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(2017)Objective
Exenatide - To assess cardiovascular safety and efficacy of once-weekly exenatide in patients with type 2 diabetes with or without prior cardiovascular disease.
Study Summary
• Exenatide did not significantly reduce MACE compared with Placebo.
Intervention
Multinational, double-blind, placebo-controlled RCT. 14,752 patients with type 2 diabetes randomized to weekly extended-release exenatide (2 mg) or placebo. Median follow-up: 3.2 years. Primary endpoint was time to first occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke.
Inclusion Criteria
Adults with type 2 diabetes (HbA1c 6.5–10%) with or without cardiovascular disease. 73% had established CV disease at baseline.
Study Design
Arms: Exenatide vs. Placebo
Patients per Arm: Exenatide: 7356; Placebo: 7396
Outcome
• Fatal or nonfatal stroke: 2.5% vs. 2.9%; HR 0.85 (95% CI, 0.70–1.03)
• CV death: 4.6% vs. 5.2%; HR 0.88 (95% CI, 0.76–1.02)
• All-cause mortality: 6.9% vs. 7.9%; HR 0.86 (95% CI, 0.77–0.97)
• Hospitalization for HF: 3.0% vs. 3.1%; HR 0.94 (95% CI, 0.78–1.13)
• Hospitalization for ACS: 8.2% vs. 7.7%; HR 1.05 (95% CI, 0.94–1.18)
Bottom Line
Exenatide was noninferior but not superior to placebo for cardiovascular safety in patients with type 2 diabetes, and showed no statistically significant reduction in major adverse cardiovascular events (MACE).
Major Points
- Large pragmatic RCT (N=14,752) assessing once-weekly exenatide vs. placebo in type 2 diabetes.
- Median follow-up 3.2 years; 73% had prior cardiovascular disease.
- Primary MACE outcome occurred in 11.4% (exenatide) vs. 12.2% (placebo); HR 0.91 (95% CI 0.83–1.00); P<0.001 for noninferiority, P=0.06 for superiority.
- No significant difference in cardiovascular death, MI, stroke, or hospitalization for heart failure.
- Exenatide showed modest reductions in HbA1c, weight, SBP, but increased heart rate.
- Overall cancers similar (355 vs. 361); however more patients on exenatide had thyroid papillary carcinomas (10 vs. 4). Pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and severe hypoglycemia did not differ significantly.
Study Design
- Study Type
- Multicenter, double-blind, placebo-controlled, randomized trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 14752
- Follow-up
- Median 3.2 years (up to 6.8 years)
- Centers
- 687
- Countries
- 35 countries including USA, UK, India, China, Australia, Europe, Latin America
Primary Outcome
Definition: First occurrence of MACE (CV death, nonfatal MI, nonfatal stroke)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 12.2% (905/7396) | 11.4% (839/7356) | 0.91 (0.83–1.00) | 0.06 (superiority); <0.001 (noninferiority) |
Limitations & Criticisms
- High premature discontinuation of trial regimen (mean time on regimen 76.0% exenatide vs 75.0% placebo), primarily driven by patient decision
- Modest treatment effect on metabolic parameters
- Placebo group had more use of other cardioprotective agents (SGLT-2, GLP-1RA)
- Shorter exposure time and lower baseline HbA1c than LEADER/SUSTAIN-6
Citation
N Engl J Med 2017;377:1228–1239. DOI: 10.1056/NEJMoa1612917