Nathan D. Wong, PhD, FACC, FAHA, FNLA, FASPC Professor and Director

Heart Disease Prevention Program Division of Cardiology

University of California, Irvine

President, Pacific Lipid Association Past President, American Society for Preventive Cardiology

Cardiodiabetology: Evidence and Strategies for Optimizing

Cardiovascular Risk Reduction

Presenter Disclosures • Research support through institution from Amarin,

Amgen, Boehringer-Ingelheim, Novo Nordisk, Gilead, and Pfizer

• Speaker, Sanofi

{

IDF Atlas 2015

Rank by Country/Territory 2015 vs. 2040 in Number of People with Diabetes: China, India and USA the Top 3

IDF Atlas 2015

Causes of Mortality in Patients With Diabetes

0

1

2

3

4

5

6

7

CHD Mortality CVD Mortality Total Mortality

Relat

ive R

isk

None

MetS

Diabetes

CVD

CVD+Diabetes

Metabolic Syndrome and Diabetes in Relation to CHD, CVD, and Total Mortality: U.S. Men and Women Ages 30-74

* p

Age-adjusted Biennial Rate Age-adjusted Per 1000 Risk Ratio Cardiovascular Event Men Women Men Women Coronary Disease 39 21 1.5** 2.2*** Stroke 15 6 2.9*** 2.6*** Peripheral Artery Dis. 18 18 3.4*** 6.4*** Cardiac Failure 23 21 4.4*** 7.8*** All CVD Events 76 65 2.2*** 3.7*** Subjects 35-64 36-year Follow-up **P

Most Cardiovascular Patients Have Abnormal Glucose Metabolism

35% 31%

34%

37% 18%

45%

37% 27%

36%

GAMI n = 164

EHS n = 1920

CHS n = 2263

GAMI = Glucose Tolerance in Patients with Acute Myocardial Infarction study; EHS = Euro Heart Survey; CHS = China Heart Survey

Prediabetes Normoglycemia

Type 2 Diabetes

Anselmino M, et al. Rev Cardiovasc Med. 2008;9:29-38.

Initial Presentations of CVD in DM: CALIBER UK Cohort (Shah et al, Lancet Diab Endocrinol 2015) n=1.9 M PAD (16.2%) and Heart

Failure (14.7%) were the most common first manifestations of CVD in DM, followed by angina and nonfatal MI

Suggests the need for earlier screening of subclinical PAD/HF and consideration of newer therapies to address these conditions

Diabetes: A CHD Equivalent?

10

DM without prior MI has a 43% lower risk of developing total CHD events compared to those without DM with prior MI, suggesting DM is not a coronary risk equivalent.

Bulugahapitiya U, et al. Diabetic Med 2008; 26(2): 142–148

1

1.4

1.8

2.2

2.6

3

DM

Annual CHD Event Rates (in %) by Calcium Score Events by CAC Categories in Subjects with DM, MetS, or Neither Disease (Malik and Wong et al., Diabetes Care 2011)

Coronary Heart Disease

Coronary Artery Calcium Score

ACCF/AHA 2010 Guideline: CAC Scoring for CV risk assessment in asymptomatic adults aged 40 and over with diabetes (Class IIa-B)

0 1-99 100-399400+

Neither MetS/DMMetS

DM

0.4

1.5 1.9

4

0.20.8

2.1

3.5

0.1 0.41.3

2.2

00.5

11.5

22.5

33.5

4

Annual CHD Event Rate

{

ACC/AHA Guidelines: ASCVD Risk Estimator

• Provides 10-year ASCVD risk for persons aged 40-79 years and lifetime risk estimate for people aged 20-59 years without known ASCVD

• Compared to Caucasians, the risk of ASCVD is generally lower among Asian populations–further research needed to stratify risk in this population

• Intended to drive discussion of greater adherence to heart-healthy lifestyle

• Not an automatic prescription for a statin or other therapy

• NOT appropriate for use in those with known ASCVD who are by definition at high risk.

Goff DC, et al. J Am Coll Cardiol 2014;63:2935-59

Those with DM and >7.5% 10-year risk eligible for high intensity statin Premature family Hx, hs-CRP, CAC, and ABI can further risk stratify and inform the treatment decision when uncertain from global risk assessment

UKPDS Risk Engine for Diabetes

14

• T2DM specific risk calculator • Based on 53,000 patients years of

data from the UK Prospective Diabetes Study

• Risk estimates and 95% confidence intervals in individuals with type 2 diabetes not known to have heart disease, for:

- Non-fatal and fatal coronary heart disease

- Fatal coronary heart disease

- Non-fatal and fatal stroke - fatal stroke

http://www.dtu.ox.ac.uk/riskengine/

http://www.dtu.ox.ac.uk/ukpds/index.phphttp://www.dtu.ox.ac.uk/ukpds/index.phphttp://www.dtu.ox.ac.uk/riskengine/

Strategy Complication Reduction of Complication

Blood glucose control

Heart attack ↓ 39%1

Blood pressure control

▪ Cardiovascular disease ▪ Heart failure ▪ Stroke ▪ Diabetes-related deaths

↓ 51%2 ↓ 56%3 ↓ 44%3 ↓ 32%3

Lipid control ▪ Coronary heart disease mortality

▪ Major coronary heart disease event

▪ Any atherosclerotic event

▪ Cerebrovascular disease event

↓35%4 ↓55%5 ↓37%5 ↓53%4

Clinical Trial and Epidemiologic Evidence Inform the Value of Multiple Risk Factor Control: Treating ABCs Reduces Diabetes Complications

15 1 UKPDS Group. Lancet 1998;352:854-65 . 2 Hansson L, et al. Lancet. 1998;351:1755-1762. 3 UKPDS Study Group (UKPDS 38). BMJ. 1998;317:703-713. 4 Grover SA, et al. Circulation. 2000;102:722-727. 5 Pyŏrälä K, et al. Diabetes Care. 1997;20:614-620.

A = Assess risk Antiplatelet therapy Atrial fibrillation B = BP C = Cholesterol Cigarette cessation D = Diet + weight management Diabetes prevention + treatment E = Exercise F = Heart failure

56% HbA1C

Steno-2: Effects of Multifactorial Intervention on CV Outcomes

N = 160 with type 2 diabetes and microalbuminuria

Gæde P et al. N Engl J Med. 2003;348:383-93.

53% risk reduction P = 0.01

Follow-up (months)

Primary composite outcome*

(%)

*CV death, MI, stroke, revascularization, amputation

Conventional

Intensive

60

50

40

30

20

10

0 0 12 24 36 48 60 72 84 96

Gaede P et al. N Engl J Med 2008;358:580-591

Steno-2: 13 year mortality 40% lower

Gaede P et al. NEJM 2008;358:580-91.

2.5%

6.3% 30%

50%

51.1

29.6 34.3

19.3 26.7

14.7 20.6

13.7

0

10

20

30

40

50

60Ev

ent R

ates

(per

100

0 Pe

rson

-Yea

rs)

No Risk Factor ControlledAny One Risk Factor ControlledAny Two Risk Factors ControlledAll Three Risk Factors Controlled

CVD Events CHD Events

Wong ND, Zhao Y et al. Diabetes Care. 2016;39:668-676

CVD and CHD Event Rates by Number of Risk Factors Controlled: Pooling of ARIC, JACKSON,

and MESA Study DM Subjects

Multivariable adjusted risks of CVD events 62% lower and CHD events 60% lower with all 3 risk factors controlled (versus none at control)

{

Risk of total mortality, MI, and stroke when all 5 RFs at target similar to controls; only HF still significantly higher in DM eve when 5 RFs at target 271,174 DM Ptss and Matched Controls in the Swedish National Diabetes Registry (Rawshani et al., NEJM 2018)

RFs include HbA1c, LDL-C, BP, Smoking, Albuminuria

Cardiometabolic Risk Effect of Moderate Weight Loss

Percent changes from initial visit to

final visit

Case CC, et al. Diabetes, Obes Metabol. 2002;4(6):407-414.

2013 AHA/ACC Lifestyle Management Recommendations

*Diet: DASH, USDA, AHA

Physical activity: 150 min x 3 days/week moderate intensity

Resistance training at least 3X/week

BP + lipid control

Eckel RH, et al. J Am Coll Cardiol. 2014;63(25_PA) and ADA Standards of Care 2018

*Class Ia Recommendation: Consume a dietary pattern that emphasizes intake of vegetables, fruits, and whole grains; includes low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils and nuts; and limits intake of sweets, sugar-sweetened beverages, and red meats.

ADA Standards of Care 2018: Prevention or Delay of T2DM: Recommendations

1) At least annual monitoring for the development of diabetes in those with prediabetes is suggested. E

2) Patients with prediabetes should be referred to an intensive behavioral lifestyle intervention program modeled on the Diabetes Prevention Program to achieve and maintain 7% loss of initial body weight and increase moderate-intensity physical activity (such as brisk walking) to at least 150 min/week. A

Prevention or Delay of Type 2 Diabetes: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S51-S54

PREDIMED STUDY

Estruch R, et al. New Engl J Med. 2013;368(14):1279-1290.

Risk of composite CVD end point was reduced by 30% in

both Mediterranean diet groups

Primary Prevention of High Risk Pts with DM or 3+ Risk Factors Randomized to Mediterranean Diet with Extra Virgin Olive Oil or Nuts vs. AHA Diet

1. Steering Committee of the Physicians' Health Study Research Group. NEJM 1989;321:129-35

2. ETDRS Investigators. JAMA 1992;268:1292 3. Antiplatelet Trialists' Collaboration. BMJ 1994; 308:81

0

5

10

15

20

25

PHS ETDRS APT BIP PPP POPADAD JPAD

Endp

oint

(%)

No ASAASA

n= 533 3711 4502 2368 1031 1276 2539 Endpoint 5 yr MI 7 yr MI 1 yr MCE 5 yr CV Death 4 yr MCE 7yr MCE 4 yr MCE # Events 26 vs 11 283 vs 241 502 vs 415 183 vs 133 20 vs 22 117 vs 116 86 vs 68

Diabetes Mellitus: Effect of Aspirin

4. Harpaz D et al. Am J Med 1998;105:494 3. Sacco M et al. Diabetes Care 2003;26:3264 4. Belch J et al. BMJ 2008; 337:a1840 5. Ogawa H et al. JAMA 2008; 300: 2134

p=.04 p < 0.001

p

ASCEND Trial: Effect of aspirin on Serious Vascular Events in Diabetes (ESC, NEJM 2018)

0 1 2 3 4 5 6 7 8 9 0

5

10

15

20

Years of Follow-up

Part

icip

ants

with

Eve

nt (%

)

Placebo

Aspirin

Rate ratio 0.88 (0.79-0.97) P=0.01

Placebo

743 (9.6%)

Aspirin

658 (8.5%)

15480 pts with DM and no prior CVD in UK, randomized to 100 mg aspirin vs. placebo.

Major bleeding HR=1.29, p10%

28

UKPDS

UK Prospective Diabetes Study Group. BMJ. 1998; 317:703-713.

Effects of Tight vs.

Less-Tight Blood

Pressure Control

UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713.

Diabetes Mellitus: Effect of Blood Pressure Control in ACCORD

Pati

en

ts w

ith

Ev

en

ts (

%)

0

5

10

15

20

Years Post-Randomization0 1 2 3 4 5 6 7 8

Pati

en

ts w

ith

Ev

en

ts (

%)

0

5

10

15

20

Years Post-Randomization0 1 2 3 4 5 6 7 8

Tota

l Str

oke

HR=0.88 95% CI (0.73-1.06)

HR=0.59 95% CI (0.39-0.89)

4,733 diabetic patients randomized to intensive BP control (target SBP

Diabetes Mellitus: ACC/AHA 2017 BP Guidelines

COR LOE Recommendations for Treatment of Hypertension in Patients With DM

I

SBP: B-RSR

In adults with DM and hypertension, antihypertensive drug treatment should be initiated at a BP of 130/80 mm Hg or higher with a treatment goal of less than 130/80 mm Hg.

DBP: C-EO

I ASR In adults with DM and hypertension, all first-line classes of antihypertensive agents (i.e., diuretics, ACE inhibitors, ARBs, and CCBs) are useful and effective.

IIb B-NR In adults with DM and hypertension, ACE inhibitors or ARBs may be considered in the presence of albuminuria.

SR indicates systematic review.

Ask and document tobacco use status

Advise Provide a strong, personalized message

Assess Readiness to quit in next 30 days

Prevent Relapse Congratulate successes Encourage Discuss benefits experienced by patient Address weight gain, negative mood, lack of support

Increase Motivation Relevance to personal situation Risks: short and long-term, environmental Rewards: potential benefits of quitting Roadblocks: identify barriers and solutions Repetition: repeat motivational intervention Reassess readiness to quit

Assist: Negotiate plan STAR** Discuss pharmacotherapy Social support Provide educational materials

Arrange Follow-up to check plan or adjust meds Call right before and after quit date Weekly follow-up x 2 weeks, then monthly x 6 months Ask about difficulties (withdrawal, depressed mood) Build upon successes Seek commitment to stay tobacco-free

**STAR Set quit date Tell family, friends, and coworkers Anticipate challenges: withdrawal, breaks Remove tobacco from the house, car etc.

Recent Quitter (

Statins in Type 2 Diabetes

%

Major Vascular Events

All-Cause Mortality

Effect of lipid lowering analyzed in 14

randomized statin trials (N=18,686 people

with diabetes)

Mean duration of follow-up: 4.3 years

Cholesterol Treatment Trialist Collaborators. Lancet. 2008;37(9607):117

2013 ACC/AHA Cholesterol Guideline Recommendations for Adults with Diabetes

Adults aged 40-75 years without ASCVD but with DM + LDL-C 70-189 mg/dL

Moderate-intensity statin

If 10-y ASCVD risk = ≥7.5% Consider high-intensity statin

Stone NJ, et al. J Am Coll Cardiol. 2014;63(25):2889-2934.

AACE Lipid Targets for Patients with Type 2 Diabetes

Jellinger, P. S., Handelsman, Y., Rosenblit, P. D., Bloomgarden, Z. T., Fonseca, V. A., Garber, A. J., ... & Pessah-Pollack, R. (2017). AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY GUIDELINES FOR MANAGEMENT OF DYSLIPIDEMIA AND PREVENTION OF CARDIOVASCULAR DISEASE. Endocrine Practice, 23(s2), 1-87.

a Major independent risk factors are high LDL-C, polycystic ovary syndrome, cigarette smoking, hypertension (blood pressure ≥140/90 mm Hg or on hypertensive medication), low HDL-C (45; women>55 years years). Subtract 1 risk factor if the person has high HDL-C. b Framingham risk scoring is applied to determine 10-year risk.

Abbreviations: ACS = acute coronary syndrome; ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; DM = diabetes mellitus; HDL-C = high-density lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol; MESA = Multi-Ethnic Study of Atherosclerosis; NR = not recommended; UKPDS = United Kingdom Prospective Diabetes Study.

ACC/AHA Non-Statin Consensus Pathway 2017

Non-Statin therapies may be used in selected high risk patients if >=50% LDL-C reduction (or LDL-C

Improve-IT : Primary Endpoint — ITT

Simva — 34.7% 2742 events

EZ/Simva — 32.7% 2572 events

HR 0.936 CI (0.887, 0.988) p=0.016

Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization (≥30 days), or stroke

7-year event rates

NNT= 50

6% relative risk reduction, but 2% absolute risk reduction

IMPROVE-IT Diabetes Subgroup Analyses

Giugliano RP, et al. Presented at ESC Congress, 2015, London, England. Abstract 1947

0.0

0.5

1.0

1.5

2.0

2.5

3.0

0 12 24 36 48 60 72 84 96 108 120 132 144

LDL

Chol

este

rol (

mm

ol/L

)

Weeks

0.0

0.5

1.0

1.5

2.0

2.5

3.0

0 12 24 36 48 60 72 84 96 108120132144

LDL

Chol

este

rol (

mm

ol/L

)

Weeks

LDL-C Reduction with Evolocumab Patients w/o Diabetes at Baseline Patients w/ Diabetes at Baseline

57% mean reduction P

Effect of Evolocumab on Primary Endpoint

Patients w/o Diabetes at Baseline

Patients w/ Diabetes at Baseline

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

Months after Randomization

CV

Dea

th, M

I, St

roke

, H

osp

for U

A, o

r Cor

Rev

asc

0 6 12 18 24 30 36 0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

Hazard Ratio 0.83 (95% CI 0.75-0.93)

P=0.0008 14.4%

17.1%

0 6 12 18 24 30 36

Hazard Ratio 0.87 (95% CI 0.79-0.96)

P=0.0052

11.4%

13.0%

Pinteraction=0.60

∆ 2.7% NNT 37

∆ 1.6% NNT 62

Evolocumab

Placebo

Sabatine et al., Lancet Endocrinology, 2017

Approach to the Management of Hyperglycemia

low high

newly diagnosed long-standing

long short

absent severe Few/mild

absent severe Few/mild

highly motivated, adherent, excellent self-care capabilities

readily available limited

less motivated, nonadherent, poor self-care capabilities

A1C 7%

more stringent

less stringent Patient/Disease Features

Risk of hypoglycemia/drug adverse effects

Disease Duration

Life expectancy

Important comorbidities

Established vascular complications

Patient attitude & expected treatment efforts

Resources & support system

Glycemic Targets: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S55-S64

ADA Standards of Diabetes Care 2018 • A reasonable HbA1c target for most adults with diabetes is

ADA Guidelines Recommend a 2nd Agent of Proven CVD Benefit in DM and CVD

Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85

Drugs with ASCVD Benefit: Metformin (potential benefit) Canagliflozin Empagliflozin Liraglutide Pioglitazone (potential benefit) ADA 2018

aAll surviving patients entered the post-trial monitoring program after completion of the interventional trial 1. Data from UKPDS Group. Lancet 1998;352:854-65 2. Data from Holman et al. N Engl J Med 2008;359:1577-89

UKPDS 34: Evidence for Beneficial CV Effects of Metformin in Overweight Patients

Significant Reduction in MI Maintained Over 10 Years’ Post-trial Follow-upa,2

Metformin vs. conventional p=.01

30

Time from Randomization (Years) 0 3 6 9 12 15

0

10

20

Prop

ortio

n of

Pat

ient

s W

ith M

I Intensive (n=951; events=139) Conventional (n=411; events=73)

Metformin (n=342; events=39)

Risk of MI is 39% Lower with Metformin vs. Conventional Therapy in Obese Patients1

1.4

1.2

1.0

0.8

0.6

0.4 H

R (9

5% C

I)

RR 0.611 p=.01

RR 0.67 p=.005

Overall values at study end in 1997

Annual values during 10-year post-trial monitoring period

0.4 1997 1999 2001 2003 2005 2007

No. of events: Conventional

therapy 73 83 92 106 118 126

Metformin 39 45 55 64 68 81

{

Paneni, F & Luscher, TF. Am J Cardiol 2017;120[suppl];S17-S27.

No ASCVD Benefit from DPP4-Inhibitors

Primary outcomea: HR, 0.90 (95% CI, 0·80-1·02); p=.095 Secondary outcomeb: HR, 0.84 (95% CI, 0·72-0·98); p=.027 aPrimary outcome was all-cause mortality, nonfatal MI, stroke, acute coronary syndrome, coronary or leg revascularization, leg amputation bSecondary outcome was composite of all-cause mortality, nonfatal MI, and stroke Data from Dormandy JA et al. Lancet 2008;366:1279-89

PROactive: Primary Outcome

20

15

10

5

0 0

6 12 18 24 30 36 Time From Randomization (Months)

Prop

ortio

n of

Eve

nts

(%)

Pioglitazone (514 Events)

HR, 0.90 (95% CI, 0.80-1.02) p=.095

Placebo (572 Events)

25

No. at risk Pioglitazone 2536 2487 2435 2381 2336 396 Placebo 2566 2504 2442 2371 2315 390

Primary outcome was composite of all-cause mortality, nonfatal MI, stroke, acute coronary syndrome, coronary or leg revascularization, leg amputation

MACE1 Myocardial Infarction1 Stroke2

p=.033 Composite of nonfatal MI

(excluding silent MI), coronary revascularization, acute coronary syndrome,

and cardiac death in patients with prior MI

p=.045 Fatal and nonfatal MI in patients with prior MI

p=.009 Fatal and nonfatal stroke in patients with prior stroke

1. Erdmann E et al. J Am Coll Cardiol 2007;49:1772-80 2. Wilcox R et al. Stroke 2007;38:865-73

PROactive: Pioglitazone Significantly Reduced the Incidence of Macrovascular Events

-28%

-47%

Cha

nge

in R

isk

(%)

0

-10

-20

-30

-40

-50

-19%

{

Pioglitazone ↓MACE (NFMI, NF

CVA & CVD Mortality)

IRIS Trial of Pioglitazone after Ischemic Stroke or TIA. Kernan, WN. NEJM, 2016;374:1321-31

5y ARR 2.8%, NNT 36

{

BP Arterial stiffness

Glucose Insulin

Albuminuria

Uric acid

Other

↑LDL-C ↑HDL-C

Triglycerides

Oxidative stress

Sympathetic nervous system

activity

Weight Visceral adiposity

Sodium Glucose CoTransporter 2 (SGLT2) Inhibition in the Kidney

Study design: Multicenter, randomized, double-blind, placebo-controlled study Primary objective: To assess the effects of empagliflozin vs. placebo on CV morbidity and mortality in patients with T2DM

who were at high risk for CV events and were receiving standard care

aHbA1c 7.0%-9.0% in patients who did not receive any glucose lowering agents ≥12 weeks prior to randomization bPooled empagliflozin group Zinman B et al. N Engl J Med 2015;373:2117-28

EMPA-REG OUTCOME: Study Design and Objectives

Eligibility Criteria1: • T2DM with

HbA1c 7.0%-10.0%a

• Age ≥18 years • BMI ≤45 kg/m2 • GFR ≥30 mL/min/

1.73 m2 • Had established

CV disease

Empagliflozin (10 mg or 25 mg QD) + Standard Care

N=4687b

Placebo + Standard Care

N=2333

R 1:1:1

Primary Outcome: • Composite of CV death,

nonfatal MI, or nonfatal stroke

Key Secondary Outcome • Composite of CV death,

nonfatal MI, nonfatal stroke, or hospitalization for UA

Zinman B et al. N Engl J Med 2015. DOI: 10.1056/NEJMoa1504720

EMPA-REG: Cardiovascular Outcomes and Death from Any Cause Empagliflozin:

reduced hospitalization for heart failure by 35%

reduced CV death by 38%

improved survival by reducing all-cause mortality by 32%

reduced risk for 3-point MACE by 14%

* 3-Point MACE = CV Death, Non-Fatal MI, Non-Fatal Stroke

Study design: Multicenter, randomized, double-blind, placebo-controlled, parallel group study Primary objective: To determine the effects of canagliflozin compared to placebo (against a background of standard care) on the risk of CV disease and to provide data on safety and tolerability Study start - expected completion: December 2009 - February 2017

Neal B et al. Am Heart J 2013;166(2):217-223.e11

CANVAS: Study Design and Objectives

Eligibility Criteria: • T2DM with HbA1c

7.0%-10.5% • Elevated risk for CV

disease

Canagliflozin (100 mg) N=1445

Placebo N=1441

R 1:1:1

Primary Outcome: • Composite of CV death,

nonfatal MI, or nonfatal stroke

Key Secondary Outcome • Composite of CV death,

nonfatal MI, nonfatal stroke, hospitalization for UA

Canagliflozin (300 mg) N=1441

Primary effects of increased beta cell response to insulin secretion, suppressed glucagon secretion by alpha cells, reduced appetite, slowed gastric emptying Secondary effects of reduced glucagon-stimulated hepatic glucose production, insulin-stimulated increased peripheral utilization of glucose, reduced postprandial glucose excursions

{

{ But Decreases in ASCVD Appear Not to be a Class-Effect

Study design: International, randomized, placebo-controlled study Primary objective: To evaluate the effect of liraglutide compared to placebo

on the incidence of CV events in adults with type 2 diabetes aCoronary heart disease, cerebrovascular disease, peripheral vascular disease, CKD stage ≥3, chronic heart failure NYHA class II/III bMicroalbumiuria or proteinuria, hypertension and left ventricular hypertrophy, left ventricular systolic or diastolic dysfunction, or an ankle-brachial index (the ratio of the systolic BP at the ankle to the systolic BP in the arm) of

aThe primary composite outcome in the time-to-event analysis was the first occurrence of CV death, nonfatal MI, or nonfatal 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 were truncated at 54 months, because

1. Study design: Multicenter, randomized, placebo-controlled, double-blind study

2. Primary objective: To evaluate cardiovascular and other long-term outcomes with semaglutide in subjects with type 2 diabetes

https://clinicaltrials.gov/ct2/show/NCT01720446

SUSTAIN 6: Study Design and Objectives

Eligibility Criteria: • T2DM with HbA1c

≥7.0% • Age ≥50 years with

evidence of CVD or ≥60 years with subclinical evidence of CVD

• Drug naïve or treated with 1-2 OADs or insulin

Semaglutide (0.5 mg or 1.0 mg once a week) + Standard Care

Placebo + Standard Care

R 1:1

Primary Outcome: • Composite of CV death,

nonfatal MI, or nonfatal stroke

Key secondary Outcome • Expanded composite CV

outcome

SUSTAIN-6: Semaglutide Reduces Cardiovascular Outcomes in DM2

Marso, SP. NEJM 2016;375:1834-44.

CV safety trial showed 24% reduction in primary composite outcome and 39% reduction in stroke

The Cardiodiabetes Care Team

Cardiologist Diabetologist

Lifestyle Interventionalists: exercise physiologists, dietitians, stress management

Nurse / nurse practitioner Pharmacist

Other Specialists: Nephrologists, Podiatrists, Cardio-thoracic and vascular surgeons

Primary Care

Physician

Wong ND, Rosenblit PD, Lepor N, Acc.org 12/16 and Cardiovasc Endocrinol 2016

{

The ACC Diabetes and Cardiometabolic Clinical Community

Presentation Progression

Management

Quality & Outcomes

Transforming the Future of Care from Real World Data

The Diabetes Collaborative Registry® is a large-scale, multispecialty, real-world data collaboration that allows for:

• Longitudinal study of diabetes presentation, progression, management and outcomes, even as patients receive treatment from multidisciplinary care teams, including primary care physicians, endocrinologists, cardiologists, and other diabetes care providers

• National benchmarking and reporting mechanisms to continuously inform practices and providers of their performance against evidence-based measures and metrics in diabetes care

(Launched in 2014)

Most people with DM remain suboptimally treated for CVD risk and will die of CVD-related consequences

The risk for CVD events is heterogeneous in people with DM: Risk assessment is key

Screening for subclinical atherosclerosis may improve risk factors and motivate patients

Evidence points to combined BP, lipid, and glycemic control to in people with DM to reduce CVD events

Newer antiglycemic agents hold promise in reducing CVD risk •SGLT2i appear to have hemodynamic effects benefitting HF and CVD death

•GLP1-RA may have more antiathersclerotic effects vs. HF benefits

Key Take-Aways

American Society for Preventive Cardiology

www.aspconline.org

Thank you for your attention

www.heart.uci.edu

www.lipid.org

Slide Number 1Presenter DisclosuresSlide Number 3Slide Number 4Causes of Mortality in Patients With Diabetes Metabolic Syndrome and Diabetes in Relation to CHD, CVD, and Total Mortality: U.S. Men and Women Ages 30-74Risk of Cardiovascular Events in Diabetics Framingham StudyMost Cardiovascular Patients Have Abnormal Glucose MetabolismInitial Presentations of CVD in DM: CALIBER UK Cohort (Shah et al, Lancet Diab Endocrinol 2015) n=1.9 M�Diabetes: A CHD Equivalent? Slide Number 11Annual CHD Event Rates (in %) by Calcium Score Events by CAC Categories in Subjects with DM, MetS, or Neither Disease�(Malik and Wong et al., Diabetes Care 2011)ACC/AHA Guidelines: ASCVD Risk EstimatorUKPDS Risk Engine for DiabetesClinical Trial and Epidemiologic Evidence Inform the Value of Multiple Risk Factor Control:�Treating ABCs Reduces Diabetes ComplicationsCVD Risk Factor Control in DM Remains Poor and We Can do Better!Steno-2: Effects of Multifactorial Intervention on CV OutcomesSteno-2: 13 year mortality 40% lowerSlide Number 19Slide Number 20Slide Number 21Cardiometabolic Risk�Effect of Moderate Weight Loss2013 AHA/ACC Lifestyle Management Recommendations ADA Standards of Care 2018: Prevention or Delay of T2DM: RecommendationsPREDIMED STUDYSlide Number 26ASCEND Trial: Effect of aspirin on Serious Vascular Events in Diabetes (ESC, NEJM 2018)UKPDSSlide Number 29Diabetes Mellitus: ACC/AHA 2017 BP GuidelinesTobacco Cessation AlgorithmStatins in Type 2 Diabetes2013 ACC/AHA Cholesterol Guideline Recommendations for Adults with DiabetesAACE Lipid Targets for Patients with Type 2 DiabetesACC/AHA Non-Statin Consensus Pathway 2017Improve-IT : Primary Endpoint — ITTIMPROVE-IT Diabetes Subgroup AnalysesSlide Number 38LDL-C Reduction with EvolocumabEffect of Evolocumab�on Primary EndpointApproach to the Management of HyperglycemiaADA Guidelines Recommend a 2nd Agent of Proven CVD Benefit in DM and CVDSlide Number 43UKPDS 34: Evidence for Beneficial CV Effects of Metformin in Overweight PatientsSlide Number 45PROactive: Primary OutcomePROactive: Pioglitazone Significantly Reduced the Incidence of Macrovascular EventsPioglitazone ↓MACE �(NFMI, NF CVA & CVD Mortality)Slide Number 49Slide Number 50EMPA-REG OUTCOME: �Study Design and ObjectivesZinman B et al. N Engl J Med 2015. DOI: 10.1056/NEJMoa1504720CANVAS: �Study Design and ObjectivesSlide Number 54Slide Number 55Slide Number 56Slide Number 57Slide Number 58LEADER: �Study Design and ObjectivesLEADER: Primary Outcomea�CV Death, Nonfatal MI, or Nonfatal StrokeSUSTAIN 6: �Study Design and ObjectivesSUSTAIN-6: Semaglutide Reduces Cardiovascular Outcomes in DM2Slide Number 63Slide Number 64Transforming the Future of Care�from Real World DataKey Take-AwaysSlide Number 67