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Diabetes: New Opportunities to Combat

the Unwelcome but Frequent Partner

in Convalescent ACS

Lawrence A. Leiter, MD, FRCPC, FACP, FACE, FAHADivision of Endocrinology & Metabolism, St Michael’s Hospital

Professor of Medicine & Nutritional Sciences, University of Toronto

Disclosures

Relationships with commercial interests:

Grants/Research Support; Speakers Bureau; and/or Honoraria: AstraZeneca,

Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Merck,

NovoNordisk, Pfizer, Sanofi, Servier and Takeda

Mortality Following STEMI and NSTEACS in

Patients With and Without Diabetes11 TIMI Studies 1997-2006; N = 62,036; 17.1% with DM

Donahoe SM, et al. JAMA 2007; 298:765-75.

0

14

0

12

10

8

6

4

2

30 90 180 270 360

Days after ACS

Mo

rtality

(%

)

DM STEMI

DM NSTEACS

Non-DM STEMI

Non-DM NSTEACS

Prevalence of Dysglycemia in CAD

ESC Euro Heart Survey 2003 (N=4,961)

Rydén et al. ESC Release, November 14, 2003

Bartnik et al. Eur Heart J 2004;25:1880–90

Pre

vale

nce (

%)

General population 6–8%

100

80

60

40

20

0

ACS Elective

Known diabetes

New diabetes

New IGT

Impaired fasting glucose

Normal glucose tolerance

2935

2222

1510

31 30

ACS=acute hospital admissions

Ominous Octet: Core Defects in Type 2 Diabetes

Adapted from DeFronzo RA. Diabetes. 2009;58:773-795.

IncreasedHGP

Hyperglycemia

ETIOLOGY OF T2DM

DEFN75-3/99 Decreased GlucoseUptake

Impaired InsulinSecretion Increased Lipolysis

Hyperglycemia

Islet– cell

DecreasedInsulinSecretion

DecreasedIncretinEffect

IncreasedLipolysis

IncreasedGlucoseReabsorption

DecreasedGlucose Uptake

NeurotransmitterDysfunctionIncreased

Hepatic GlucoseProduction

Increased GlucagonSecretion

Ominous Octet: Targeting the Core Defects in

Type 2 Diabetes

Adapted from DeFronzo RA. Diabetes. 2009;58:773-795.

IncreasedHGP

Hyperglycemia

ETIOLOGY OF T2DM

DEFN75-3/99 Decreased GlucoseUptake

Impaired InsulinSecretion Increased Lipolysis

Hyperglycemia

Islet– cell

DecreasedInsulinSecretion

DecreasedIncretinEffect Increased

Lipolysis

IncreasedGlucoseReabsorption

DecreasedGlucose Uptake

NeurotransmitterDysfunctionIncreased

Hepatic GlucoseProduction

Increased GlucagonSecretion

SU

DPP-4i

GLP-1RA

DPP-4i

GLP-1RA

MET

DPP-4i

GLP-1RA

TZD GLP-1RA

DPP-4i

GLP-1RATZD

SGLT2i

TZD

What do we know about glucose control and the effects of

specific antihyperglycemic agents post ACS?

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

1

DIGAMI: Benefit of Tight Glycemic Control in AMI:Major Benefit in “No Insulin - Low Risk” Cohort

Malmberg, K et al BMJ 1997; 314: 1512-1515

Insulin-glucose

Infusion

Control

Mortality

Years in Study

n = 314

n = 306

0 2 3 4 5

p = .0111

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

1

Insulin-glucose

Infusion

Control

Mortality

Years in Study

n = 133

n = 139

0 2 3 4 5

p = .004

Total Cohort No Insulin - Low Risk

19% @ 1 year

26%

CHF accounted for 66% of all deaths

EXAMINE: Primary End Point(ACS within15 to 90 days)

Composite of death from CV causes, nonfatal MI, or nonfatal stroke

CI, confidence interval; CV, cardiovascular; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care

in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome; MI, myocardial infarction.

White WB et al. N Engl J Med. 2013;369:1327-35.

No. at Risk

Placebo 2679 2299 1891 1375 805 286

Alogliptin 2701 2316 1899 1394 821 296

Months

0 6 12 18 24 30

0

6

12

18

24

Cu

mu

lati

ve In

cid

ence

of

Pri

mar

y E

nd

-

Po

int

Eve

nts

(%

)

Alogliptin

Placebo

HR (95% CI) = 0.96 (≤1.16)

P < 0.001 for noninferiority

P = 0.32 for superiority

Alogliptin was non-inferior but not superior

to placebo with respect to the primary end point

ELIXA: Primary End Point(ACS within 180 days)

Time to the first occurrence of the primary CV event(CV death, non-fatal MI, non-fatal stroke, hospitalization for UA)

CV, cardiovascular; ELIXA, Evaluation of LIXisenatide in Acute Coronary Syndrome; MI, myocardial infarction; UA, unstable angina.Pfeffer MA et al. N Engl J Med. 2015;373:2247-57.

Lixisenatide 406/3034 = 13.4%

0

5

10

15

20

0 12 24 36

Pe

rce

nt

Months

Placebo 399/3034 = 13.2%

Number at risk

Placebo 3034 2759 1566 476Lixisenatide 3034 2785 1558 484

HR = 1.02 (0.89, 1.17)Lixisenatide was non-inferior but not superior to placebo with respect to the primary end point

What do we know about the effects of specific

antihyperglycemic agents in stable CAD?

Hypoglycemia May Affect CV Events

Desouza CV et al. Diabetes Care 2010; 33:1389-94.

Blood

coagulation

abnormalities

Sympathoadrenal response

Inflammation

Endothelial

dysfunction

Vasodilation

Rhythm abnormalities Hemodynamic changes

Adrenaline

Contractility

Oxygen consumption

Heart workload

VEGF IL-6CRP

Neutrophil

activation

Platelet

activation

Factor VII

Heart rate variability

Hypoglycemia

SAVOR-TIMI 53, EXAMINE & TECOS

ACS, acute coronary syndrome; CVD, cardiovascular disease; FU, follow-up; MI, myocardial infarction; R, randomization; UA, unstable angina.Green JB et al. N Engl J Med. 2015;373:232-42; Scirica BM et al. N Engl J Med. 2013;369:1317-26; White WB et al. N Engl J Med. 2013;369:1327-35.

Median Duration of Follow-up

CV death, Nonfatal MI, Nonfatal stroke, or UA requiring hospitalization

Randomization Year 3Year 2Year 1

RSaxagliptin

Placebo6.5–12.0

A1C , % Primary End pointDuration of Treatment(as part of usual care)

CV death, Nonfatal MI,or Nonfatal stroke

CV death, Nonfatal MI,or Nonfatal strokeEstablished CVD

and/or multiple risk factors

ACS within15 to 90 days

Preexisting CVD

RAlogliptin

Placebo6.5–11.0

RSitagliptin

Placebo6.5–8.0

MedianFU, y

2.1

3.0

1.5

HR(95% CI)

1.00(0.89, 1.12)

0.98(0.89, 1.08)

0.96(≤1.16)

EXAMINE, SAVOR-TIMI 53, and TECOSHospitalization for Heart Failure

Adapted from Armstrong PW, Van de Werf F. Trial Evaluating Cardiovascular Outcomes with Sitagliptin in patients with type-2 Diabetes: TECOS. European Society of Cardiology 2015, August 29-September 2, 2015, London, United Kingdom; Scirica BM et al. N Engl J Med. 2013;369:1317-26; EXAMINE: Zannad F et al. Lancet. 2015;385:2067-76; ; TECOS: Green JB et al. N Engl J Med.2015;373:232-42.

Study Drugn/N (%)

Placebon/N (%)

Hazard Ratio

95%CI

P Value

SAVOR-TIMI 53(saxagliptin vsplacebo)

289/8280(3.5%)

228/8212(2.8%)

1.27 1.07, 1.51 0.007

EXAMINE(alogliptin vsplacebo)

106/2701(3.9%)

89/2679(3.3%)

1.19 0.89, 1.59 0.235

TECOS(sitagliptin vsplacebo)

228/7332(3.1%)

229/7339(3.1%)

1.00 0.84, 1.20 1.000

SAVOR-TIMI 53 + EXAMINE+ TECOS

623/18313(3.4%)

546/18230(3.0%)

1.14 0.97, 1.34 0.102

Favours Treatment Favours Placebo0 1 2

Test for heterogeneity for 3 trials:p=0.16, I2=44.9%

EMPA-REG OUTCOMEStudy Design

Randomisation

(n = 7042)*

Placeborun-in

2 weeks

Empagliflozin 10 mg QD

Empagliflozin 25 mg QD

Placebo

Screening (n =

11,507)

Background therapy

adjustment

allowed after Week 12

12 weeks of

stable

background

therapy

Visit 1

Week

4 8 12 16 28 40 520-2-3

Visit 2 Visit 3 Visits 4–7every 4 weeks

Visits 8–10every 12 weeks

Visits every 14 weeks

QD, once daily.*7042 patients were randomised, 7034 of whom comprised the treated set.

• Age ≥ 18 years • HbA1C ≥ 7% and ≤ 10% or ≥ 7% and

≤ 9% (drug-naïve)• BMI ≤ 45 kg/m2 And to have ≥ 1 of the following criteria:• History of MI (> 2 months prior to

enrolment)• Evidence of CAD in ≥ 2 major vessels

or left main coronary artery• Evidence of single-vessel CAD with

no scheduled revascularisation/previously unsuccessful revascularisation and:

- Positive non-invasive, functional stress test for ischaemia (ECG, echo or nuclear), or

- Hospital discharge due to unstable angina pectoris ≤ 12 months before enrolment

Inclusion Criteria

Zinman B, et al. Cardiovasc Diabetol. 2014;13:102.

Empagliflozin (pooled)HR 0.86

(95.02% CI 0.74, 0.99)p=0.0382*

Empagliflozin 25 mgHR 0.86 (95% CI 0.73, 1.02),p=0.0865

Empagliflozin 10 mgHR 0.85 (95% CI 0.72, 1.01), p=0.0668

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)Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med Sep 17, 2015. 10.1056/NEJMoa1504720

Primary outcome:3-point MACE: CV Death, Non-Fatal MI or

Non-Fatal Stroke

EMPA-REG Outcome3-point MACE and 4-point MACE

Cox regression analysis.*95.02% CI and two-sided p-value. †Nominal p-value RRR for 3P-MACE 14%; ARR for 3P-MACE 1.6%, AR rate difference for 3P-MACE: –6.5; RRR for CV death 38%; ARR for CV death 2.2%, AR rate difference in CV death: –7.7AR, absolute risk; CV, cardiovascular; HR, hazard ratio; MACE, major adverse cardiovascular event; MI, myocardial infarction; UA, unstable anginaZinman B et al. N Engl J Med. 2015;373:2117-28.

Patients with event/analyzed

Empagliflozin Placebo HR (95% CI) p-value

3-point MACE490/4687 (10.5%)

282/2333 (12.1%)

0.86 (0.74, 0.99)* 0.04*

CV death172/4687

(3.7%)137/2333

(5.9%)0.62 (0.49, 0.77) <0.001†

Non-fatal MI213/4687

(4.5%)121/2333

(5.2%)0.87 (0.70, 1.09) 0.22†

Non-fatal stroke150/4687

(3.2%)60/2333 (2.6%)

1.24 (0.92, 1.67) 0.16†

4-point MACE599/4687 (12.8%)

333/2333 (14.3%)

0.89 (0.78, 1.01)* 0.08*

Hospitalization for UA133/4687

(2.8%)66/2333 (2.8%)

0.99 (0.74, 1.34) 0.97†

0.25 0.50 1.00 2.00

Favours empagliflozin Favours placebo

CV death


(95% CI 0.49, 0.77)p<0.0001



Cumulative incidence function. HR, hazard ratio Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med Sep 17, 2015. 10.1056/NEJMoa1504720

Hospitalization for heart failure


(95% CI 0.50, 0.85)p=0.0017



Cumulative incidence function. HR, hazard ratio Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med Sep 17, 2015. 10.1056/NEJMoa1504720

LEADER: Study Design

*Daily single-blind SC injection of placeboA1C, glycated hemoglobin; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results; OAHA, oral antihyperglycemicagent; SC, subcutaneous; T2DM, type 2 diabetes mellitus.Adapted from Marso SP et al. Am Heart J. 2013;166:823-30.

RANDOMIZATION

(1:1)

Key inclusion criteria

Adult T2DM patients:• A1C >7.0%• Antidiabetic drug naive; or• Treated with one or more

OAHAs; or• Treated with basal or

premix insulin (alone or in combination with OAHAs)

N=9340 Standard of care + liraglutide

(0.6–1.8 mg once daily)

Standard of care + placebo*

3.5–5 year follow-up

Placebo* run-in period of ≥2 weeksPatients demonstrating ≥50% adherence to regimen and willingness to continue with injection protocol for duration of trial proceeded to randomization

LEADERKey Inclusion Criteria

• Adults with T2DM and A1C ≥7.0% at screening• Prior CVD cohort

– Age ≥50 years and at least one of the following:• Cardiovascular disease• Cerebrovascular disease• Peripheral vascular disease• Chronic renal failure • Chronic heart failure

• No prior CVD cohort– Age ≥60 years and at least one of the following:

• Micro- or macroalbuminuria• Hypertension and left ventricular hypertrophy by ECG or imaging• Left ventricular systolic or diastolic dysfunction by imaging• Ankle-brachial index <0.9

CVD, cardiovascular disease; ECG, electrocardiogram; A1C, glycated hemoglobin; T2DM, type 2 diabetes mellitus.Marso SP et al. Am Heart J. 2013;166:823-30.

LEADER: Primary CV outcomes

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.

Adapted from Marso SP et al. N Engl J Med. 2016. DOI: 10.1056/NEJMoa1603827; and presentation at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

MACE: CV death, non-fatal myocardial infarction, or non-fatal stroke

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

P la ce b oP

atie

nts

wit

h a

n e

ven

t (%

)

Time from randomization (months)Patients at risk

Liraglutide

Placebo

4668

4672

4593

4588

4496

4473

4400

4352

4280

4237

4172

4123

4072

4010

3982

3914

1562

1543

424

407

HR=0.8795% CI (0.78 ; 0.97)

p<0.001 for non-inferiorityp=0.01 for superiority

0 6 12 18 24 30 36 42 48 54

0

5

10

15

20

L ira g lu t id e

0 6 12 18 24 30 36 42 48 540

5

10

15

20

LEADER: MACE and individual components

Hazard ratio(95% CI) p value

Liraglutide (N=4668)Placebo

(N=4672)

N % R N % R

Primary outcome 0.87 (0.78–0.97) 0.01 608 13.0 3.4 694 13.9 3.9

CV death 0.78 (0.66–0.93) 0.007 219 4.7 1.2 278 6.0 1.6

Non-fatal MI 0.88 (0.75–1.03) 0.11 281 6.0 1.6 317 6.8 1.8

Non-fatal stroke 0.89 (0.72–1.11) 0.30 159 3.4 0.9 177 3.8 1.0

Hazard ratios and p-values were estimated with the use of a Cox proportional-hazards model with treatment as a covariate.%, percentage of group; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; N, number of patients; R, incidence rate per 100 patient-years of observation. Adapted from Marso SP et al. N Engl J Med. 2016. DOI: 10.1056/NEJMoa1603827; and presentation at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

0.50 1.50

Favours Placebo

Hazard ratio (95% CI)

Favours Liraglutide

Overview of CVOTs of Glucose-Lowering Drugs

Timings represent estimated completion dates as per ClinicalTrials.gov.

Adapted from Johansen OE. World J Diabetes. 2015;6:1092-6.

CANVAS-R8

(n = 5700)Albuminuria

2013 2014 2015 2016 2017 2018 2019

SAVOR-TIMI 531

(n = 16,492)1,222 3P-MACE

EXAMINE2

(n = 5380)621 3P-MACE

TECOS4

(n = 14,724)≥ 1300 4P-MACE

LEADER6

(n = 9340)≥ 611 3P-MACE

SUSTAIN-67

(n = 3297)3P-MACE

DECLARE-TIMI 5815

(n = 17,150)≥ 1390 3P-MACE

EMPA-REG OUTCOME®5

(n = 7034)≥ 691 3P-MACE

CANVAS10

(n = 4365)≥ 420 3P-MACE

CREDENCE17

(n = 3700)Renal + 5P-MACE

CAROLINA®11

(n = 6000)≥ 631 4P-MACE

ITCA CVOT9

(n = 4000)4P-MACE

EXSCEL14

(n = 14,000)≥ 1591 3P-MACE

DPP4 inhibitor CVOTs

SGLT2 inhibitor CVOTs

GLP1 CVOTsErtugliflozinCVOT18

(n = 3900)3P-MACE

OMNEON13

(n = 4000)4P-MACE

CARMELINA12

(n = 8300)4P-MACE + renal

REWIND16

(n = 9622)≥ 1067 3P-MACE

2021

ELIXA3

(n = 6068)≥ 844 4P-MACE

HARMONY Outcomes19

(n = 9400) 3P-MACE

guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca

Copyright © 2013 Canadian Diabetes Association

Add another agent best suited to the individual by prioritizing patient

characteristics:

Degree of hyperglycemia

Risk of hypoglycemia

Overweight or obesity

CV disease or multiple risk factors

Comorbidities (renal, CHF, hepatic)

Preferences & access to treatment

Consider relative A1C lowering

Rare hypoglycemia

Weight loss or weight neutral

Effect on cardiovascular outcome

See therapeutic considerations

See cost column; consider access

PATIENT CHARACTERISTIC CHOICE OF AGENT

PRIORITY:

Clinical Cardiovascular Disease

SGLT2 inhibitor with

demonstrated CV outcome

benefit

2016

SUMMARY

• Diabetes mellitus has a major impact during and after ACS but we have no definitive evidence that glucose lowering post ACS will reduce CV risk

• In patients with stable CAD:-Recent clinical trials have demonstrated the overall CV safety, but not

superiority, of DPP-4 inhibitors (with perhaps some heterogeneity in the HF signal) and 1GLP-1RA

-Data from 2 trials with GLP-1RAs have demonstrated CV benefit-The one completed trial with an SGLT2 inhibitor has demonstrated significant

reductions in CV mortality and HF• Most patients will require multiple antihyperglycemic agents in order to

achieve glycemic targets

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