Cardiovascular Outcomes With Newer Diabetes Drugs:

Results From The EMPA-REG and LEADER Trials

Rajiv Roy, MD Endocrinology

Sharp Rees-Stealy Medical Group

Background

Between 1990 and 2010: • Incidence of acute MI dropped by approximately 1/3 • Incidence of stroke did not change significantly

Background

In the diabetic population: • Incidence of MI decreased by 2/3 • Incidence of stroke decreased by 1/2

Background

Despite improvements in care, diabetics still have a 1.5X higher incidence of CV death

Background

• Because of the high risk of CV, microvascular and other complications, regulatory authorities have mandated CV safety assessments of new diabetes medications

• Today we will review data from 2 trials which assessed CV risk of 2 newer classes of DM medications

• It is important to note that not CV outcome trials are created equal; number of patients, duration of follow up, patient characteristics all important in analysis

• Ongoing research and data collection/review are very important

Liraglutide versus placebo in type 2 diabetics with high CV risk

Demonstrated that LIRAGLUTIDE (LIRA) in addition to standard of care reduced risk of combined endpoint of CV death, non fatal MI and non fatal stroke vs placebo in adults with type 2 DM and high CV risk

More recently, LIRA has received a new indication to reduce the risk of major cardiovascular events, MI, stroke and CV death in adults with type 2 DM and established CV disease

LEADER STUDY DESIGN

410 sites in 31 countries

9340 patients randomized

4668 LIRA, 4672 PBO

Inclusion Criteria:

Adults with T2DM on Tx or Tx naïve

Age > 50 with at least 1 CV condition or CKD (CHD, CVD, PVD, CKD 3 or higher, NYHA CHF class 2 or 3)

Age > 60 with 2 CV risk factors (increased urine microalbumin, proteinuria, LVH, systolic or diastolic dysfunction, ABI < 0.9)

Exclusion: T1DM, GLP-1 Tx, DPP4-i Tx, MEN2, MTC, acute CV event 14d before study entry

LEADER STUDY DESIGN: PATIENTS

• Study groups were well matched

• 2/3 Male

• Median age 64

• Mean BMI 32.5

• Mean A1c 8.7

• Mean duration of diabetes 12.8 years LIRA, 12.9 years PBO

• Median follow up: 3.5 years

• 81% had CVD, 25% had CKD > or =3, 16% both

LEADER STUDY DESIGN

• After a 2 week run in, patients were randomized to:

• LIRAGLUTIDE + Standard of Care (titrated to 1.8 mg QD)

• PLACEBO + Standard of Care

• Medications were adjusted for patients not at goal (but not given GLP-1, DPP4i, pramlintide)

• Follow up 1 MO, 3 MO, 6 MO, then q 6 MO

LEADER:PRIMARY AND SECONDARY OUTCOMES

• PRIMARY ENDPOINT: Composite of CV death, non fatal MI, non fatal stroke

• SECONDARY ENDPOINTS

• Composite of CV death, nonfatal MI (including silent MI), nonfatal stroke, coronary revascularization, and hospitalization for unstable angina or HF

• All cause mortality

• Composite renal and retinal microvascular events

• Neoplasms

• Pancreatitis

LEADER TRIAL: RESULTS

Cardiovascular outcomes: PRIMARY: HR 0.87 (95% CI 0.78 TO 0.97); P = 0.01 FOR SUPERIORITY (608 vs 694 pts) DEATH FROM CV CAUSES: HR 0.78 (95% CI, 0.66-0.93); P = 0.007 (219 vs 278 pts)

LEADER TRIAL: RESULTS

NO STATISTICALLY SIGNIFICANT DIFFERENCE IN NONFATAL MI OR NONFATAL STROKE

LEADER TRIAL: RESULTS

DEATH FROM ANY CAUSE: HR 0.85; P = 0.02 (381 vs 447 pts) HOSPITALIZATION FOR CHF: HR: 0.87; P = 0.14 (NOT STATISTICALLY SIGNIFICANT) (218 vs 248 pts)

CV DATA FOR OTHER GLP-1 ANALOGS • In SUSTAIN 6, inpatients with type 2 diabetes at high cardiovascular

risk treated with once weekly semaglutide the rate of 3 point MACE was reduced; no reduction in CV death

• In ELIXA, type 2 diabetics with recent MI or USA, addition of lixisenatide did not alter rate of 1˚ endpoint (CV death, MI, stroke HHF)

• In HARMONY, no statistically significant difference between and albiglutide versus placebo

• In EXSCEL, weekly exenatide did not increase rate of 3 point MACE; vs PBO (noninferior); superiority vs PBO in reducing 3 point MACE p = 0.061

• REWIND trial (dulaglutide) is ongoing

Marso SP et al. NEJM 2016;375:1834-1844

SUSTAIN-6 TRIAL RESULTS

Holman RR et. Al, NEJM 2017;377:1228-1239

EXSCEL TRIAL RESULTS

LEADER TRIAL TAKE HOME POINTS

• Patients treated with LIRAGLUTIDE had a statistically significant reduction in primary endpoint of CV death, nonfatal MI, nonfatal stroke

• Significantly lower rate of all cause mortality

• Significantly lower rate of CV death

• Increased risk of GI side effects in LIRAGLUTIDE treated patients

• Lower incidence of pancreatitis in LIRA group but not statistically significant

• Additional CVOTs of GLP-1 analogs are ongoing

Empagliflozin versus placebo in type 2 diabetics with known cardiovascular disease

Demonstrated that EMPAGLIFLOZIN (EMPA), in addition to standard of care, reduced 3 point MACE of cardiovascular death, non fatal MI and non fatal stroke versus placebo in a high risk population of type 2 diabetic adults with established CV disease

Risk of CV death was significantly reduced versus placebo

EMPA-REG STUDY DESIGN

• 590 sites in 42 countries

• 7020 patients randomized

• 4687 EMPA, 2333 PBO

• Inclusion Criteria:

• Adults with T2DM AND established CVD (CAD, USA, hx of MI, hx of stroke)

• BMI < 45 kg/m²

• GFR > 30 ml/min

• A1c 7-10%

EMPA-REG STUDY DESIGN

• After a 2 week placebo run-in, patients were randomized to:

• EMPA 10 mg QD + Standard of Care

• EMPA 25 mg QD + Standard of Care

• Placebo + Standard of Care

• Medications were not adjusted for the first 12 weeks of the trial; afterward adjusted to goal

EMPA-REG: ENDPOINTS

• PRIMARY ENDPOINT: Time to first occurrence of any of the primary composite endpoint (3 point MACE): CV death, non fatal MI, non fatal stroke

• SECONDARY ENDPOINTS: CV death, non fatal MI, non fatal stroke

EMPA-REG STUDY DESIGN: PATIENTS

• Study groups were well matched

• 63% male

• Mean age: 63

• Mean BMI 31

• 99% had established CV disease (76% CAD, 46% hx of MI, 24% hx of stroke, 21% PAD)

• Median follow up 3.1 years

EMPA-REG TRIAL: RESULTS

14% reduction in 3 point composite endpoint (MACE): HR 0.86; p=0.04 superiority 38% reduction in cardiovascular death: HR 0.62; p < 0.001 32% reduction in all cause mortality: HR 0.68; p < 0.001 35% reduction in CHF hospitalization: HR 0.65; p = 0.002

Zinman B et al, NEJM 2015; 373:2117-2128

Composite endpoint (3 point MACE) occurred in 10.5% EMPA patients vs 12.1% PBO 1.6% absolute risk reduction, 14% relative risk reduction

CV Death occurred in 3.7% of EMPA group vs 5.9% PBO group EMPA treated patients had a 2.2 % absolute risk reduction, 38% relative risk reduction versus placebo (p < 0.001) Non fatal MI and non fatal stroke: No significant difference between EMPA and PBO groups. Difference in CV death drove 3 point MACE

Zinman B et al, NEJM 2015; 373:2117-2128

Death from any cause occurred in 5.7% in EMPA group vs 8.3% in PBO group ACM: 2.6% absolute risk reduction and 32% relative risk reduction in EMPA treated patients versus placebo (p<0.001)

Heart failure hospitalization occurred in 2.7% EMPA patients vs 4.1% PBO Absolute risk reduction in EMPA group: 1.4%; Relative risk reduction 35% (p=0.002)

EMPA-REG TRIAL TAKE HOME POINTS

• EMPA therapy resulted in a 14% reduction in composite endpoint of CV death, non fatal MI and non fatal stroke

• There were also significant reductions in cardiovascular death, all cause mortality, and heart failure hospitalization in EMPA treated patients

• Main side effects were UTI and genital mycotic infections

DATA FOR OTHER SGLT-2 INHIBITORS

• In a similar analysis of canagliflozin treated patients (CANVAS and CANVAS-R), there was a statistically significant reduction in 3 point MACE but no statistically significant reduction in all cause mortality or CV death (26.9 vs 31.5 participants per 1000 pt years; HR 0.86)

• In CANVAS was a higher risk of lower extremity amputations in CANA treated patients vs PBO (6.3 vs 3.4 participants per 1000 patient yrs; HR 1.97). Not seen in previous canagliflozin trials. Mechanism unknown

• Another large multinational study of 300,000 pts (CVD-REAL) in which patients were on CANA (53%) or DAPA(42%) or EMPA(5%) showed a 39% reduction in CHF admission, 51% reduction in death, and 46% reduction in composite of heart failure or death. Only 13% had CVD at baseline.

CANVAS AND CANVAS-R RESULTS

Neal B et. Al, NEJM 2017;377:644-657

CANVAS AND CANVAS-R RESULTS

Neal B et. Al, NEJM 2017;377:644-657

Neal B et. Al, NEJM 2017;377:644-657

CANVAS AND CANVAS-R RESULTS

Neal B et. Al, NEJM 2017;377:644-657

CANVAS AND CANVAS-R RESULTS

Neal B et. Al, NEJM 2017;377:644-657

CANVAS AND CANVAS-R RESULTS

SUMMARY

• Newer therapies for diabetes include GLP-1 analogs and SGLT2 inhibitors

• In addition to glucose lowering ability, drugs in both classes of medications have either a neutral or beneficial cardiovascular profile

• Both liraglutide and empagliflozin have been shown to have benefit in reducing risk of the 3 point MACE including CV death, non fatal MI and non fatal stroke

• Ongoing trials will determine whether these benefits are representative of a class effect