CLINICAL QUESTION: Does oral semaglutide decrease major cardiovascular events in patients with type 2 diabetes and cardiovascular disease and/or chronic kidney disease?
BACKGROUND: Approximately 828 million adults have diabetes, with 90% having type 2. The injectable form of semaglutide has demonstrated cardiovascular safety and effectiveness in type 2 diabetics with atherosclerotic cardiovascular disease, chronic kidney disease, or both. Meanwhile, the oral form has not yet been fully studied for cardiovascular efficacy. This trial targeted individuals with known cardiovascular disease, representing about 32% of the diabetic population.
STUDY DESIGN: Double-blinded, placebo-controlled, event-driven, superiority trial
SETTING: 444 sites across 33 countries
SYNOPSIS: The Semaglutide Cardiovascular Outcomes (SOUL) Trial enrolled 9,650 participants from 33 countries between June 2019 and March 2021. Half of the participants received 14 mg of semaglutide daily (escalated from 3 mg), and the other half received a placebo. The primary outcome was major cardiovascular events—a three-point composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. In the semaglutide group, a primary outcome event occurred in 12% of participants, compared to 13.8% in the placebo group (hazard ratio [HR], 0.86; CI, 0.77 to 0.96). The absolute risk reduction for the semaglutide group compared to placebo was 2%, with a number needed to treat of 50. Semaglutide showed positive results for secondary outcomes. Statistical significance was not demonstrated for major kidney disease events. The overall findings align with trials evaluating injectable GLP-1s. Both groups experienced similar adverse events, but gastrointestinal issues and medication discontinuation were more common with semaglutide. Although the safety profile of oral GLP-1 medications has been established, this trial highlights their cardiovascular benefits.
BOTTOM LINE: Oral semaglutide lowers major adverse cardiovascular events in individuals with type 2 diabetes and cardiovascular disease, chronic kidney disease, or both.
CITATION: McGuire DK, et al. Oral semaglutide and cardiovascular outcomes in high-risk type 2 diabetes. N Engl J Med. 2025;392(20):2001-2012. doi: 10.1056/NEJMoa2501006.
Mr. Andree
Mr. Andree is a physician assistant at the Nebraska Medical Center and an adjunct assistant professor at the University of Nebraska Medical Center, both in Omaha, Neb.