Husain M, Birkenfeld AL, Donsmark M, et al. – Researchers conducted an event-driven, randomized, double-blind, placebo-controlled trial involving patients at high cardiovascular risk to determine the cardiovascular outcomes of oral semaglutide in patients with type 2 diabetes (T2D). First occurrence of a major adverse cardiovascular event was considered the primary outcome, and the study was designed to eliminate 80% excess cardiovascular risk vs placebo, with a noninferiority margin of 1.8 for the upper boundary of the 95% CI for the HR for the primary outcome. Study participants (mean age: 66 years) included over 3,100 patients who were randomized to receive either oral semaglutide or placebo. The median time in the trial was 15.9 months. In the oral semaglutide group (n = 1,591), 3.8% of patients experienced major adverse cardiovascular events, and in the placebo group (n = 1,592), 4.8%. In the oral semaglutide group, 0.9%, 2.3%, and 0.8% of patients died from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke, respectively; in the placebo group, 1.9%, 1.9%, and 1.0%, respectively. Death from any cause occurred in 1.4% in the oral semaglutide group and 2.8% in the placebo group. Gastrointestinal adverse events leading to discontinuation of oral semaglutide or placebo were more prevalent with oral semaglutide. Thus, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo in this trial involving patients with T2D.