• Semaglutide improved many parameters and risk factors compared with placebo in the SELECT trial.
• The CV benefits of semaglutide could not be explained by any factor alone, including weight loss.

Weight loss alone does not explain all of the cardiovascular benefits observed with semaglutide 2.4 mg in the SELECT trial, according to an analysis published in the European Heart Journal.

“Several major trials have established that GLP-1 receptor agonists reduce serious cardiovascular disease, primarily in people with type 2 diabetes. SELECT was the first trial to show that these drugs can also lower cardiovascular disease in people who did not have diabetes,” Helen M. Colhoun, MD, FRCP, professor and AXA chair in medical informatics and life course epidemiology at the University of Edinburgh, Scotland, said in a press release. “In this study, we analyzed data from the trial to ascertain whether the reductions in known cardiovascular risk factors that we saw in the trial could fully account for the reduction in heart disease.”

The researchers analyzed data from 17,604 patients from SELECT (mean age, 62 years; 72% men), all of whom had overweight or obesity but none of whom had diabetes, to determine which of the following mediated the CV benefits seen in SELECT of semaglutide 2.4 mg (Wegovy, Novo Nordisk) over placebo: body weight, waist circumference, plasma high-sensitivity C-reactive protein, HbA1c, lipids, BP, estimated glomerular filtration rate and urine albumin-creatinine ratio.

During a mean follow-up of 39.8 months, semaglutide improved all potential mediators compared with placebo (P < .05 for all), Colhoun and colleagues found.

The estimates for percentage of mediation were largest for waist circumference (64%; 95% CI, 27.5%-179.6%), hsCRP (42.1%; 95% CI, 17.9%-110.5%), HbA1c (29%; 95% CI, 20.7% to 120.5%) and body weight (19.5%; 95% CI, 33% to 110.7%), but all potential mediators when analyzed individually had wide confidence intervals, the researchers wrote.

The researchers estimated the joint mediation for all potential mediators combined as 31.4% (95% CI, 30.1% to 143.6%) and as 46% (95% CI, 6% to 161%) when variables other than body weight and waist circumference were considered.

“Our analyses could not fully ascribe the effects of semaglutide on cardiovascular disease to known risk factors with any certainty,” Colhoun said in the release. “Whether we combine all risk factors together or look at some subsets of the risk factors, no more than half of the reduction in heart disease could be explained by the changes in these risk factors. These results suggest that semaglutide should be considered as a cardiovascular disease reduction drug and not just as a weight-loss drug. We don’t know how else semaglutide could be preventing heart disease, but many other mechanisms have been proposed. These include anti-inflammatory effects not fully captured by the risk factors measured in the trial, and other direct effects on heart muscle or on the lining of blood vessels. We need more research to fully explore other potential mechanisms of how semaglutide reduces cardiovascular disease.”