ankle-brachial index lt098 Elevated lifetime risk of ASCVD

Stone NJ Robinson J Lichtenstein AH et al 2013 ACCAHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults A Report of the American College of CardiologyAmerican Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 2013

daggerEvidence from 1 RCT only down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (47)DaggerAlthough simvastatin 80 mg was evaluated in RCTs initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy including rhabdomyolysis

High Moderate and Low-Intensity Statin Therapy (Used in the RCTs reviewed by the Expert Panel)

High-Intensity StatinTherapy

Moderate-Intensity StatinTherapy

Low-Intensity StatinTherapy

Daily dose lowers LDLndashC by approximately ge50

Daily dose lowers LDLndashC by approximately 30 to lt50

Daily dose lowers LDLndashC by lt30

Atorvastatin (40dagger)ndash80 mg Rosuvastatin 20 (40) mg

Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin 20ndash40 mgDagger Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2ndash4 mg

Simvastatin 10 mg Pravastatin 10ndash20 mg Lovastatin 20 mg Fluvastatin 20ndash40 mg Pitavastatin 1 mg

Treat patients aggressively with the right statin dose and intensity for the patients thatrsquos been proven to benefit most from statin treatment

LDL-C targets should NOT be the ONLY determination factor to initiate statin treatment Treat to reduce the CV risk and not just the LDL-C numbers alone

Jones P et al Comparison of the efficacy and safety of rosuvastatin versus atorvastatin simvastatin and pravastatin across doses (STELLAR Trial) Am J Cardiol 200392152-160

The STELLAR study

Rosuvastatin

Atorvastatin

Simvastatin

Pravastatin

X

X

X

ndash60

ndash50

ndash40

ndash30

ndash20

ndash10

0

Dose mg (log scale)10 20 40 80

X

n = 648

n = 473n = 634

n = 485

daggerDagger

Cha

nge

in L

DL-

C fr

om

base

line

() X

Plt002 vs atorvastatin 10 mg simvastatin 10 20 40 mg pravastatin 10 20 40 mgdaggerPlt002 vs atorvastatin 20 40 mg simvastatin 20 40 80 mg pravastatin 20 40 mgDaggerPlt002 vs atorvastatin 40 mg simvastatin 40 80 mg pravastatin 40 mg

dagger

Dagger

Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease the Scandinavian Simvastatin Survival Study (4S) Lancet 19943441383-1389

085

080

000

00

100

095

090

Pro

porti

on a

live

Years since randomisation

Placebo

Simvastatin

64321 5

Log rank P = 0003

Non-statins have been investigated for potential benefit in atherosclerotic cardiovascular disease (ASCVD)

This presentation surveys the clinical evidence to date

bull Cholesterol absorption inhibitors (ezetimibe)

bull Fibrates

bull Omega-3 polyunsaturated fatty acids (PUFAs)

bull Niacin

bull Emerging products

bull PCSK9 inhibitors

bull Cholesterylester transfer protein (CETP) inhibitors

ACCAHA guidelines (2014) do not support routine use of non-statins alone or in combination with statins1

Benefits not acceptable relative to potential adverse effects NICE lipid guidelines (2014) recommend against

non-statins23

No evidence of benefit ESCEAS guidelines (2012) recommend non-statins in limited

situations4

Lipid target not reached with maximally tolerated statin

Statin not tolerated 1 Stone NJ et al J Am Coll Cardiol 2014632889ndash29342 Rabar S et al BMJ 2014349g4356 doi101136bmjg4356

3 National Institute for Health and Care ExcellenceLipid modification July 2014 httpwwwniceorgukGuidanceCG181

4 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash1701

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

FIELD Fenofibrate did not reduce primary outcome (CHD death or nonfatal

MI) in patients with diabetes

FIELD fenofibrate 200 mgd vs placebo in 9795 patients with type 2 diabetesMedian follow-up 5 years

307

11

193

31

11

20

26

112

187

243

113147

00

05

10

15

20

25

30

35

LDL-C HDL-C TGs

Placebo baseline Fenofibrate baseline

Placebo study end Fenofibrate study end

Mea

n lip

id le

vel (

mm

olL

)R

ate

1000

per

son-

year

s

104

44

64 64

142

119117

37

8471

129

150

02468

10121416

Primary outcome CHD mortality Nonfatal MI Stroke All-cause mortality Coronary revascularization

Fenofibrate PlaceboHR 089

95 CI 075 to 105p=016dagger

p=022

p=036

p=018

HR 07695 CI 062 to 094

p=001

HR 07995 CI 068 to 093

p=0003

Keech A et al Lancet 20053661849ndash1861

CHD mortality or nonfatal MIdaggerARR over course of study=07 NNT=143NNT number needed to treat

Keech p7 ndash 1E

Meta-analysis Fibrates may reduce CV events

but not all-cause mortality

151005

090 (082 to 100) p=0048I2=470 p for heterogeneity=0110

087 (081 to 093) plt00001I2=221 p for heterogeneity=0202

081 (075 to 089) plt00001I2=145 p for heterogeneity=0310

100 (093 to 108) p=0918I2=194 p for heterogeneity=0237

Relative risk (95 CI)

5Major CV events

16Coronary event

10Nonfatal coronary events

16All-cause mortality

Number of studies included

Favors placeboFavors fibrateRelative risk (95 CI)

Jun M et al Lancet 20103621563ndash1574Reprinted from The Lancet Volume 362 Jun M et al Effects of fibrates on cardiovascular outcomes

a systematic review and meta-analysis 1563ndash1574 Copyright 2010 with permission from ElsevierMI and stroke

Meta-analysis of 18 placebo-controlled fibrate trials (45 058 patients)

Docosahexenoic acid (DHA)

Eicosapentenoic acid (EPA)

PUFAs Found in fish oil and Mediterranean diet1

Have been used to lower TG1

Omega-3 fatty acids

EPA1

Marketed omega-3 fatty acids include Vascepa (ethyl-EPA)2

Lovaza (mixture of ethyl-esterified EPA DHA and other fish oils)3

1 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash17012 Vascepa Prescribing Information httpwwwdrugscomprovascepahtml

3 Lovaza Prescribing Information httpswwwgsksourcecomgskprmhtdocsdocumentsLOVAZA-PI-PILPDF

Placebo-controlled trials of omega-3 fatty acids

have reported beneficial effects on CV outcomes

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin vs placebo

DART1Men previous MI(n=2033)

Dietary fish intakeMean 2 years

No significant change in total-C over 2 years

All-cause mortality darr29 (plt005)

GISSI-P2 Recent MI (n=11 324)

Omega-3 PUFA1 gd vs control Mean 35 years

LDL-C uarr99 (p=0002) HDL-C uarr88 (p=NS)TGs darr34 (p=0001)

Death nonfatal MI or nonfatal stroke darr10 (p=0048)

GISSI-HF3 Chronic HF(n=6975)

Omega-3 PUFA1 gd vs placebo Median 39 years

TGs darr from 142 to 134 mmolL over 3 years with PUFA (plt00001 vs placebo)

All-cause death darr9 (p=0041)All-cause death or CV hospitalization darr8 (p=0009)

1 Burr ML et al Lancet 19892757ndash7612 GISSI-Prevenzione Investigators Lancet 1999354447ndash455

3 GISSI-HF Investigators Lancet 20083721223ndash1230

Statin use was 5 at study baseline rising to 46 after 42 monthsrsquo follow-upPatients were also randomized to rosuvastatin or placebo no interaction was recorded between PUFA and statin

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Cholesterol absorption inhibitor

Ezetimibe

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Tight LMSTight ostial RCA

More emphasise on diet and healthy lifestyle Statin remains the mainstay treatment then combination

therapy with ezetimibe and as a third line the new PCSK9 inhibitors

Focus on ASCVD risk reduction 4 statin benefit groups

Clinical ASCVD

Diabetes aged 40-75 years with LDL-C 70-189 mgdL

LDL-C level gt190mgdl

Estimated 10-year risk of ASCVD of gt75aged 40-75 years with

LDL-C 70-189 mgdL

Stone NJ Robinson J Lichtenstein AH et al 2013 ACCAHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults A Report of the American College of CardiologyAmerican Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 2013

ASCVD atherosclerotic cardiovascular disease LDL-C Low-density lipoprotein cholesterol

Stone NJ et al J Am Coll Cardiol 2013 doi101016jjacc201311002 Available at httpcontentonlinejaccorgarticleaspxarticleid=1770217 Accessed November 13 2013

11

ASCVD Statin Benefit GroupsHeart healthy lifestyle habits are the foundation of ASCVD prevention

ASCVD prevention benefit of statin therapy may be less clear in other groups Consider additional factors influencing ASCVD risk potential ASCVD risk benefits and adverse effects drug-drug interactions and patient preferences for statin treatment

With LDL-C of 70-189 mgdLdagger Estimated using the Pooled Cohort Risk Assessment Equations

Clinical ASCVD

bull High-Intensity statin (age le75 years)

bull Moderate-intensity statin if gt75 years or not a candidate for high-intensity statin

LDL-C ge49 mmolL

bull High-intensity statin

bull Moderate-intensity statin if not a candidate for high-intensity statin

Diabetes age 40-75 years

bull Moderate-intensity statin

bull High-intensity statin if estimated 10 year ASCVD risk ge75

Estimated 10-yr ASCVD risk ge75dagger

age 40-75 years

bull Moderate- to high-intensity statin

Look at1 Family history of premature ASCVD2 LDL-C gt160 mgdl (42mmolL)3 hsCRP ge2 mgdl4 Calcium score ge300 Agatston units or ge75th 5 Sex6 Ethnicity7 Ankle-brachial index lt098 Elevated lifetime risk of ASCVD

Stone NJ Robinson J Lichtenstein AH et al 2013 ACCAHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults A Report of the American College of CardiologyAmerican Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 2013

daggerEvidence from 1 RCT only down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (47)DaggerAlthough simvastatin 80 mg was evaluated in RCTs initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy including rhabdomyolysis

High Moderate and Low-Intensity Statin Therapy (Used in the RCTs reviewed by the Expert Panel)

High-Intensity StatinTherapy

Moderate-Intensity StatinTherapy

Low-Intensity StatinTherapy

Daily dose lowers LDLndashC by approximately ge50

Daily dose lowers LDLndashC by approximately 30 to lt50

Daily dose lowers LDLndashC by lt30

Atorvastatin (40dagger)ndash80 mg Rosuvastatin 20 (40) mg

Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin 20ndash40 mgDagger Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2ndash4 mg

Simvastatin 10 mg Pravastatin 10ndash20 mg Lovastatin 20 mg Fluvastatin 20ndash40 mg Pitavastatin 1 mg

Treat patients aggressively with the right statin dose and intensity for the patients thatrsquos been proven to benefit most from statin treatment

LDL-C targets should NOT be the ONLY determination factor to initiate statin treatment Treat to reduce the CV risk and not just the LDL-C numbers alone

Jones P et al Comparison of the efficacy and safety of rosuvastatin versus atorvastatin simvastatin and pravastatin across doses (STELLAR Trial) Am J Cardiol 200392152-160

The STELLAR study

Rosuvastatin

Atorvastatin

Simvastatin

Pravastatin

X

X

X

ndash60

ndash50

ndash40

ndash30

ndash20

ndash10

0

Dose mg (log scale)10 20 40 80

X

n = 648

n = 473n = 634

n = 485

daggerDagger

Cha

nge

in L

DL-

C fr

om

base

line

() X

Plt002 vs atorvastatin 10 mg simvastatin 10 20 40 mg pravastatin 10 20 40 mgdaggerPlt002 vs atorvastatin 20 40 mg simvastatin 20 40 80 mg pravastatin 20 40 mgDaggerPlt002 vs atorvastatin 40 mg simvastatin 40 80 mg pravastatin 40 mg

dagger

Dagger

Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease the Scandinavian Simvastatin Survival Study (4S) Lancet 19943441383-1389

085

080

000

00

100

095

090

Pro

porti

on a

live

Years since randomisation

Placebo

Simvastatin

64321 5

Log rank P = 0003

Non-statins have been investigated for potential benefit in atherosclerotic cardiovascular disease (ASCVD)

This presentation surveys the clinical evidence to date

bull Cholesterol absorption inhibitors (ezetimibe)

bull Fibrates

bull Omega-3 polyunsaturated fatty acids (PUFAs)

bull Niacin

bull Emerging products

bull PCSK9 inhibitors

bull Cholesterylester transfer protein (CETP) inhibitors

ACCAHA guidelines (2014) do not support routine use of non-statins alone or in combination with statins1

Benefits not acceptable relative to potential adverse effects NICE lipid guidelines (2014) recommend against

non-statins23

No evidence of benefit ESCEAS guidelines (2012) recommend non-statins in limited

situations4

Lipid target not reached with maximally tolerated statin

Statin not tolerated 1 Stone NJ et al J Am Coll Cardiol 2014632889ndash29342 Rabar S et al BMJ 2014349g4356 doi101136bmjg4356

3 National Institute for Health and Care ExcellenceLipid modification July 2014 httpwwwniceorgukGuidanceCG181

4 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash1701

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

FIELD Fenofibrate did not reduce primary outcome (CHD death or nonfatal

MI) in patients with diabetes

FIELD fenofibrate 200 mgd vs placebo in 9795 patients with type 2 diabetesMedian follow-up 5 years

307

11

193

31

11

20

26

112

187

243

113147

00

05

10

15

20

25

30

35

LDL-C HDL-C TGs

Placebo baseline Fenofibrate baseline

Placebo study end Fenofibrate study end

Mea

n lip

id le

vel (

mm

olL

)R

ate

1000

per

son-

year

s

104

44

64 64

142

119117

37

8471

129

150

02468

10121416

Primary outcome CHD mortality Nonfatal MI Stroke All-cause mortality Coronary revascularization

Fenofibrate PlaceboHR 089

95 CI 075 to 105p=016dagger

p=022

p=036

p=018

HR 07695 CI 062 to 094

p=001

HR 07995 CI 068 to 093

p=0003

Keech A et al Lancet 20053661849ndash1861

CHD mortality or nonfatal MIdaggerARR over course of study=07 NNT=143NNT number needed to treat

Keech p7 ndash 1E

Meta-analysis Fibrates may reduce CV events

but not all-cause mortality

151005

090 (082 to 100) p=0048I2=470 p for heterogeneity=0110

087 (081 to 093) plt00001I2=221 p for heterogeneity=0202

081 (075 to 089) plt00001I2=145 p for heterogeneity=0310

100 (093 to 108) p=0918I2=194 p for heterogeneity=0237

Relative risk (95 CI)

5Major CV events

16Coronary event

10Nonfatal coronary events

16All-cause mortality

Number of studies included

Favors placeboFavors fibrateRelative risk (95 CI)

Jun M et al Lancet 20103621563ndash1574Reprinted from The Lancet Volume 362 Jun M et al Effects of fibrates on cardiovascular outcomes

a systematic review and meta-analysis 1563ndash1574 Copyright 2010 with permission from ElsevierMI and stroke

Meta-analysis of 18 placebo-controlled fibrate trials (45 058 patients)

Docosahexenoic acid (DHA)

Eicosapentenoic acid (EPA)

PUFAs Found in fish oil and Mediterranean diet1

Have been used to lower TG1

Omega-3 fatty acids

EPA1

Marketed omega-3 fatty acids include Vascepa (ethyl-EPA)2

Lovaza (mixture of ethyl-esterified EPA DHA and other fish oils)3

1 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash17012 Vascepa Prescribing Information httpwwwdrugscomprovascepahtml

3 Lovaza Prescribing Information httpswwwgsksourcecomgskprmhtdocsdocumentsLOVAZA-PI-PILPDF

Placebo-controlled trials of omega-3 fatty acids

have reported beneficial effects on CV outcomes

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin vs placebo

DART1Men previous MI(n=2033)

Dietary fish intakeMean 2 years

No significant change in total-C over 2 years

All-cause mortality darr29 (plt005)

GISSI-P2 Recent MI (n=11 324)

Omega-3 PUFA1 gd vs control Mean 35 years

LDL-C uarr99 (p=0002) HDL-C uarr88 (p=NS)TGs darr34 (p=0001)

Death nonfatal MI or nonfatal stroke darr10 (p=0048)

GISSI-HF3 Chronic HF(n=6975)

Omega-3 PUFA1 gd vs placebo Median 39 years

TGs darr from 142 to 134 mmolL over 3 years with PUFA (plt00001 vs placebo)

All-cause death darr9 (p=0041)All-cause death or CV hospitalization darr8 (p=0009)

1 Burr ML et al Lancet 19892757ndash7612 GISSI-Prevenzione Investigators Lancet 1999354447ndash455

3 GISSI-HF Investigators Lancet 20083721223ndash1230

Statin use was 5 at study baseline rising to 46 after 42 monthsrsquo follow-upPatients were also randomized to rosuvastatin or placebo no interaction was recorded between PUFA and statin

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Cholesterol absorption inhibitor

Ezetimibe

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

More emphasise on diet and healthy lifestyle Statin remains the mainstay treatment then combination

therapy with ezetimibe and as a third line the new PCSK9 inhibitors

Focus on ASCVD risk reduction 4 statin benefit groups

Clinical ASCVD

Diabetes aged 40-75 years with LDL-C 70-189 mgdL

LDL-C level gt190mgdl

Estimated 10-year risk of ASCVD of gt75aged 40-75 years with

LDL-C 70-189 mgdL

Stone NJ Robinson J Lichtenstein AH et al 2013 ACCAHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults A Report of the American College of CardiologyAmerican Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 2013

ASCVD atherosclerotic cardiovascular disease LDL-C Low-density lipoprotein cholesterol

Stone NJ et al J Am Coll Cardiol 2013 doi101016jjacc201311002 Available at httpcontentonlinejaccorgarticleaspxarticleid=1770217 Accessed November 13 2013

11

ASCVD Statin Benefit GroupsHeart healthy lifestyle habits are the foundation of ASCVD prevention

ASCVD prevention benefit of statin therapy may be less clear in other groups Consider additional factors influencing ASCVD risk potential ASCVD risk benefits and adverse effects drug-drug interactions and patient preferences for statin treatment

With LDL-C of 70-189 mgdLdagger Estimated using the Pooled Cohort Risk Assessment Equations

Clinical ASCVD

bull High-Intensity statin (age le75 years)

bull Moderate-intensity statin if gt75 years or not a candidate for high-intensity statin

LDL-C ge49 mmolL

bull High-intensity statin

bull Moderate-intensity statin if not a candidate for high-intensity statin

Diabetes age 40-75 years

bull Moderate-intensity statin

bull High-intensity statin if estimated 10 year ASCVD risk ge75

Estimated 10-yr ASCVD risk ge75dagger

age 40-75 years

bull Moderate- to high-intensity statin

Look at1 Family history of premature ASCVD2 LDL-C gt160 mgdl (42mmolL)3 hsCRP ge2 mgdl4 Calcium score ge300 Agatston units or ge75th 5 Sex6 Ethnicity7 Ankle-brachial index lt098 Elevated lifetime risk of ASCVD

Stone NJ Robinson J Lichtenstein AH et al 2013 ACCAHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults A Report of the American College of CardiologyAmerican Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 2013

daggerEvidence from 1 RCT only down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (47)DaggerAlthough simvastatin 80 mg was evaluated in RCTs initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy including rhabdomyolysis

High Moderate and Low-Intensity Statin Therapy (Used in the RCTs reviewed by the Expert Panel)

High-Intensity StatinTherapy

Moderate-Intensity StatinTherapy

Low-Intensity StatinTherapy

Daily dose lowers LDLndashC by approximately ge50

Daily dose lowers LDLndashC by approximately 30 to lt50

Daily dose lowers LDLndashC by lt30

Atorvastatin (40dagger)ndash80 mg Rosuvastatin 20 (40) mg

Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin 20ndash40 mgDagger Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2ndash4 mg

Simvastatin 10 mg Pravastatin 10ndash20 mg Lovastatin 20 mg Fluvastatin 20ndash40 mg Pitavastatin 1 mg

Treat patients aggressively with the right statin dose and intensity for the patients thatrsquos been proven to benefit most from statin treatment

LDL-C targets should NOT be the ONLY determination factor to initiate statin treatment Treat to reduce the CV risk and not just the LDL-C numbers alone

Jones P et al Comparison of the efficacy and safety of rosuvastatin versus atorvastatin simvastatin and pravastatin across doses (STELLAR Trial) Am J Cardiol 200392152-160

The STELLAR study

Rosuvastatin

Atorvastatin

Simvastatin

Pravastatin

X

X

X

ndash60

ndash50

ndash40

ndash30

ndash20

ndash10

0

Dose mg (log scale)10 20 40 80

X

n = 648

n = 473n = 634

n = 485

daggerDagger

Cha

nge

in L

DL-

C fr

om

base

line

() X

Plt002 vs atorvastatin 10 mg simvastatin 10 20 40 mg pravastatin 10 20 40 mgdaggerPlt002 vs atorvastatin 20 40 mg simvastatin 20 40 80 mg pravastatin 20 40 mgDaggerPlt002 vs atorvastatin 40 mg simvastatin 40 80 mg pravastatin 40 mg

dagger

Dagger

Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease the Scandinavian Simvastatin Survival Study (4S) Lancet 19943441383-1389

085

080

000

00

100

095

090

Pro

porti

on a

live

Years since randomisation

Placebo

Simvastatin

64321 5

Log rank P = 0003

Non-statins have been investigated for potential benefit in atherosclerotic cardiovascular disease (ASCVD)

This presentation surveys the clinical evidence to date

bull Cholesterol absorption inhibitors (ezetimibe)

bull Fibrates

bull Omega-3 polyunsaturated fatty acids (PUFAs)

bull Niacin

bull Emerging products

bull PCSK9 inhibitors

bull Cholesterylester transfer protein (CETP) inhibitors

ACCAHA guidelines (2014) do not support routine use of non-statins alone or in combination with statins1

Benefits not acceptable relative to potential adverse effects NICE lipid guidelines (2014) recommend against

non-statins23

No evidence of benefit ESCEAS guidelines (2012) recommend non-statins in limited

situations4

Lipid target not reached with maximally tolerated statin

Statin not tolerated 1 Stone NJ et al J Am Coll Cardiol 2014632889ndash29342 Rabar S et al BMJ 2014349g4356 doi101136bmjg4356

3 National Institute for Health and Care ExcellenceLipid modification July 2014 httpwwwniceorgukGuidanceCG181

4 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash1701

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

FIELD Fenofibrate did not reduce primary outcome (CHD death or nonfatal

MI) in patients with diabetes

FIELD fenofibrate 200 mgd vs placebo in 9795 patients with type 2 diabetesMedian follow-up 5 years

307

11

193

31

11

20

26

112

187

243

113147

00

05

10

15

20

25

30

35

LDL-C HDL-C TGs

Placebo baseline Fenofibrate baseline

Placebo study end Fenofibrate study end

Mea

n lip

id le

vel (

mm

olL

)R

ate

1000

per

son-

year

s

104

44

64 64

142

119117

37

8471

129

150

02468

10121416

Primary outcome CHD mortality Nonfatal MI Stroke All-cause mortality Coronary revascularization

Fenofibrate PlaceboHR 089

95 CI 075 to 105p=016dagger

p=022

p=036

p=018

HR 07695 CI 062 to 094

p=001

HR 07995 CI 068 to 093

p=0003

Keech A et al Lancet 20053661849ndash1861

CHD mortality or nonfatal MIdaggerARR over course of study=07 NNT=143NNT number needed to treat

Keech p7 ndash 1E

Meta-analysis Fibrates may reduce CV events

but not all-cause mortality

151005

090 (082 to 100) p=0048I2=470 p for heterogeneity=0110

087 (081 to 093) plt00001I2=221 p for heterogeneity=0202

081 (075 to 089) plt00001I2=145 p for heterogeneity=0310

100 (093 to 108) p=0918I2=194 p for heterogeneity=0237

Relative risk (95 CI)

5Major CV events

16Coronary event

10Nonfatal coronary events

16All-cause mortality

Number of studies included

Favors placeboFavors fibrateRelative risk (95 CI)

Jun M et al Lancet 20103621563ndash1574Reprinted from The Lancet Volume 362 Jun M et al Effects of fibrates on cardiovascular outcomes

a systematic review and meta-analysis 1563ndash1574 Copyright 2010 with permission from ElsevierMI and stroke

Meta-analysis of 18 placebo-controlled fibrate trials (45 058 patients)

Docosahexenoic acid (DHA)

Eicosapentenoic acid (EPA)

PUFAs Found in fish oil and Mediterranean diet1

Have been used to lower TG1

Omega-3 fatty acids

EPA1

Marketed omega-3 fatty acids include Vascepa (ethyl-EPA)2

Lovaza (mixture of ethyl-esterified EPA DHA and other fish oils)3

1 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash17012 Vascepa Prescribing Information httpwwwdrugscomprovascepahtml

3 Lovaza Prescribing Information httpswwwgsksourcecomgskprmhtdocsdocumentsLOVAZA-PI-PILPDF

Placebo-controlled trials of omega-3 fatty acids

have reported beneficial effects on CV outcomes

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin vs placebo

DART1Men previous MI(n=2033)

Dietary fish intakeMean 2 years

No significant change in total-C over 2 years

All-cause mortality darr29 (plt005)

GISSI-P2 Recent MI (n=11 324)

Omega-3 PUFA1 gd vs control Mean 35 years

LDL-C uarr99 (p=0002) HDL-C uarr88 (p=NS)TGs darr34 (p=0001)

Death nonfatal MI or nonfatal stroke darr10 (p=0048)

GISSI-HF3 Chronic HF(n=6975)

Omega-3 PUFA1 gd vs placebo Median 39 years

TGs darr from 142 to 134 mmolL over 3 years with PUFA (plt00001 vs placebo)

All-cause death darr9 (p=0041)All-cause death or CV hospitalization darr8 (p=0009)

1 Burr ML et al Lancet 19892757ndash7612 GISSI-Prevenzione Investigators Lancet 1999354447ndash455

3 GISSI-HF Investigators Lancet 20083721223ndash1230

Statin use was 5 at study baseline rising to 46 after 42 monthsrsquo follow-upPatients were also randomized to rosuvastatin or placebo no interaction was recorded between PUFA and statin

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Cholesterol absorption inhibitor

Ezetimibe

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Focus on ASCVD risk reduction 4 statin benefit groups

Clinical ASCVD

Diabetes aged 40-75 years with LDL-C 70-189 mgdL

LDL-C level gt190mgdl

Estimated 10-year risk of ASCVD of gt75aged 40-75 years with

LDL-C 70-189 mgdL

Stone NJ Robinson J Lichtenstein AH et al 2013 ACCAHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults A Report of the American College of CardiologyAmerican Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 2013

ASCVD atherosclerotic cardiovascular disease LDL-C Low-density lipoprotein cholesterol

Stone NJ et al J Am Coll Cardiol 2013 doi101016jjacc201311002 Available at httpcontentonlinejaccorgarticleaspxarticleid=1770217 Accessed November 13 2013

11

ASCVD Statin Benefit GroupsHeart healthy lifestyle habits are the foundation of ASCVD prevention

ASCVD prevention benefit of statin therapy may be less clear in other groups Consider additional factors influencing ASCVD risk potential ASCVD risk benefits and adverse effects drug-drug interactions and patient preferences for statin treatment

With LDL-C of 70-189 mgdLdagger Estimated using the Pooled Cohort Risk Assessment Equations

Clinical ASCVD

bull High-Intensity statin (age le75 years)

bull Moderate-intensity statin if gt75 years or not a candidate for high-intensity statin

LDL-C ge49 mmolL

bull High-intensity statin

bull Moderate-intensity statin if not a candidate for high-intensity statin

Diabetes age 40-75 years

bull Moderate-intensity statin

bull High-intensity statin if estimated 10 year ASCVD risk ge75

Estimated 10-yr ASCVD risk ge75dagger

age 40-75 years

bull Moderate- to high-intensity statin

Look at1 Family history of premature ASCVD2 LDL-C gt160 mgdl (42mmolL)3 hsCRP ge2 mgdl4 Calcium score ge300 Agatston units or ge75th 5 Sex6 Ethnicity7 Ankle-brachial index lt098 Elevated lifetime risk of ASCVD

Stone NJ Robinson J Lichtenstein AH et al 2013 ACCAHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults A Report of the American College of CardiologyAmerican Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 2013

daggerEvidence from 1 RCT only down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (47)DaggerAlthough simvastatin 80 mg was evaluated in RCTs initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy including rhabdomyolysis

High Moderate and Low-Intensity Statin Therapy (Used in the RCTs reviewed by the Expert Panel)

High-Intensity StatinTherapy

Moderate-Intensity StatinTherapy

Low-Intensity StatinTherapy

Daily dose lowers LDLndashC by approximately ge50

Daily dose lowers LDLndashC by approximately 30 to lt50

Daily dose lowers LDLndashC by lt30

Atorvastatin (40dagger)ndash80 mg Rosuvastatin 20 (40) mg

Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin 20ndash40 mgDagger Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2ndash4 mg

Simvastatin 10 mg Pravastatin 10ndash20 mg Lovastatin 20 mg Fluvastatin 20ndash40 mg Pitavastatin 1 mg

Treat patients aggressively with the right statin dose and intensity for the patients thatrsquos been proven to benefit most from statin treatment

LDL-C targets should NOT be the ONLY determination factor to initiate statin treatment Treat to reduce the CV risk and not just the LDL-C numbers alone

Jones P et al Comparison of the efficacy and safety of rosuvastatin versus atorvastatin simvastatin and pravastatin across doses (STELLAR Trial) Am J Cardiol 200392152-160

The STELLAR study

Rosuvastatin

Atorvastatin

Simvastatin

Pravastatin

X

X

X

ndash60

ndash50

ndash40

ndash30

ndash20

ndash10

0

Dose mg (log scale)10 20 40 80

X

n = 648

n = 473n = 634

n = 485

daggerDagger

Cha

nge

in L

DL-

C fr

om

base

line

() X

Plt002 vs atorvastatin 10 mg simvastatin 10 20 40 mg pravastatin 10 20 40 mgdaggerPlt002 vs atorvastatin 20 40 mg simvastatin 20 40 80 mg pravastatin 20 40 mgDaggerPlt002 vs atorvastatin 40 mg simvastatin 40 80 mg pravastatin 40 mg

dagger

Dagger

Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease the Scandinavian Simvastatin Survival Study (4S) Lancet 19943441383-1389

085

080

000

00

100

095

090

Pro

porti

on a

live

Years since randomisation

Placebo

Simvastatin

64321 5

Log rank P = 0003

Non-statins have been investigated for potential benefit in atherosclerotic cardiovascular disease (ASCVD)

This presentation surveys the clinical evidence to date

bull Cholesterol absorption inhibitors (ezetimibe)

bull Fibrates

bull Omega-3 polyunsaturated fatty acids (PUFAs)

bull Niacin

bull Emerging products

bull PCSK9 inhibitors

bull Cholesterylester transfer protein (CETP) inhibitors

ACCAHA guidelines (2014) do not support routine use of non-statins alone or in combination with statins1

Benefits not acceptable relative to potential adverse effects NICE lipid guidelines (2014) recommend against

non-statins23

No evidence of benefit ESCEAS guidelines (2012) recommend non-statins in limited

situations4

Lipid target not reached with maximally tolerated statin

Statin not tolerated 1 Stone NJ et al J Am Coll Cardiol 2014632889ndash29342 Rabar S et al BMJ 2014349g4356 doi101136bmjg4356

3 National Institute for Health and Care ExcellenceLipid modification July 2014 httpwwwniceorgukGuidanceCG181

4 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash1701

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

FIELD Fenofibrate did not reduce primary outcome (CHD death or nonfatal

MI) in patients with diabetes

FIELD fenofibrate 200 mgd vs placebo in 9795 patients with type 2 diabetesMedian follow-up 5 years

307

11

193

31

11

20

26

112

187

243

113147

00

05

10

15

20

25

30

35

LDL-C HDL-C TGs

Placebo baseline Fenofibrate baseline

Placebo study end Fenofibrate study end

Mea

n lip

id le

vel (

mm

olL

)R

ate

1000

per

son-

year

s

104

44

64 64

142

119117

37

8471

129

150

02468

10121416

Primary outcome CHD mortality Nonfatal MI Stroke All-cause mortality Coronary revascularization

Fenofibrate PlaceboHR 089

95 CI 075 to 105p=016dagger

p=022

p=036

p=018

HR 07695 CI 062 to 094

p=001

HR 07995 CI 068 to 093

p=0003

Keech A et al Lancet 20053661849ndash1861

CHD mortality or nonfatal MIdaggerARR over course of study=07 NNT=143NNT number needed to treat

Keech p7 ndash 1E

Meta-analysis Fibrates may reduce CV events

but not all-cause mortality

151005

090 (082 to 100) p=0048I2=470 p for heterogeneity=0110

087 (081 to 093) plt00001I2=221 p for heterogeneity=0202

081 (075 to 089) plt00001I2=145 p for heterogeneity=0310

100 (093 to 108) p=0918I2=194 p for heterogeneity=0237

Relative risk (95 CI)

5Major CV events

16Coronary event

10Nonfatal coronary events

16All-cause mortality

Number of studies included

Favors placeboFavors fibrateRelative risk (95 CI)

Jun M et al Lancet 20103621563ndash1574Reprinted from The Lancet Volume 362 Jun M et al Effects of fibrates on cardiovascular outcomes

a systematic review and meta-analysis 1563ndash1574 Copyright 2010 with permission from ElsevierMI and stroke

Meta-analysis of 18 placebo-controlled fibrate trials (45 058 patients)

Docosahexenoic acid (DHA)

Eicosapentenoic acid (EPA)

PUFAs Found in fish oil and Mediterranean diet1

Have been used to lower TG1

Omega-3 fatty acids

EPA1

Marketed omega-3 fatty acids include Vascepa (ethyl-EPA)2

Lovaza (mixture of ethyl-esterified EPA DHA and other fish oils)3

1 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash17012 Vascepa Prescribing Information httpwwwdrugscomprovascepahtml

3 Lovaza Prescribing Information httpswwwgsksourcecomgskprmhtdocsdocumentsLOVAZA-PI-PILPDF

Placebo-controlled trials of omega-3 fatty acids

have reported beneficial effects on CV outcomes

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin vs placebo

DART1Men previous MI(n=2033)

Dietary fish intakeMean 2 years

No significant change in total-C over 2 years

All-cause mortality darr29 (plt005)

GISSI-P2 Recent MI (n=11 324)

Omega-3 PUFA1 gd vs control Mean 35 years

LDL-C uarr99 (p=0002) HDL-C uarr88 (p=NS)TGs darr34 (p=0001)

Death nonfatal MI or nonfatal stroke darr10 (p=0048)

GISSI-HF3 Chronic HF(n=6975)

Omega-3 PUFA1 gd vs placebo Median 39 years

TGs darr from 142 to 134 mmolL over 3 years with PUFA (plt00001 vs placebo)

All-cause death darr9 (p=0041)All-cause death or CV hospitalization darr8 (p=0009)

1 Burr ML et al Lancet 19892757ndash7612 GISSI-Prevenzione Investigators Lancet 1999354447ndash455

3 GISSI-HF Investigators Lancet 20083721223ndash1230

Statin use was 5 at study baseline rising to 46 after 42 monthsrsquo follow-upPatients were also randomized to rosuvastatin or placebo no interaction was recorded between PUFA and statin

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Cholesterol absorption inhibitor

Ezetimibe

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Stone NJ et al J Am Coll Cardiol 2013 doi101016jjacc201311002 Available at httpcontentonlinejaccorgarticleaspxarticleid=1770217 Accessed November 13 2013

11

ASCVD Statin Benefit GroupsHeart healthy lifestyle habits are the foundation of ASCVD prevention

ASCVD prevention benefit of statin therapy may be less clear in other groups Consider additional factors influencing ASCVD risk potential ASCVD risk benefits and adverse effects drug-drug interactions and patient preferences for statin treatment

With LDL-C of 70-189 mgdLdagger Estimated using the Pooled Cohort Risk Assessment Equations

Clinical ASCVD

bull High-Intensity statin (age le75 years)

bull Moderate-intensity statin if gt75 years or not a candidate for high-intensity statin

LDL-C ge49 mmolL

bull High-intensity statin

bull Moderate-intensity statin if not a candidate for high-intensity statin

Diabetes age 40-75 years

bull Moderate-intensity statin

bull High-intensity statin if estimated 10 year ASCVD risk ge75

Estimated 10-yr ASCVD risk ge75dagger

age 40-75 years

bull Moderate- to high-intensity statin

Look at1 Family history of premature ASCVD2 LDL-C gt160 mgdl (42mmolL)3 hsCRP ge2 mgdl4 Calcium score ge300 Agatston units or ge75th 5 Sex6 Ethnicity7 Ankle-brachial index lt098 Elevated lifetime risk of ASCVD

Stone NJ Robinson J Lichtenstein AH et al 2013 ACCAHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults A Report of the American College of CardiologyAmerican Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 2013

daggerEvidence from 1 RCT only down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (47)DaggerAlthough simvastatin 80 mg was evaluated in RCTs initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy including rhabdomyolysis

High Moderate and Low-Intensity Statin Therapy (Used in the RCTs reviewed by the Expert Panel)

High-Intensity StatinTherapy

Moderate-Intensity StatinTherapy

Low-Intensity StatinTherapy

Daily dose lowers LDLndashC by approximately ge50

Daily dose lowers LDLndashC by approximately 30 to lt50

Daily dose lowers LDLndashC by lt30

Atorvastatin (40dagger)ndash80 mg Rosuvastatin 20 (40) mg

Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin 20ndash40 mgDagger Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2ndash4 mg

Simvastatin 10 mg Pravastatin 10ndash20 mg Lovastatin 20 mg Fluvastatin 20ndash40 mg Pitavastatin 1 mg

Treat patients aggressively with the right statin dose and intensity for the patients thatrsquos been proven to benefit most from statin treatment

LDL-C targets should NOT be the ONLY determination factor to initiate statin treatment Treat to reduce the CV risk and not just the LDL-C numbers alone

Jones P et al Comparison of the efficacy and safety of rosuvastatin versus atorvastatin simvastatin and pravastatin across doses (STELLAR Trial) Am J Cardiol 200392152-160

The STELLAR study

Rosuvastatin

Atorvastatin

Simvastatin

Pravastatin

X

X

X

ndash60

ndash50

ndash40

ndash30

ndash20

ndash10

0

Dose mg (log scale)10 20 40 80

X

n = 648

n = 473n = 634

n = 485

daggerDagger

Cha

nge

in L

DL-

C fr

om

base

line

() X

Plt002 vs atorvastatin 10 mg simvastatin 10 20 40 mg pravastatin 10 20 40 mgdaggerPlt002 vs atorvastatin 20 40 mg simvastatin 20 40 80 mg pravastatin 20 40 mgDaggerPlt002 vs atorvastatin 40 mg simvastatin 40 80 mg pravastatin 40 mg

dagger

Dagger

Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease the Scandinavian Simvastatin Survival Study (4S) Lancet 19943441383-1389

085

080

000

00

100

095

090

Pro

porti

on a

live

Years since randomisation

Placebo

Simvastatin

64321 5

Log rank P = 0003

Non-statins have been investigated for potential benefit in atherosclerotic cardiovascular disease (ASCVD)

This presentation surveys the clinical evidence to date

bull Cholesterol absorption inhibitors (ezetimibe)

bull Fibrates

bull Omega-3 polyunsaturated fatty acids (PUFAs)

bull Niacin

bull Emerging products

bull PCSK9 inhibitors

bull Cholesterylester transfer protein (CETP) inhibitors

ACCAHA guidelines (2014) do not support routine use of non-statins alone or in combination with statins1

Benefits not acceptable relative to potential adverse effects NICE lipid guidelines (2014) recommend against

non-statins23

No evidence of benefit ESCEAS guidelines (2012) recommend non-statins in limited

situations4

Lipid target not reached with maximally tolerated statin

Statin not tolerated 1 Stone NJ et al J Am Coll Cardiol 2014632889ndash29342 Rabar S et al BMJ 2014349g4356 doi101136bmjg4356

3 National Institute for Health and Care ExcellenceLipid modification July 2014 httpwwwniceorgukGuidanceCG181

4 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash1701

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

FIELD Fenofibrate did not reduce primary outcome (CHD death or nonfatal

MI) in patients with diabetes

FIELD fenofibrate 200 mgd vs placebo in 9795 patients with type 2 diabetesMedian follow-up 5 years

307

11

193

31

11

20

26

112

187

243

113147

00

05

10

15

20

25

30

35

LDL-C HDL-C TGs

Placebo baseline Fenofibrate baseline

Placebo study end Fenofibrate study end

Mea

n lip

id le

vel (

mm

olL

)R

ate

1000

per

son-

year

s

104

44

64 64

142

119117

37

8471

129

150

02468

10121416

Primary outcome CHD mortality Nonfatal MI Stroke All-cause mortality Coronary revascularization

Fenofibrate PlaceboHR 089

95 CI 075 to 105p=016dagger

p=022

p=036

p=018

HR 07695 CI 062 to 094

p=001

HR 07995 CI 068 to 093

p=0003

Keech A et al Lancet 20053661849ndash1861

CHD mortality or nonfatal MIdaggerARR over course of study=07 NNT=143NNT number needed to treat

Keech p7 ndash 1E

Meta-analysis Fibrates may reduce CV events

but not all-cause mortality

151005

090 (082 to 100) p=0048I2=470 p for heterogeneity=0110

087 (081 to 093) plt00001I2=221 p for heterogeneity=0202

081 (075 to 089) plt00001I2=145 p for heterogeneity=0310

100 (093 to 108) p=0918I2=194 p for heterogeneity=0237

Relative risk (95 CI)

5Major CV events

16Coronary event

10Nonfatal coronary events

16All-cause mortality

Number of studies included

Favors placeboFavors fibrateRelative risk (95 CI)

Jun M et al Lancet 20103621563ndash1574Reprinted from The Lancet Volume 362 Jun M et al Effects of fibrates on cardiovascular outcomes

a systematic review and meta-analysis 1563ndash1574 Copyright 2010 with permission from ElsevierMI and stroke

Meta-analysis of 18 placebo-controlled fibrate trials (45 058 patients)

Docosahexenoic acid (DHA)

Eicosapentenoic acid (EPA)

PUFAs Found in fish oil and Mediterranean diet1

Have been used to lower TG1

Omega-3 fatty acids

EPA1

Marketed omega-3 fatty acids include Vascepa (ethyl-EPA)2

Lovaza (mixture of ethyl-esterified EPA DHA and other fish oils)3

1 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash17012 Vascepa Prescribing Information httpwwwdrugscomprovascepahtml

3 Lovaza Prescribing Information httpswwwgsksourcecomgskprmhtdocsdocumentsLOVAZA-PI-PILPDF

Placebo-controlled trials of omega-3 fatty acids

have reported beneficial effects on CV outcomes

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin vs placebo

DART1Men previous MI(n=2033)

Dietary fish intakeMean 2 years

No significant change in total-C over 2 years

All-cause mortality darr29 (plt005)

GISSI-P2 Recent MI (n=11 324)

Omega-3 PUFA1 gd vs control Mean 35 years

LDL-C uarr99 (p=0002) HDL-C uarr88 (p=NS)TGs darr34 (p=0001)

Death nonfatal MI or nonfatal stroke darr10 (p=0048)

GISSI-HF3 Chronic HF(n=6975)

Omega-3 PUFA1 gd vs placebo Median 39 years

TGs darr from 142 to 134 mmolL over 3 years with PUFA (plt00001 vs placebo)

All-cause death darr9 (p=0041)All-cause death or CV hospitalization darr8 (p=0009)

1 Burr ML et al Lancet 19892757ndash7612 GISSI-Prevenzione Investigators Lancet 1999354447ndash455

3 GISSI-HF Investigators Lancet 20083721223ndash1230

Statin use was 5 at study baseline rising to 46 after 42 monthsrsquo follow-upPatients were also randomized to rosuvastatin or placebo no interaction was recorded between PUFA and statin

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Cholesterol absorption inhibitor

Ezetimibe

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Look at1 Family history of premature ASCVD2 LDL-C gt160 mgdl (42mmolL)3 hsCRP ge2 mgdl4 Calcium score ge300 Agatston units or ge75th 5 Sex6 Ethnicity7 Ankle-brachial index lt098 Elevated lifetime risk of ASCVD

Stone NJ Robinson J Lichtenstein AH et al 2013 ACCAHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults A Report of the American College of CardiologyAmerican Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 2013

daggerEvidence from 1 RCT only down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (47)DaggerAlthough simvastatin 80 mg was evaluated in RCTs initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy including rhabdomyolysis

High Moderate and Low-Intensity Statin Therapy (Used in the RCTs reviewed by the Expert Panel)

High-Intensity StatinTherapy

Moderate-Intensity StatinTherapy

Low-Intensity StatinTherapy

Daily dose lowers LDLndashC by approximately ge50

Daily dose lowers LDLndashC by approximately 30 to lt50

Daily dose lowers LDLndashC by lt30

Atorvastatin (40dagger)ndash80 mg Rosuvastatin 20 (40) mg

Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin 20ndash40 mgDagger Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2ndash4 mg

Simvastatin 10 mg Pravastatin 10ndash20 mg Lovastatin 20 mg Fluvastatin 20ndash40 mg Pitavastatin 1 mg

Treat patients aggressively with the right statin dose and intensity for the patients thatrsquos been proven to benefit most from statin treatment

LDL-C targets should NOT be the ONLY determination factor to initiate statin treatment Treat to reduce the CV risk and not just the LDL-C numbers alone

Jones P et al Comparison of the efficacy and safety of rosuvastatin versus atorvastatin simvastatin and pravastatin across doses (STELLAR Trial) Am J Cardiol 200392152-160

The STELLAR study

Rosuvastatin

Atorvastatin

Simvastatin

Pravastatin

X

X

X

ndash60

ndash50

ndash40

ndash30

ndash20

ndash10

0

Dose mg (log scale)10 20 40 80

X

n = 648

n = 473n = 634

n = 485

daggerDagger

Cha

nge

in L

DL-

C fr

om

base

line

() X

Plt002 vs atorvastatin 10 mg simvastatin 10 20 40 mg pravastatin 10 20 40 mgdaggerPlt002 vs atorvastatin 20 40 mg simvastatin 20 40 80 mg pravastatin 20 40 mgDaggerPlt002 vs atorvastatin 40 mg simvastatin 40 80 mg pravastatin 40 mg

dagger

Dagger

Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease the Scandinavian Simvastatin Survival Study (4S) Lancet 19943441383-1389

085

080

000

00

100

095

090

Pro

porti

on a

live

Years since randomisation

Placebo

Simvastatin

64321 5

Log rank P = 0003

Non-statins have been investigated for potential benefit in atherosclerotic cardiovascular disease (ASCVD)

This presentation surveys the clinical evidence to date

bull Cholesterol absorption inhibitors (ezetimibe)

bull Fibrates

bull Omega-3 polyunsaturated fatty acids (PUFAs)

bull Niacin

bull Emerging products

bull PCSK9 inhibitors

bull Cholesterylester transfer protein (CETP) inhibitors

ACCAHA guidelines (2014) do not support routine use of non-statins alone or in combination with statins1

Benefits not acceptable relative to potential adverse effects NICE lipid guidelines (2014) recommend against

non-statins23

No evidence of benefit ESCEAS guidelines (2012) recommend non-statins in limited

situations4

Lipid target not reached with maximally tolerated statin

Statin not tolerated 1 Stone NJ et al J Am Coll Cardiol 2014632889ndash29342 Rabar S et al BMJ 2014349g4356 doi101136bmjg4356

3 National Institute for Health and Care ExcellenceLipid modification July 2014 httpwwwniceorgukGuidanceCG181

4 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash1701

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

FIELD Fenofibrate did not reduce primary outcome (CHD death or nonfatal

MI) in patients with diabetes

FIELD fenofibrate 200 mgd vs placebo in 9795 patients with type 2 diabetesMedian follow-up 5 years

307

11

193

31

11

20

26

112

187

243

113147

00

05

10

15

20

25

30

35

LDL-C HDL-C TGs

Placebo baseline Fenofibrate baseline

Placebo study end Fenofibrate study end

Mea

n lip

id le

vel (

mm

olL

)R

ate

1000

per

son-

year

s

104

44

64 64

142

119117

37

8471

129

150

02468

10121416

Primary outcome CHD mortality Nonfatal MI Stroke All-cause mortality Coronary revascularization

Fenofibrate PlaceboHR 089

95 CI 075 to 105p=016dagger

p=022

p=036

p=018

HR 07695 CI 062 to 094

p=001

HR 07995 CI 068 to 093

p=0003

Keech A et al Lancet 20053661849ndash1861

CHD mortality or nonfatal MIdaggerARR over course of study=07 NNT=143NNT number needed to treat

Keech p7 ndash 1E

Meta-analysis Fibrates may reduce CV events

but not all-cause mortality

151005

090 (082 to 100) p=0048I2=470 p for heterogeneity=0110

087 (081 to 093) plt00001I2=221 p for heterogeneity=0202

081 (075 to 089) plt00001I2=145 p for heterogeneity=0310

100 (093 to 108) p=0918I2=194 p for heterogeneity=0237

Relative risk (95 CI)

5Major CV events

16Coronary event

10Nonfatal coronary events

16All-cause mortality

Number of studies included

Favors placeboFavors fibrateRelative risk (95 CI)

Jun M et al Lancet 20103621563ndash1574Reprinted from The Lancet Volume 362 Jun M et al Effects of fibrates on cardiovascular outcomes

a systematic review and meta-analysis 1563ndash1574 Copyright 2010 with permission from ElsevierMI and stroke

Meta-analysis of 18 placebo-controlled fibrate trials (45 058 patients)

Docosahexenoic acid (DHA)

Eicosapentenoic acid (EPA)

PUFAs Found in fish oil and Mediterranean diet1

Have been used to lower TG1

Omega-3 fatty acids

EPA1

Marketed omega-3 fatty acids include Vascepa (ethyl-EPA)2

Lovaza (mixture of ethyl-esterified EPA DHA and other fish oils)3

1 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash17012 Vascepa Prescribing Information httpwwwdrugscomprovascepahtml

3 Lovaza Prescribing Information httpswwwgsksourcecomgskprmhtdocsdocumentsLOVAZA-PI-PILPDF

Placebo-controlled trials of omega-3 fatty acids

have reported beneficial effects on CV outcomes

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin vs placebo

DART1Men previous MI(n=2033)

Dietary fish intakeMean 2 years

No significant change in total-C over 2 years

All-cause mortality darr29 (plt005)

GISSI-P2 Recent MI (n=11 324)

Omega-3 PUFA1 gd vs control Mean 35 years

LDL-C uarr99 (p=0002) HDL-C uarr88 (p=NS)TGs darr34 (p=0001)

Death nonfatal MI or nonfatal stroke darr10 (p=0048)

GISSI-HF3 Chronic HF(n=6975)

Omega-3 PUFA1 gd vs placebo Median 39 years

TGs darr from 142 to 134 mmolL over 3 years with PUFA (plt00001 vs placebo)

All-cause death darr9 (p=0041)All-cause death or CV hospitalization darr8 (p=0009)

1 Burr ML et al Lancet 19892757ndash7612 GISSI-Prevenzione Investigators Lancet 1999354447ndash455

3 GISSI-HF Investigators Lancet 20083721223ndash1230

Statin use was 5 at study baseline rising to 46 after 42 monthsrsquo follow-upPatients were also randomized to rosuvastatin or placebo no interaction was recorded between PUFA and statin

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Cholesterol absorption inhibitor

Ezetimibe

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Stone NJ Robinson J Lichtenstein AH et al 2013 ACCAHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults A Report of the American College of CardiologyAmerican Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 2013

daggerEvidence from 1 RCT only down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (47)DaggerAlthough simvastatin 80 mg was evaluated in RCTs initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy including rhabdomyolysis

High Moderate and Low-Intensity Statin Therapy (Used in the RCTs reviewed by the Expert Panel)

High-Intensity StatinTherapy

Moderate-Intensity StatinTherapy

Low-Intensity StatinTherapy

Daily dose lowers LDLndashC by approximately ge50

Daily dose lowers LDLndashC by approximately 30 to lt50

Daily dose lowers LDLndashC by lt30

Atorvastatin (40dagger)ndash80 mg Rosuvastatin 20 (40) mg

Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin 20ndash40 mgDagger Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2ndash4 mg

Simvastatin 10 mg Pravastatin 10ndash20 mg Lovastatin 20 mg Fluvastatin 20ndash40 mg Pitavastatin 1 mg

Treat patients aggressively with the right statin dose and intensity for the patients thatrsquos been proven to benefit most from statin treatment

LDL-C targets should NOT be the ONLY determination factor to initiate statin treatment Treat to reduce the CV risk and not just the LDL-C numbers alone

Jones P et al Comparison of the efficacy and safety of rosuvastatin versus atorvastatin simvastatin and pravastatin across doses (STELLAR Trial) Am J Cardiol 200392152-160

The STELLAR study

Rosuvastatin

Atorvastatin

Simvastatin

Pravastatin

X

X

X

ndash60

ndash50

ndash40

ndash30

ndash20

ndash10

0

Dose mg (log scale)10 20 40 80

X

n = 648

n = 473n = 634

n = 485

daggerDagger

Cha

nge

in L

DL-

C fr

om

base

line

() X

Plt002 vs atorvastatin 10 mg simvastatin 10 20 40 mg pravastatin 10 20 40 mgdaggerPlt002 vs atorvastatin 20 40 mg simvastatin 20 40 80 mg pravastatin 20 40 mgDaggerPlt002 vs atorvastatin 40 mg simvastatin 40 80 mg pravastatin 40 mg

dagger

Dagger

Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease the Scandinavian Simvastatin Survival Study (4S) Lancet 19943441383-1389

085

080

000

00

100

095

090

Pro

porti

on a

live

Years since randomisation

Placebo

Simvastatin

64321 5

Log rank P = 0003

Non-statins have been investigated for potential benefit in atherosclerotic cardiovascular disease (ASCVD)

This presentation surveys the clinical evidence to date

bull Cholesterol absorption inhibitors (ezetimibe)

bull Fibrates

bull Omega-3 polyunsaturated fatty acids (PUFAs)

bull Niacin

bull Emerging products

bull PCSK9 inhibitors

bull Cholesterylester transfer protein (CETP) inhibitors

ACCAHA guidelines (2014) do not support routine use of non-statins alone or in combination with statins1

Benefits not acceptable relative to potential adverse effects NICE lipid guidelines (2014) recommend against

non-statins23

No evidence of benefit ESCEAS guidelines (2012) recommend non-statins in limited

situations4

Lipid target not reached with maximally tolerated statin

Statin not tolerated 1 Stone NJ et al J Am Coll Cardiol 2014632889ndash29342 Rabar S et al BMJ 2014349g4356 doi101136bmjg4356

3 National Institute for Health and Care ExcellenceLipid modification July 2014 httpwwwniceorgukGuidanceCG181

4 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash1701

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

FIELD Fenofibrate did not reduce primary outcome (CHD death or nonfatal

MI) in patients with diabetes

FIELD fenofibrate 200 mgd vs placebo in 9795 patients with type 2 diabetesMedian follow-up 5 years

307

11

193

31

11

20

26

112

187

243

113147

00

05

10

15

20

25

30

35

LDL-C HDL-C TGs

Placebo baseline Fenofibrate baseline

Placebo study end Fenofibrate study end

Mea

n lip

id le

vel (

mm

olL

)R

ate

1000

per

son-

year

s

104

44

64 64

142

119117

37

8471

129

150

02468

10121416

Primary outcome CHD mortality Nonfatal MI Stroke All-cause mortality Coronary revascularization

Fenofibrate PlaceboHR 089

95 CI 075 to 105p=016dagger

p=022

p=036

p=018

HR 07695 CI 062 to 094

p=001

HR 07995 CI 068 to 093

p=0003

Keech A et al Lancet 20053661849ndash1861

CHD mortality or nonfatal MIdaggerARR over course of study=07 NNT=143NNT number needed to treat

Keech p7 ndash 1E

Meta-analysis Fibrates may reduce CV events

but not all-cause mortality

151005

090 (082 to 100) p=0048I2=470 p for heterogeneity=0110

087 (081 to 093) plt00001I2=221 p for heterogeneity=0202

081 (075 to 089) plt00001I2=145 p for heterogeneity=0310

100 (093 to 108) p=0918I2=194 p for heterogeneity=0237

Relative risk (95 CI)

5Major CV events

16Coronary event

10Nonfatal coronary events

16All-cause mortality

Number of studies included

Favors placeboFavors fibrateRelative risk (95 CI)

Jun M et al Lancet 20103621563ndash1574Reprinted from The Lancet Volume 362 Jun M et al Effects of fibrates on cardiovascular outcomes

a systematic review and meta-analysis 1563ndash1574 Copyright 2010 with permission from ElsevierMI and stroke

Meta-analysis of 18 placebo-controlled fibrate trials (45 058 patients)

Docosahexenoic acid (DHA)

Eicosapentenoic acid (EPA)

PUFAs Found in fish oil and Mediterranean diet1

Have been used to lower TG1

Omega-3 fatty acids

EPA1

Marketed omega-3 fatty acids include Vascepa (ethyl-EPA)2

Lovaza (mixture of ethyl-esterified EPA DHA and other fish oils)3

1 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash17012 Vascepa Prescribing Information httpwwwdrugscomprovascepahtml

3 Lovaza Prescribing Information httpswwwgsksourcecomgskprmhtdocsdocumentsLOVAZA-PI-PILPDF

Placebo-controlled trials of omega-3 fatty acids

have reported beneficial effects on CV outcomes

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin vs placebo

DART1Men previous MI(n=2033)

Dietary fish intakeMean 2 years

No significant change in total-C over 2 years

All-cause mortality darr29 (plt005)

GISSI-P2 Recent MI (n=11 324)

Omega-3 PUFA1 gd vs control Mean 35 years

LDL-C uarr99 (p=0002) HDL-C uarr88 (p=NS)TGs darr34 (p=0001)

Death nonfatal MI or nonfatal stroke darr10 (p=0048)

GISSI-HF3 Chronic HF(n=6975)

Omega-3 PUFA1 gd vs placebo Median 39 years

TGs darr from 142 to 134 mmolL over 3 years with PUFA (plt00001 vs placebo)

All-cause death darr9 (p=0041)All-cause death or CV hospitalization darr8 (p=0009)

1 Burr ML et al Lancet 19892757ndash7612 GISSI-Prevenzione Investigators Lancet 1999354447ndash455

3 GISSI-HF Investigators Lancet 20083721223ndash1230

Statin use was 5 at study baseline rising to 46 after 42 monthsrsquo follow-upPatients were also randomized to rosuvastatin or placebo no interaction was recorded between PUFA and statin

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Cholesterol absorption inhibitor

Ezetimibe

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Treat patients aggressively with the right statin dose and intensity for the patients thatrsquos been proven to benefit most from statin treatment

LDL-C targets should NOT be the ONLY determination factor to initiate statin treatment Treat to reduce the CV risk and not just the LDL-C numbers alone

Jones P et al Comparison of the efficacy and safety of rosuvastatin versus atorvastatin simvastatin and pravastatin across doses (STELLAR Trial) Am J Cardiol 200392152-160

The STELLAR study

Rosuvastatin

Atorvastatin

Simvastatin

Pravastatin

X

X

X

ndash60

ndash50

ndash40

ndash30

ndash20

ndash10

0

Dose mg (log scale)10 20 40 80

X

n = 648

n = 473n = 634

n = 485

daggerDagger

Cha

nge

in L

DL-

C fr

om

base

line

() X

Plt002 vs atorvastatin 10 mg simvastatin 10 20 40 mg pravastatin 10 20 40 mgdaggerPlt002 vs atorvastatin 20 40 mg simvastatin 20 40 80 mg pravastatin 20 40 mgDaggerPlt002 vs atorvastatin 40 mg simvastatin 40 80 mg pravastatin 40 mg

dagger

Dagger

Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease the Scandinavian Simvastatin Survival Study (4S) Lancet 19943441383-1389

085

080

000

00

100

095

090

Pro

porti

on a

live

Years since randomisation

Placebo

Simvastatin

64321 5

Log rank P = 0003

Non-statins have been investigated for potential benefit in atherosclerotic cardiovascular disease (ASCVD)

This presentation surveys the clinical evidence to date

bull Cholesterol absorption inhibitors (ezetimibe)

bull Fibrates

bull Omega-3 polyunsaturated fatty acids (PUFAs)

bull Niacin

bull Emerging products

bull PCSK9 inhibitors

bull Cholesterylester transfer protein (CETP) inhibitors

ACCAHA guidelines (2014) do not support routine use of non-statins alone or in combination with statins1

Benefits not acceptable relative to potential adverse effects NICE lipid guidelines (2014) recommend against

non-statins23

No evidence of benefit ESCEAS guidelines (2012) recommend non-statins in limited

situations4

Lipid target not reached with maximally tolerated statin

Statin not tolerated 1 Stone NJ et al J Am Coll Cardiol 2014632889ndash29342 Rabar S et al BMJ 2014349g4356 doi101136bmjg4356

3 National Institute for Health and Care ExcellenceLipid modification July 2014 httpwwwniceorgukGuidanceCG181

4 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash1701

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

FIELD Fenofibrate did not reduce primary outcome (CHD death or nonfatal

MI) in patients with diabetes

FIELD fenofibrate 200 mgd vs placebo in 9795 patients with type 2 diabetesMedian follow-up 5 years

307

11

193

31

11

20

26

112

187

243

113147

00

05

10

15

20

25

30

35

LDL-C HDL-C TGs

Placebo baseline Fenofibrate baseline

Placebo study end Fenofibrate study end

Mea

n lip

id le

vel (

mm

olL

)R

ate

1000

per

son-

year

s

104

44

64 64

142

119117

37

8471

129

150

02468

10121416

Primary outcome CHD mortality Nonfatal MI Stroke All-cause mortality Coronary revascularization

Fenofibrate PlaceboHR 089

95 CI 075 to 105p=016dagger

p=022

p=036

p=018

HR 07695 CI 062 to 094

p=001

HR 07995 CI 068 to 093

p=0003

Keech A et al Lancet 20053661849ndash1861

CHD mortality or nonfatal MIdaggerARR over course of study=07 NNT=143NNT number needed to treat

Keech p7 ndash 1E

Meta-analysis Fibrates may reduce CV events

but not all-cause mortality

151005

090 (082 to 100) p=0048I2=470 p for heterogeneity=0110

087 (081 to 093) plt00001I2=221 p for heterogeneity=0202

081 (075 to 089) plt00001I2=145 p for heterogeneity=0310

100 (093 to 108) p=0918I2=194 p for heterogeneity=0237

Relative risk (95 CI)

5Major CV events

16Coronary event

10Nonfatal coronary events

16All-cause mortality

Number of studies included

Favors placeboFavors fibrateRelative risk (95 CI)

Jun M et al Lancet 20103621563ndash1574Reprinted from The Lancet Volume 362 Jun M et al Effects of fibrates on cardiovascular outcomes

a systematic review and meta-analysis 1563ndash1574 Copyright 2010 with permission from ElsevierMI and stroke

Meta-analysis of 18 placebo-controlled fibrate trials (45 058 patients)

Docosahexenoic acid (DHA)

Eicosapentenoic acid (EPA)

PUFAs Found in fish oil and Mediterranean diet1

Have been used to lower TG1

Omega-3 fatty acids

EPA1

Marketed omega-3 fatty acids include Vascepa (ethyl-EPA)2

Lovaza (mixture of ethyl-esterified EPA DHA and other fish oils)3

1 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash17012 Vascepa Prescribing Information httpwwwdrugscomprovascepahtml

3 Lovaza Prescribing Information httpswwwgsksourcecomgskprmhtdocsdocumentsLOVAZA-PI-PILPDF

Placebo-controlled trials of omega-3 fatty acids

have reported beneficial effects on CV outcomes

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin vs placebo

DART1Men previous MI(n=2033)

Dietary fish intakeMean 2 years

No significant change in total-C over 2 years

All-cause mortality darr29 (plt005)

GISSI-P2 Recent MI (n=11 324)

Omega-3 PUFA1 gd vs control Mean 35 years

LDL-C uarr99 (p=0002) HDL-C uarr88 (p=NS)TGs darr34 (p=0001)

Death nonfatal MI or nonfatal stroke darr10 (p=0048)

GISSI-HF3 Chronic HF(n=6975)

Omega-3 PUFA1 gd vs placebo Median 39 years

TGs darr from 142 to 134 mmolL over 3 years with PUFA (plt00001 vs placebo)

All-cause death darr9 (p=0041)All-cause death or CV hospitalization darr8 (p=0009)

1 Burr ML et al Lancet 19892757ndash7612 GISSI-Prevenzione Investigators Lancet 1999354447ndash455

3 GISSI-HF Investigators Lancet 20083721223ndash1230

Statin use was 5 at study baseline rising to 46 after 42 monthsrsquo follow-upPatients were also randomized to rosuvastatin or placebo no interaction was recorded between PUFA and statin

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Cholesterol absorption inhibitor

Ezetimibe

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Jones P et al Comparison of the efficacy and safety of rosuvastatin versus atorvastatin simvastatin and pravastatin across doses (STELLAR Trial) Am J Cardiol 200392152-160

The STELLAR study

Rosuvastatin

Atorvastatin

Simvastatin

Pravastatin

X

X

X

ndash60

ndash50

ndash40

ndash30

ndash20

ndash10

0

Dose mg (log scale)10 20 40 80

X

n = 648

n = 473n = 634

n = 485

daggerDagger

Cha

nge

in L

DL-

C fr

om

base

line

() X

Plt002 vs atorvastatin 10 mg simvastatin 10 20 40 mg pravastatin 10 20 40 mgdaggerPlt002 vs atorvastatin 20 40 mg simvastatin 20 40 80 mg pravastatin 20 40 mgDaggerPlt002 vs atorvastatin 40 mg simvastatin 40 80 mg pravastatin 40 mg

dagger

Dagger

Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease the Scandinavian Simvastatin Survival Study (4S) Lancet 19943441383-1389

085

080

000

00

100

095

090

Pro

porti

on a

live

Years since randomisation

Placebo

Simvastatin

64321 5

Log rank P = 0003

Non-statins have been investigated for potential benefit in atherosclerotic cardiovascular disease (ASCVD)

This presentation surveys the clinical evidence to date

bull Cholesterol absorption inhibitors (ezetimibe)

bull Fibrates

bull Omega-3 polyunsaturated fatty acids (PUFAs)

bull Niacin

bull Emerging products

bull PCSK9 inhibitors

bull Cholesterylester transfer protein (CETP) inhibitors

ACCAHA guidelines (2014) do not support routine use of non-statins alone or in combination with statins1

Benefits not acceptable relative to potential adverse effects NICE lipid guidelines (2014) recommend against

non-statins23

No evidence of benefit ESCEAS guidelines (2012) recommend non-statins in limited

situations4

Lipid target not reached with maximally tolerated statin

Statin not tolerated 1 Stone NJ et al J Am Coll Cardiol 2014632889ndash29342 Rabar S et al BMJ 2014349g4356 doi101136bmjg4356

3 National Institute for Health and Care ExcellenceLipid modification July 2014 httpwwwniceorgukGuidanceCG181

4 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash1701

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

FIELD Fenofibrate did not reduce primary outcome (CHD death or nonfatal

MI) in patients with diabetes

FIELD fenofibrate 200 mgd vs placebo in 9795 patients with type 2 diabetesMedian follow-up 5 years

307

11

193

31

11

20

26

112

187

243

113147

00

05

10

15

20

25

30

35

LDL-C HDL-C TGs

Placebo baseline Fenofibrate baseline

Placebo study end Fenofibrate study end

Mea

n lip

id le

vel (

mm

olL

)R

ate

1000

per

son-

year

s

104

44

64 64

142

119117

37

8471

129

150

02468

10121416

Primary outcome CHD mortality Nonfatal MI Stroke All-cause mortality Coronary revascularization

Fenofibrate PlaceboHR 089

95 CI 075 to 105p=016dagger

p=022

p=036

p=018

HR 07695 CI 062 to 094

p=001

HR 07995 CI 068 to 093

p=0003

Keech A et al Lancet 20053661849ndash1861

CHD mortality or nonfatal MIdaggerARR over course of study=07 NNT=143NNT number needed to treat

Keech p7 ndash 1E

Meta-analysis Fibrates may reduce CV events

but not all-cause mortality

151005

090 (082 to 100) p=0048I2=470 p for heterogeneity=0110

087 (081 to 093) plt00001I2=221 p for heterogeneity=0202

081 (075 to 089) plt00001I2=145 p for heterogeneity=0310

100 (093 to 108) p=0918I2=194 p for heterogeneity=0237

Relative risk (95 CI)

5Major CV events

16Coronary event

10Nonfatal coronary events

16All-cause mortality

Number of studies included

Favors placeboFavors fibrateRelative risk (95 CI)

Jun M et al Lancet 20103621563ndash1574Reprinted from The Lancet Volume 362 Jun M et al Effects of fibrates on cardiovascular outcomes

a systematic review and meta-analysis 1563ndash1574 Copyright 2010 with permission from ElsevierMI and stroke

Meta-analysis of 18 placebo-controlled fibrate trials (45 058 patients)

Docosahexenoic acid (DHA)

Eicosapentenoic acid (EPA)

PUFAs Found in fish oil and Mediterranean diet1

Have been used to lower TG1

Omega-3 fatty acids

EPA1

Marketed omega-3 fatty acids include Vascepa (ethyl-EPA)2

Lovaza (mixture of ethyl-esterified EPA DHA and other fish oils)3

1 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash17012 Vascepa Prescribing Information httpwwwdrugscomprovascepahtml

3 Lovaza Prescribing Information httpswwwgsksourcecomgskprmhtdocsdocumentsLOVAZA-PI-PILPDF

Placebo-controlled trials of omega-3 fatty acids

have reported beneficial effects on CV outcomes

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin vs placebo

DART1Men previous MI(n=2033)

Dietary fish intakeMean 2 years

No significant change in total-C over 2 years

All-cause mortality darr29 (plt005)

GISSI-P2 Recent MI (n=11 324)

Omega-3 PUFA1 gd vs control Mean 35 years

LDL-C uarr99 (p=0002) HDL-C uarr88 (p=NS)TGs darr34 (p=0001)

Death nonfatal MI or nonfatal stroke darr10 (p=0048)

GISSI-HF3 Chronic HF(n=6975)

Omega-3 PUFA1 gd vs placebo Median 39 years

TGs darr from 142 to 134 mmolL over 3 years with PUFA (plt00001 vs placebo)

All-cause death darr9 (p=0041)All-cause death or CV hospitalization darr8 (p=0009)

1 Burr ML et al Lancet 19892757ndash7612 GISSI-Prevenzione Investigators Lancet 1999354447ndash455

3 GISSI-HF Investigators Lancet 20083721223ndash1230

Statin use was 5 at study baseline rising to 46 after 42 monthsrsquo follow-upPatients were also randomized to rosuvastatin or placebo no interaction was recorded between PUFA and statin

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Cholesterol absorption inhibitor

Ezetimibe

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease the Scandinavian Simvastatin Survival Study (4S) Lancet 19943441383-1389

085

080

000

00

100

095

090

Pro

porti

on a

live

Years since randomisation

Placebo

Simvastatin

64321 5

Log rank P = 0003

Non-statins have been investigated for potential benefit in atherosclerotic cardiovascular disease (ASCVD)

This presentation surveys the clinical evidence to date

bull Cholesterol absorption inhibitors (ezetimibe)

bull Fibrates

bull Omega-3 polyunsaturated fatty acids (PUFAs)

bull Niacin

bull Emerging products

bull PCSK9 inhibitors

bull Cholesterylester transfer protein (CETP) inhibitors

ACCAHA guidelines (2014) do not support routine use of non-statins alone or in combination with statins1

Benefits not acceptable relative to potential adverse effects NICE lipid guidelines (2014) recommend against

non-statins23

No evidence of benefit ESCEAS guidelines (2012) recommend non-statins in limited

situations4

Lipid target not reached with maximally tolerated statin

Statin not tolerated 1 Stone NJ et al J Am Coll Cardiol 2014632889ndash29342 Rabar S et al BMJ 2014349g4356 doi101136bmjg4356

3 National Institute for Health and Care ExcellenceLipid modification July 2014 httpwwwniceorgukGuidanceCG181

4 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash1701

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

FIELD Fenofibrate did not reduce primary outcome (CHD death or nonfatal

MI) in patients with diabetes

FIELD fenofibrate 200 mgd vs placebo in 9795 patients with type 2 diabetesMedian follow-up 5 years

307

11

193

31

11

20

26

112

187

243

113147

00

05

10

15

20

25

30

35

LDL-C HDL-C TGs

Placebo baseline Fenofibrate baseline

Placebo study end Fenofibrate study end

Mea

n lip

id le

vel (

mm

olL

)R

ate

1000

per

son-

year

s

104

44

64 64

142

119117

37

8471

129

150

02468

10121416

Primary outcome CHD mortality Nonfatal MI Stroke All-cause mortality Coronary revascularization

Fenofibrate PlaceboHR 089

95 CI 075 to 105p=016dagger

p=022

p=036

p=018

HR 07695 CI 062 to 094

p=001

HR 07995 CI 068 to 093

p=0003

Keech A et al Lancet 20053661849ndash1861

CHD mortality or nonfatal MIdaggerARR over course of study=07 NNT=143NNT number needed to treat

Keech p7 ndash 1E

Meta-analysis Fibrates may reduce CV events

but not all-cause mortality

151005

090 (082 to 100) p=0048I2=470 p for heterogeneity=0110

087 (081 to 093) plt00001I2=221 p for heterogeneity=0202

081 (075 to 089) plt00001I2=145 p for heterogeneity=0310

100 (093 to 108) p=0918I2=194 p for heterogeneity=0237

Relative risk (95 CI)

5Major CV events

16Coronary event

10Nonfatal coronary events

16All-cause mortality

Number of studies included

Favors placeboFavors fibrateRelative risk (95 CI)

Jun M et al Lancet 20103621563ndash1574Reprinted from The Lancet Volume 362 Jun M et al Effects of fibrates on cardiovascular outcomes

a systematic review and meta-analysis 1563ndash1574 Copyright 2010 with permission from ElsevierMI and stroke

Meta-analysis of 18 placebo-controlled fibrate trials (45 058 patients)

Docosahexenoic acid (DHA)

Eicosapentenoic acid (EPA)

PUFAs Found in fish oil and Mediterranean diet1

Have been used to lower TG1

Omega-3 fatty acids

EPA1

Marketed omega-3 fatty acids include Vascepa (ethyl-EPA)2

Lovaza (mixture of ethyl-esterified EPA DHA and other fish oils)3

1 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash17012 Vascepa Prescribing Information httpwwwdrugscomprovascepahtml

3 Lovaza Prescribing Information httpswwwgsksourcecomgskprmhtdocsdocumentsLOVAZA-PI-PILPDF

Placebo-controlled trials of omega-3 fatty acids

have reported beneficial effects on CV outcomes

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin vs placebo

DART1Men previous MI(n=2033)

Dietary fish intakeMean 2 years

No significant change in total-C over 2 years

All-cause mortality darr29 (plt005)

GISSI-P2 Recent MI (n=11 324)

Omega-3 PUFA1 gd vs control Mean 35 years

LDL-C uarr99 (p=0002) HDL-C uarr88 (p=NS)TGs darr34 (p=0001)

Death nonfatal MI or nonfatal stroke darr10 (p=0048)

GISSI-HF3 Chronic HF(n=6975)

Omega-3 PUFA1 gd vs placebo Median 39 years

TGs darr from 142 to 134 mmolL over 3 years with PUFA (plt00001 vs placebo)

All-cause death darr9 (p=0041)All-cause death or CV hospitalization darr8 (p=0009)

1 Burr ML et al Lancet 19892757ndash7612 GISSI-Prevenzione Investigators Lancet 1999354447ndash455

3 GISSI-HF Investigators Lancet 20083721223ndash1230

Statin use was 5 at study baseline rising to 46 after 42 monthsrsquo follow-upPatients were also randomized to rosuvastatin or placebo no interaction was recorded between PUFA and statin

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Cholesterol absorption inhibitor

Ezetimibe

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Non-statins have been investigated for potential benefit in atherosclerotic cardiovascular disease (ASCVD)

This presentation surveys the clinical evidence to date

bull Cholesterol absorption inhibitors (ezetimibe)

bull Fibrates

bull Omega-3 polyunsaturated fatty acids (PUFAs)

bull Niacin

bull Emerging products

bull PCSK9 inhibitors

bull Cholesterylester transfer protein (CETP) inhibitors

ACCAHA guidelines (2014) do not support routine use of non-statins alone or in combination with statins1

Benefits not acceptable relative to potential adverse effects NICE lipid guidelines (2014) recommend against

non-statins23

No evidence of benefit ESCEAS guidelines (2012) recommend non-statins in limited

situations4

Lipid target not reached with maximally tolerated statin

Statin not tolerated 1 Stone NJ et al J Am Coll Cardiol 2014632889ndash29342 Rabar S et al BMJ 2014349g4356 doi101136bmjg4356

3 National Institute for Health and Care ExcellenceLipid modification July 2014 httpwwwniceorgukGuidanceCG181

4 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash1701

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

FIELD Fenofibrate did not reduce primary outcome (CHD death or nonfatal

MI) in patients with diabetes

FIELD fenofibrate 200 mgd vs placebo in 9795 patients with type 2 diabetesMedian follow-up 5 years

307

11

193

31

11

20

26

112

187

243

113147

00

05

10

15

20

25

30

35

LDL-C HDL-C TGs

Placebo baseline Fenofibrate baseline

Placebo study end Fenofibrate study end

Mea

n lip

id le

vel (

mm

olL

)R

ate

1000

per

son-

year

s

104

44

64 64

142

119117

37

8471

129

150

02468

10121416

Primary outcome CHD mortality Nonfatal MI Stroke All-cause mortality Coronary revascularization

Fenofibrate PlaceboHR 089

95 CI 075 to 105p=016dagger

p=022

p=036

p=018

HR 07695 CI 062 to 094

p=001

HR 07995 CI 068 to 093

p=0003

Keech A et al Lancet 20053661849ndash1861

CHD mortality or nonfatal MIdaggerARR over course of study=07 NNT=143NNT number needed to treat

Keech p7 ndash 1E

Meta-analysis Fibrates may reduce CV events

but not all-cause mortality

151005

090 (082 to 100) p=0048I2=470 p for heterogeneity=0110

087 (081 to 093) plt00001I2=221 p for heterogeneity=0202

081 (075 to 089) plt00001I2=145 p for heterogeneity=0310

100 (093 to 108) p=0918I2=194 p for heterogeneity=0237

Relative risk (95 CI)

5Major CV events

16Coronary event

10Nonfatal coronary events

16All-cause mortality

Number of studies included

Favors placeboFavors fibrateRelative risk (95 CI)

Jun M et al Lancet 20103621563ndash1574Reprinted from The Lancet Volume 362 Jun M et al Effects of fibrates on cardiovascular outcomes

a systematic review and meta-analysis 1563ndash1574 Copyright 2010 with permission from ElsevierMI and stroke

Meta-analysis of 18 placebo-controlled fibrate trials (45 058 patients)

Docosahexenoic acid (DHA)

Eicosapentenoic acid (EPA)

PUFAs Found in fish oil and Mediterranean diet1

Have been used to lower TG1

Omega-3 fatty acids

EPA1

Marketed omega-3 fatty acids include Vascepa (ethyl-EPA)2

Lovaza (mixture of ethyl-esterified EPA DHA and other fish oils)3

1 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash17012 Vascepa Prescribing Information httpwwwdrugscomprovascepahtml

3 Lovaza Prescribing Information httpswwwgsksourcecomgskprmhtdocsdocumentsLOVAZA-PI-PILPDF

Placebo-controlled trials of omega-3 fatty acids

have reported beneficial effects on CV outcomes

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin vs placebo

DART1Men previous MI(n=2033)

Dietary fish intakeMean 2 years

No significant change in total-C over 2 years

All-cause mortality darr29 (plt005)

GISSI-P2 Recent MI (n=11 324)

Omega-3 PUFA1 gd vs control Mean 35 years

LDL-C uarr99 (p=0002) HDL-C uarr88 (p=NS)TGs darr34 (p=0001)

Death nonfatal MI or nonfatal stroke darr10 (p=0048)

GISSI-HF3 Chronic HF(n=6975)

Omega-3 PUFA1 gd vs placebo Median 39 years

TGs darr from 142 to 134 mmolL over 3 years with PUFA (plt00001 vs placebo)

All-cause death darr9 (p=0041)All-cause death or CV hospitalization darr8 (p=0009)

1 Burr ML et al Lancet 19892757ndash7612 GISSI-Prevenzione Investigators Lancet 1999354447ndash455

3 GISSI-HF Investigators Lancet 20083721223ndash1230

Statin use was 5 at study baseline rising to 46 after 42 monthsrsquo follow-upPatients were also randomized to rosuvastatin or placebo no interaction was recorded between PUFA and statin

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Cholesterol absorption inhibitor

Ezetimibe

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

ACCAHA guidelines (2014) do not support routine use of non-statins alone or in combination with statins1

Benefits not acceptable relative to potential adverse effects NICE lipid guidelines (2014) recommend against

non-statins23

No evidence of benefit ESCEAS guidelines (2012) recommend non-statins in limited

situations4

Lipid target not reached with maximally tolerated statin

Statin not tolerated 1 Stone NJ et al J Am Coll Cardiol 2014632889ndash29342 Rabar S et al BMJ 2014349g4356 doi101136bmjg4356

3 National Institute for Health and Care ExcellenceLipid modification July 2014 httpwwwniceorgukGuidanceCG181

4 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash1701

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

FIELD Fenofibrate did not reduce primary outcome (CHD death or nonfatal

MI) in patients with diabetes

FIELD fenofibrate 200 mgd vs placebo in 9795 patients with type 2 diabetesMedian follow-up 5 years

307

11

193

31

11

20

26

112

187

243

113147

00

05

10

15

20

25

30

35

LDL-C HDL-C TGs

Placebo baseline Fenofibrate baseline

Placebo study end Fenofibrate study end

Mea

n lip

id le

vel (

mm

olL

)R

ate

1000

per

son-

year

s

104

44

64 64

142

119117

37

8471

129

150

02468

10121416

Primary outcome CHD mortality Nonfatal MI Stroke All-cause mortality Coronary revascularization

Fenofibrate PlaceboHR 089

95 CI 075 to 105p=016dagger

p=022

p=036

p=018

HR 07695 CI 062 to 094

p=001

HR 07995 CI 068 to 093

p=0003

Keech A et al Lancet 20053661849ndash1861

CHD mortality or nonfatal MIdaggerARR over course of study=07 NNT=143NNT number needed to treat

Keech p7 ndash 1E

Meta-analysis Fibrates may reduce CV events

but not all-cause mortality

151005

090 (082 to 100) p=0048I2=470 p for heterogeneity=0110

087 (081 to 093) plt00001I2=221 p for heterogeneity=0202

081 (075 to 089) plt00001I2=145 p for heterogeneity=0310

100 (093 to 108) p=0918I2=194 p for heterogeneity=0237

Relative risk (95 CI)

5Major CV events

16Coronary event

10Nonfatal coronary events

16All-cause mortality

Number of studies included

Favors placeboFavors fibrateRelative risk (95 CI)

Jun M et al Lancet 20103621563ndash1574Reprinted from The Lancet Volume 362 Jun M et al Effects of fibrates on cardiovascular outcomes

a systematic review and meta-analysis 1563ndash1574 Copyright 2010 with permission from ElsevierMI and stroke

Meta-analysis of 18 placebo-controlled fibrate trials (45 058 patients)

Docosahexenoic acid (DHA)

Eicosapentenoic acid (EPA)

PUFAs Found in fish oil and Mediterranean diet1

Have been used to lower TG1

Omega-3 fatty acids

EPA1

Marketed omega-3 fatty acids include Vascepa (ethyl-EPA)2

Lovaza (mixture of ethyl-esterified EPA DHA and other fish oils)3

1 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash17012 Vascepa Prescribing Information httpwwwdrugscomprovascepahtml

3 Lovaza Prescribing Information httpswwwgsksourcecomgskprmhtdocsdocumentsLOVAZA-PI-PILPDF

Placebo-controlled trials of omega-3 fatty acids

have reported beneficial effects on CV outcomes

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin vs placebo

DART1Men previous MI(n=2033)

Dietary fish intakeMean 2 years

No significant change in total-C over 2 years

All-cause mortality darr29 (plt005)

GISSI-P2 Recent MI (n=11 324)

Omega-3 PUFA1 gd vs control Mean 35 years

LDL-C uarr99 (p=0002) HDL-C uarr88 (p=NS)TGs darr34 (p=0001)

Death nonfatal MI or nonfatal stroke darr10 (p=0048)

GISSI-HF3 Chronic HF(n=6975)

Omega-3 PUFA1 gd vs placebo Median 39 years

TGs darr from 142 to 134 mmolL over 3 years with PUFA (plt00001 vs placebo)

All-cause death darr9 (p=0041)All-cause death or CV hospitalization darr8 (p=0009)

1 Burr ML et al Lancet 19892757ndash7612 GISSI-Prevenzione Investigators Lancet 1999354447ndash455

3 GISSI-HF Investigators Lancet 20083721223ndash1230

Statin use was 5 at study baseline rising to 46 after 42 monthsrsquo follow-upPatients were also randomized to rosuvastatin or placebo no interaction was recorded between PUFA and statin

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Cholesterol absorption inhibitor

Ezetimibe

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

FIELD Fenofibrate did not reduce primary outcome (CHD death or nonfatal

MI) in patients with diabetes

FIELD fenofibrate 200 mgd vs placebo in 9795 patients with type 2 diabetesMedian follow-up 5 years

307

11

193

31

11

20

26

112

187

243

113147

00

05

10

15

20

25

30

35

LDL-C HDL-C TGs

Placebo baseline Fenofibrate baseline

Placebo study end Fenofibrate study end

Mea

n lip

id le

vel (

mm

olL

)R

ate

1000

per

son-

year

s

104

44

64 64

142

119117

37

8471

129

150

02468

10121416

Primary outcome CHD mortality Nonfatal MI Stroke All-cause mortality Coronary revascularization

Fenofibrate PlaceboHR 089

95 CI 075 to 105p=016dagger

p=022

p=036

p=018

HR 07695 CI 062 to 094

p=001

HR 07995 CI 068 to 093

p=0003

Keech A et al Lancet 20053661849ndash1861

CHD mortality or nonfatal MIdaggerARR over course of study=07 NNT=143NNT number needed to treat

Keech p7 ndash 1E

Meta-analysis Fibrates may reduce CV events

but not all-cause mortality

151005

090 (082 to 100) p=0048I2=470 p for heterogeneity=0110

087 (081 to 093) plt00001I2=221 p for heterogeneity=0202

081 (075 to 089) plt00001I2=145 p for heterogeneity=0310

100 (093 to 108) p=0918I2=194 p for heterogeneity=0237

Relative risk (95 CI)

5Major CV events

16Coronary event

10Nonfatal coronary events

16All-cause mortality

Number of studies included

Favors placeboFavors fibrateRelative risk (95 CI)

Jun M et al Lancet 20103621563ndash1574Reprinted from The Lancet Volume 362 Jun M et al Effects of fibrates on cardiovascular outcomes

a systematic review and meta-analysis 1563ndash1574 Copyright 2010 with permission from ElsevierMI and stroke

Meta-analysis of 18 placebo-controlled fibrate trials (45 058 patients)

Docosahexenoic acid (DHA)

Eicosapentenoic acid (EPA)

PUFAs Found in fish oil and Mediterranean diet1

Have been used to lower TG1

Omega-3 fatty acids

EPA1

Marketed omega-3 fatty acids include Vascepa (ethyl-EPA)2

Lovaza (mixture of ethyl-esterified EPA DHA and other fish oils)3

1 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash17012 Vascepa Prescribing Information httpwwwdrugscomprovascepahtml

3 Lovaza Prescribing Information httpswwwgsksourcecomgskprmhtdocsdocumentsLOVAZA-PI-PILPDF

Placebo-controlled trials of omega-3 fatty acids

have reported beneficial effects on CV outcomes

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin vs placebo

DART1Men previous MI(n=2033)

Dietary fish intakeMean 2 years

No significant change in total-C over 2 years

All-cause mortality darr29 (plt005)

GISSI-P2 Recent MI (n=11 324)

Omega-3 PUFA1 gd vs control Mean 35 years

LDL-C uarr99 (p=0002) HDL-C uarr88 (p=NS)TGs darr34 (p=0001)

Death nonfatal MI or nonfatal stroke darr10 (p=0048)

GISSI-HF3 Chronic HF(n=6975)

Omega-3 PUFA1 gd vs placebo Median 39 years

TGs darr from 142 to 134 mmolL over 3 years with PUFA (plt00001 vs placebo)

All-cause death darr9 (p=0041)All-cause death or CV hospitalization darr8 (p=0009)

1 Burr ML et al Lancet 19892757ndash7612 GISSI-Prevenzione Investigators Lancet 1999354447ndash455

3 GISSI-HF Investigators Lancet 20083721223ndash1230

Statin use was 5 at study baseline rising to 46 after 42 monthsrsquo follow-upPatients were also randomized to rosuvastatin or placebo no interaction was recorded between PUFA and statin

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Cholesterol absorption inhibitor

Ezetimibe

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

FIELD Fenofibrate did not reduce primary outcome (CHD death or nonfatal

MI) in patients with diabetes

FIELD fenofibrate 200 mgd vs placebo in 9795 patients with type 2 diabetesMedian follow-up 5 years

307

11

193

31

11

20

26

112

187

243

113147

00

05

10

15

20

25

30

35

LDL-C HDL-C TGs

Placebo baseline Fenofibrate baseline

Placebo study end Fenofibrate study end

Mea

n lip

id le

vel (

mm

olL

)R

ate

1000

per

son-

year

s

104

44

64 64

142

119117

37

8471

129

150

02468

10121416

Primary outcome CHD mortality Nonfatal MI Stroke All-cause mortality Coronary revascularization

Fenofibrate PlaceboHR 089

95 CI 075 to 105p=016dagger

p=022

p=036

p=018

HR 07695 CI 062 to 094

p=001

HR 07995 CI 068 to 093

p=0003

Keech A et al Lancet 20053661849ndash1861

CHD mortality or nonfatal MIdaggerARR over course of study=07 NNT=143NNT number needed to treat

Keech p7 ndash 1E

Meta-analysis Fibrates may reduce CV events

but not all-cause mortality

151005

090 (082 to 100) p=0048I2=470 p for heterogeneity=0110

087 (081 to 093) plt00001I2=221 p for heterogeneity=0202

081 (075 to 089) plt00001I2=145 p for heterogeneity=0310

100 (093 to 108) p=0918I2=194 p for heterogeneity=0237

Relative risk (95 CI)

5Major CV events

16Coronary event

10Nonfatal coronary events

16All-cause mortality

Number of studies included

Favors placeboFavors fibrateRelative risk (95 CI)

Jun M et al Lancet 20103621563ndash1574Reprinted from The Lancet Volume 362 Jun M et al Effects of fibrates on cardiovascular outcomes

a systematic review and meta-analysis 1563ndash1574 Copyright 2010 with permission from ElsevierMI and stroke

Meta-analysis of 18 placebo-controlled fibrate trials (45 058 patients)

Docosahexenoic acid (DHA)

Eicosapentenoic acid (EPA)

PUFAs Found in fish oil and Mediterranean diet1

Have been used to lower TG1

Omega-3 fatty acids

EPA1

Marketed omega-3 fatty acids include Vascepa (ethyl-EPA)2

Lovaza (mixture of ethyl-esterified EPA DHA and other fish oils)3

1 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash17012 Vascepa Prescribing Information httpwwwdrugscomprovascepahtml

3 Lovaza Prescribing Information httpswwwgsksourcecomgskprmhtdocsdocumentsLOVAZA-PI-PILPDF

Placebo-controlled trials of omega-3 fatty acids

have reported beneficial effects on CV outcomes

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin vs placebo

DART1Men previous MI(n=2033)

Dietary fish intakeMean 2 years

No significant change in total-C over 2 years

All-cause mortality darr29 (plt005)

GISSI-P2 Recent MI (n=11 324)

Omega-3 PUFA1 gd vs control Mean 35 years

LDL-C uarr99 (p=0002) HDL-C uarr88 (p=NS)TGs darr34 (p=0001)

Death nonfatal MI or nonfatal stroke darr10 (p=0048)

GISSI-HF3 Chronic HF(n=6975)

Omega-3 PUFA1 gd vs placebo Median 39 years

TGs darr from 142 to 134 mmolL over 3 years with PUFA (plt00001 vs placebo)

All-cause death darr9 (p=0041)All-cause death or CV hospitalization darr8 (p=0009)

1 Burr ML et al Lancet 19892757ndash7612 GISSI-Prevenzione Investigators Lancet 1999354447ndash455

3 GISSI-HF Investigators Lancet 20083721223ndash1230

Statin use was 5 at study baseline rising to 46 after 42 monthsrsquo follow-upPatients were also randomized to rosuvastatin or placebo no interaction was recorded between PUFA and statin

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Cholesterol absorption inhibitor

Ezetimibe

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Meta-analysis Fibrates may reduce CV events

but not all-cause mortality

151005

090 (082 to 100) p=0048I2=470 p for heterogeneity=0110

087 (081 to 093) plt00001I2=221 p for heterogeneity=0202

081 (075 to 089) plt00001I2=145 p for heterogeneity=0310

100 (093 to 108) p=0918I2=194 p for heterogeneity=0237

Relative risk (95 CI)

5Major CV events

16Coronary event

10Nonfatal coronary events

16All-cause mortality

Number of studies included

Favors placeboFavors fibrateRelative risk (95 CI)

Jun M et al Lancet 20103621563ndash1574Reprinted from The Lancet Volume 362 Jun M et al Effects of fibrates on cardiovascular outcomes

a systematic review and meta-analysis 1563ndash1574 Copyright 2010 with permission from ElsevierMI and stroke

Meta-analysis of 18 placebo-controlled fibrate trials (45 058 patients)

Docosahexenoic acid (DHA)

Eicosapentenoic acid (EPA)

PUFAs Found in fish oil and Mediterranean diet1

Have been used to lower TG1

Omega-3 fatty acids

EPA1

Marketed omega-3 fatty acids include Vascepa (ethyl-EPA)2

Lovaza (mixture of ethyl-esterified EPA DHA and other fish oils)3

1 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash17012 Vascepa Prescribing Information httpwwwdrugscomprovascepahtml

3 Lovaza Prescribing Information httpswwwgsksourcecomgskprmhtdocsdocumentsLOVAZA-PI-PILPDF

Placebo-controlled trials of omega-3 fatty acids

have reported beneficial effects on CV outcomes

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin vs placebo

DART1Men previous MI(n=2033)

Dietary fish intakeMean 2 years

No significant change in total-C over 2 years

All-cause mortality darr29 (plt005)

GISSI-P2 Recent MI (n=11 324)

Omega-3 PUFA1 gd vs control Mean 35 years

LDL-C uarr99 (p=0002) HDL-C uarr88 (p=NS)TGs darr34 (p=0001)

Death nonfatal MI or nonfatal stroke darr10 (p=0048)

GISSI-HF3 Chronic HF(n=6975)

Omega-3 PUFA1 gd vs placebo Median 39 years

TGs darr from 142 to 134 mmolL over 3 years with PUFA (plt00001 vs placebo)

All-cause death darr9 (p=0041)All-cause death or CV hospitalization darr8 (p=0009)

1 Burr ML et al Lancet 19892757ndash7612 GISSI-Prevenzione Investigators Lancet 1999354447ndash455

3 GISSI-HF Investigators Lancet 20083721223ndash1230

Statin use was 5 at study baseline rising to 46 after 42 monthsrsquo follow-upPatients were also randomized to rosuvastatin or placebo no interaction was recorded between PUFA and statin

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Cholesterol absorption inhibitor

Ezetimibe

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Docosahexenoic acid (DHA)

Eicosapentenoic acid (EPA)

PUFAs Found in fish oil and Mediterranean diet1

Have been used to lower TG1

Omega-3 fatty acids

EPA1

Marketed omega-3 fatty acids include Vascepa (ethyl-EPA)2

Lovaza (mixture of ethyl-esterified EPA DHA and other fish oils)3

1 Fifth Joint Task Force on CVD Prevention in Clinical Practice Eur Heart J 2012331635ndash17012 Vascepa Prescribing Information httpwwwdrugscomprovascepahtml

3 Lovaza Prescribing Information httpswwwgsksourcecomgskprmhtdocsdocumentsLOVAZA-PI-PILPDF

Placebo-controlled trials of omega-3 fatty acids

have reported beneficial effects on CV outcomes

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin vs placebo

DART1Men previous MI(n=2033)

Dietary fish intakeMean 2 years

No significant change in total-C over 2 years

All-cause mortality darr29 (plt005)

GISSI-P2 Recent MI (n=11 324)

Omega-3 PUFA1 gd vs control Mean 35 years

LDL-C uarr99 (p=0002) HDL-C uarr88 (p=NS)TGs darr34 (p=0001)

Death nonfatal MI or nonfatal stroke darr10 (p=0048)

GISSI-HF3 Chronic HF(n=6975)

Omega-3 PUFA1 gd vs placebo Median 39 years

TGs darr from 142 to 134 mmolL over 3 years with PUFA (plt00001 vs placebo)

All-cause death darr9 (p=0041)All-cause death or CV hospitalization darr8 (p=0009)

1 Burr ML et al Lancet 19892757ndash7612 GISSI-Prevenzione Investigators Lancet 1999354447ndash455

3 GISSI-HF Investigators Lancet 20083721223ndash1230

Statin use was 5 at study baseline rising to 46 after 42 monthsrsquo follow-upPatients were also randomized to rosuvastatin or placebo no interaction was recorded between PUFA and statin

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Cholesterol absorption inhibitor

Ezetimibe

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Placebo-controlled trials of omega-3 fatty acids

have reported beneficial effects on CV outcomes

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin vs placebo

DART1Men previous MI(n=2033)

Dietary fish intakeMean 2 years

No significant change in total-C over 2 years

All-cause mortality darr29 (plt005)

GISSI-P2 Recent MI (n=11 324)

Omega-3 PUFA1 gd vs control Mean 35 years

LDL-C uarr99 (p=0002) HDL-C uarr88 (p=NS)TGs darr34 (p=0001)

Death nonfatal MI or nonfatal stroke darr10 (p=0048)

GISSI-HF3 Chronic HF(n=6975)

Omega-3 PUFA1 gd vs placebo Median 39 years

TGs darr from 142 to 134 mmolL over 3 years with PUFA (plt00001 vs placebo)

All-cause death darr9 (p=0041)All-cause death or CV hospitalization darr8 (p=0009)

1 Burr ML et al Lancet 19892757ndash7612 GISSI-Prevenzione Investigators Lancet 1999354447ndash455

3 GISSI-HF Investigators Lancet 20083721223ndash1230

Statin use was 5 at study baseline rising to 46 after 42 monthsrsquo follow-upPatients were also randomized to rosuvastatin or placebo no interaction was recorded between PUFA and statin

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Cholesterol absorption inhibitor

Ezetimibe

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Cholesterol absorption inhibitor

Ezetimibe

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Cholesterol absorption inhibitor

Ezetimibe

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

ENHANCE Simvastatin + ezetimibe did not significantly reduce intima-medial

thickness vs simvastatin alone

00111

00058

0000

0005

0010

0015

Simvastatin + ezetimibe Simvastatin + placebo

Diff

eren

ce fr

om b

asel

ine

at M

onth

24

(mm

)

p=029

44

46

48

50

52

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Mea

n H

DL-

C (m

gdL

)

100

120

140

160

180

Baseline Month 24

Simvastatin + placeboSimvastatin + ezetimibe

Med

ian

TGs

(mg

dL)

0

100

200

300

400

Baseline Month 24

Simvastatin + placebo

Simvastatin + ezetimibe

Mea

n LD

L-C

(mg

dL)

plt001

p=078

plt001

Primary endpointChange in carotid intima-medial thickness at

Month 24

ENHANCE ezetimibe 10 mgd vs placebo (added to simvastatin 80 mgd) in 720 patients with familial hypercholesterolemia (follow-up 24 months)1

1 Kastelein JJP et al N Engl J Med 20083581431ndash14432 Zocor (simvastatin calcium) Prescribing Information Merck Sharp amp Dohme Ltd October 2012No longer a recommended dose of simvastatin2

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Fibrates

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

ACCORD Fenofibrate had no significant effect on CV endpoints when added to a

statin in patients with diabetes

36

37

38

39

40

41

42

Baseline Study end

Placebo Fenofibrate

Mea

n H

DL-

C

chol

este

rol (

mg

dL)

100

120

140

160

180

Baseline Study end

Placebo Fenofibrate

Mea

n TG

s (m

gdL

)

224

258

132

038

147

241

270

144

036

161

00

05

10

15

20

25

30

Primary outcome Major coronary eventdagger Nonfatal MI Stroke All-cause mortality

Fenofibrate Placebo

Out

com

e ra

tey

r(

) p=NS for all endpoints(Primary outcome HR 092 95 CI 079 to 108 p=032 ARR 017 per year NNT 588 to avoid one event over 1 year)

p=001

plt0001

ACCORD fenofibrate (starting dose 160 mgd) vs placebo in 5518 patients with type 2 diabetes treated with open-label simvastatin (mean follow-up 47 years)

Ginsberg HN et al N Engl J Med 20103621563ndash1574Nonfatal MI nonfatal stroke or CV deathdaggerFatal coronary event nonfatal MI or unstable angina

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Niacin

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

55

60

65

70

75

Baseline Year 3

Statin + placebo Statin + niacin

162

15

47

09

4051

164

12

54

16

3747

02468

1012141618

Primary endpoint Death from CHD Nonfatal MI Ischemic stroke Hospitalization for ACS Revascularizationdagger

Statin + placebo Statin + niacin

AIM-HIGH trial of niacin

Discontinued early due to lack of efficacy

AIM-HIGH extended-release niacin 1500ndash2000 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 3414 patients with established CV disease Stopped after mean follow-up 3 yr

Patie

nts

(cum

ulat

ive

)

3032343638404244

Baseline Year 3

Statin + placebo Statin + niacin

Med

ian

HD

L-C

(mg

dL)

100

120

140

160

180

Baseline Year 3

Statin + placeboStatin + niacin

Med

ian

TGs

(mg

dL)

Med

ian

LDL-

C (m

gdL

)

plt0001

p=080

Boden WE et al N Engl J Med 20113652255ndash2267

Death from CHD nonfatal MI ischemic stroke hospitalization for ACS or symptom-driven coronary or cerebral revascularizationdaggerSymptom-driven coronary or cerebral revascularization

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

137

54

39

70

132

5239

63

0

2

4

6

8

10

12

14

16

Primary outcome Any major coronary event Any stroke Any revascularization

Statin + placebo Statin + niacin-laropiprant

HPS-2-THRIVE Niacinndashlaropiprant had no effect on major vascular events

and increased serious AEs

HPS-2-THRIVE extended-release niacin 2000 mgd + laropiprant 40 mgd vs placebo (added to simvastatin plusmn ezetimibe) in 25 673 patients with vascular disease Median follow-up 39 year

-10

6

-33-40

-30

-20

-10

0

10

LDL-C HDL-C TGs

Cha

nge

in li

pids

nia

cin-

laro

pipr

antv

s pl

aceb

o (m

gdL

) Lipid levels

HR 09695 CI 090ndash103

p=029

p=051

p=056

Patie

nts

with

outc

ome

()

3830

04

66

19

4348

37

07

80

25

57

0

2

4

6

8

10

Gastrointestinal Musculoskeletal Skin Infection Bleeding New-onset diabetes

Statin + placebo Statin + niacin-laropiprant

plt0001

plt0001

p=0003

plt0001

plt0001

plt0001

Patie

nts

with

serio

us A

E (

)

HR 09095 CI 082ndash099

p=003

Haynes R et al N Engl J Med 2014371203ndash212Major vascular event (nonfatal MI death from coronary causes stroke or arterial revascularization

ARR 05NNT 200 over 39 years

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Omega-3 fatty acids

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin vs statin alone

JELIS118 645 total-C gt65 mmolL

Statin + EPA 18 gd vs statin + placeboMean 46 years

LDL-C darr25 in both groupsTGs darr9 vs 4 (plt00001)

Major coronary events darr19 (p=0011)No difference for coronary or sudden cardiac death

OMEGA2 Prior MI(n=3851)

Omega-3 PUFA 1 gd vs placeboMean 1 year94 taking statin

TGs 137 vs 143 mmolL at study end (plt001)LDL-C 246 mmolL in both groups

Sudden cardiac death 15 in both groups (p=NS)

Alpha-Omega3

Prior MI(n=4837)

EPAndashDHA 400 mgd vs placeboMedian 34 years86 taking lipid-lowering drugs (mainly statins)

No significant differences in TGs or other risk markers

Fatal and nonfatal CV events and cardiac interventions 140 vs 138 (p=093)

ORIGIN4Dysglycemia + high CV risk(n=12 536)

Omega-3 ethyl esters 1 gd vs placeboMedian 62 yearsasymp54 taking statin

TGs darr235 mgdL with PUFA vs darr90 with placebo (plt00001)Other lipids NS

Death from CV causes 91 vs 93 (p=072)

Omega-3 fatty acids do not appear to augment the beneficial effects of

statins on CV outcomes

1 Yokoyama M et al Lancet 20073691090ndash10982 Rauch B et al Circulation 20101222152ndash2159

3 Kromhout D et al N Engl J Med 20103632015ndash20264 Bosch J et al N Engl J Med 2012367309ndash318

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

1 Non-statin vs placebo

2 Non-statin vs placebo (on background of statin-based lipid lowering therapy)

3 Non-statin + statin vs placebo

Clinical trials of non-statin treatments

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Ezetimibe

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

-15

-10

-05

00

05 Placebo Simvastatin + ezetimibe

SHARP Simvastatin + ezetimibe reduced major atherosclerotic events

compared with placebo in CKD

SHARP simvastatin 20 mgd + ezetimibe 10 mgd or placebo in 9270 patients with CKDMedian follow-up 49 years

LDL-

C a

bsol

ute

chan

ge

(mm

olL

)

8ndash13 26ndash31 44ndash49

Time (months)

5

38

76

46

28

61

0

2

4

6

8

10

Any major coronary event Any non-hemorrhagic stroke Any revascularization

Placebo Simvastatin + ezetimibe

Patie

nts

() p=037

Risk ratio 07595 CI 060 to 094

p=001

25

00 1 2 3 4 5

5

10

15

20

Peop

le s

uffe

ring

even

ts

()

Rate reduction 17 (95 CI 6 to 26)Log-rank p=00021ARR 21 NNT 48 over 49 years

Time (years)

Primary endpoint1

PlaceboSimvastatin + ezetimibe

Risk ratio 07995 CI 068 to 093

p=00036

Nonfatal MI or coronary death non-hemorrhagic stroke or any arterial revascularization procedure

1Figure reprinted with permission from Elsevier (The Lancet 20113772181ndash2192)Baigent C et al Lancet 20113772181ndash2192

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

SEAS Simvastatin + ezetimibe did not reduce major CV events in patients with

asymptomatic aortic stenosis

SEAS simvastatin 40 mgd + ezetimibe 10 mgd vs placebo in 1873 patients with mild-to-moderate asymptomatic aortic stenosis Median follow-up 522 months

Patie

nts

()

38

538

0

20

40

60

Placebo Simvastatin + ezetimibe

Red

uctio

nin

LD

L-C

() plt0001

062 061

0

02

04

06

08

Placebo Simvastatin + ezetimibe

Cha

nge

in p

eak

aort

ic

flow

vel

ocity

(ms

ec)

p=083

382

6

299

28

108

353

50

283

18

73

0

10

20

30

40

Primary outcome Death from CV causes Aortic valve replacement Nonfatal MI CABG

Placebo Simvastatin + ezetimibe

HR 09695 CI 083 to 112

p=059

p=034

p=097

p=015

HR 06895 CI 050 to 093

p=002

Rosseboslash A et al N Engl J Med 20083591343ndash1356Death from CV causes aortic valve replacement nonfatal MI hospitalization for acute angina HF coronary artery bypass grafting percutaneous coronary intervention and non-hemorrhagic stroke

ARR 29NNT 34 over 1 year

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Non-statin trials Summary

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Clinical trials of fenofibrate have reported limited effects on CV endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin vs placebo

FIELD1 Type 2 diabetes(n=9795)

Fenofibrate 200 mgPlaceboMedian 5 years

Final TGsFenofibrate 147 mmolLPlacebo 187 mmolL

CHD mortality or nonfatal MI darr11 (p=016)Nonfatal MI darr24 (p=001)Coronary revascularizaion darr21 (p=003)

Non-statin + statin vs statin alone

ACCORD2 Type 2 diabetes receiving simvastatin (n=5518)

Fenofibrate 160 mgPlaceboMean 47 years

Final TGsFenofibrate 122 mgdLPlacebo 144 mgdL

Major CV event darr8 (p=032)Major coronary eventdarr8 (p=026)All-cause mortalitydarr9 (p=033)

1 Keech A et al Lancet 20053661849ndash18612 Ginsberg HN et al N Engl J Med 20103621563ndash1574

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Clinical trials of ezetimibe have reported inconsistent effects on CV events

Study Population Regimen follow-up Lipid effects CV endpointsNon-statin + statin vs statin alone

ENHANCE1FH (n=720)Receiving simva-statin 80 mg

Ezetimibe 10 mgPlacebo24 months

Final LDL-CEzetimibe 141 mgdLPlacebo 193 mgdL

Change in carotid IMT00111 vs 00058 mm(p=029)

IMPROVE-IT23Post-ACS (n=18 144)Receiving simva-statin 40ndash80 mg

Ezetimibe 10 mgPlaceboasymp6 years

Final LDL-CEzetimibe 532 mgdLPlacebo 699 mgdL

Primary endpointdarr64 (p=0016)

Non-statin + statin vs placebo

SHARP4 CKD(n=9270)

Ezetimibe 10 mg + simvastatin 20 mgPlaceboMedian 49 years

LDL-C darr(months 44ndash49)ES 084 mmolLPlacebo 008 mmolL

Major atherosclerotic events darr17 (p=00021)

SEAS5 Aortic stenosis (n=1873)

Ezetimibe 10 mg + simvastatin 40 mgPlaceboMedian 522 months

LDL-C darrES 538Placebo 38

Primary CV endpointdarr4 (p=059)

1Kastelein JJP et al N Engl J Med 20083581431ndash1443 2 Blazing MA et al Am Heart J 2014168205ndash2123 Cannon C AHA Chicago IL November 17 2014 4 Baigent C et al Lancet 20113772181ndash2192

5 Rosseboslash A et al N Engl J Med 20083591343ndash1356

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Large endpoint trials of niacin reported no significant effect on primary CV

endpoints

Study PopulationRegimenfollow-up Lipid effects CV endpoints

Non-statin + statin plusmn ezetimibe vs statin plusmn ezetimibe alone

AIM-HIGH1 Established CVD (n=3414)

Niacin 1500ndash2000 mgPlaceboAdded to simvastatin plusmnezetimibeMean 3 years

Final HDL-CNiacin 42 mgdLPlacebo 37 mgdL

Primary CV endpointuarr2 (p=080)

HPS2-THRIVE2Established vascular disease(n=25673)

Niacin 2000 mg + laropiprant40 mgdPlaceboAdded to simvastatin plusmnezetimibeMedian 39 years

HDL-C uarr6 vs placebo Major vascular eventsdarr4 (p=029)

1 Boden WE et al N Engl J Med 20113652255ndash22672 Haynes R et al N Engl J Med 2014371203ndash212

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Non-statins on the horizon

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Non-statins on the horizon

PCSK9 inhibitors PCSK9 degrades LDL receptor and inhibits take-up and degradation of LDL1

Loss of PCSK9 reduces LDL-C and protects against CHD1

Monoclonal antibodies against PCSK9 are under development1

Preliminary results in heterozygous FH or high-risk patients receiving maximally tolerated statins2

ndash Marked reduction of LDL-Cndash Potential decrease in CV events

CETP inhibitors1

Torcetrapib withdrawn due to excess CV events Dalcetrapib no effect on recurrent CV events Next-generation CETP inhibitors are in development (anacetrapib evacetrapib)

Mipomersen1

Antisense oligonucleotide inhibitor of apo B synthesis (weekly injections) Approved in USA for homozygous familial hypercholesterolemia

1 Tomkin GH et al Expert Opin Investig Drugs 2014231411ndash14212 Robinson JG et al ESC Congress 2014

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Supplements

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Supplements are not primary treatment

Seeds and Grains Hypocholesterolemic effects and antioxidant activity in an ethyl acetate extract of fenugreek seed which may

be partly due to the presence of flavonoids especially naringenin1

Results from oat bran studies shows it had the ability to lower serum cholesterol levels in part by altering bile acid metabolism2

The few whole-grain studies show improvements in biomarkers blood lipid improvement3

Algae Antihypertensive and antihypercholesterolemic activities were found in some green brown and red algae

seaweeds4

Spirulina

Many pre-clinical studies and a few clinical studies suggest ability to reduce cholesterol 5

1 Belguith-Hadriche O1 Bouaziz M et al Lipid-lowering and antioxidant effects of an ethyl acetate extract of fenugreek seeds in high-cholesterol-fed rats J Agric Food Chem 2010 Feb 2458(4)2116-222 2Jusith AM Kathryn Bhet al Mechanisnm of serumcholesterol reduction by oat bran Hepatology (1994)20 (6) pages 1450ndash1457 3Joanne Slavin Why whole grains are protectrivebiological mechanisms Proceedings of the Nutrition Society (2003) 62 129ndash134 4 Dalin R Hiroyuki N et al Study on antihypertensive and antihyperlipidemiceffects of marine algae Fisheries science(1994) 60 (1) 83-88 5 Amha B Yoshimichi O et Al Current knowledge on potential health benefits of spirulina Journal of Applied Phycology (1993)5 (2) 235-241

Conclusions

The primary objective of lipid-modifying therapy is to reduce CV events

Guidelines recommend statins as first-line drugs for lipid-modifying therapy1ndash3

Guidelines do not recommend non-statins except in very limited circumstances1ndash3

In patients at high risk or with established CVD high-intensity statin is recommended rather than addition of a non-statin12

There are no data from RCTs supporting routine use of fibrates niacin or omega-3 fatty acids added to statin therapy to further reduce ASCVD12

Addition of ezetimibe to a moderate-intensity statin produces a modest further reduction in ASCVD events after ACS4

1 Stone NJ et al J Am Coll Cardiol 2014632889ndash2934 2 Rabar S et al BMJ 2014 349g4356 doi101136bmjg43563 Fifth Joint Task Force Eur Heart J 2012331635ndash1701 4 Cannon C AHA Chicago IL November 17 2014 LBCT02

5 Sever PS et al Lancet 20033611149ndash1158 6 Koren MD et al J Am Coll Cardiol 2004441772ndash1779 7 Colhoun HM et al Lancet 2004364685ndash6968 LaRosa JC et al N Engl J Med 20053521425ndash14359 Cannon CP et al N Engl J Med 20043501495ndash1504 10 Newman C et al Am J Cardiol 20069761ndash67