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Newer Diabetes Medications and CV 

OutcomesPriya Vellanki MD

Division of Endocrinology, Metabolism and LipidsEmory University 

Clinical Director, Endocrinology ClinicGrady Memorial Hospital

External Industry Relationships *

Company Name(s) Role

Equity, stock, or options in biomedical industry companies or publishers

None None

Industry funds to Emory University for research

Boehringer IngelheimSanofi Novo-Nordisk

Co-investigator (Investigator-Initiated Research Projects)

IndustryAdvisory/Consultant activities

Merck Boehringer Ingelheim

Consultant activities

Conflicts of interest  

Objectives

• Review cardiovascular epidemiology in diabetes

• Discuss rationale and background for CV outcome trials in diabetes

• Review results of CV outcomes trials with diabetes medication

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Diabetes is associated with significant loss of  life years

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

.

0

7

6

5

4

3

2

1

040 50 60 70 80 90

Age (years)

Yearsof life lost

Men7

6

5

4

3

2

1

040 50 60 70 80 900

Age (years)

Women

Non‐vascular deaths

Vascular deaths

Cumulative incidence of coronary events by prevalent CHD and diabetes status 

Mondesir et al. Am Heart J 2016;181:43‐51 

Diabetes and h/o CHD

CHD only Diabetes only (“SEVERE”) 

Severe diabetes: Insulin use or microalbuminuria 

Diabetes only No diabetes nor CHD 

Question

• CV events and mortality is increasing in patients with diabetes.

A) True 

B) False

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Global Mortality for CVD and Diabetes

Data from GBD Mortality and Causes of Death Collaborators. (1980–2015)

Pasquel FJ, Gregg EW & Ali MK Endocrinol Metab Clin North Am. 2018 Mar;47(1):1‐32

T2DM and CV Events Over Time

Rawshani A, et al. N Engl J Med. 2017;376:1407-1418.

Swedish National Diabetes Register from 1998 through 2012 and followed through 2014

Question

• Does treatment of diabetes lower cardiovascular events? 

A) Yes

B) No 

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A1C and Complications: UKPDS

UKPDS Group. Lancet. 1998;352:837-853.

All patients assigned to regimen

IntensiveConventional

Time from randomization (y)60 3 9 12 15

0

HbA1c

7

8

9

6

MedianHbA1c

(%)

UKPDS: Risk Reductions With Intensive Therapy (Median HbA1c = 7.0%)

% R

isk

Red

uct

ion

-50 -46

-12

-25

-29

-24

-33

-16

-45

-40

-35

-30

-25

-20

-15

-10

-5

0 Any Diabetes

Related Endpoint

Microvascular Endpoints Laser Rx Cataract Albuminuria Myocardial

Infarction Sudden Death

P = 0.029

P = 0.0031

P = 0.046

P = 0.000054

P = 0.052

P < 0.047

P = 0.0099

UKPDS Group. Lancet 1998;352:837-853.

Microvascular complications

Myocardial infarction

HbA1c

37%

14%

Lowering HbA1c reduces the risk of complications

Deaths related to diabetes21%

1%

Stratton IM, et al. BMJ 2000; 321:405–412.

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Severe Hypoglycemia in 3 Outcome Trials of Intensive Glucose Control in Type 2 Diabetes

0

5

10

15

20

25

VADT ACCORD ADVANCE

% P

atie

nts

with

at l

east

one

sev

ere

hypo

glyc

emic

eve

nt d

urin

g th

e tri

al

Intensive Control Standard Control

p < .001

p < .001

p < .001

Adapted from: 1. The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med. 2008;358:2545-2559. 2. The ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572. 3. Duckworth W, et al.. N Engl J Med. 2009;360:129-139.

Question

• Does treatment of diabetes lower cardiovascular events? 

A) Yes

B) No 

Yes, treatment of diabetes does lower CV events BUT… intensive glucose control (HbA1c < 6.5%) does NOT lower CV events

EFFICACY

Lowering HgA1c

SAFETY

Hypoglycemia Prevention

Management of Type 2 Diabetes

Individualized Algorithm

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0

2

4

6

8

10

12

14

1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 2020

Soluble insulin

SGLT-2 inhibitor

Bromocriptine-QR

Bile acid sequestrant

DPP-4 inhibitor

AmylinGLP-1 RA

Basal insulin analogGlinideThiazolidinedione

MetforminHuman insulin

Sulphonylurea

Phenformin

Intermediate-acting insulin

α-glucosidase-I

Num

ber o

f Cla

sses

of

Antih

yper

glyc

emic

Agen

ts

YearUGDP, DCCT and UKPDS studies.

Anti-diabetic Agents Over Time

Rapid-acting insulin analog

Current Antihyperglycemic Medications

Sulfonylureas

Generalized insulin

secretagogue

12 Groups with Different Mechanisms of Action

-GlucosidaseInhibitors

Delay CHO absorption

Biguanide

Reduces hepaticinsulin

resistance

TZDs

Reduce peripheral insulin

resistance

Amylin Analog

Suppressesglucagon

GLP-1 Analogs

Stimulate cellsSuppress glucagon

Colesevelam

Bile acid sequestrant

Bromocriptine

Hypothalamicpituitary reset

InsulinReplacement

Therapy

SGLT-2 Inhibitors

Block renal glucose reabsorption

Glinides

Restore postprandial 

insulin patterns

Glinides

Restore postprandial 

insulin patterns

DPP-4 Inhibitors

RestoreGLP-1 Level

EFFICACY

Lowering HgA1c

SAFETY

Hypoglycemia Prevention

Management of Type 2 Diabetes: 2017

Cardiovascular Disease

Prevention

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FDA 2008: Evaluating CV Risk in Drugs Intended to Treat T2D

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116994.htm

FDA Recommendations

• Independent CV endpoints committee to adjudicate (blinded) CV events during all phase 2 and phase 3 trials

• Events: • 1) CV mortality, 2) MI, and 3) stroke,

and can include: hospitalization for ACS, urgent revascularization, other endpoints.

• Enough endpoints, high risk population

MACE 

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FDA Criteria for Assessing CV Risk

Pre‐Approval

Post‐Approval

Noninferiority

Noninferiority

Superiority

HR 1.3      HR 1.8   

0.4     0.6      0.8     1.0     1.2     1.4      1.6     1.8     2.0     2.2

Hirshberg B, et al. Diabetes Care. 2011;134(suppl 2):S101-S106.

HR, hazard ratio.

Hazard Ratio

Outcome: MACE = 1) CV mortality, 2) MI, and 3) stroke, and can include: hospitalization for ACS, urgent revascularization

MACE 

CONFIDENTIAL

2008 2020

EXSCEL (exenatide)EXSCEL (exenatide)

LEADER (liraglutide)LEADER (liraglutide)

REWIND (dulaglutide)REWIND (dulaglutide)

ELIXA (lixisenatide)

2014

SUSTAIN-6 (semaglutide)

2010 2012 2016

CANVAS (canagliflozin)

DECLARE (dapagliflozin)

EMPA-Reg(empagliflozin)

2018

GLP1 Receptor Agonists

SGLT-2 Inhibitors

EXAMINE (alogliptin)

CARMELINA (linagliptin)

TECOS (sitagliptin)

SAVOR (saxagliptin)

DPP-4 Inhibitors

23

Reported

Not-Reported

Cardiovascular Safety Studies

Harmony (Albiglutide)

VERTIS (ertigliflozin)

Let’s talk about old drugs 

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Metformin‐ initial drug to treat type 2 diabetes

METFORMIN:  UKPDS 34 provided some evidence for beneficial CV effects of metformin in overweight patients

1. UKPDS 34. Lancet 1998;352:854–65.  2. http://www.medicines.org.uk/emc/medicine/23244/SPC.3. Holman et al. N Engl J Med 2008;359:1577–89.

Significant reduction in MI maintained over 10 years’ follow‐up3

1997 1999 2001 2003 2005 2007

No. of events:

Conventional therapy 73 83 92 106 118 126

Metformin 39 45 55 64 68 81

Myocardial infarction

Metformin vs conventionalp = 0.01

Time from randomisation (years)

0 3 6 9 12 15

0.0

10

20

30

Proportion of patients w

ith eve

nts

(%)

Intensive (n = 951; events = 139)

Conventional (n = 411; events = 73)

Metformin (n = 342; events = 89)

Risk of MI is 39% lower with metformin vs conventional therapy in obese patients1,2

1.4

1.2

1.0

0.8

0.6

0.4

HR

(95

% C

I)

RR 0.611

p = 0.01RR 0.67p = 0.005

Overall values at study end in 1997

Annual values during 10‐year post‐trial monitoring period

0.4

Total # patients* Total # events*

36 1452 3

283 9

672 55

3041 610

587 4

400 4

630 14

1250 15

1805 46

2222 312

1035 4

96 2

458 4

145 2

300 26

2097 61

4351 72

858 13

495 13

543 24

262 5

2789 34

374 11

1551 38502 11

272 4801 3

1172 4

29,783 1495

SulfonylureasMeta‐analysis of SU CV safety trials (115 trials, ≥ 6 months) 

found no consistent association with MACE risk  

*SU + comparator groups combined.Monami et al.Diabetes Obes Metab 2013;15:938–53.

First author (year)

Birkeland 1996Chou 2008

Perriello 2006Gerstein 2010

UKPDS 33 1998Hanefeld 2007

Seino 2010

Charbonnel 2005 Matthews 2005

Rubin 2008Home 2009

Arechavaleta 2011va der Laar 2004

Mazzone 2006

Riddle 1998

Giles 2010

Tolman 2009

Kahn 2006

Goke 2010

Garber 2009

Nissen 2008

Ristic 2007

Ferrannini 2009

Bakris 2006 

Gallwitz 2012 

Jain 2006 

Johnston 1998

Nauck 2011 

Seck 2010 

Overall

0.01 0.1 1 10 100

Favours SUs Favours comparators

MH‐OR (95% CI)

Overall MACE risk estimate for SU vs comparators was not increased: MH‐OR 1.08 (95% CI: 0.86–1.36); p = 0.52

‘CV safety of SUs cannot be considered established unless evaluated in long‐term CVOTs’4

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CAROLINA Study Design

CAROLINA (CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D)

CAROLINA (CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with T2D)

• Multi‐national, randomized, double‐blind, active‐controlled clinical trial 

• 6,033 adults with T2D with increased cardiovascular risk or established cardiovascular disease, median duration of more than 6 years. 

• Aim: cardiovascular safety of linagliptin (5 mg once daily) compared with the sulfonylurea glimepiride (both added to stable background glucose‐lowering medication).

ADA 2019: No difference in cardiovascular outcome!

https://clinicaltrials.gov/ct2/show/NCT01243424

Question 

• What is the CV outcome safety for DPP‐4 inhibitors?

A) No difference in CV safety

B) Increased events (harm)

C) Decreased events (benefit)

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DPP4‐i: For the primary outcome, all completed CVOTs fall within the FDA mandated upper 95% CI limit of 1.3

.

†Total event rate, %.

1. Scirica et al. N Engl J Med 2013;369:1317–26.  2. White et al. N Engl J Med 2013;369:1327–35.  3. Green et al. N Engl J Med 2015; DOI: 10.1056/NEJMoa1501352.

4. Rossenstock JAMA 2018

1.0 2.00.80.6

HR (95% CI)

1.3

Number of events(event rate, % per 100 person‐years)

Placebo+ usual care 

Comparator + usual care 

DPP4 inhibitor trials

SAVOR‐TIMI 531 609 (3.7%) 613 (3.7%)

CARMELINA 434 (12.4†%) 420 (12.1†%)

EXAMINE2 316 (11.8%†) 305 (11.3%†)

TECOS3 851 (4.17%) 839 (4.06%)

Favours comparator Favours placebo

FDA Safety recommendation: Saxagliptin and Alogliptin

http://www.fda.gov/Drugs/DrugSafety/ucm486096.htm

CONFIDENTIAL

Cardiovascular events in high risk patients with T2D

DPP4 inhibitors

• SAVOR (Saxagliptin) • EXAMINE (Alogliptin) 

• TECOS (Sitagliptin)   • CARMELINA (Linagliptin)

33

Neutral Effect

Cardiovascular Safety Studies

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Question 

• Which 2 GLP1‐RA do not show an effect on CV outcomes ?

A) Exenatide and Lixisenatide

B) Albiglutide and Dulaglutide

C) Semaglutide and Liraglutide

Cardiovascular Trials: GLP1‐RAsCardiovascular Trials: GLP1‐RAs

Short-acting:• Exenatide• Lixisenatide

Long-acting:• Exenatide- weekly• Albiglutide• Liraglutide• Dulaglutide• Semaglutide

FDA Approved GLP1-RA

CV Death, Non-fatal MI or Non-fatal Stroke

Marso SP, et al. N Engl J Med. 2016;375:311-322.

CV Death, Non-fatal MI or Non-fatal Stroke

Marso SP, et al. N Engl J Med. 2016;375:1834-1844.

Harmony‐ Albiglutide

Hernandez et al. Lancet 2018; 392: 1519–29

Liraglutide‐ Leader

GLP1-RA Cardiovascular Outcome Trials

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GLP‐1RA Cardiovascular Outcomes

• Exscel Study  (exenatide weekly) and ELIXA (lixisenatide) 

• No difference in CV outcomes

• Some caveats• Semaglutide – worsening retinopathy, ? Had prior retinopathy

Question 

• Which 2 GLP1‐RA do not show an effect on CV outcomes ?

A) Exenatide and Lixisenatide

B) Albiglutide and Dulaglutide

C) Semaglutide and Liraglutide

CONFIDENTIAL

Cardiovascular events in high risk patients with T2D

DPP4 inhibitors

• SAVOR (Saxagliptin) • EXAMINE (Alogliptin) 

• TECOS (Sitagliptin)   • CARMELINA (Linagliptin)

GLP‐1 RA

• ELIXA (Lixisenatide)

• EXSCEL (Exenatide weekly)

• LEADER (Liraglutide)

• SUSTAIN (Semaglutide)

• REWIND (Dulaglutide)

• HARMONY (Albiglutide)39

Reduced CV Events

Cardiovascular Safety Studies

Neutral Effect

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Cardiovascular Trials: SGLT2‐InhibitorsCardiovascular Trials: SGLT2‐Inhibitors

FDA Approved SGLT2-I

• Canagliflozin• Dapagliflozin• Empagliflozin• Ertugliflozin

Question 

• Which SGLT2‐I show a benefit on CV outcomes ?

A) Empagliflozin

B) Canagliflozin

C) Dapagliflozin

D) All of them 

SGLT‐2 Inhibitor – kidney is target organRenal glucose reabsorption

Glucose

Proximal tubuleS1 segment

SGLT2~90% glucose reabsorption

SGLT-1~10% glucose reabsorption

S3 segment

Collectingducts

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SGLT‐2 Inhibitor – Mechanism of Action

Glucose

SGLT-2Inhibitors

Glucosuria Loss of calories

EMPA‐REG (Empagliflozin) CANVAS (Canagliflozin) Dapagliflozin (DECLARE)

CANA: 26.9% vs. PBO: 31.5% event per 1000 patient-years (hazard ratio, 0.86; 95% CI, 0.75 to 0.97)

DAPA: 8.8% vs. PBO: 9.4% event per 1000 patient-years (hazard ratio, 0.93; 95% CI, 0.84 to 1.03)

EMPA: 10.5% vs. PBO: 12.1% event per 1000 patient-years (hazard ratio, 0.86; 95% CI, 0.74 to 0.99)

1. Zinman B et al. N Engl J Med. 2015;373:2117-2128. 2. Neal B et al. N Engl J Med. 2017;377:644-657. 3. Wiviott et al. NEJM 2018, on line November 2018

The SGLT2‐i CV Outcome TrialsPrimary outcome: 3‐point MACE (CV death, MI, stroke)

Hospitalization from Heart Failure, SGLT2‐I CVOTs

EMPA‐REG (Empagliflozin) CANVAS (Canagliflozin) Dapagliflozin (DECLARE)

HR: 0.65; 95% CI, 0.50 to 0.85)

HR: 0.67; 95% CI, 0.52 to 0.87)

HR: 0.73; 95% CI, 0.61 to 0.88)

1. Zinman B et al. N Engl J Med. 2015;373:2117-2128. 2. Neal B et al. N Engl J Med. 2017;377:644-657. 3. Wiviott et al. NEJM 2018, on line November 2018

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The SGLT‐2 Inhibitors and Renal Outcome

The EMPA‐REG, CANVAS and DECLARE trials showed empagliflozin, canagliflozin and dapagliflozin were associated with slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care.1. Zinman B et al. N Engl J Med. 2015;373:2117-2128. 2. Neal B et al. N Engl J Med. 2017;377:644-657. 3. Wiviott et al. NEJM 2018, on line November 2018

Caveats for SGLT‐2i

• Genital mycotic infections

• UTI 

• Orthostatic hypotension

• Euglycemic DKA (rare)

• Increased risk of amputations (canagloflozin)

Number needed to treat (NNT) to prevent one death across landmark trials in patients with high CV risk

48

1. 4S investigator. Lancet 1994; 344: 1383‐89, http://www.trialresultscenter.org/study2590‐4S.htm; 2. HOPE investigator N Engl J Med 2000;342:145‐53, http://www.trialresultscenter.org/study2606‐HOPE.htm

Simvastatin1

for 5.4 years

High CV risk  5% diabetes, 26% hypertension

1994  2000 2015  

Pre‐statin era

High CV risk38% diabetes, 46% hypertension   

Ramipril2

for 5 years

Pre‐ACEi/ARB era 

<29% statin

Empagliflozin for 3 years

T2DM with high CV risk 92% hypertension 

>80% ACEi/ARB  

>75% statin

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ADA Standards of Care, 2019; volume 42 issue Supplement 1

Das et al. J Am Coll Cardiol 2018;72: 3200

Diabetes Drugs for Patients with ASCVD

CONFIDENTIAL

Cardiovascular events in high risk patients with T2D

DPP4 inhibitors• SAVOR (Saxagliptin) • EXAMINE (Alogliptin) • TECOS (Sitagliptin)   • CARMELINA (Linagliptin)GLP‐1 RA• ELIXA (Lixisenatide)• EXSCEL (Exenatide weekly)• LEADER (Liraglutide)• SUSTAIN (Semaglutide)• REWIND (Dulaglutide)• HARMONY (Albiglutide)SGLT2‐I• EMPA‐REG (Empagliflozin)• DECLARE‐TIMI (Dapagliflozin)• CANVAS (Canagliflozin)

51

Reduced CV Events

Cardiovascular Safety Studies

Neutral Effect

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Management of Diabetes in 2019

SU TZD DPP4‐i SGLT2‐i GLP1‐RA

Insulin

Efficacy ++ ++ + ++ +++ +++

Hypoglycemia XX ++ +++ ++ ++ XX

Heart Failure ? XX (X)/‐ ++++ ++ ?

ASCVD +/‐ ++ ‐ +++ ++++ ‐

Renal protection + ‐ ‐ ++++ ++ +

Additional Safety Concerns/ AE

CV risk with old SU, 

weight gain

Bladder Cancer (?), fractures, weight gain

Pancreatitis 

(+)

eDKA,amputations 

(?cana) Yeast infections 

Pancreatitis (?)

Weight gain 

Take home points

• CV disease is common in patients with diabetes

• Intensive glucose control does not change CV outcomes

• Metformin is first line for treatment of diabetes

• If ASCVD, still start with metformin and add an SGLT2i or a GLP‐1RA with proven CV benefit 

• DPP4‐I are neutral for CV outcomes

But remember

• None of these studies are for primary prevention

Questions?  

pvellan@emory.edu 

AcknowledgementsSupported by K12-HD085850, K23 DK11324-01A1 (start 8/2019) from the

National Institutes of Health