Oral Semaglutide Reduces Heart Attack and Stroke Risk in High-Risk Type 2 Diabetes Patients

This was a double-blind, placebo-controlled, event-driven, superiority trial (SOUL). Participants aged 50+ with type 2 diabetes (HbA1c 6.5-10.0%) and established atherosclerotic cardiovascular disease, chronic kidney disease, or both were randomized to once-daily oral semaglutide (up to 14 mg) or placebo, added to standard care. The primary outcome was time to first major adverse cardiovascular event (MACE: cardiovascular death, nonfatal MI, or nonfatal stroke).

While injectable semaglutide had already shown cardiovascular benefits, this is the first large-scale trial proving the oral formulation also protects the heart. For the millions of patients who prefer pills over injections, this is a game-changer — they can now get cardiovascular protection from an oral GLP-1 drug. Published in the NEJM with nearly 10,000 participants and 4 years of follow-up, this represents the highest tier of clinical evidence.

The SOUL trial is a milestone in GLP-1 therapeutics. It establishes oral semaglutide not just as a glucose-lowering agent but as a cardiovascular protective therapy for high-risk diabetic patients. Combined with the SELECT trial (injectable semaglutide in obesity) and FLOW trial (semaglutide in kidney disease), this further cements GLP-1 receptor agonists as multi-benefit therapies spanning metabolic, cardiovascular, and potentially renal disease — now available in an oral formulation.

The confirmatory secondary outcome for kidney disease events was not significantly different, so oral semaglutide's renal benefits remain unproven. The trial population was predominantly high-risk with established cardiovascular or kidney disease, so results may not generalize to lower-risk patients. The maximum oral dose of 14 mg is lower than injectable semaglutide doses used for weight loss, and the cardiovascular benefit may be partially driven by weight loss and metabolic improvements rather than direct cardiac effects. The trial was funded by Novo Nordisk, the manufacturer.