FDA
Oral semaglutide approved for CV risk reduction
On October 17, 2025, FDA approved Rybelsus (semaglutide) for reducing risk of major adverse cardiovascular events (MACE) such as CV death, nonfatal MI, or nonfatal stroke in adults with type 2 diabetes who are at high risk for these events, whether they've had a prior CV event or not (primary and secondary prevention).
Efficacy
Approval of the new indication was based on results from the phase 3b SOUL trial (NCT03914326) that evaluated the effects of oral semaglutide 14 mg, in addition to standard of care, on reducing MACE risk in adults with type 2 diabetes at high risk for major CV events. The primary endpoint of the study was the time to first occurrence of MACE (a 3-point composite of CV death, non-fatal MI, or nonfatal stroke). MACE events occurred in 12.0% of the semaglutide group and 13.8% of the placebo group (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.77-0.96; p=0.006). Compared with placebo, oral semaglutide 14 mg demonstrated a statistically significant 14% relative reduction in risk of MACE at 4 years (2% absolute risk reduction at 3 years).
Safety
The overall safety profile of oral semaglutide 14 mg in the SOUL trial was consistent with that seen in previous trials. The most common serious adverse events (SAEs) in the oral semaglutide 14 mg and placebo groups were cardiac disorders (17.8% and 19.8%, respectively) and infections/infestations (15.0% and 16.5%, respectively). SAEs were less common with oral semaglutide 14 mg (47.9%) than with placebo (50.3%), although there was a higher incidence of GI disorders with oral semaglutide 14 mg (5.0% vs. 4.4%).
Sources:
Rybelsus (semaglutide) [package insert]. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/213051s024,s028s029lbl.pdf Revised October 2025. Accessed October 21, 2025.
FDA approves Novo Nordisk’s oral semaglutide for cardiovascular (CV) risk reduction in adults with type 2 diabetes who are at high risk, including those who have not had a prior CV event. [News release]. 2025. https://www.novonordisk-us.com/media/news-archive/news-details.html?id=916435