SELECT (Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity) is the largest cardiovascular outcome trial of a GLP-1 receptor agonist in adults without diabetes. Results led to the first FDA approval of a weight-management drug for a cardiovascular outcome.

Trial design

SELECT (Lincoff et al., NEJM 2023) enrolled 17,604 adults with BMI ≥27 and established CVD, without diabetes. Randomized to semaglutide 2.4 mg weekly or placebo, on top of standard CV care.

Results

Endpoint	Semaglutide	Placebo	Effect
MACE (3-point)	6.5%	8.0%	20% relative 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 52 wk	−9.4%	−0.9%	−8.5% difference

Median follow-up 39.8 months. MACE benefit emerged early (within 6 months) and persisted.

Mechanism beyond weight loss

The CV benefit appears larger than would be predicted from weight loss alone. Proposed mechanisms: direct GLP-1 effects in vascular endothelium and myocardium, reduced systemic inflammation, improved insulin sensitivity, blood pressure reduction.

Regulatory and coverage implications

March 2024: FDA approved Wegovy for cardiovascular event reduction in adults with BMI ≥27 + established CVD. First weight-management drug ever approved for a CV outcome.
April 2026: CMS expanded Part D coverage for Wegovy under SELECT-aligned indication.
Commercial plans: increasingly covering Wegovy under PA criteria mirroring SELECT enrollment.

What "established CVD" means

SELECT enrolled patients with any of: prior MI, prior ischemic or hemorrhagic stroke, or symptomatic PAD. Patients with diabetes were excluded.

What we don't yet know

Primary prevention in obesity without established CVD — not studied.
Tirzepatide CV outcomes — SURPASS-CVOT reads out 2026.
Long-term effects beyond 5 years — no GLP-1 CV trial has reported past 5-year follow-up in obesity without diabetes.

See our detailed cardiovascular conditions page.