Diabetes drugs and cardiovascular outcomes...

Diabetes drugs and cardiovascular outcomes trials

2017

Karol E. Watson, MD, PhD, FACC

Professor of Medicine/Cardiology

Co-director, UCLA Program in Preventive Cardiology

Director, UCLA Barbra Streisand Women's Heart Health Program

David Geffen School of Medicine at UCLA

John Mazziotta, M.D., Ph.D. Term Chair in Medicine

Disclosures

• Research grants: NHLBI, NIDDK, NIH BD2K

• Consultant: Amarin, Amgen, Behringher Ingelheim

• Speaker’s Bureau: Behringher Ingelheim

Diabetes Drugs and CVOT - 2017

• Approval process for diabetes drugs

• Rationale for Cardiovascular

Outcomes trials (CVOT)

• CVOT results

– DPP-4 inhibitors

– GLP-1 receptor agonists

– SGLT2 inhibitors

• Mechanisms?

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insulinsulfonylureas

Biguanides

angiotensin II receptorblockers

ACE Inhibitors

Ca2+ channel blockers

β-blockers

diuretics

centralα-2 agonists

peripheralα-1 blockers

adrenergicneuronal blockers

renin inhibitors

vasodilators

SGLT-2inhibitors

-glucosidaseinhibitors

thiazolidinediones

meglitinides

GLP-1 analogues

DPP-4 inhibitors

amylin mimetics

biguanides

bile acidsequestrants

dopamine agonistszz12

Courtesy of Silvio Inzucchi, MD, Yale University

HTN & Diabetes meds through the years

FDA Approval Process for glucose lowering drugs

• Diabetes drugs are approved for the primary indication

of improving glycemic control

• HbA1c is the primary efficacy endpoint

• But the primary cause of death for people with diabetes

is cardiovascular disease

• The effects of diabetes medications on cardiovascular

(CV) endpoints or outcomes was not assessed

N Engl J Med. 2008; 358:2560-72

N Engl J Med. 1993; 329:977-86 Diabetes Care. 2004; 27: 1761-73

Lancet. 1998; 352:837-53

There is an epidemiologic association between HbA1c and CVD

Data from 11,092 black and white subjects in the

Atherosclerosis Risk in Communities (ARIC) study

Median follow approximately 14 years.

Sabin et al. NEJM March 2010





• CVOT results




• Mechanisms?

Anti-diabetes medication and cardiovascular outcomes

Udell, et al., Lancet Diabetes Endocrinol., published online 16 March 2015,

Favors diabetic med Favors placebo

“Although cardiovascular disease is the cause of

death in 75% of diabetics, there exist no well-

designed, adequately-powered comparative

effectiveness trials evaluating macrovascular

outcomes for diabetes drugs”

Steve Nissen, MD - Cleveland Clinic

The irrational belief that lowering blood sugar using virtually any

pharmacological means will produce a reliable reduction in adverse outcomes

glu-co-cen-tricity |ˈgloōkō senˈtrisitē

noun

In 2008 the FDA offered guidance to industry on cardiovascular safety of diabetes drugs

• FDA recommendation: “To establish safety of a new antidiabetic therapy to treat Type 2 diabetes, sponsors should demonstrate that the therapy will not result in an unacceptable increase in cardiovascular risk.”

• The CV outcomes trials are characterized by:

– Inclusion of high-risk patients

– Non-inferiority design

– If the non-inferiority threshold is met, these trials can also assess for superiority.

• Due to their long duration and large numbers, these trials can generate an enormous amount of data on other safety endpoints (pancreatitis, cancer, and hypoglycemia).

• FDA still approves diabetes drugs on the basis of HbA1chttps://www.fda.gov/downloads/Drugs/.../Guidances/ucm071627.pdf





• CVOT results– DPP-4 inhibitors



• Mechanisms?

CV Outcomes Trials in Type 2 DM

More than 200,000 T2DM patients

The DPP-4

inhibitor

Studies

SAVOR

EXAMINE

TECOS

Clinical Outcomes with Alogliptin: EXAMINE

• N=5380 patients with T2D

and ACS

• Randomization

– Alogliptin: n=2701

– Placebo: n=2679

• Noninferiority study:

• Primary composite endpoint:

CV death, nonfatal MI, or

nonfatal stroke

• Median follow-up: 18 months

• A1C: -0.36% for alogliptin vs

placebo

• Noninferior to placebo for

cardiovascular outcomes

• Also no difference in

pancreatitis, cancer, renal

impairment, angioedema, or

severe hypoglycemia

EXAMINE

EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care; HR, hazard ratio; MI, myocardial infarction.

White W, et al. N Engl J Med. 2013;369:1327-1335.

• Key Results• Study Design

Clinical Outcomes with Saxagliptin: SAVOR

• N=16,492 patients with T2D

and CVD or CVD risk

• Randomization

– Saxagliptin: n=8280

– Placebo: n=8212

• Superiority study with

noninferiority provision

• Primary composite endpoint: CV

death, nonfatal MI, or nonfatal

ischemic stroke

• Median follow-up: 2.1 years

• A1C -0.36% for saxagliptin vs

placebo



• Higher incidence of HF

hospitalization w/ saxagliptin

• No difference in pancreatitis;

fewer cases of pancreatic

cancer in saxagliptin group;

more cases of nonfatal

angioedema in saxagliptin

group (8 vs 1)

SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction.

Scirica BM, et al. N Engl J Med. 2013;369,1317-1326.

• Key Results• Study Design

• N=14,671 patients with T2D and

CVD

• Randomization

– Sitagliptin: n=7332

– Placebo: n=7339


• Primary composite outcome:

cardiovascular death, nonfatal

myocardial infarction, nonfatal

stroke, or hospitalization for

unstable angina

• Key Results


• A1C: -0.29% for sitagliptin vs

placebo



• Also no difference infections,

cancer, renal failure,

hypoglycemia, or

noncardiovascular death

Clinical Outcomes with Sitagliptin: TECOS

TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin.

Green JB, et al. N Engl J Med. 2015;373:232-242.

• Study Design

TIMI STUDY GROUP / HADASSAH MEDICAL ORG

8.0

7.67.5

7.9 7.8

6

7

8

9

Rand 1 year 2 year

Hb

A1

c (

%)

Saxagliptin Placebo

**

*p<0.001

Difference Between the

Alogliptin and Placebo Groups

at the Last Visit: –0.36%; P<0.001

Scirica BM, et al. NEJM 2013; 369:1317-1326 White WB et al, NEJM 2013; 369:1327-35Green JB et al. NEJM 2015;

Modest HbA1c Response

Comparison of Primary Endpoint Rates

8

4

6 12 18 24

2y KM

Saxagliptin 7.3%

Placebo 7.2%

10

14

12

6

2

Months

0

TIMI STUDY GROUP / HADASSAH MEDICAL ORG

11.6%11.5%

All Trials met non-inferiority boundary of <1.3

Scirica BM, et al. NEJM 2013; 369:1317-1326 White WB et al, NEJM 2013; 369:1327-35Green JB et al. NEJM 2015;

SAVOR-TIMI 53, EXAMINE, and TECOS: Hospitalization for Heart Failure

Trial HR (95% CI) P-Value

SAVOR-TIMI1.27

(1.07–1.51) 0.007

EXAMINE1.19

(0.89–1.59)0.235

TECOS1.00

(0.84–1.20)0.99

SAVOR-TIMI + EXAMINE + TECOS

1.14

(0.97–1.34)0.102

McGuire DK, et al. JAMA Cardiology 2016, epub April 13, 2016

FDA Drug Safety Communication: FDA adds

warnings about heart failure risk to labels of

type 2 diabetes medicines containing

saxagliptin and alogliptin

FDA April 5, 2016

DPP-4 inhibitors and CV safety

• Dipeptidyl peptidase (DPP)-4 inhibitors do not

increase or reduce the risk of major CV events.

– Increased HF events with saxagliptin and per FDA,

alogliptin





• CVOT results




• Mechanisms?

The GLP1-RA

Studies

SUSTAIN 6

ELIXA

LEADER


recent ACS (<180 days)

• Randomization

– Lixisenatide: n=3034

– Placebo: n=3034





stroke, or hospitalization for

unstable angina

• Key Results

• Median follow-up: 25 months

• A1C: -0.27% for lixisenatide

vs placebo



• Also no difference in severe

hypoglycemia, pancreatitis,

pancreatic cancer, or allergic

reactions

Clinical Outcomes with Lixisenatide: ELIXA

ELIXA: Lixisenatide in Type 2 Diabetes and Acute Coronary Syndrome

N Engl J Med 2016; 374:1094-1096

• Study Design

GLP -1: ELIXA TRIAL

Pfeffer et al. NEJM. 2015;373(23):2247-57

805 Events


high CV risk

• Randomization

– Liraglutide: n=4,668

– Placebo: n=4,672





stroke

• Key Results


• A1C: -0.40% for liraglutide vs

placebo

• 13% RRR in CV events with

liraglutide [p<0.001 for noninferiority;

p<0.01 for superiority]

• Liraglutide was also associated

with a NS increase in

pancreatic cancer (13 vs 5), a

NS decrease in prostate cancer

(26 vs 47) and leukemia (5 vs

14); no difference in severe

hypoglycemia or pancreatitis

Clinical Outcomes with Liraglutide: LEADER

LEADER, Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes.

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

• Study Design

LEADER Trial

Primary Endpoint

Myocardial Infarction

CV Death

Stroke

1302 Events

22% RRR

NNT = 98

13% RRR

NNT = 66

NS NS


CVD, CKD or both

• Randomization

– Semaglutide: n=1,648






stroke

• Key Results


• A1C: -1.1% for .5 mg semaglutide

and -1.4% for 1 mg semaglutide

• 26% RRR in 1o outcome with

semaglutide [p<0.001 for noninferiority;

p=0.04 for superiority]

• Semaglutide was also associated

with more retinopathy

complications (HR 1.76 p=0.02),

fewer nephropathy complications

(HR .64 p=0.005), and a greater # of

discontinuations due to GI side

effects

Clinical Outcomes with Semaglutide: SUSTAIN 6

SUSTAIN 6, Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

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

• Study Design

Once weekly SGLT2i

SUSTAIN 6 Trial

Primary Endpoint

Myocardial Infarction

CV Death

Stroke

254 Events

26% RRR

NNT = 43

NS

NS

39% RRR

NNT = 91

• The Glucagon-Like Peptide-1 Receptor Agonist

lixisenatide does not increase or reduce the risk of

major CV events (including no increase in heart failure

events).

• The GLP-1 receptor agonists liraglutide and

semaglutide reduce the risk of major CV events.

GLP-1 RA and CV safety





• CVOT results




• Mechanisms?

The SGLT-2i

Studies

EMPA-REG

CANVAS


CVD

• Randomization

– Empagliflozin: n=4,687






stroke

• Key Results


• A1C: -.54% for 10 mg

empagliflozin and -.60% for 25 mg

• 14% RRR in 1o outcome with

empagliflozin [p=0.04]

• Empagliflozin was also associated

with 38% RRR in CV death

(p<0.001), but no significant change

in nonfatal MI or nonfatal stroke.

There were significantly more

genital infections with empagliflozin

but no other AEs

Clinical Outcomes with Empagliflozin: EMPA-REG

EMPA-REG, Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes

Zinman et. al. N Engl J Med 2015; 373:2117-2128.

• Study Design

EMPA-REG Primary outcome:(CV death, MI, stroke)

35

HR 0.86

(95.02% CI 0.74, 0.99)

p=0.0382*

772 Events

Zinman B et al. N Engl J Med 2015; 373: 2117-28

14% RRR

NNT = 63

Patients with event/analysed

Empagliflozin Placebo HR (95% CI) p-value

3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382

CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001

Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189

Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638

0.25 0.50 1.00 2.00

CV death, MI and stroke

Favours empagliflozin Favours placebo


Placebo

Empagliflozin

EMPA-REG OUTCOME: Cardiovascular Mortality

38% RRR

NNT = 45

EMPA-REG OUTCOME: Hospitalization for heart failure

HR 0.65

(95% CI 0.50, 0.85)

p=0.0017


35% RRR

NNT = 71

EMPA-REG OUTCOME: Renal Outcomes


eGFR

Worsening nephropathy

Doubling of serum Cr


high CV risk

• Randomization

– Canagliflozin: n=5,795






stroke

• Key Results


• A1C: -.58% for 100 mg 300 mg

canagliflozin groups pooled

• 14% RRR in 1o composite

outcome with canagliflozin [p=0.02]

None of the individual components

was significantly reduced and a

17% RRR in progression of

albuminuria .

• With canagliflozin there were more

genital infections, a 26% increase

in fractures (CI 1.04-1.52) and a

significant increase in amputations

HR 1.97 (CI 1.41-2.75)

Clinical Outcomes with Canagliflozin: CANVAS

Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

Zinman et. al. N Engl J Med 2015; 373:2117-2128.

• Study Design

Neal B et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1611925

Cardiovascular Outcomes in the Integrated CANVAS Program.

CANVAS Trial: Primary Outcome components

CV death, MI, Stroke CV death

Nonfatal stroke Nonfatal MI

13% RRR

NNT = 200

NS NS

NS

Neal B et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1611925

Rates of Hospitalization for Heart Failure, Death from Any Cause, and Renal Outcomes in the Integrated

CANVAS Program.

CANVAS Trial: Secondary Outcomes

Hospitalization for heart failure Total mortality

Progression of albuminuria Progression of renal failure or death

From renal causes

40% RRR

NNT = 250

33% RRR

NNT = 250

NS

NS

Canagliflozin and Amputations

• 5/18/2016

• FDA warns of increase risk of leg and foot amputations,

mostly affecting the toes, with the diabetes medicine

canaglfilozin

• CANVAS Trial Interim analysis showed higher risk of amputation (particularly

toe) in canagliflozin than placebo

• 7/1000 with canagliflozin 100mg daily

• 5/1000 with canagliflozin 300mg daily

• 3/1000 with placebo daily

– Study permitted to continue

• Mechanism unclear– Volume depletion?

– Higher risk of amputations has also been noted with diuretic use

NNH = 330





• CVOT results




• Mechanisms?

Filtered glucose load 180 g/day

SGLT1~10%

SGLT2~ 90%

Gerich JE. Diabet Med. 2010;27:136–142.

Renal glucose re-absorption in healthy individuals

SODIUM

GLP-1 Modulates Numerous Functions in Humans

Stomach:Helps regulate

gastric emptying

Promotes satiety and

reduces appetite

Liver:

Glucagon reduces

hepatic glucose outputBeta cells:Enhances glucose-dependent

insulin secretion

Alpha cells: Glucose-dependent

postprandial

glucagon secretion

GLP-1: Secreted upon

the ingestion of food

Data from Flint A, et al. J Clin Invest 1998;101:515-520. Data from Larsson H, et al. Acta Physiol Scand 1997;160:413-422.

Data from Nauck MA, et al. Diabetologia 1996;39:1546-1553. Data from Drucker DJ. Diabetes 1998;47:159-169.

Controlled Phase 2b/3

Pooled Population

Saxagliptin Trials

All Saxa

Control

HR 0.44(95% CI 0.24-0.82)

41 total events

Frederich R, et al. Postgraduate Medicine 2010;122(3). doi: 10.3810/pgm.2010.05.2138.

Why CVOT are important

24 37 50 63 76 89 102 115 128BL

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CV

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Saxagliptin 7.3%

Placebo 7.2%

Months

SAVOR-TIMI 53

CV

De

ath

, M

I o

r Is

ch

em

ic C

VA

(%

)

• DPP-4 inhibitors do not increase CV events.

– Increased HF events with saxagliptin and ?alogliptin

• The GLP-1 RA lixisenatide does not increase or CV

events

• The GLP-1 RAs liraglutide and semaglutide reduce the

risk of CV events and CV death

• The SGLT2 inhibitors empagliflozin and canagliflozin

reduce the risk of CV events and renal events

– an outsized reduction in HF events

• Empagliflozin reduces CV death

• Canagliozin increases amputation risk

Conclusions

Why we must prevent cardiovascular events in patients with diabetes

If we keep on doing what we've always done...we'll keep on getting what we've always gotten…

Diabetes drugs and cardiovascular outcomes...

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