Semaglutide significantly reduced major adverse cardiovascular events in patients with overweight or obesity with cardiovascular disease but without diabetes, as per recent research study conducted by University College London.
In a trial, Patients aged 45 years or older with a BMI of at least 27 kg/m² were enrolled across 41 countries (804 sites) and randomly assigned (1:1) to receive once-weekly semaglutide 2.4 mg or placebo. The primary endpoint was the time to first major adverse cardiovascular event (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Measures of adiposity included body weight and waist circumference.
This analysis evaluated MACE risk occurring after 20 weeks based on adiposity changes during the first 20 weeks, and in a separate analysis, assessed all in-trial MACE in relation to adiposity changes over 104 weeks. The trial is registered at ClinicalTrials.gov (NCT03574597).
Researchers stated that In the SELECT trial, semaglutide was superior to placebo for MACE reduction at all levels of baseline weight or waist circumference from early in the study. We now show that early in-trial weight loss, however, was not related to the cardiovascular benefit after 20 weeks. By contrast, there was a linear relationship between waist circumference (a measure of central adiposity) and treatment effects of semaglutide.
Despite the association between the benefit of semaglutide on MACE and the magnitude of waist circumference decrease, this mediated or marked only 33% of the semaglutide treatment effect. Several potential mechanisms might explain the cardiovascular benefits of semaglutide on MACE beyond adiposity reduction. Direct effects on endothelial function and other atherosclerotic pathways have been demonstrated.
Our analyses based on changes in adiposity by week 20 and subsequent risk of MACE examined temporal relationships, but of necessity made no use of the earliest observed differences in risk of MACE across treatment groups. The additional analyses of associations between cumulative weight loss at week 104 and the risk of MACE benefit from using all the MACE endpoints and the greater precision in characterising individual cumulative weight changes, but cannot consider temporal relationships between the timing of changes in adiposity and the timing of MACE
Researchers further stated that our findings have substantial implications for both clinical practice and health-care policy. Most patients who are treated for cardiovascular disease have a BMI of at least 27 kg/m², suggesting that many patients may benefit from semaglutide to reduce adverse cardiovascular outcomes. The early cardiovascular benefits of semaglutide in SELECT were not related to weight change and only modestly related to waist circumference change. This is in keeping with studies of other drug classes and different GLP1-RAs, which have shown cardiovascular outcome benefit in association with little or no weight loss.
The study is published in The Lancet.
