Background
Obesity is an independent risk factor for major adverse cardiovascular events (MACE). While GLP-1 receptor agonists had previously demonstrated cardiovascular benefit in patients with type 2 diabetes (LEADER, SUSTAIN-6), it was unknown whether these benefits extended to patients without diabetes. SELECT was designed to answer this question in a high-risk non-diabetic population.
Methods
A phase 3b, double-blind, randomized, placebo-controlled, event-driven superiority trial at 804 sites in 41 countries. Participants were adults aged ≥45 years with BMI ≥27, established cardiovascular disease (prior MI, stroke, or peripheral arterial disease), and no current or prior type 2 diabetes.
Primary endpoint: first occurrence of MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke).
Key Findings
| Outcome | Semaglutide | Placebo | HR (95% CI) |
|---|---|---|---|
| Primary MACE | 6.5% | 8.0% | 0.80 (0.72–0.90) |
| Cardiovascular death | 2.5% | 3.0% | 0.85 (0.71–1.01) |
| Nonfatal MI | 3.7% | 4.7% | 0.72 (0.61–0.85) |
| Nonfatal stroke | 1.5% | 1.9% | 0.79 (0.62–1.01) |
| Mean weight loss | −9.4% | −0.9% | — |
Clinical Significance
SELECT demonstrated for the first time that a GLP-1 receptor agonist reduces cardiovascular events in people without diabetes — purely based on its cardiometabolic effects. The 20% relative risk reduction in MACE is clinically meaningful and supports a role for semaglutide beyond glycemic control.
The FDA subsequently approved a cardiovascular risk reduction indication for semaglutide (Wegovy) in March 2024, making it the first weight loss drug with a proven CV benefit label.
Limitations
- Generalizability: only patients with established CVD were enrolled
- Mechanism unclear: weight loss vs. direct vascular effects vs. metabolic improvements
- Long-term data beyond ~3 years not yet available