The SELECT Trial: Semaglutide Cut Major Cardiovascular Events by 20% in People Without Diabetes

For years the central question about newer weight-management medicines was whether losing weight with a drug actually translates into fewer heart attacks and strokes. The SELECT trial, published in the New England Journal of Medicine in 2023 by A. Michael Lincoff and colleagues, was designed to answer exactly that for semaglutide, and it did so in a population that did not have diabetes. The headline result, a 20% relative reduction in major cardiovascular events, marked a shift in how this class of drugs is understood.

Semaglutide is a GLP-1 receptor agonist, a peptide that mimics the gut hormone glucagon-like peptide-1. At the 2.4 mg once-weekly dose it is used for weight management, while lower doses are used in type 2 diabetes. SELECT tested whether that weight-management dose could prevent cardiovascular events in people who were overweight or obese and already had established cardiovascular disease but did not have diabetes, isolating the question from glucose lowering.

The trial was large and rigorous: a double-blind, randomized, placebo-controlled study of 17,604 adults aged 45 or older with a body-mass index of 27 or higher and a history of prior heart attack, stroke, or peripheral artery disease. Participants received once-weekly subcutaneous semaglutide titrated to 2.4 mg or a matching placebo, on top of usual care, and were followed for a mean of roughly 40 months. The primary endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

A primary endpoint event occurred in 6.5% of participants assigned to semaglutide versus 8.0% assigned to placebo. That corresponds to a hazard ratio of 0.80 (95% confidence interval 0.72 to 0.90), a statistically significant 20% relative reduction in the risk of major adverse cardiovascular events (p<0.001). Because participants did not have diabetes, the finding pointed to a cardiovascular benefit not explained by glucose control alone.

Participants on semaglutide also lost weight, with a mean reduction of about 9.4% of body weight. That average is smaller than the reductions reported in some dedicated obesity trials, but it was sustained over years in a cardiovascular population. Subsequent analyses of the same trial have examined effects on progression to diabetes and other outcomes, but the prespecified cardiovascular endpoint is the central result.

An important nuance is that the trial does not settle how the benefit arises. The event reduction could stem from weight loss, from direct effects on blood vessels and inflammation, from improvements in blood pressure and lipids, or from a combination of these. The event curves for treatment and placebo began to separate relatively early, which some researchers have argued is difficult to attribute to weight change alone, but the mechanism remains an open scientific question.

More participants discontinued semaglutide than placebo because of adverse events, predominantly gastrointestinal, consistent with the known profile of the class. The trial population was also specific: older adults with pre-existing cardiovascular disease, and predominantly male and white participants, which limits how directly the findings apply to other groups, including people in primary prevention. Absolute risk reductions, while meaningful at a population level, were modest for any single individual.

SELECT was influential because it moved semaglutide from a weight and glucose medicine toward a cardiovascular-prevention framing, and it later supported a regulatory label expansion for reducing cardiovascular risk in this population. Even so, the study speaks to a defined high-risk group rather than to the general public, and it does not establish benefit in people without established heart disease. These are population-level research findings, not individual medical or dosing guidance.