(P104) SEMAGLUTIDE AND CARDIOVASCULAR OUTCOMES IN PEOPLE WITH OVERWEIGHT OR OBESITY WHO DO NOT HAVE DIABETES

Background: Semaglutide, a long-acting agonist of the glucagon-like peptide-1 receptor, is approved for use in people with type 2 diabetes and overweight or obesity. It has been shown to reduce the risk of adverse cardiac events in those with type 2 diabetes. There is paucity of information on whether semaglutide can reduce cardiovascular (CV) risk associated with overweight and obesity in the absence of diabetes.

METHODS AND RESULTS: In a multicenter, randomized, double-blind, placebo-controlled event-driven superiority trial, we enrolled 17,604 participants ≥45-year-old with pre-existing CV disease and body mass index ≥27 kg/m2, but without diabetes. Participants were randomly assigned to receive once-weekly subcutaneous semaglutide 2.4 mg or placebo. The primary CV efficacy endpoint was any component of the composite of death from CV causes, non-fatal myocardial infarction, or non-fatal stroke in a time-to-first-event analysis. Confirmatory secondary endpoints, assessed in a time-to-first-event analyses and tested in hierarchical order, were death from CV causes, a heart failure composite of death from CV causes or hospitalization or urgent medical visit for heart failure, and death from any cause. Supportive secondary endpoints, also assessed in a time-to-first-event analyses but without control for multiplicity, included expanded CV composite endpoints, individual components of CV composite endpoints, a composite nephropathy endpoint, progression to diabetes, or progression to prediabetes as diagnosed by glycated hemoglobin levels. Changes from randomization to week-104 in body weight, glycated hemoglobin concentrations, and other CV risk factors were measured. The trial met its primary objective, with a 20% reduction (hazard ratio 0.80, 95% confidence interval: 0.72 – 0.90) in the primary endpoint by semaglutide (events occurred in 6.5% of participants) compared with placebo (events occurred in 8.0% of participants) The benefit occurred early and was concordant across subgroups and CV endpoints (Figure). Adverse events leading to permanent discontinuation of the trial product occurred in 1,461 participants (16.6%) in the semaglutide group and 718 participants (8.2%) in the placebo group (P < 0.001).

Conclusion: In people with pre-existing CV disease and overweight or obesity, but without diabetes, once-weekly subcutaneous semaglutide 2.4 mg was superior to placebo in reducing the incidence of major adverse CV events.