Lancet analysis of SELECT finds cardiovascular benefit across adiposity levels

A prespecified analysis of the SELECT cardiovascular outcomes trial, published in The Lancet, found that semaglutide's protection against major heart problems held up across all levels of starting body weight and waist size, not just among the heaviest patients ^[1]. The finding adds new detail to the debate over whether GLP-1 drugs protect the heart mainly by shrinking body fat or through other biological pathways.

The analysis drew on 17,604 people enrolled in SELECT, all at least 45 years old, with a BMI of 27 or higher and existing cardiovascular disease but no diabetes, randomly assigned to once-weekly semaglutide 2.4 mg or placebo ^[1]. Researchers tracked major adverse cardiovascular events, a combined measure of cardiovascular death, non-fatal heart attack, and non-fatal stroke ^[1].

Among people taking semaglutide, those who started with lower body weight or a smaller waist still saw fewer cardiovascular events than heavier or larger-waisted participants on the drug, but the drug's overall benefit compared with placebo showed up at every starting weight and waist category ^[1]. In the semaglutide group, each 5 kg of lower starting body weight was tied to a 4% lower risk of a cardiovascular event (hazard ratio 0.96, p=0.001), and each 5 cm of smaller starting waist circumference showed the same 4% lower risk (hazard ratio 0.96, p=0.004) ^[1].

The placebo group told a different story. There, a smaller starting waist was linked to lower risk (hazard ratio 0.96, p=0.007), but starting body weight was not linked to risk at all (hazard ratio 0.99, p=0.28) ^[1]. Oddly, among placebo patients, losing weight during the trial was associated with a higher, not lower, risk of a cardiovascular event ^[1].

Within the semaglutide group, how much weight a person lost by week 20 did not predict their later cardiovascular risk. But a larger reduction in waist circumference by week 20, and again by week 104, was linked to lower risk of a cardiovascular event during the trial ^[1]. Using statistical modeling, the study authors estimated that about 33% of semaglutide's overall cardiovascular benefit could be explained by waist circumference reduction, after adjusting for changes in waist size over time (hazard ratio 0.86, 95% CI 0.77–0.97) ^[1].

The study authors concluded that semaglutide's heart protection was independent of how much a person weighed at the start or how much weight they lost, and only partly tied to waist circumference changes, pointing to some other mechanism of benefit beyond fat loss itself ^[1]. The trial was funded by Novo Nordisk, the maker of semaglutide ^[1].

Why it matters for patients

For people taking semaglutide (sold as Ozempic, Wegovy, or Rybelsus) for cardiovascular risk reduction, this analysis suggests the heart benefit is not limited to those who start heaviest or who lose the most weight ^[1]. Someone with a lower starting BMI, or someone whose weight loss is modest, may still see meaningful cardiovascular protection according to this data ^[1]. The finding also complicates a common assumption that GLP-1 drugs help the heart mainly by helping people shed pounds; the SELECT data suggest something else may be happening in the body, though the exact mechanism is not identified in this analysis ^[1].

The placebo-group finding, that weight loss without the drug was linked to higher cardiovascular risk, is a reminder that weight loss on its own is not interchangeable with drug treatment when it comes to heart outcomes in this population ^[1]. What that means for people who lose weight through diet, illness, or other means outside of semaglutide treatment is not addressed in this analysis.

What happens next

The analysis was published in The Lancet's November 8–14, 2025 issue ^[1]. The sources reviewed do not describe any planned follow-up studies or regulatory actions tied to this specific analysis, so what additional research may address the underlying mechanism is not yet known from the available material.