Semaglutide heart benefit holds across all weight and waist groups in SELECT analysis

A prespecified analysis of the SELECT trial reports that semaglutide's cardiovascular protection held across every baseline weight and waist-circumference group, and that only about a third of the benefit was explained by reductions in waist size. The analysis appears in The Lancet, dated 8–14 November 2025 (volume 406, issue 10516, pages 2257–2268), and was funded by Novo Nordisk ^[1].

SELECT enrolled 17,604 people aged 45 or older with a BMI of at least 27 kg/m² and established cardiovascular disease but without diabetes, at 804 sites in 41 countries. Participants were randomly assigned to once-weekly semaglutide 2.4 mg or placebo. The main outcome was time to a first major adverse cardiovascular event (MACE), a composite of cardiovascular death, non-fatal heart attack, or non-fatal stroke ^[1].

Within the semaglutide group, analyses for linear trend found that lower baseline bodyweight was linked to lower MACE incidence — an average 4% lower risk for every 5 kg lower bodyweight (hazard ratio 0.96, 95% CI 0.94–0.99; p=0.001). The same pattern held for waist circumference, with a 4% lower risk per 5 cm smaller waist (0.96, 0.93–0.99; p=0.004) ^[1].

In the placebo group the picture differed. Smaller baseline waist circumference was associated with lower MACE risk (0.96, 0.94–0.99; p=0.007), but baseline bodyweight was not (0.99, 0.97–1.01; p=0.28). Among placebo recipients, weight loss was "paradoxically associated with increased MACE risk," the authors wrote. The analysis does not explain why that pattern appeared ^[1].

When the researchers looked at changes over time in the semaglutide group, there was no linear trend linking weight loss at week 20 to later MACE risk. Greater waist reduction at week 20 was associated with lower subsequent MACE risk, and waist reduction by week 104 was associated with lower in-trial MACE risk. The authors estimate that 33% of the observed MACE benefit was mediated through waist circumference reduction (0.86, 95% CI 0.77–0.97 after adjustment for time-varying changes in waist circumference) ^[1].

The authors' interpretation states that "the cardioprotective effects of semaglutide were independent of baseline adiposity and weight loss and had only a small association with waist circumference, suggesting some mechanisms for benefit beyond adiposity reduction" ^[1].

Why it matters for patients

The finding speaks to a common question about these medicines: whether the heart benefit is mostly a side effect of weight loss, and whether people who lose less weight still gain anything. In SELECT, the reduction in MACE was consistent across all baseline weight and waist categories, so the benefit was not confined to participants who started out heaviest ^[1]. That does not mean every patient gets the same result, and these are group-level findings from one trial population, not individual predictions.

SELECT enrolled people who already had cardiovascular disease and did not have diabetes. Whether the same patterns apply to people without established heart disease, or to people with diabetes, has not been reported in this analysis ^[1].

The placebo-group finding — that weight loss tracked with higher MACE risk — is a reminder that weight change on its own can reflect other things happening in the body. The analysis does not offer an explanation, and it should not be read as evidence that losing weight is harmful ^[1].

Waist circumference, not just scale weight, was the adiposity measure most consistently tied to outcomes in this analysis, including in the mediation estimate ^[1]. How much any individual should read into their own waist measurement, or change how they track progress, is not addressed by the trial data.

The study was funded by Novo Nordisk, the maker of semaglutide, a detail relevant when weighing the findings ^[1]. No further milestones or follow-up analyses from this prespecified analysis have been disclosed.