In such patients, weekly injections of semaglutide lowered the incidence of adverse cardiovascular events.

In a previously published trial, weekly injections of the glucagon-like peptide-1 (GLP-1) agonist semaglutide lowered the incidence of major adverse cardiovascular (CV) events in patients with type 2 diabetes and known CV disease or CV risk factors (NEJM JW Cardiol Nov 2016 and N Engl J Med 2016; 375: 1834-1844). In this new industry-sponsored, randomised trial, researchers examined semaglutide’s CV effects in high-risk patients with obesity or overweight, but without diabetes.

The trial included about 18,000 patients with body mass index 27kg/m² or higher (mean BMI, 33kg/m²), glycated haemoglobin below 42mmol/mol (6.5%), mean HbA_1c, 40mmol/mol (5.8%), and histories of myocardial infarction, stroke or symptomatic peripheral arterial disease. Patients received either subcutaneously injected semaglutide (titrated up to 2.4mg weekly, if tolerated) or placebo. During average follow up of 40 months, these outcomes occurred:

• incidence of the primary outcome (i.e. myocardial infarction, stroke or CV-related death) was significantly lower with semaglutide than with placebo (6.5% vs 8.0%)
• each component of the primary outcome trended in favour of semaglutide
• weight loss was substantially greater with semaglutide than with placebo
• semaglutide recipients were significantly more likely than placebo recipients to withdraw from the trial due to adverse events (16.6% vs 8.2%) – gastrointestinal side effects accounted for this difference.

Comment: We now have compelling evidence that a GLP-1 agonist has a role in secondary prevention among patients with known CV disease who are overweight or obese but do not have diabetes. However, injectable semaglutide (Wegovy) is extra-ordinarily expensive (list price in the USA, about US$17,000 [A$25,300] annually), and about 70 patients like those in this trial would need to be treated for three years to prevent one major CV event. We do not know whether oral semaglutide would have a similar effect in this patient population. And finally, gastrointestinal side effects are problematic for a nontrivial minority of patients.

Allan S. Brett, MD, Clinical Professor of Medicine, University of Colorado School of Medicine, Aurora, USA.

Lincoff AM et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med 2023; 389: 2221-2232.

This summary is taken from the following Journal Watch titles: General Medicine, Cardiology, Ambulatory Medicine, Hospital Medicine.