Largest CV outcome trial of a GLP-1 RA in adults without diabetes. Results led to first FDA approval of a weight-management drug for a CV outcome.
Trial design
Lincoff et al. (NEJM 2023): 17,604 adults BMI ≥27 + established CVD, no diabetes. Sema 2.4 mg weekly vs placebo on top of standard CV care.
Results
| Endpoint | Sema | Placebo | Effect |
|---|---|---|---|
| MACE (3-point) | 6.5% | 8.0% | 20% reduction (HR 0.80, p<0.001) |
| CV death | 2.5% | 3.0% | HR 0.85 |
| Non-fatal MI | 2.7% | 3.7% | HR 0.72 |
| Non-fatal stroke | 1.7% | 1.9% | HR 0.93 |
| Weight at 104 wk | −9.4% | −0.9% | −8.5% |
Median follow-up 39.8 months. MACE benefit emerged within 6 months and persisted.
Mechanism beyond weight loss
CV benefit larger than weight loss alone would predict. Proposed: direct vascular endothelium and myocardium effects, reduced inflammation, improved insulin sensitivity, BP reduction.
Regulatory implications
- March 2024: Wegovy approved for CV event reduction in BMI ≥27 + CVD — first weight-management drug ever approved for CV outcome
- Medicare GLP-1 Bridge (July 1, 2026 to December 31, 2027): a $50 copay for eligible Part D enrollees for Foundayo, Wegovy or the Zepbound KwikPen; people with type 2 diabetes, moderate-to-severe sleep apnea or fatty liver disease are not eligible and use their Part D plan instead.
- Commercial plans increasingly covering under SELECT-mirroring PA criteria
Established CVD
Prior MI, prior ischemic or hemorrhagic stroke, or symptomatic PAD.