Subcutaneous glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to reduce risk of major adverse cardiac events (MACE) for patients with type 2 diabetes (T2DM) who have or are at high risk of cardiovascular disease, but the evaluation of cardiovascular efficacy of oral GLP-1 RAs has yet to be performed. This article reviews results from the SOUL (Semaglutide Cardiovascular Outcomes) trial, whose aim was to assess the cardiovascular benefit in oral semaglutide in high-risk individuals. SOUL was a randomized, double blind, parallel-group, placebo-controlled superiority trial that enrolled 9,650 adults with T2DM who had established atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or both, to receive a maximum daily dose of 14 mg oral semaglutide or placebo. The primary outcome in this study was a composite of time to first CV death, non-fatal MI, or non-fatal stroke. In prespecified secondary analyses, treatment groups were analyzed for an expanded list of CV, CKD, PAD, and HF outcomes. Over a median follow-up of 49.5 months, the risk for MACE was significantly lower in the oral semaglutide compared with the placebo group (HR 0.86; 95% CI, 0.77; 0.96; p = 0.006), and these results were consistent across subgroup analysis, including by sodium glucose co-transporter 2 inhibitor (SGLT2i) drug use. Oral semaglutide reduces the risk of MACE in high-risk patients with T2DM.
Keywords: Cardiovascular disease; Chronic kidney disease; GLP-1 receptor agonists; SGLT2 inhibitors; Semaglutide; Type 2 diabetes.
© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.