Semaglutide CV Effects Appear Independent of Baseline Adiposity, Suggesting Disease-Modifying Potential

A prespecified analysis of the SELECT trial, published in The Lancet, reveals that semaglutide’s cardiovascular (CV) benefits in adults with overweight or obesity and established cardiovascular disease (CVD) extend well past its effects on body weight. This GLP-1 receptor agonist reduced major adverse cardiovascular events (MACE) by 20% compared with placebo, independently of baseline adiposity or the degree of weight loss achieved on treatment.

“This study shows that semaglutide markedly lowers the risk of heart attack, stroke, or cardiovascular death in patients carrying excess weight, even when those benefits cannot be explained by the amount of weight lost. These results confirm that we need to think differently about obesity—treating it as a root cause of cardiovascular disease, not simply a cosmetic issue,” John Deanfield, CBE, professor of cardiology at University College London, director of the National Institute for Cardiovascular Outcomes Research, and lead global investigator, and colleagues wrote.

CV Benefits Across Weight Categories

The SELECT trial enrolled 17,604 participants aged 45 years or older with a BMI of at least 27 kg/m² and established cardiovascular disease but without diabetes. Participants were randomly assigned to once-weekly semaglutide 2.4 mg or placebo for a median of 3.3 years. Semaglutide reduced the incidence of MACE—a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke—consistently across baseline BMI and waist circumference categories. Lower baseline weight and waist circumference predicted modestly lower cardiovascular risk, but semaglutide’s benefits did not vary by these measures, suggesting effectiveness across the adiposity spectrum.

Weight Loss Not Driving Cardiovascular Benefit

At 20 weeks, semaglutide-treated participants lost an average 6.4% body weight with a 5.0-cm decrease in waist circumference vs 0.8% and 1.1 cm reductions in the placebo arm. However, the magnitude of weight loss did not predict subsequent MACE risk among those receiving semaglutide. Patients who lost more than 5% body weight had similar cardiovascular outcomes to those with smaller weight loss, and even those who gained weight did not exhibit increased risk compared with placebo.

In contrast, waist circumference changes showed a modest association: greater reduction correlated with a lower risk of CV events (hazard ratio 0.91, 95% CI 0.84–0.98; P =.02). Mediation models estimated that waist circumference reduction accounted for only one-third of the treatment effect; adjusting for weight loss did not attenuate the benefits. This indicates semaglutide’s CV effects involve mechanisms beyond body fat reduction.

“Abdominal fat is more dangerous for our cardiovascular health than overall weight and therefore it is not surprising to see a link between reduction in waist size and cardiovascular benefit. However, this still leaves two thirds of the heart benefits of semaglutide unexplained," Deanfield said in a statement.

Clinical and Policy Implications

These findings challenge the narrative that GLP-1 receptor agonist CV benefit is solely attributable to weight loss. The authors advise reconsidering prescribing restrictions based on BMI thresholds or weight-loss targets, as the benefit extended across adiposity levels and weight-loss responses.

These findings reframe what we think this medication is doing. It is labelled as a weight loss jab but its benefits for the heart are not directly related to the amount of weight lost, Deanfield said. The findings have implications for clinical practice, he added. "You don’t have to lose a lot of weight and you don’t need a high BMI to gain cardiovascular benefit. If your aim is to reduce cardiovascular disease, restricting its use to a limited time only and for those with the highest BMIs doesn’t make sense."

The authors point out that SELECT’s large international cohort, rigorous adjudication of CV endpoints, and long follow-up strengthen confidence in these results. They also acknowledge the study's limitations, including a predominantly White and male cohort, which may limit generalizability. In addition, associations between adiposity change and event risk may be confounded or biased by reverse causality, as illness-related weight loss can occur in placebo patients.

"Our findings, combined with existing evidence, suggest that semaglutide and perhaps other GLP1-RAs should be reconceptualised as disease-modifying treatments rather than solely medications for glycaemic control or weight loss," they concluded.

References

1. Deanfield J, Lincoff AM, Kahn SE, et al. Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial. Lancet. 2025 Oct 22.
2. "Weight loss" drug helps heart regardless of amount of weight lost. News release. University College London. October 22, 2025. Accessed October 23, 2025. https://www.ucl.ac.uk/news/2025/oct/weight-loss-drug-helps-heart-regardless-amount-weight-lost