Semaglutide may lower CVD risk regardless of how much weight is lost

By Sasha Ellery BM BCh

Weekly injection of semaglutide reduces the risk of major adverse cardiovascular events (MACE) regardless of how much weight is lost while taking the medication, according to a new analysis of the SELECT trial. This finding, say the study authors, suggests that semaglutide and similar glucagon-like peptide-1 (GLP-1) receptor agonists should be viewed as disease-modifying treatments rather than solely medications for glycaemic control or weight loss.

The industry-funded SELECT trial, published in 2023, found that, compared with placebo, semaglutide reduced the risk of MACE (a composite of cardiovascular death, nonfatal heart attack or nonfatal stroke) by 20% in 17,604 adults aged 45 years or older who had a body mass index of at least 27 kg/m² and established atherosclerotic cardiovascular disease but no history of diabetes. Participants had been randomly assigned to weekly injections of semaglutide 2.4 mg or placebo.

In the new analysis, researchers found that this reduction in MACE was similar regardless of participants’ weight at the start of the trial, with those with the lowest BMI having similar benefits to those with the highest BMIs. These benefits were also largely independent of how much weight was lost during the first 20 weeks of the trial.

The researchers did, however, find that reductions in  waist circumference – reflecting central or visceral fat  loss – were associated with lower MACE risk over two years. However, mediation analysis suggested that waist circumference reduction accounted for no more than 33% of the MACE effect.

Commenting on the analysis, Professor Gerald Watts, Director of the Cardiometabolic Service at the Royal Perth Hospital and Winthrop Professor of Cardiometabolic Medicine at the University of Western Australia, Perth, said that central fat referred principally to the accumulation of adipose tissue around the waist, which reflected locations under the skin and, more importantly, in the peritoneum.

‘This intraperitoneal fat is metabolically very active and drives fatty acid delivery in the portal vein directly to the liver, where it leads to a wide spectrum of factors that lead to inflammation, dyslipidaemia, insulin resistance and diabetes, hypertension and coagulation disorders. These collectively cause atherosclerotic cardiovascular disease.’

Professor Watts said most of semaglutide’s benefit was intriguingly independent of weight loss. ‘This demonstrates that the drug has effects that go beyond the reduction of adipose tissue, or so-called pleiotropic effects.’ He added that mechanisms underlying such an effect might include improvements in inflammation, oxidative stress and endothelial function via direct activation  of GLP-1 receptors in the arterial wall, but this needed further investigation.

Although Professor Watts thought the results of the analysis were interesting, he said further data were still needed.

‘Mediation analyses are subject to error, and they would not be conclusive unless confirmed in other trials. Thinking about other potential implications, the findings could suggest that GLP-1 receptor agonists could be used to treat people with coronary disease who are not overweight, to directly reduce arterial inflammation and the development of atherosclerosis … but one would really need to test this hypothesis in a dedicated clinical outcomes trial.’

Lancet 2025; https://doi.org/10.1016/ S0140-6736(25)01375-3.