REWIND

Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes

Clinical Question

What is the effect of the GLP-1 agonist dulaglutide on cardiovascular outcomes in T2DM patients with established cardiovascular disease or increased risk for cardiovascular events?

Bottom Line

In T2DM patients with established cardiovascular disease or increased risk for cardiovascular events the addition of dulaglutide to standard therapy resulted in statistically lower rates of the primary composite outcome, driven primarily by a reduction in non-fatal stroke. The was no increase in rates of pancreatitis or cancer in the dulaglutide treatment group compared to placebo.

Major Points

The primary composite outcome (first occurrence of vascular death, non-fatal myocardial infarction or non-fatal stroke) occurred at statistically lower rates in the dulaglutide treatment group compared to placebo. This was driven primarily by a reduction in the individual component of non-fatal stroke. The other components of the primary composite outcome were not statistically different from placebo.

The results from this trial demonstrate than the GLP-1 agonist dulaglutide (in addition to standard therapy) is superior to placebo in terms of reducing cardiovascular outcomes. However, it is important to note that sub-group analysis of those with or without baseline cardiovascular disease failed to demonstrate statistically lower rates of the primary composite outcome. Additionally, only ~31% of patients had baseline cardiovascular disease which is notably lower compared to the LEADER trial (~81% baseline cardiovascular disease). This may limit the applicability of the trial results as the majority of the patients did not have baseline cardiovascular disease and sub-group analysis of those who did failed to demonstrate statistically lower rates of the primary composite outcome.

Guidelines

ADA Standards of Care 2019

Design

• Multicenter, double-blind, randomized, controlled trial
• Superiority trial
• Primary efficacy outcome: time to first occurrence of vascular death, non-fatal myocardial infarction or non-fatal stroke
  • Determined that 9600 patients and 1200 primary outcomes were required to achieve 90% power (alpha = 0.05)
  • All efficacy and safety analysis were performed using the ITT population
• A total of 9901 patients underwent randomization
• Baseline patient characteristics were similar between treatment groups
• Median follow-up of 5.4 years

Population

Inclusion Criteria

• T2DM patients with A1C ≤ 9.5%
• Receiving max 2 oral agents +/- basal insulin
• BMI ≥ 23
• Age ≥ 50 with established vascular disease, OR
• Age ≥ 55 with myocardial ischemia, artery stenosis ≥ 50%, LV hypertrophy, eGFR < 60 mL/min or albuminuria, OR
• Age ≥ 60 with 2 of following: tobacco use, dyslipidemia, HTN or abdominal obesity

Exclusion Criteria

• eGFR < 15 mL/min
• Cancer within prior 5 years
• Severe hypoglycemia within 1 year prior
• Life expectancy < 1 year
• Coronary/cerebrovascular event within 2 months prior
• Plans for revascularization

Baseline Characteristics

• Average age ~66 years
• Primarily male (~53%)
• Baseline A1C ~7.3%
• Baseline cardiovascular disease ~31% (rest had risk factors)

Interventions

• Eligible patients were randomized 1:1 to receive dulaglutide (in addition to standard therapy) or matching placebo
  • Dulaglutide 1.5 mg weekly subcutaneous injections (N=4949)
  • Placebo (N=4952)
• Use of incretin-based therapies (DPP-4 inhibitors or GLP-1 agonists) was not allowed during trial

Outcomes

Comparisons are dulaglutide versus placebo

Primary Efficacy Outcomes

Primary efficacy composite (vascular death, non-fatal myocardial infarction, non-fatal stroke)

594 (12.0%) vs. 663 (13.4%); HR 0.88 (0.79-0.99); p=0.026

ARR 1.37%; NNT 73

Vascular death

317 (6.41%) vs. 346 (6.99%); HR 0.91 (0.78-1.06); p=0.21

Non-fatal myocardial infarction

205 (4.14%) vs. 212 (4.28%); HR 0.96 (0.79-1.16); p=0.65

Non-fatal stroke

135 (2.73%) vs. 175 (3.53%); HR 0.76 (0.61-0.95); p=0.017

ARR 0.81%; NNT 125

Overall mean A1C difference between treatment groups was -0.61% favoring dulaglutide over placebo (p<0.001)

Sub-group analysis

History of cardiovascular disease: HR 0.87 (0.74-1.02)

No history of cardiovascular disease: HR 0.87 (0.74-1.02)

Safety Outcomes

There was no statistical difference between treatment groups in the rates of discontinuation, pancreatitis, pancreatic cancer, thyroid cancer, serious GI events or any cancer

Gastrointestinal ADRs were statistically higher in the dulaglutide group than placebo (47.4% vs 34.1%; p<0.0001)