Atherosclerosis, dyslipidaemia and diabetes slides.ppt

Atherosclerosis, Atherosclerosis, Dyslipidaemia and Dyslipidaemia and

DiabetesDiabetes

Section 1 - Epidemiology and Risk Factors Section 2 - Classification of Dyslipidaemias and Pathogenesis

of Atherosclerosis Section 3 - Lipoproteins and Lipid Metabolism Section 4 - Guidelines and Unmet Need Section 5 - Statins and Lipid-modifying Therapies Section 6 - Key Statin Trials Section 7 - Diabetes: a Risk Factor for CHD? Section 8 - The Metabolic Syndrome Section 9 - Outcome Trials in Diabetes

Atherosclerosis, Dyslipidaemia and Atherosclerosis, Dyslipidaemia and Diabetes Diabetes ContentsContents

Section 1 Section 1

Epidemiology and Risk FactorsEpidemiology and Risk Factors

0

500

1000

CVD deathsCHD deaths

Mortality from CVD and CHD in Mortality from CVD and CHD in Selected CountriesSelected Countries

Mor

talit

y ra

te p

er 1

00

,00

0 p

opu

lati

onM

orta

lity

rate

per

10

0,0

00

pop

ula

tion

(men

aged

35

(men

aged

35 -

- 74

yea

rs)

74

yea

rs)

Adapted from I nternational Cardiovascular Disease Statistics 200Adapted from I nternational Cardiovascular Disease S tatistics 200 3; American Heart Association3; American Heart Association

The Framingham Study: The Framingham Study: Relationship Between Cholesterol Relationship Between Cholesterol

and CHD Riskand CHD Risk

0

Adapted from Castelli WP. Am J Med 1984;76:4–12

25

50

75

100

125

150

<204 205–234 235–264 265–294 >295

CHD

inci

denc

e pe

r 10

00

Serum cholesterol (mg/100 mL)

35

Seven Countries Study: Seven Countries Study: Relationship of Relationship of Serum Cholesterol to MortalitySerum Cholesterol to Mortality

Adapted from Verschuren WM et al. J Am Med Assoc 1995;274(2):131–136

Serum total cholesterol (mmol/L)

30

25

20

15

10

5

0

Dea

th r

ate

from

CH

D/1

000

men

2.60 3.25 3.90 4.50 5.15 5.80 6.45 7.10 7.75 8.40 9.05

Northern Europe

United States

Southern Europe, Inland

Southern Europe, Mediterranean

Japan

Serbia

Cholesterol: A Modifiable Cholesterol: A Modifiable Risk FactorRisk Factor

In the USA, 37% (102 million) have elevated total cholesterol (>200 mg/dL, 5.2 mmol/L)1

In EUROASPIRE II, 58% of patients with established CHD had elevated cholesterol (5 mmol/L, 190 mg/dL)2

10% reduction in total cholesterol results in: 15% reduction in CHD mortality (p<0.001) 11% reduction in total mortality (p<0.001)3

LDL-cholesterol is the primary target to prevent CHD

Adapted from: 1. American Heart Association. Heart and Stroke Statistical Update; 2002; 2. EUROASPIRE II Adapted from: 1. American Heart Association. Heart and Stroke Statistical Update; 2002; 2. EUROASPIRE II Study Group. Study Group. Eur Heart JEur Heart J 2001; 2001;2222:554–572; 3. Gould AL :554–572; 3. Gould AL et al. Circulationet al. Circulation 1998; 1998;9797:946–952:946–952

Risk Factors for Cardiovascular DiseaseRisk Factors for Cardiovascular Disease

Modifiable Smoking Dyslipidaemia

• Raised LDL-cholesterol• Low HDL-cholesterol• Raised triglycerides

Raised blood pressure Diabetes mellitus Obesity Dietary factors Thrombogenic factors Lack of exercise Excess alcohol consumption

Non-modifiable Personal history of CHD Family history of CHD Age Gender

Adapted from: Pyörälä K Adapted from: Pyörälä K et al. Eur Heart Jet al. Eur Heart J 1994; 1994;1515:1300–1331:1300–1331

Levels of Risk Associated with Smoking, Levels of Risk Associated with Smoking, Hypertension and HypercholesterolaemiaHypertension and Hypercholesterolaemia

x1.6 x4

x3

x6

x16x4.5 x9

HypertensionHypertension(SBP 195 mmHg)(SBP 195 mmHg)

Serum cholesterol levelSerum cholesterol level(8.5 mmol/L, 330 mg/dL)(8.5 mmol/L, 330 mg/dL)

SmokingSmoking

Adapted from Poulter N et al., 1993

Section 2Section 2

Classification of Dyslipidaemias and Classification of Dyslipidaemias and Pathogenesis of AtherosclerosisPathogenesis of Atherosclerosis

Classification of Dyslipidaemias:Classification of Dyslipidaemias:Fredrickson (WHO) ClassificationFredrickson (WHO) Classification

LDL – low-density lipoprotein; IDL – intermediate-density lipoprotein; VLDL – very low-density lipoprotein. (High-density lipoprotein (HDL) cholesterol levels are not consideredin the Fredrickson classification.)

Phenotype

I

IIa

IIb

III

IV

V

Lipoproteinelevated

Chylomicrons

LDL

LDL and VLDL

IDL

VLDL

VLDL and chylomicrons

Atherogenicity

None seen

+++

+++

+++

+

+

Prevalence

Rare

Common

Common

Intermediate

Common

Rare

Serumcholesterol

Normal to

Normal to

Normal to

Serumtriglyceride

Normal

Adapted from Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379–391

Normal Arterial WallNormal Arterial Wall

Tunica adventitiaTunica mediaTunica intima

Endothelium

Subendothelial connective tissue

Smooth muscle cellInternal elastic membrane

Elastic/collagen fibres

External elastic membrane

Adapted from Weissberg PL. Eur Heart J Supplements 1999:1:T13–18

Pathogenesis of Atherosclerotic Pathogenesis of Atherosclerotic PlaquesPlaques

Protective response results in production of cellular adhesion molecules

Monocytes and T lymphocytes attach to ‘sticky’ surface of endothelial cells

Migrate through arterial wall to subendothelial space

Lipid-rich foam cells

Endothelial damage

Macrophages take up oxidised LDL-cholesterol

Fatty streak and plaque

CELLULAR ADHESION MOLECULES

induces cell proliferation and a prothrombic state

activated activated endotheliumendothelium

attracts monocytes and T lymphocytes

which adhere to endothelial cells

cytokines (e.g. IL-1, TNF-)

chemokines (e.g.MCP-1, IL-8)

growth factors (e.g. PDGF, FGF)

Adapted from Koenig W. Eur Heart J 1999;1(Suppl T);T19–26

The ‘Activated’ EndotheliumThe ‘Activated’ Endothelium

Adapted from Adapted from Ross RRoss R. N Engl J Med. N Engl J Med 1999; 1999;362362:115–126:115–126

Endothelial Dysfunction in Endothelial Dysfunction in AtherosclerosisAtherosclerosis

Upregulation of endothelial

adhesion molecules

Increased endothelial

permeability

Migration of leukocytesinto the

artery wall

Leukocyteadhesion

Adapted from Ross R. N Engl J Med 1999;362:115–126

Fatty Streak Formation in Fatty Streak Formation in AtherosclerosisAtherosclerosis

Formationof foam cells

Activation of T cells

Adherence and aggregation ofplatelets

Adherence andentry of

leukocytes

Migration ofsmooth

muscle cells


Formation of the Complicated Formation of the Complicated Atherosclerotic PlaqueAtherosclerotic Plaque

Formation of the fibrous cap

Accumulation ofmacrophages

Formation ofnecrotic core


The Unstable Atherosclerotic PlaqueThe Unstable Atherosclerotic Plaque

Rupture of the

fibrous cap

Thinning of thefibrous cap Haemorrhage from

plaquemicrovessels

Adapted from Weissberg PL. Eur Heart J Supplements 1999:1:T13–18

Atherosclerotic Plaque Rupture and Atherosclerotic Plaque Rupture and Thrombus FormationThrombus Formation

Intraluminal thrombus Growth of thrombus

Intraplaque thrombus Lipid pool

Blood FlowBlood Flow

Adapted from Libby P. Circulation 1995;91:2844–2850

The Synthesis and Breakdown ofThe Synthesis and Breakdown of Atheromatous Plaques

Adapted from Libby P. Circulation 1995;91:2844–2850

The Vulnerable Atherosclerotic PlaqueThe Vulnerable Atherosclerotic Plaque

Clinical Manifestations of Clinical Manifestations of AtherosclerosisAtherosclerosis

Coronary heart disease Angina pectoris, myocardial infarction,

sudden cardiac death Cerebrovascular disease

Transient ischaemic attacks, stroke Peripheral vascular disease

Intermittent claudication, gangrene

Section 3Section 3

Lipoproteins and Lipid MetabolismLipoproteins and Lipid Metabolism

Structure of LipoproteinsStructure of Lipoproteins

Free cholesterol

Phospholipid Triglyceride

Cholesteryl esterApolipoprotein

Classification of LipoproteinsClassification of Lipoproteins

Based on density: Chylomicrons Very low-density lipoprotein (VLDL) Intermediate-density lipoprotein (IDL) Low-density lipoprotein (LDL) High-density lipoprotein (HDL)

LDL-CholesterolLDL-Cholesterol

Strongly associated with atherosclerosisand CHD events

10% increase results in a 20% increasein CHD risk

Risk associated with LDL-C is increased by other risk factors: low HDL-cholesterol smoking hypertension diabetes

TriglyceridesTriglycerides Associated with increased risk of CHD events Link with increased CHD risk is complex

may be related to:• low HDL levels• highly atherogenic forms of LDL-cholesterol• hyperinsulinaemia/insulin resistance• procoagulation state• hypertension• abdominal obesity

May have accompanying dyslipidaemias Normal triglyceride levels <150 mg/dL Very high triglycerides (>1000 mg/dL,

11.3 mmol/L) increase pancreatitis risk

HDL-CholesterolHDL-Cholesterol

HDL-cholesterol has a protective effect for risk of atherosclerosis and CHD

The lower the HDL-cholesterol level, the higher the risk for atherosclerosis and CHD low level (<40 mg/dL) increases risk

HDL-cholesterol tends to be low when triglycerides are high

HDL-cholesterol is lowered by smoking, obesity and physical inactivity

ApolipoproteinsApolipoproteins

Main protein content of lipoproteins Functions include:

Facilitation of lipid transport Activation of three enzymes in lipid

metabolism• lecithin cholesterol acyltransferase

(LCAT)• lipoprotein lipase (LPL)• hepatic triglyceride lipase (HTGL)

Binding to cell surface receptors

IntestineIntestine

Skeletal muscleSkeletal muscle

Adipose tissue

Adipose tissue

ChylomicronChylomicron

Chylomicron remnant

Chylomicron remnant

Remnant receptorRemnant receptor

LiverLiver

Dietary triglycerides and cholesterol

Dietary triglycerides and cholesterol

LP lipaseLP lipase

Exogenous Pathway of Lipid Metabolism

Exogenous Pathway of Lipid Exogenous Pathway of Lipid MetabolismMetabolism

to atheromato atheroma

FFAFFA

Endogenous Pathway of Lipid Metabolism

Endogenous Pathway of Lipid Endogenous Pathway of Lipid MetabolismMetabolism

IDLIDLIDL

Large VLDL

Large VLDL

SmallVLDLSmallVLDL

LDLreceptorLDLreceptor

LiverLiver

LPL Lipoprotein lipaseLPL Lipoprotein lipase

HL Hepatic lipaseHL Hepatic lipase

LDLLDL

LPLLPL

LPLLPL

LPLLPL

HLHL

HLHL

HLHL

Reverse cholesterol transportReverse Cholesterol Transport

Peripheraltissuestissues

CellCellmembranemembrane

VLDL, IDL, LDLVLDL, IDL, LDL

LDLLDL receptorreceptor

LCATLCAT CETPCETPFCFC

CECECECE

TGTGHDLHDL HDL3HDL3

TGTGCECE

Free cholesterolFree cholesterolTriglyceridesTriglyceridesCholesterol estersCholesterol esters

CETPCETP Cholesteryl ester transfer proteinCholesteryl ester transfer proteinLCATLCAT Lecithin cholesterol acyl transferaseLecithin cholesterol acyl transferase

SRB1SRB1

FCFC

ABCA1ABCA1

LiverLiver

Section 4Section 4

Guidelines and Unmet NeedGuidelines and Unmet Need

Joint European Guidelines: ESC, Joint European Guidelines: ESC, EAS, ESH, ISBM, ESGP/FM, EHN EAS, ESH, ISBM, ESGP/FM, EHN

Estimate absolute CV risk using chart and initial TC value

Absolute CHD risk <20% over 10 years, TC 5 mmol/L

Absolute CHD risk 20% over 10 years

Measure fasting lipids, give lifestyle advice, with repeat lipids after

3 months

Lifestyle adviceAim: TC<5 mmol/L and

LDL-C <3.0 mmol/L Follow-up at 5-year intervals

TC <5 mmol/L and LDL-C <3.0 mmol/LMaintain lifestyle advice with annual

follow-up

TC 5 mmol/L and/or LDL-C 3 mmol/LMaintain lifestyle advice with drug

therapy

Adapted from Wood D et al. Atherosclerosis 1998;140:199–270

NCEP ATP III: Focus on NCEP ATP III: Focus on Multiple Risk factorsMultiple Risk factors

Uses Framingham projections of 10-year absolute CHD risk to identify certain patients with 2 risk factors for more intensive treatment

Raises persons with diabetes without CHD to the level of CHD risk equivalent

Identifies persons with multiple metabolic risk factors (metabolic syndrome) as candidates for intensified TLC*

National Cholesterol Education Program, Adult Treatment Panel III, 2001. JAMA 2001:285;2486–2497

*TLC: therapeutic lifestyle changes*TLC: therapeutic lifestyle changes

NCEP ATP III: Modifications of NCEP ATP III: Modifications of Lipid ClassificationLipid Classification

Identifies LDL-cholesterol <100 mg/dL (2.6 mmol/L) as optimal

Raises categorical low HDL-cholesterol from <35 to <40 mg/dL (<0.9 to <1 mmol/L)

Lowers TG cutpoints to: normal: <150 mg/dL (<1.7 mmol/L) borderline high: 150–199 mg/dL

(1.7–2.2 mmol/L) high: 200–499 mg/dL (2.2–5.6 mmol/L) very high: 500 mg/dL (5.6 mmol/L)


NCEP ATP III GuidelinesNCEP ATP III Guidelines

Patients withPatients with Drug therapy Drug therapy considered if LDLconsidered if LDL-C

* TLC: therapeutic lifestyle changes* TLC: therapeutic lifestyle changes

National Cholesterol Education Program, Adult Treatment Panel III. National Cholesterol Education Program, Adult Treatment Panel III. JAMA JAMA 2001;2001;285285:2486–2497:2486–2497

Initiate TLC* Initiate TLC* if LDLif LDL-CC

LDLLDL-C C treatment treatment

goalgoal

00-1 risk factors1 risk factors 160 mg/dL160 mg/dL†† 190 mg/dL 190 mg/dL (160(160 – 189 mg/dL:189 mg/dL:

drug optional)drug optional)

<160 mg/dL<160 mg/dL††

2 risk factors2 risk factors(10(10-year risk year risk 20%)20%)

130 mg/dL130 mg/dL†† -1010 year risk 10year risk 10–

20%: 20%: 130 mg/dL 130 mg/dL 10-year risk <10%:10-year risk <10%:

160 mg/dL160 mg/dL

<130 mg/dL<130 mg/dL††

CHD and CHD risk CHD and CHD risk equivalentsequivalents(10(10- year risk >20%)year risk >20%)

100 mg/dL100 mg/dL†† <100 mg/dL<100 mg/dL††

†† 100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L

130 mg/dL 130 mg/dL

drug optional)drug optional)(100–129 mg/dL:(100–129 mg/dL:

NCEP ATP III: LDL-Cholesterol Goals NCEP ATP III: LDL-Cholesterol Goals


CHD or CHD risk

equivalents

<2 risk factors

≥2 risk factors

LDL-

chol

este

rol l

evel

100 -

160 -

130 -

190 -

Target 100mg/dL

Target 130mg/dL

Target 160mg/dL

100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L

NCEP ATP III Guidelines Increase the NCEP ATP III Guidelines Increase the Number of Patients Eligible for TreatmentNumber of Patients Eligible for Treatment

RiskRisk NCEP NCEP ATP IIATP II

NCEP NCEP ATP IIIATP III

% increase in % increase in drug-eligible drug-eligible

patientspatients

HighHighModerate Moderate LowLow

TotalTotal

8,6128,61219,55519,5551,2641,264

29,43129,431

14,71314,71323,66323,6631,2641,264

39,64039,640

7171212100

3535

Adapted from Davidson MH. Am J Cardiol 2002;89(Suppl 5A):1C–2C

L-TAP: Achieving NCEP ATP II Goal L-TAP: Achieving NCEP ATP II Goal on Lipid-modifying Therapyon Lipid-modifying Therapy

0

20

40

60

80

100Pe

rcen

tage

of p

atie

nts

85% of patients

received lipid-modifying therapy

39% of patients receiving

lipid-modifying therapy reached

NCEP ATP II LDL-C goal

* LDL-C 100 mg/dL

(n=4888) (n=4137)

<20% of CHD patients who receiving lipid-modifying

therapy reached NCEP ATP II LDL-C goal*

(n=1352)

Adapted from Pearson TA et al. Arch Intern Med 2000;160:459–467

EUROASPIRE II: Achieving Joint EUROASPIRE II: Achieving Joint European TC GoalEuropean TC Goal

0

20

40

60

80

100Pe

rcen

tage

of p

atie

nts

61% of high-risk

patients* received lipid-modifying

therapy

51% of patients

reached Joint European TC

goal**

*CABG, PTCA, MI or ischaemia, ** TC <5 mmol/L

Adapted from EUROASPIRE II. Euro Heart J 2001;22:554–772

Section 5Section 5

Statins and Lipid-modifying Statins and Lipid-modifying TherapiesTherapies

Effect of lipid-modifying therapies Effect of lipid-modifying therapies on lipids on lipids

Therapy

Bile acidsequestrantsNicotinic acid

Fibrates(gemfibrozil)Probucol

Statins*

Ezetimibe

TC–total cholesterol, LDL–low density lipoprotein, HDL–high density lipoprotein, TG–triglyceride. * Daily dose of 40mg of each drug, excluding rosuvastatin.

TC

Down 20%

Down 25%

Down 15%

Down 25%

Down 15–30%

LDL

Down 15–30%Down 25%

Down 5–15%Down

10–15%Down

24–50%Down

15–20%

HDL

Up 3–5%Up

15–30%Up 20%

Down20–30%

Up 6–12%

Up4–9%

TG

Neutral or up

Down 20–50%Down

20–50%Neutral

Down 10–29%

Patienttolerability

Poor

Poor toreasonable

Good

Reasonable

Good

Good

Adapted from Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379–391, Knopp RH. N Engl J Med 1999;341:498–511, Gupta EK, Ito MK. Heart Dis 2002;4:399–409

Mechanism of Action of Statins: Mechanism of Action of Statins: Cholesterol Synthesis PathwayCholesterol Synthesis Pathway

acetyl CoA

HMG-CoA

mevalonic acid

mevalonate pyrophosphate

isopentenyl pyrophosphate

geranyl pyrophosphate

farnesyl pyrophosphate

squalene

cholesterol

dolicholsubiquinones

HMG-CoA synthase

HMG-CoA reductase

Squalene synthase

X Statins

Statin Protein binding

(%)

Metabolisedby CYP450

Lipophilic Half-life (h)

rosuvastatinatorvastatinsimvastatin pravastatinfluvastatin

~90%>98%95–8%~50%>98%

NoYesYes No Yes

NoYesYes No No

~19~15~3~2~3

Pharmacokinetics of StatinsPharmacokinetics of Statins

Adapted from Horsmans Y. Eur Heart J Supplements 1999;1(Suppl T):T7–12, Vaughan CJ et al. J Am Coll Cardiol 2000;35:1–10. Rosuvastatin data from Core Data Sheet

Effects of Statins on LipidsEffects of Statins on Lipids

rosuvastatin (10 mg)atorvastatin (10 mg)simvastatin (20 mg)pravastatin (20 mg)fluvastatin (20 mg)

LDL-C% change

-52-39-38-32-22

HDL-C% change

+14+6+8+2+3

TG% change

-10-19-19-11-12

Adapted from Product Data Sheets.

Pleiotropic Effects of StatinsPleiotropic Effects of Statins

Improving or restoring endothelial function Enhancing the stability of atherosclerotic

plaques Decreasing oxidative stress Decreasing vascular inflammation Anti-thrombotic effects

Adapted from Takemoto M, Liao JK. Arterioscler Thromb Vasc Biol 2001;21:1712–1719

Section 6Section 6

Key Statin TrialsKey Statin Trials

Design of Key Statin TrialsDesign of Key Statin Trials

4S1

WOSCOPS2

CARE3

LIPID4

AFCAPS/TexCAPS5

HPS6

ASCOT-LLA7

Statin

Existing CHD

Patients Cholesterol

Follow-up (years)

simvastatin20 mg od

pravastatin 40 mg od



lovastatin 40 mg od

Yes

No MI,angina(5%)

Yes

Yes

No

Raised Mean LDL-C 4.87 mmol/L,

188 mg/dL

Raised Mean LDL-C 4.97 mmol/L,

192 mg/dL

Average Mean LDL-C 3.59 mmol/L,

139 mg/dL


147 mg/dL


150 mg/dL

5.4

4.9

5.0

6.1

5.2

4444 male and female, aged 35–70

6595 male, aged 45–64




Study

YesYes

In some In some patientspatients

simvastatinsimvastatin40 mg od40 mg od

20536 male 20536 male and female, and female, aged 40–80aged 40–80

Low/average Low/average Mean LDL-C 3.4 mmol/L, Mean LDL-C 3.4 mmol/L,

130 mg/dL130 mg/dL

5.05.0

3.33.3atorvastatinatorvastatin10 mg od10 mg od

Low/averageLow/averageMean LDL-C 3.4 mmol/L, Mean LDL-C 3.4 mmol/L,

130 mg/dL130 mg/dL

10305 male 10305 male and female, and female, aged 40–79aged 40–79

Key Statin Trials and Key Statin Trials and Spectrum of Risk Spectrum of Risk

4S4S11

LIPIDLIPID22

CARECARE44

WOSCOPSWOSCOPS66

AFCAPS/TexCAPSAFCAPS/TexCAPS77

CHD/high cholesterol

CHD/average to high cholesterol

CHD/average cholesterol

No MI/high cholesterol

No CHD/average cholesterol

HPSHPS33 CHD*/average to high cholesterol

*CHD or CHD risk equivalent, e.g. diabetes

Increasing absolute CHD risk

ASCOT-LLAASCOT-LLA55 Some patients with CHD/average cholesterol

simvastatin(n=2221)

4S Cardiovascular Endpoints4S Cardiovascular EndpointsPost-MI or Angina Patients with Raised CholesterolPost-MI or Angina Patients with Raised Cholesterol

Number of events

Outcomes placebo

(n=2223)

Risk reduction (%)

p-value

Total mortality*

Coronary death

Major coronary events

PCTA/CABG

256

189

622

383

182

111

431

252

30

42

34

37

<0.001

<0.001

<0.001

<0.001

* primary endpoint

The Scandinavian Simvastatin Survival Study Group. Lancet 1994;344:1383–1389

4S: Total Mortality4S: Total Mortality

0.85

0.80

0.000.0

1.00

0.95

0.90

Prop

ortio

n al

ive

Years since randomisation

placeboplacebosimvastatinsimvastatin

64321 5

Log rank p=0.0003

This improvement in survival is accounted for by the 42% reduction in coronary death.

The Scandinavian Simvastatin Survival Study Group. Lancet 1994;344:1383–1389

placebo

(n=3293)

pravastatin(n=3302)

Risk reduction (%)

p-value

Non-fatal MI/CHD death*CHD deathNon-fatal MIPCTA/CABGStrokeAll cardiovascular deathsTotal mortality#

248

52204805173

135

174

38143514650

106

31

283137032

22

<0.001

ns<0.0010.009

ns0.033

0.051

* primary endpoint# study not powered to detect differences in this endpoint

WOSCOPS: Cardiovascular EndpointsWOSCOPS: Cardiovascular EndpointsSubjects with No Previous MI but Raised CholesterolSubjects with No Previous MI but Raised Cholesterol

Outcomes

Number of events

Shepherd J et al. N Engl J Med 1995;333:1301–1307

WOSCOPS: Non-fatal MI and CHD WOSCOPS: Non-fatal MI and CHD DeathDeath

YearsYears

0011

22

44

66

Perc

ent w

ith e

vent

Perc

ent w

ith e

vent

88

1010

1212

22 3 3 44 55 66

pravastatin (n=3302)pravastatin (n=3302)placebo (n=3293)placebo (n=3293)

31% 31% relativerelativerisk risk reductionreductionpp<0.001<0.001

Shepherd J et al. N Engl J Med 1995;333:1301–1307

placebo(n=2078)

pravastatin(n=2081)

Risk reduction (%)

p-value

Non-fatal MI/CHD death*CHD deathNon-fatal MIPCTA/CABGUnstable anginaStroke

274

11917339135978

212

9613529431754

24

2023271331

0.003

ns0.020.0090.070.03

CARE: Cardiovascular EndpointsCARE: Cardiovascular EndpointsPost-MI Patients with Average CholesterolPost-MI Patients with Average Cholesterol

* primary endpoint

Outcomes

Number of events

Sacks FM et al. N Engl J Med 1996;335:1001–1009

CARE: Non-fatal MI or CHD DeathCARE: Non-fatal MI or CHD Death

0

5

10

Incid

ence

%

Years0.0

15

54321

Change in risk,Change in risk,24% reduction24% reductionpp=0.003=0.003

pravastatinpravastatinplaceboplacebo

Sacks FM et al. N Engl J Med 1996;335:1001–1009

placebo(n=4502)

pravastatin(n=4512)

Riskreduction (%)

p-value

CHD death*CVD deathAll-cause mortalityCHD death or non-fatal MIAny MIPCTA or CABGHosp. for unstable anginaStroke

373433633715

463708

1106

204

287331498557

336585

1005

169

24252224

292012

19

<0.001<0.001<0.001<0.001

<0.001<0.0010.005

0.048

* primary endpoint

Outcomes

LIPID: Cardiovascular EndpointsLIPID: Cardiovascular EndpointsPost-MI or Unstable Angina Patients with Average/raised Post-MI or Unstable Angina Patients with Average/raised

CholesterolCholesterol

Number of events

LIPID. N Engl J Med 1998;339:1349–1357

LIPID: Cumulative Risk of Death LIPID: Cumulative Risk of Death from CHDfrom CHD

Years after Years after randomisationrandomisation

0011

55

Cum

ulat

ive

risk

(%)

Cum

ulat

ive

risk

(%)

1010

22 3 3 44 55 77

pravastatinpravastatinplaceboplacebo 24% risk 24% risk

reductionreductionpp<0.001<0.001

6600

LIPID. N Engl J Med 1998;339:1349–1357

AFCAPS/TexCAPS: Cardiovascular EndpointsAFCAPS/TexCAPS: Cardiovascular EndpointsSubjects with No History of CHD and Average CholesterolSubjects with No History of CHD and Average Cholesterol

placeboplacebo((n=3301n=3301))

lovastatinlovastatin((n=3304n=3304))

RiskRiskreduction (%)reduction (%)

pp-value-value

Fatal or non-fatal MI + unstable angina + sudden cardiac death*RevascularisationsFatal and non-fatal MIUnstable angina

183

15795

87

116

1065760

37

334032

<0.001

<0.0010.0020.02

* primary endpoint

OutcomesOutcomes

Number of eventsNumber of events

Downs JR et al. J Am Med Assoc 1998;279:1615–1622

AFCAPS/TexCAPS: Fatal/Non-fatal MI, AFCAPS/TexCAPS: Fatal/Non-fatal MI, Sudden Cardiac Death, Unstable AnginaSudden Cardiac Death, Unstable Angina

0.03

0.06

0.04

0.010.00

Cum

ulat

ive

incid

ence

Years of follow-upYears of follow-up0.0 >5

0.07

54321

0.05

0.02

37% riskreductionp<0.001

lovastatinlovastatinplaceboplacebo

Downs JR et al. J Am Med Assoc 1998;279:1615–1622

Meta-analysis of 38 primary and secondary intervention trials Meta-analysis of 38 primary and secondary intervention trials

Benefits of Cholesterol LoweringBenefits of Cholesterol Lowering

Total mortality (Total mortality (pp=0.004)=0.004)CHD mortality (CHD mortality (pp=0.012)=0.012)

% in cholesterol reduction% in cholesterol reduction

Mor

talit

y lo

g od

ds ra

tioM

orta

lity

log

odds

ratio

00 44 88 1212 1616 2020 2424 2828 3232 3636-1.0-1.0

-0.8-0.8

-0.6-0.6

-0.4-0.4

-0.2-0.2

-0.0-0.0

4040 4444 4848 5252

Adapted from Gould AL et al. Circulation. 1998;97:946–952

HPS: Statin Benefits Patients with HPS: Statin Benefits Patients with Low Baseline Cholesterol LevelsLow Baseline Cholesterol Levels

RR - relative reduction vs. placebo

0

10

20

30

40

All-causemortality

Major vascularevents

All stroke

Inci

denc

e %

placebo (n=10,267)

simvastatin(n=10,269)-13% RR

P=0.0003

-24% RRp<0.0001

-25% RRp<0.0001

Adapted from HPS Collaborative Group, Lancet 2002;360:7–22

ASCOT-LLA: Statin Benefits ASCOT-LLA: Statin Benefits Hypertensive Patients with Average Hypertensive Patients with Average or Low Baseline Cholesterol Levelsor Low Baseline Cholesterol Levels

Adapted from Sever PS et al. Lancet 2003;361:1149–1158

placeboplacebo((n=5137n=5137))

atorvastatinatorvastatin((n=5168n=5168))

Hazard Hazard ratioratio

pp-value-value

154

486

247

137

121

* primary endpoint, # includes silent MI, excludes silent MI

OutcomesOutcomesNumber of eventsNumber of events

Non-fatal MI# plus fatal CHD*

Total CV events and procedures

Total coronary events

Non-fatal MI plus fatal CHD

Fatal and non-fatal stroke

100

389

178

86

89

0.64

0.79

0.71

0.62

0.73

0.0005

0.0005

0.0005

0.0005

0.0236

Section 7Section 7

Diabetes: a Risk Factor for CHD?Diabetes: a Risk Factor for CHD?

Diabetes MellitusDiabetes Mellitus

One of the most common non-communicable diseases

Fourth or fifth leading cause of death in most developed countries

More than 177 million people with diabetes worldwide

Incidence of diabetes is increasing – estimated to rise to 300 million by 2025 expected to triple in Africa, the Eastern Mediterranean and

Middle East, and South-East Asia to double in the Americas to almost double in Europe

Adapted from: International Diabetes Federation websiteAdapted from: International Diabetes Federation website

The Chronic Complications of The Chronic Complications of Diabetes MellitusDiabetes Mellitus

Macrovascular complications: Heart disease

Leading cause of diabetes related deaths (increases mortality and stroke by 2 to 4 times)

Microvascular complications: Retinopathy

Leading cause of adult blindness Nephropathy

Accounts for 43% of new cases of ESRD Neuropathy

60–70% of patients with diabetes have nervous system damage

Adapted from National Diabetes Statistics US 2000

UKPDS: Typical Lipid Profile in Patients with UKPDS: Typical Lipid Profile in Patients with Diabetes Compared with No DiabetesDiabetes Compared with No Diabetes

Adapted from UKPDS. Adapted from UKPDS. Diabetes CareDiabetes Care 1997; 1997;20:20:1683–16871683–1687

p<0.001 p<0.001MenMen WomenWomen

no DMDM DMno DM

1

1.2

1.4

1.6

1.8

2

Triglycerides (mmol/ L)

5

5.2

5.4

5.6

5.8

6

Total cholesterol (mmol/ L)

MenMen

WomenWomen

DMno DM

no DM DM

1

1.2

1.4

1.6

HDL-cholesterol (mmol/ L)

DM DMno DM

no DM

p<0.001

p<0.001

MenMen

WomenWomen

3

3.2

3.4

3.6

3.8

4

LDL-cholesterol (mmol/ L)

p<0.001

MenMen

DMno DM

no DM DM

WomenWomen

PROCAM: Combination of Risk PROCAM: Combination of Risk Factors Increases Risk of MIFactors Increases Risk of MI

0

20

40

60

80

100

120

Inci

denc

e of

MI/

1000

pts

None

Hyper

tensio

n

only

Diabet

es on

ly

Hyper

tens

+

diabete

s

Dyslip

idaem

ia

Dyslip

idaem

ia +

hype

rtens

+/-

diabe

tes

Prevalence (%): 54.9 22.9 2.6 2.3 9.4 8.0

Adapted from Assman G, Schulte H. Am Heart J 1988;116:1713–1724

Adapted from Malmberg K et al. Circulation 2000;102:1014–1019

OASIS:OASIS: Patients with Diabetes at Similar Patients with Diabetes at Similar Risk to No Diabetes with CVDRisk to No Diabetes with CVD

BARI: Diabetes Results in Less Favourable BARI: Diabetes Results in Less Favourable Outcome After Angioplasty Than No Outcome After Angioplasty Than No

DiabetesDiabetes

0

5

10

15

20

25

30

35

No diabetesNo diabetes DiabetesDiabetes

5-ye

ar m

orta

lity

(%)

CABG PTCA

Adapted from BARI Investigators. N Engl J Med 1996:335:217–225

NHANES: Smaller Changes in CAD Mortality NHANES: Smaller Changes in CAD Mortality Rates in Patients with Diabetes than No Rates in Patients with Diabetes than No

Diabetes Over TimeDiabetes Over Time

-50

-40

-30

-20

-10

0

10

20

% c

hang

e in

mor

talit

y

MenWomen

*p<0.001 vs. baseline

*

DiabetesDiabetes No diabetesNo diabetes

Adapted from Gu K et al. JAMA;281:1291–1297

Section 8Section 8

The Metabolic SyndromeThe Metabolic Syndrome

The Metabolic Syndrome andThe Metabolic Syndrome andAssociated CVD Risk FactorsAssociated CVD Risk Factors

AtherosclerosisAtherosclerosis

Endothelial Dysfunction

Hypertension

Abdominal obesity

Hyperinsulinaemia

Dyslipidaemia• high TGs

• small dense LDL• low HDL-C

Diabetes

Hypercoagulability

Insulin Resistance

NCEP ATP III: The Metabolic SyndromeNCEP ATP III: The Metabolic Syndrome

<40 mg/dL (1.0 mmol/L)<50 mg/dL (1.3 mmol/L)

MenWomen

>102 cm (>40 in)>88 cm (>35 in)

MenWomen

110 mg/dL (6.0 mmol/L)Fasting glucose130/85 mm HgBlood pressure

HDL-C150 mg/dL (1.7 mmol/L)TG

Abdominal obesity (Waist circumference)

Defining LevelRisk Factor

Diagnosis is established when 3 of these risk factors are present


WHO: The Metabolic SyndromeWHO: The Metabolic Syndrome

A working definition is glucose intolerance, IGT or diabetes mellitus and/or insulin resistance together with two or more of the following:

• Impaired glucose regulation or diabetes• Insulin resistance• Raised arterial pressure 160/90 mmHg• Raised plasma triglycerides (1.7 mmol/L, 150 mg/dL)

and/or low HDL-C (men <0.9 mmol/L, 35 mg/dl; women <1.0 mmol/L, 39 mg/dL)

• Central obesity• Microalbuminuria (UAER 20 g/min or albumin:

creatinine ratio 20 mg/g)

Alberti KGMM, Zimmet PZ for the WHO. Diabet Med 1998:15;539–553

AIR: LDL Particle Size is Related to AIR: LDL Particle Size is Related to the Metabolic Syndromethe Metabolic Syndrome

25

25.5

26

26.5

27LD

L pe

ak p

arti

cle

size

(nm

)

Metabolic Syndrome (n=62)No Metabolic syndrome but 1 or more risk factors (n=252)No risk factors (n=77)

p<0.001

Adapted from Hulthe J et al. Arterioscler Thromb Vasc Biol 2000;20:2140–2147

PARIS: CHD Mortality Increases with PARIS: CHD Mortality Increases with Increased Impaired Glucose ToleranceIncreased Impaired Glucose Tolerance

0

1

2

3

4

5

CHD

mor

talit

y ra

te/1

000

G <140 mg/dL

IGT G 200 mg/dLNewly

diagnosed diabetes

Known diabetes

p<0.001

n=6055 n=690 n=158 n=135

Adapted from Eschwege E et al. Horm Metab Res 1995;17(Suppl):41–46

G - glucoseG - glucose

Section 9Section 9

Outcome Trials in DiabetesOutcome Trials in Diabetes

Trials with Fibrates in Patients with Trials with Fibrates in Patients with DiabetesDiabetes

Frick MH et al. N Engl J Med 1987;317:1237–1245, Koskinen P et al. Diabetes Care 1992;15:820–825, Elkeles RS, Diamond JR, Poulter C et al. Diabetes Care 1998;21(4):641–648, Rubins HB et al. N Engl J

Med 1999;341:410–418, DAIS Investigators. Lancet 2001;357:905–910

Study Effect p-value Comment

Helsinki Helsinki Heart StudyHeart Study(gemfibrozil)(gemfibrozil)

75% 75% eventsevents

nsns Primary prevention; Primary prevention; post-hoc subgroup analysispost-hoc subgroup analysis

SENDCAPSENDCAP(bezafibrate)(bezafibrate)

65% 65% eventsevents

0.010.01 Specifically conducted in Specifically conducted in Type 2 diabetes; post-hoc Type 2 diabetes; post-hoc analysis for IHDanalysis for IHD

VA-HITVA-HIT(gemfibrozil)(gemfibrozil)

24%24%eventsevents

0.050.05 Secondary intervention; Secondary intervention; pre-planned subgroup pre-planned subgroup analysisanalysis

DAISDAIS(fenofibrate)(fenofibrate)

40-42%40-42%focal angio focal angio changeschanges

0.020.02 Specifically conducted in Specifically conducted in Type 2 diabetes; mixed Type 2 diabetes; mixed primary and secondary primary and secondary intervention; angio studyintervention; angio study

Statins Reduce CHD Risk in Patients Statins Reduce CHD Risk in Patients with Diabeteswith Diabetes

StudyStudy % LDL-C % LDL-C loweringlowering

% CHD risk % CHD risk reduction reduction (overall)(overall)

% CHD risk % CHD risk reduction reduction (diabetes)(diabetes)

Primary preventionPrimary preventionAFCAPS/TexCAPSAFCAPS/TexCAPS11 (lovastatin; n=239) (lovastatin; n=239) 2525 37 (37 (pp<0.001)<0.001) 4343

Secondary preventionSecondary preventionCARECARE2 2 (pravastatin; n=586) (pravastatin; n=586)4S4S33 (simvastatin; n=202) (simvastatin; n=202)LIPIDLIPID44 (pravastatin; n=782) (pravastatin; n=782)

28283636

25*25*

23 (23 (pp<0.001)<0.001)32 (32 (pp<0.001)<0.001)

2525

25 (25 (pp=0.05)=0.05)55 (55 (pp=0.002)=0.002)

1919

* value for overall group

Adapted from Kreisberg RA. Am J Cardiol 1998;82:67U–73U

4S/CARE: LDL Lowering in Patients 4S/CARE: LDL Lowering in Patients with Diabeteswith Diabetes

Adapted from Pyörälä K et al. Diabetes Care 1997;20:614–620

4S: CHD Event Reduction in Patients 4S: CHD Event Reduction in Patients with Diabeteswith Diabetes

WOSCOPS: Statin Treatment WOSCOPS: Statin Treatment Protects Against Development of Protects Against Development of

DiabetesDiabetes

Total Total number of number of patientspatients

Patients Patients developing developing diabetesdiabetes

% risk % risk reductionreduction

pp-value-value

59745974 139139 3030 0.0420.042

Adapted from Freeman DJ et al. Circulation 2001;103:357–362

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Atherosclerosis, dyslipidaemia and diabetes slides.ppt