On Oct. 17, 2025, Novo Nordisk announced that the US Food and Drug Administration (FDA) has approved Rybelsus^®, the only oral GLP-1 medication available, for reducing the risk of major adverse cardiovascular events (MACE) such as cardiovascular (CV) death, heart attack, or 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). Results of the SOUL trial reinforce the clinical profile of the semaglutide molecule, which has been studied across a variety of therapeutic areas.

This new indication makes Rybelsus^® the only oral GLP-1 medicine approved to reduce the risk of MACE in adults with type 2 diabetes who are at high risk for these events. It serves for both primary prevention (reducing the risk of major adverse cardiovascular events by preventing or managing risk factors in adults who are at high risk for these events) and secondary prevention (reducing the risk of another event in people who have had a serious CV event). 

The primary objective of the phase 3b SOUL trial was to evaluate the effects of oral semaglutide 14 mg, in addition to standard of care, on reducing the risk of MACE in adults with type 2 diabetes at high risk for major cardiovascular events. The primary endpoint of the study was the time to first occurrence of MACE (a 3-point composite of CV death, non-fatal myocardial infarction, or nonfatal stroke). MACE events occurred in 579/4825 participants (12.0%) of the semaglutide group and 668/4825 participants (13.8%) of the placebo group (HR 0.86; 95% CI, 0.77-0.96; p=0.006). 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) compared with placebo. Thee results add to the extensive body of randomized clinical trial and real-world evidence supporting semaglutide.

The overall safety profile of oral semaglutide 14 mg in SOUL was consistent with that seen in previous trials, with safety data collection focused on serious adverse events, those of special interest, and those leading to discontinuation. 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 gastrointestinal disorders with oral semaglutide 14 mg (5.0% versus 4.4%). Adverse events that led to permanent discontinuation of oral semaglutide or placebo occurred in 749 participants (15.5%) in the oral semaglutide group and in 559 participants (11.6%) in the placebo group. Such events were mainly gastrointestinal disorders as well as infections or infestations.

The FDA initially approved Rybelsus^® in 2019 as the first and only GLP-1 medicine in pill form, along with diet and exercise, to improve glycemic control for adults with type 2 diabetes.