Cardiovascular Outcome Studies Is It Time for Paradigm shift?syllabus.aace.com/2018/PCP/Cerritos/presentations/Handelsman_CVOT... · CHF, now stable –ROS: Fatigue, lately sleep

Yehuda Handelsman, MD, FACP, FNLA, MACESheraton Cerritos Hotel, Saturday, March 24, 2018, Cerritos, CA

Cardiovascular Outcome Studies

Is It Time for Paradigm shift?

California Chapter of the American Association of Clinical Endocrinologists

Presents:

Hot Topics in Diabetes and Endocrinology for Primary Care

Yehuda Handelsman, MD, FACP, FNLA, MACE

Medical Director & Principal investigator

Metabolic Institute of America

Chair

AACE/ACE Diabetes & lipid Scientific Committees

President

Pacific Lipids association

Program Chair & Director

“Heart in Diabetes” 7/13-15/2018, Philadelphia, PN16th WCIRDC 11/29-12/1/2018, Los Angeles, CA

Solo practice

Endocrinology, Diabetes & Metabolism

Tarzana, California

Handelsman Disclosures

Research grant- Amgen, AZ, BMS, BI, Gan & Lee, Grifolis,

Hamni, Lexicon, Merck, Mylan, Novo Nordisk, Sanofi

Consultant – Aegerion, Amarin, Amgen, BMS, BI, Gilead,

Janssen, Lilly, Merck, Novo-Nordisk, Sanofi.

Speaker’s Bureau- Aegerion, Amarin, Amgen, AZ, BI-Lilly,

Janssen, Merck, Novo-Nordisk, Regeneron, Sanofi.

Dr Handelsman & his immediate family do not have ownership interest

& or stocks of any Pharmaceutical or device company

Diabetes is associated with significant loss of

life years

Seshasai et al. N Engl J Med 2011;364:829-41

4

.

0

7

6

5

4

3

2

1

040 50 60 70 80 90

Age (years)

Years

of

life lost

Men7

6

5

4

3

2

1

040 50 60 70 80 900

Age (years)

Women

Non-vascular deaths

Vascular deaths

On average, a 50-year-old individual with diabetes and no history of vascular

disease will die 6 years earlier compared to someone without diabetes

Type 2 diabetes and glycemic disorders

Dyslipidemia

– Low HDL

– Small, dense LDL

– Hypertriglyceridemia

Hypertension

Endothelial dysfunction/inflammation (hsCRP)

Impaired thrombolysis

PAI-1

Ath

ero

scle

rosis

Insulin

resistance

Glucotoxicity

Lipotoxicity

Adiponectin

Courtesy of Selwyn AP, Weissman PN.

Clinical Manifestations of Insulin Resistance

Development of T2DM and CVD- Common Soil

Type 2

Diabetes

Mellitus

Cardiovascular

Disease

Insulin -

Resistance

Adiposity

High Triglycerides

Elevated Glucose

Low HDL-C

Elevated BP

Smoking

Risk Factors

Family Hx T2DM

Family Hx CVD

High LDL-C

Age and Gender

Risk for Cardiovascular Events is Greatest When Both Diabetes and CKD Are Present

Foley RN, et al. J Am Soc Nephrol. 2005;16:489-495.

Incidence per

100 Patient-Years

x 2.8

x 2.3

x 1.7x 2.1

x 2.0

x 2.5

CHF=congestive heart failure; AMI=acute myocardial infarction;

CVA/TIA=cerebrovascular accident/transient ischemic attack;

PVD=peripheral vascular disease; ASVD=atherosclerotic vascular disease.

*ASVD was defined as the first occurrence of AMI, CVA/TIA, or PVD.

UKPDS 23

Turner RC et al. BMJ. 1998;316:823-828.

Position in Model

Variable P Value*

First Low-density lipoprotein (LDL) cholesterol <0.0001

Second High-density lipoprotein (HDL) cholesterol 0.0001

Third A1C 0.0022

Fourth Systolic blood pressure 0.0065

Fifth Smoking 0.056

Adjusted for age and sex in 2,693 white patients with type 2 diabetes with dependent variable as time to first event.*Significant for CAD (n=280). P-values indicate significance of risk factors after controlling for all other risk factors in model.

Established Major Modifiable Cardiovascular Risk Factors in Type 2 Diabetes

CAD = coronary artery disease.

Type 2 Diabetesis a

Cardiovascular Disease

Treat All Risk Factors

Handelsman Y, 1998

A: Total deaths during 13.3 years (primary endpoint)B: Death from cardiovascular disease, nonfatal stroke, nonfatal myocardial

infarction, CABG, PCI, revascularization for atherosclerotic obstructive disease, outbreak of cardiovascular events including leg amputation (secondary combined endpoint)

C: Number of each event constituting the combined endpoint (bar for A and B indicates SE)

*Outbreak of cardiovascular events, etc. was compared between the standard therapy group (conventional multi-factor treatment applied) and the intensive therapy group (treatment applied with goal set at HbA1c < 6.5%, fasting total cholesterol < 175mg/dL, fasting triglycerides < 150mg/dL, systolic blood pressure < 130 mmHg and diastolic blood pressure < 80 mmHg).

10

Intensive Intervention in T2DM Reduced CV

Death and Improved Vascular Complications

Gaede P. et al.: N Engl J Med. 358(6): 580-591, 2008

Intensive therapy group Standard therapy group

Nu

mb

er

of

card

iov

ascu

lar

ev

en

ts

40

35

30

25

20

15

10

5

0Cardiovascular

death

Stroke Myocardial

infarctionCABG PCI Revasculariz

ation

Leg

amputation

C

Cu

mu

lati

ve d

eath

Total follow-up period0 1 2 3 4 5 6 7 8 9 10 11 12 13

Intensive therapy group

Standard therapy group

80

70

60

50

40

30

20

10

0

p=0.02

Number of surviving patients followed

80 78 75 72 65 62 57 39

80 80 77 69 63 51 43 30



(%)

(year)

A

Cu

mu

lati

ve

card

iov

ascu

lar

ev

en

ts

80

70

60

50

40

30

20

10

0

p<0.001



Total follow-up period0 1 2 3 4 5 6 7 8 9 10 11 12 13

Number of event-free patients

80 72 65 61 56 50 47 31

80 70 60 46 38 29 25 14



(%)

(year)

B

Total death and outbreak of cardiovascular events

(standard therapy vs intensive therapy)*

Persons at target levels for HbA1c, BP, and LDL-C

have substantially 60% lower risks for CVD and CHD

Wong ND et al. CV Risk & CV events in DM, Diabetes Care March 2016 (ahead of print)

Diane• 59 yrs old woman comes for second Opinion

– Type 2 diabetes for 8 yrs, 2 yrs ago MI.

– Recently hospitalized for dyspnea diagnosed with CHF, now stable

– ROS: Fatigue, lately sleep disturbance, joint pain

– Social: office manager, Diet- Variable; exercise-none. Married, 2 adult children. Fx Hx- DM, CKD

– SMBG: 120–190 mg, mostly pre breakfast

– Medications: Lisinopril 10mg, torsemide 10, Atenolol 25, Metformin 1000mg BID, Atorvastatin 40mg daily

Diane: Physical findings of note: BMI 32.5; Blood

Pressure 138/87; H. R.- 84; Neck- acantosis nigricans

Lab Test Results

TSH - 1.8, FT4- 1.2

BUN- 22, Cr – 1.4 eGFR- 55

Urinary albumin - 100 mcg/min

ALT - 47

A1C - 8.4%

Lipid : TC 189 LDL 112, HDL 42, TG 175

ENDOCRINE PRACTICE Vol 21 No. 4 April 2015

American Association of Clinical Endocrinologists andAmerican College of

Endocrinology Clinical Practice Guidelines for Developing a

Diabetes Mellitus Comprehensive Care Plan

Writing Committee Cochairpersons

Yehuda Handelsman MD, FACP, FACE, FNLA

Zachary T. Bloomgarden, MD, MACE

George Grunberger, MD, FACP, FACE

Guillermo Umpierrez, MD, FACP, FACE

Robert S. Zimmerman, MD, FACE

14

Comprehensive Management of CV Risk

• Manage CV risk factorsWeight loss

Smoking cessation

Optimal glucose, blood pressure, and lipid control

• Use low-dose aspirin for secondary prevention of CV events in patients with existing CVDMay consider low-dose aspirin for primary prevention of CV events in

patients with 10-year CV risk >10%

• Measure coronary artery calcification or use coronary imaging to determine whether glucose, lipid, or blood pressure control efforts should be intensified

15

Q12. How is CVD managed in patients with diabetes?

CV = cardiovascular; CVD = cardiovascular disease.

Comprehensive Goals For Diabetes Control-

Individualized

A1C Goals AACE (ADA)

≤6.5% (≤6.9%) for most; provided safely

Less than 6% as close to 5%(<6.5% ) for newly

diagnosed, relatively young, healthy; provided safely

≥6.5% (7.5/8/8.5 %) - Less stringent for “less healthy” –

multiple co-morbidities, labile, short life expectancy.

Blood Pressure: 130/80 (140/90) - General; 120/80 with

CKD or stroke risk; >140/90 - Hypotension/dizzy Risk

Lipids : < 100 – General risk; < 70 – High risk;

< 55 Extreme Risk (statin to all)

Handelsman Y et al, AACE/ACE Diabetes Guidelines, Endocr Pract. 2015;21(Suppl 1

Diane : Obesity

BMI : 32.5

Treatment : NoneConsider : Lifestyle & Medical Intervention

Diane: Blood Pressure Control

BP : 138/87

Urinary albumin : 20 mcg/min

Med: Lisinopril 10mg, Atenolol, diuretic

Consider: Lisinopril 40mg

Diane : Lipid Control

TC : 189 LDL : 112 HDL : 42TG : 175

Med: Atorvastatin 40mgConsider: Change dose of Atorva, Combination Medication: Ezetimibe, PCSK9i, cholesvelam, niacin,

Case Study: What should be Diane’s LDL goal

A. < 100 mg/dl ( < 2.5 mmol/L)

B. < 70 mg/dl (< 1.8 mmol/L)

C. < 50 mg/dl (< 1.25 mmol/L)

D. < 55 mg/dl (< 1.4 mmol/L)

E. No goal is needed she is on High potency statin

F. LDL is not important I prefer Particle numbers

G. We should focus on Lp(a)

23

Case Study: Diane’s Lipid Control

A. Increase Atorvastatint to 80mg

B. Add Ezetimibe

C. Add Omega-3 fish oil

D. Add PCSK9i

E. Add Colesevelam

F. Add Niacin

G. Add fibrates

H. No Change

24

• Medications: atorvastatin, 80 mg• Ezetimibe 10 mg- was added

Lab 3 months later:• TC: 173 mmol/L• LDL: 94 mg/dL• HDL: 41 mg/dL• TG: 190 mg/dL

• Lp(a): 84 mg/dl


25


A. Add Omega-3 fish oil

B. Add PCSK9i

C. Add Colesevelam

D. Add Niacin

E. Add fibrates

F. No Change

26


A. Add Omega-3 fish oil (the TGL still too high)

B. Add PCSK9i (Good idea- too expensive too new)

C. Add Colesevelam (reduce LDL but increases TGL)

D. Add Niacin (Now you’re talking- this Lp(a)…)

E. Add fibrates (well still TGL & may reduce LDL)

F. No Change (So- is there Outcome data for combination Tx. …)

27

Diane : Glycemic Control

A1C : 8.4%

Med : Metformin 1000 BIDConsider : Combination Med

Case Study: What should be Diane’s A1C goal

A. < 7%

B. < 7.5%

C. > 8 %

D. < 6.5 %

E. The goal should be Glucose not A1C

30

Case Study: Diane’s Glucose Control- Add:

A. Sulfonylurea

B. DPP4i

C. GLP1-ra

D. SGLT2-i

E. Insulin

F. B & C

G. C & D

H. No Change

31

Cardiovascular Outcome in

Early Glucose Control Studies

0.12

0.10

0.08

0.06

0.02

Randomized

treatment

Intensive Glycemic Control and Long-term Macrovascular Risk in Younger Patients With Shorter Duration of Disease

33

Randomized

treatment

0.04

0.00

0 5 10 15 20

No. at Risk

Conventional 714 688 618 92

Intensive 705 683 629 113

Years

DCCT

T1DM, 5-6 years duration

(N=1441)

42% risk reductionP=0.02

Conventional

Intensive

CV

Ou

tco

me

Cu

mu

lati

ve

in

cid

en

ce

UKPDS

T2DM, newly diagnosed

(N=4209)

15% risk reductionP=0.01

1138 1013 857 578 221 20

2729 2488 2097 1459 577 66

1.0

0.8

0.6

0.4

0.2

0.0

0 5 10 20 25

Years

Conventional

Intensive

Pro

po

rtio

n W

ith

MI

15

CV, cardiovascular; DCCT, Diabetes Control and Complications Trial; MI, myocardial infarction;

UKPDS, United Kingdom Prospective Diabetes Study.

Nathan DM, et al. N Engl J Med. 2005;353:2643-2653.

Holman RR, et al. N Engl J Med. 2008;359:1577-1589.

10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes

Holman RR, et al. N Engl J Med 2008;359.

Absolu

te R

isk

SU-Insulin .91 (0.83-0.99) 0.83 (0.73-0.96) 0.87 (0.79-0.96) 0.85 (0.74-0.97) 0.76 (0.64-0.89)

Metformin 0.79 (0.66-0.95) 0.70 (0.53-0.92) 0.73 (0.59-0.89) 0.67 (0.51-0.89) 0.84 (0.60-1.17)

P=0.04

P=0.01

P=0.007

P=0.01

P=0.001

P=0.01

P=0.01

P=0.002

P=0.005

NS

Inte

ns

ive

-th

era

py

RR

R (

95

% C

I)

PROactive Study• >5,000 patients in 19 European countries involving over 320

investigators

• Investigated effect of insulin resistance on CV morbidity and mortality in patients with T2DM

• Investigated pioglitazone’s ability to prevent the progression of macrovascular disease

PROspective Actos Clinical Trial In macroVascular Events (PROactive) results. http://www.proactive-results.com/html/about_the_study.htmAccessed February 2011.

CV = cardiovascular; T2DM = type 2 diabetes mellitus

• All-cause mortality

• Stroke

• Leg revascularization

• Non-fatal MI (including silent)

• Major leg amputation (above the ankle)

• Acute coronary syndrome

• Cardiac intervention

The primary endpoint was time to first occurrence of any of the following events from time of randomization:

http://www.proactive-results.com/html/about_the_study.htm

Pioglitazone had no significant effect on the primary composite CV endpointsHowever Benefit seen in select secondary endpoints

Time to Fatal/Nonfatal MI (excluding silent MI)Time to ACS

PROactive study, secondary endpoints

CV=cardiovascular; ACS=acute coronary syndromes; MI=myocardial infarction. The official PROspective Actos Clinical Trial In macroVascular Events (PROactive) results website. Available at http://www.proactive-results.com/html/analysis.htm. PROactiveresults Web site. Available at http://www.proactive results.com /html/analysis.htm. October 10, 2006. Dormandy JA, et al. Lancet.2005;366:1279-1285.

PIO vs. placebo

Kapla

n-M

eie

r Event

Rate

2445 2397 2351 2308 2265 2222 406(139)No. at Risk:

0 6 12 18 24 30 36

Time From Randomization (mo)

.00

.01

.03

.04

.05

.06

.02

Placebo (54/1215)

PIO (35/1230)

0.63 0.41, 0.97 .035HR P Value95% CI

Placebo (88/1215)

PIO (65/1230)

Time From Randomization (mo)

Kapla

n-M

eie

r Event

Rate

.02

.04

.06

.08

.10

.00

0 12 18 24 30 36

2445 2387 2337 2293 2245 2199 399(139)No.at Risk:

HR P value

.045PIO vs placebo

6

95% CI

0.72 0.52, 0.99

ACCORD Study Group. N Engl J Med. 2008;358:2545-59.

Ev

en

ts

(%)

25

0

20

15

10

5

01 2 3 4 5 6

Standard therapy

Intensive therapy

Time (years)

HR 0.90 (0.78-1.04)

P = 0.16

ACCORD

Primary outcome

Time (years)

25

0

20

15

10

5

01 2 3 4 5 6

Standard therapy

Intensive therapyHR 1.22 (1.01-1.46)

P = 0.04

ACCORD

Secondary outcome

Trial Terminated after 3.5 yrs (mean) f/u

54 Excess Deaths in Intensive Treatment Arm

[41 were cardiovascular (includes 19 unexpected deaths]

*24% RR in MI

ACCORD Study Group. N Engl J Med. 2011;364:818-28.

ACCORD: Mortality vs On-trial A1c

Riddle MC et al. Diabetes Care. 2010;33:983-90.

Ray KK, et al. Lancet. 2009;373:1765-1772.

Glucose Control and CHD Events

39

Study SAVOR EXAMINE TECOS CAROLINA CARMELINA

DPP4-i saxagliptin alogliptin sitagliptin linagliptin linagliptin

Comparator placebo placebo placebo sulfonylurea placebo

N 16,500 5,400 14,000 6,000 8,300

Results 2013 2013 June 2015 2017 2017

Study LEADER ELIXA SUSTAIN 6 EXSCEL REWIND FREEDOM

GLP1-RA liraglutide lixisenatide semaglutide exenatide LR dulaglutide ITCA-650

Comparator placebo placebo placebo NEUTRAL Placebo Placebo

N 16,500 14,000 6,000 5,400 8,300 4000+

Results 2016 2015 2016 2018 2019 2015

Study EMPA-REG CANVAS DECLARE NCT01986881

SGLT-2-i empaglifozin canagliflozin dapagliflozin ertugliflozin

Comparator placebo POSITIVE placebo placebo

N 7300 4300 22,200 3900

Results Sept 2015 2017 2019 2020

Large non-insulin CVOTs in T2DM

NEUTRAL NEUTRAL NEUTRAL

NEUTRAL

+ +

NEUTRAL

+

POSITIVE

POSITIVEPOSITIVE

Study ORIGIN DEVOTE

Basal

Insulin

Glargine Degludec

Comparator Standard of

Care

Glargine

N 12,500 7,600

Results 2012 2016

Large Insulin CVOTs in T2DM

✓ ✓

Placebo

(n = 1,937)

Pioglitazone

(n = 1,939)

IRIS – Pioglitazone

• The primary outcome, stroke or MI, for pioglitazone

vs. placebo: 9.0% vs. 11.8%, HR 0.76, 95% CI 0.62-

0.93, p = 0.007

• All strokes: 6.5% vs. 8.0%, p = 0.19; ACS: 5.0% vs.

6.6%, p = 0.11; new-onset DM2: 3.8% vs. 7.7%, p <

0.001

• Bone fracture: 5.1% vs. 3.2%, p = 0.003; weight gain

>4.5 kg: 52.2% vs. 33.7%, p < 0.0001

•

Trial design: Patients without diabetes with a history of stroke or TIA within 6 months, with

objective evidence of insulin resistance (HOMA-IR value >3.0), were randomized to either

pioglitazone 45 mg or placebo. They were followed for 4.8 years.

Results

Conclusions

Kernan WN, et al. N Engl J Med 2016;374:1321-31

Primary endpoint

• Pioglitazone was superior to placebo in reducing the

composite of stroke/MI in patients with recent

stroke/TIA, no history of DM2, and objective

evidence of insulin resistance

• There was an increase in previously described side

effects with TZDs, including bone fractures, edema,

and weight gain

(p = 0.007)

%

http://www.acc.org/

EMPA-REG

Primary outcome: 3-point MACE

43

HR 0.86

(95.02% CI 0.74, 0.99)

p=0.0382*

Cumulative incidence function. MACE, Major Adverse

Cardiovascular Event; HR, hazard ratio.

* Two-sided tests for superiority were conducted (statistical

significance was indicated if p≤0.0498)

0

1

2

3

4

5

6

7

8

9

0 6 12 18 24 30 36 42 48

Months

Patients

with e

vent

(%)

EMPA-REG- CV death

Empagliflozin

Placebo

EMPA, empagliflozin; PBO, placebo.

HR 0.62 (95% CI 0.49, 0.77)p<0.0001

No. of Patients:EMPA 4687 4651 4608 4556 4128 3079 2617 1722 414PBO 2333 2303 2280 2243 2012 1503 1281 825 177

EMPA-REG

Hospitalization for heart failure

45

HR 0.65

(95% CI 0.50, 0.85)

p=0.0017

Cumulative incidence function. HR, hazard ratio

EMPA-REG: Renal function over time

BL, baseline; PBO, placebo; EMPA, empagliflozin; FU, follow-up; LMDT, last measurement during treatment. Wanner C et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1515920.

78

76

74

72

70

68

66

BL 4 12 28 52 66 80 94 108 122 136 150 164 178 192Week

Adju

ste

d m

ean e

GFR

(ml/

min

/1.7

3m

2) Change In eGFR Over 192 Weeks

No. at Risk:PBO 2323 2295 2267 2205 2121 2064 1927 1981 1763 1479 1262 1123 977 731 448EMPA 10mg 2322 2290 2264 2235 2162 2114 2012 2064 1839 1540 1314 1180 1024 785 513EMPA 25mg 2322 2288 2269 2216 2156 2111 2006 2067 1871 1563 1340 1207 1063 838 524

Placebo

EMPA 10mg

EMPA 25mg

LEADER: Study design

CV: cardiovascular; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA: glucagon-like peptide-1 receptor agonist; HbA1c: glycated hemoglobin;

MEN-2: multiple endocrine neoplasia type 2; MTC: medullary thyroid cancer; OAD: oral antidiabetic drug; OD: once daily; T2DM: type 2 diabetes mellitus.

Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

LEADER- Primary outcomeCV death, non-fatal myocardial infarction, or non-fatal stroke

The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, non-fatal

myocardial infarction, or non-fatal stroke. The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the

hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less

than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio.

Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

LEADER- CV death

The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio; Lira, liraglutide; PBO, placebo. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

Liraglutide

Placebo

Patients at Risk:Lira 4668 4641 4599 4558 4505 4445 4382 4322 1723 484PBO 4672 4648 4601 4546 4479 4407 4338 4267 1709 465

HR 0.78 (95% CI, 0.66-0.93)p=0.007

0

0

Patients

with e

vent

(%)

6 12 18 24 30 36 42 48 54

2

4

6

8

Time from randomization (months)

Macroalbuminuria, doubling of serum creatinine, ESRD, renal death

LEADER- Time to first renal event

The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; ESRD: end-stage renal disease; HR: hazard ratio; Lira, liraglutide; PBO, placebo. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

Liraglutide

Placebo

Patients at Risk:Lira 4668 4635 4561 4492 4400 4304 4210 4114 1632 454PBO 4672 4643 4540 4428 4316 4196 4094 3990 1613 433

HR 0.78 (95% CI, 0.67-0.92)p=0.003

0

0

Patients

with e

vent

(%)

6 12 18 24 30 36 42 48 54

2

6

8

10

Time from randomization (months)

4

Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1607141

Sustain 6: Cardiovascular Outcomes

CANVAS ProgramRandomization Differed across the Two Studies

Baseline Demographics and Disease History

Baseline Therapies

Primary MACE Outcome CANVASCV Death, Nonfatal Myocardial Infarction or Nonfatal Stroke

2 3 4

Years since randomization

5 61

Hazard ratio 0.86 (95% CI, 0.75-0.97) p <0.0001 for noninferiority

p = 0.0158 for superiority

20

18

16

14

12

10

8

6

4

2

0

0

Pati

en

tsw

ith

an

even

t (%

)

Placebo

Canagliflozin

No.ofpatients

Placebo 4

Canagliflozin 5

347 4153 2942 1240 1187 1120 789

795 5566 4343 2555 2460 2363 1661

Intent-to-treat analysis

CANVAS: Hospitalization for Heart Failure

Summary

Nonfatal stroke


CV death or hospitalization for heart failure

All-cause mortality

Primary cardiovascular outcome

CV death

Nonfatal myocardial infarction

0.90 (0.71-1.15)

0.86 (0.75-0.97)

0.87 (0.72-1.06)

0.85 (0.69-1.05)

Favors Canagliflozin

Hazard ratio (95% CI)

0.5

0.67 (0.52-0.87)

0.78 (0.67-0.91)

0.87 (0.74-1.01)

1.0 2.0

Favors Placebo


Composite of 40% Reduction in eGFR, End-stage Renal Disease, or Renal Death

4227 3029 1274 1229 1173 8195664 4454 2654 2576 2495 1781

347795

Hazard ratio 0.60 (95% CI, 0.47-0.77)

Events (n)

40% eGFR reduction 239

End-stage renaldisease/renal death

21


No.ofpatients

Placebo 4Canagliflozin 5

0 1 5 6

20

18

16

14

12

10

8

6

4

2

0

2 3 4

Years since randomization

Pati

en

tsw

ith

an

even

t (%

)

Placebo

Canagliflozin

Hazard ratio (95% CI)

1.0 2.0

Favors Placebo

0.5

Favors SGLT2i

CV death, nonfatal myocardial infarction, or nonfatal stroke

Key Outcomes in the CANVAS Programand EMPA-REG OUTCOME

*CANVAS Program endpoints comparable with EMPA-REG OUTCOME.

0.25

Zinman Bet al. N Engl J Med. 2015 ;373(22):2117-2128. Wanner K et al. N Engl J Med. 2016;375(4):323-334.

CANVAS Program

EMPA-REG OUTCOME

CV death

Nonfatal myocardial infarction Nonfatal

stroke


CV death or hospitalization for heart

failure All-cause mortality

Progression to macroalbuminuria*

Renal composite*

Kosiborod M et al. Circulation. 2017; doi.org/10.1161/CIRCULATIONAHA.117.029190

CVD Real- Data sources

Cohort 2All-cause death

and composite

HHF/all-cause

death

Cohort 1HHF

US

• Truven Health MarketScan Claims and Encounters and linked Medicare Supplemental and Coordination of Benefits (Medicare Supplemental) databases

Norway

• Linked Prescribed Drug, National Patient and Cause of Death Registries

Sweden


Denmark


UK

• Clinical Practice Research Datalink (CPRD) dataset

• The Health Improvement Network (THIN) dataset

Germany

• Diabetes-Patienten-Verlaufsdokumentation (Diabetes Prospective Follow-Up; DPV)

Patient population for all countries/databases combined

1,392,254

new users of SGLT2 inhibitor or other glucose-lowering

drug fulfilling the eligibility criteria

166,033

SGLT2 inhibitor

1,226,221

other glucose-lowering

drug

154,528

SGLT2 inhibitor

154,528

other glucose-lowering

drug

1,071,693 (87%) excluded

during 1:1 match process11,505 (7%) excluded during

1:1 match process1:1 propensity match

Kosiborod, M., et al. Circulation 2017;Online

Contribution of SGLT2 inhibitor: All countries combined

52.7%42.3%

45.3%

41.8%51.0% 49.1%

5.5% 6.7% 5.6%

0

10

20

30

40

50

60

70

80

90

100

HHF All-cause death HHF + all-causedeath

Pro

po

rtio

n o

f ex

po

sure

tim

e (%

)

Canagliflozin Dapagliflozin Empagliflozin


Contribution of SGLT2 inhibitor class: US only

75.9% 75.4%75.4%

19.0% 19.3% 19.3%

5.1% 5.3% 5.3%

0

10

20

30

40

50

60

70

80

90

100

HHF All-cause death HHF + all-causedeath

Pro

po

rtio

n o

f ex

po

sure

tim

e (%

)



Contribution of SGLT2 inhibitor class: European countries combined


6.3% 8.3% 6.1%

91.9% 90.1% 92.2%

1.8% 1.5% 1.7%


All-cause death primary analysis

P-value for SGLT2i vs other glucose-lowering drug: <0.001

Data are on treatment, unadjusted.

Heterogeneity p-value: 0.089


Hospitalization for heart failure primary analysis

P-value for SGLT2 inhibitor vs other glucose-lowering drug: <0.001

Data are on treatment, unadjusted.

Heterogeneity p-value: 0.169


Even

t R

ate

per

100

Pati

en

t-Y

ears

Established


Heart Failure Heart Failure Heart Failure

or

Death

Heart Failure

or

Death

Death Death

No Known


p<0.001 for all comparisons

SGLT-2i

oGLDSGLT-2i

oGLD

CVReal: Absolute Rates of CV Events in Patients reated with SGLT-2i- Secondary & Primary Prevention

Cavender M at al.. Presented at ADA Scientific Sessions; June 9 – May 13, 2017; San Diego, CA.

Incorporating CV Outcome

Trials Results in Guidelines

DM CVOT Impact on DM Guidelines

1. CDA- Canadian DM Assoc were the 1st to incorporate Empaglilozin then liraglutide as part of their Guidelines

2. In the trials theses medications were typically the 3rd or the 4th added drugs (occasionally 2nd) Metformin has generally been foundation of the treatment

3. ESC- European society of Cardiology in 2016 added empagliflozin as an option to manage CHF in people with DM & CHF

4. In 2017 the ADA added to their guidelines a recommendation to prefer Empaglilozin or liraglutide in uncontrolled DM patients with established ASCVD. In 2018 Canagliflozin was also added as an option for these patients

5. In its DM treatment algorithm AACE has already been recommending GLP1-RA & SGLT2i as first choice post metformin and/or as third medication; therefore AACE did not need to create new recommendations post CVOT

6. However, in its DM Med Profile, AACE recommends Empa, Cana & Lira in patients with Diabetes and established CVD due to their proven cardiac benefits.

Start metformin immediately

Consider initial combination with

another antihyperglycemic agent

Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin

A1C <8.5%Symptomatic hyperglycemia with

metabolic decompensationA1C 8.5%

Initiate

insulin +/-

metformin

If not at glycemic

target (2-3 mos)

Start / Increase

metformin

If not at glycemic targets

L

I

F

E

S

T

Y

L

E

Add another agent best suited to the individual by prioritizing patient characteristics:

Degree of hyperglycemia

Risk of hypoglycemia

Overweight or obesity

Cardiovascular disease or multiple risk factors

Comorbidities (renal, CHF, hepatic)

Preferences & access to treatment

See next page…

AT DIAGNOSIS OF TYPE 2 DIABETES

Consider relative A1C lowering

Rare hypoglycemia

Weight loss or weight neutral

Effect on cardiovascular outcome

See therapeutic considerations, consider eGFR

See cost column; consider access

PATIENT CHARACTERISTIC CHOICE OF AGENT

PRIORITY:

Clinical Cardiovascular Disease

Antihyperglycemic agent with

demonstrated CV outcome benefit

(empagliflozin, liraglutide)

11/201

6

In the 2017 ADA Standart of Care

“In patients with long-standing suboptimally controlled Type 2 Diabetes and Established Atherosclerotic Cardiovascular Disease, Empagliflozin or Liraglutide should be considered as they have been shown to reduce cardiovascular and all-cause mortality when added to standard care.

In the 2018 ADA Standart of Care

Canagliflozin was added to the recommended drugs for long-standing suboptimally controlled Type 2 Diabetes and Established Atherosclerotic Cardiovascular Disease,Ongoing studies are investigating the cardiovascular benefits of other agents in these drug classes

Case : Jack, 63 years, male

Diagnoses:

• Diabetes mellitus Type 2 for 5 years

• Obesity BMI 31.3 kg/m²

• HTN

• Hyperlipidemia

• ASCVD- TIA (CVA?) 3 years ago; ACS 6 months ago.

Presentation to office for better lipid control

Physical exam:

• Height 176 cm

• Weight 97 kg BMI 31.3

• Waist circumference 101 cm,

• Blood pressure 145/88 mmHg

• Pulse 84 min.

• Pedal pulses palpable

• Pretibial edema bilaterally


The reason of the visit:

Consult to prevention of further ASCVD

Current medications:

• Metformin 1000 mg QD

• Aspirin 100 mg QD

• Prasugrel 10 mg QD

• Ramipril 5 mg QD

• Bisoprolol 5 mg QD

• Simvastatin 20 mg QD


Lab tests:• HbA1c 7.9%• Fasting glucose 137 mg/dl • Creatinine 1.1 mg/dl; GFR 72 ml/min)• BUN 26 mg/dl • Uric acid 7.8 mg/dl • GGT 91 U/l, AST 71 U/l, ALT 55 U/l

Lipid profile (on 20 mg Simvastatin):• Total cholesterol 218 mg/dl • Triglycerides 233 mg/dl • LDL-cholesterol 138 mg/dl • HDL-cholesterol 34 mg/dl • Lipoprotein(a) 36 mg/dl


1. Better glucose control

2. Better blood pressure control

3. Better lipid control

4. All are important

5. Only blood pressure and lipids control

Case Jack: Discussion points 1

Which factor is most important with respect to preventing recurrent CAD events ?

How should the dyslipidemia be approached? Simvastatin 20mg QD TGL- 233; LDL-138; HDL- 34; Lp (a) 36


1. Wait until better glucose control is achieved

2. Increase dose of statin / change statin

3. Combine statin with fibrate

4. Combine statin with ezetimibe

5. Combine statin with omega-3 fatty acids

6. Add PCSK9i

7. Other Combinations

How should the HTN be approached?

Currently on Ramipril 5mg QD BP- 145/88


1. Increase Ramipril 10mg

2. Switch to HCTZ

3. Add Aplodipine 5

4. Change to Losartan 50mg

5. Add Beta Blocker

6. 1 & 3

7. No Change

How should the hyperglycemia be approached?

Currently on Metformin 1000 mg QD A1C- 7.9%


1. Increase Metformin to 2000mg daily

2. Add GLP1-ra

3. Switch to DPP41

4. Add SGLT2i

5. Add Pioglitazone

6. Switch to SU

7. Add Liraglutide & Pioglitazone

Cardiovascular outcome trials (CVOT) Impact on Clinical Practice▪ Traditionally the approach to preventing & managing CVD in

diabetes, led by AACE, has been a comprehensive approach

addressing all risk factors

▪ The outcome evidence from recent CVOTs of SGLT2-i & GLP1-ra impact DM guidelines for 'glucose-lowering' medications by positioning these therapies as preferred in people with DM and established CVD.

▪ Paradigm shift #1 People with T2D in the appropriate groups (established CVD, high CV risk, progressive renal disease) should be offered such therapies potentially for their properties beyond glucose control. This does not obviate the need for continued

attention to glucose control

▪ Paradigm shift #2: Cardiologists are recognizing DM as a high CV risk requiring comprehensive intensive therapy

▪ d

Conclusions- reduce CVD in DM

The obesity epidemic contributes to diabetes & CVD epidemics

Utilize lifestyle modification for prevention & treatment

Consider comprehensive care of all risk factors, with combination medications, to reduce CVD & complication

Target multiple conditions to reduce risk: intensive glycemic control, LDL-lowering, Control HTN specifically use ACE/ARB.

In people with DM & Established CVD when appropriate Consider adding SGLT2i: Empagliflozin, Canagliflozin or GLP1-ra: Liraglutide.

Pioglitazone in PreDM and history of strokes, may also be beneficial in people with DM & established Disease

THANK YOU QUESTIONS?

Documents

Cardiovascular Outcome Studies Is It Time for Paradigm shift?syllabus.aace.com/2018/PCP/Cerritos/presentations/Handelsman_CVOT... · CHF, now stable –ROS: Fatigue, lately sleep