Analysis of the SELECT trial—assessing the cardiovascular impact of the diabetes and anti-obesity medication semaglutide (Wegovy, Novo Nordisk)—has found that the use of the drug significantly reduced the risk of major adverse cardiovascular events (MACE) regardless of the amount of weight individuals lost.
Findings of the prespecified analysis of the trial, published in The Lancet, suggest that semaglutide and possibly other glucagon-like peptide-1 receptor agonists (GLP-1Ras) should be reconceptualised as disease-modifying treatments rather than solely medications for glycaemic control or weight loss, the study’s authors have suggested.
Results of the SELECT trial, which originally studied over 17,000 adults with heart disease and a body mass index (BMI) ≥27kg/m², comparing semaglutide to placebo, demonstrated that that those taking the drug for more than three years had a 20% lower risk of heart attack, stroke or death due to cardiovascular disease and lost an average of 9.4% of their body weight.
In their latest study, the researchers found that the reduction in MACE was similar regardless of a participants’ weight at the start of the trial—with those only marginally classed as overweight (BMI of 27kg/m2) seeing similar benefits to those with a much higher BMI. Greater waist circumference reduction at 20 months was associated with a lower subsequent MACE risk, they reported, which accounted for an estimated 33% of the observed benefit of the drug.
“These findings suggest that the cardioprotective effects of semaglutide extend beyond its impact on adiposity, with important implications for clinical practice and understanding of the mechanisms responsible for the benefits from GLP1-Ras,” John Deanfield (University College London, London, UK) and colleagues write in their Lancet paper detailing the results.
Several potential mechanisms may explain the cardiovascular benefit of semaglutide beyond adiposity reduction, the study’s authors suggest, including effects on endothelial function and other atherosclerotic pathways, modulation of inflammation, or effects on blood pressure control, for example.
“These pleiotropic effects of GLP-1Ras on multiple organ systems indicate a complex network of beneficial mechanisms that might be independent of adipose tissue reductions reflected by weight or waist circumference change,” the authors write. “Furthermore, adipose tissue biology undoubtedly changes before the mass of adipose tissue is measurably reduced, and this may in part mediate the earliest effects of semaglutide on MACE.”
The temporal dissociation between weight loss and MACE reduction observed in our study supports the hypothesis that these and other mechanisms may play a key role in vascular protection, the authors add.
“This work has implications for how semaglutide is used in clinical practice,” Deanfield said of the findings. “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.”
“At the same time, the benefits need to be weighed against potential side effects. Investigations of side effects become especially important given the broad range of people this medicine and others like it could help.”
The authors of the study note some limitations, including the predominantly white male population, and that analysis of MACE outcomes according to post-randomisation changes in weight or waist circumference within the treatment groups is subject to confounding and therefore cannot prove causation or define mechanisms.
