In March 2024, the FDA approved Wegovy (semaglutide 2.4 mg) for an additional indication: reducing the risk of cardiovascular death, nonfatal heart attack, and nonfatal stroke in adults with obesity or overweight who already have established cardiovascular disease. This approval was based on the SELECT trial, which was the first large randomized trial to demonstrate cardiovascular benefit from a weight loss medication in people with obesity.

The finding changed the clinical framing of semaglutide from a weight loss drug to a cardiovascular intervention, a distinction that has significant implications for insurance coverage, clinical prescribing, and how patients and physicians think about treatment goals.

The SELECT Trial Design

The SELECT trial (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) enrolled 17,604 adults at 41 countries. Participants met specific criteria:

  • Age 45 or older
  • BMI 27 or higher
  • Established cardiovascular disease (prior MI, stroke, or peripheral arterial disease)
  • No diabetes at enrollment, this is a critical distinguishing feature

Participants received semaglutide 2.4 mg weekly or placebo. They were followed for a mean of 39.8 months (approximately 3.3 years). The primary endpoint was a composite of cardiovascular death, nonfatal MI, and nonfatal stroke.

What SELECT Found

Semaglutide reduced the primary cardiovascular endpoint by 20% compared to placebo (hazard ratio 0.80, 95% CI 0.72-0.90, p<0.001). In absolute terms, the event rate was 6.5% in the semaglutide group versus 8.0% in the placebo group over the study period.

Secondary endpoints also favored semaglutide:

  • Cardiovascular death: 15% reduction (not statistically significant individually)
  • Nonfatal heart attack: 28% reduction
  • Nonfatal stroke: 7% reduction (not statistically significant)
  • Hospitalization for heart failure: 18% reduction
  • Death from any cause: 19% reduction

The weight loss in SELECT averaged approximately 9% in the semaglutide group, less than the 14.9% in STEP-1, likely because this was an older population with cardiovascular disease using additional medications that may have attenuated weight loss.

Why the Benefit May Not Be Purely From Weight Loss

Researchers expected that cardiovascular benefit from a weight loss drug would be proportional to weight loss. In SELECT, the cardiovascular benefit appeared regardless of the degree of weight loss achieved, even participants who lost less than 5% of body weight showed benefit, suggesting that semaglutide may have direct cardiovascular effects beyond its weight-reducing action.

Proposed mechanisms:

  • Anti-inflammatory effects of GLP-1 receptor activation
  • Direct effects on cardiac muscle and blood vessels through GLP-1 receptors in heart tissue
  • Reduced appetite reducing post-prandial lipemia (fat in the blood after eating)
  • Improved blood pressure and lipid profiles

This is an area of active research. The cardiovascular benefit from GLP-1 medications appears multifactorial.

Insurance Coverage Implications

The SELECT trial and subsequent FDA approval for cardiovascular risk reduction significantly strengthened the insurance coverage case for semaglutide. Prior to this approval, many payers excluded semaglutide specifically as a “weight loss drug.” After the cardiovascular indication, the argument that semaglutide is purely a weight loss medication became less tenable.

Coverage decisions are made by individual payers and have continued to evolve. As of early 2026, coverage remains inconsistent, but the clinical case for coverage has strengthened considerably.

Who Qualifies for the Cardiovascular Indication

The SELECT trial enrolled patients with BMI 27+ and established cardiovascular disease without diabetes. The FDA approval reflects this population. A patient who qualifies for the cardiovascular indication may have a stronger insurance coverage argument than one who qualifies only for the weight management indication.

Eligibility for this indication requires discussion with the prescribing clinician, who must document the qualifying cardiovascular history.

For the core weight loss evidence, see What Is Semaglutide and How Does It Work for Weight Loss?. For the cost implications of the expanded indication, see How Much Does Semaglutide Cost Without Insurance?.