Oral Semaglutide Wins Approval to Reduce Risk of MACE in Adults with T2D at High Risk

The FDA has approval oral semaglutide (Rybelsus) to reduce the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes (T2D) who are at high risk, whether or not they have had a previous CV event, according to developer Novo Nordisk.¹

The only FDA-approved oral GLP-1 receptor agonist, semaglutide tablets (7 mg, 14 mg) now carries an indication for both both primary and secondary prevention of events that include CV death, nonfatal myocardial infarction (MI), or nonfatal stroke, the company stated.¹

In making its decision the FDA considered results from the phase 3b SOUL trial, which enrolled 9,650 participants with T2D at high CV risk.² The study was initiated in 2019 with a mean follow up of 4 years. The primary outcome was time-to-first occurrence of MACE). Oral semaglutide 14 mg added to standard therapy reduced the risk of MACE by 14% relative to placebo (hazard ratio [HR] 0.86; 95% CI, 0.77–0.96; P =.006). Event rates were 12.0% in the semaglutide group versus 13.8% in the placebo group, representing a 2% absolute risk reduction at 3 years.²

“Even in the absence of a previous heart attack or stroke, adults with type 2 diabetes face an increased risk of cardiovascular events, underscoring the need for therapies that go beyond managing blood sugar,” John B. Buse, MD, PhD, distinguished professor of medicine, director of the UNC Diabetes Care Center, and steering committee cochair of the SOUL trial, in a statement.¹ “Having an oral GLP-1 therapy to help improve glycemic control was an innovation in and of itself. This new indication ... marks even further advancement and showcases the versatility of semaglutide while expanding options for millions of people.”¹

Safety data from SOUL were consistent with previous trials. Serious adverse events occurred in 47.9% of participants receiving oral semaglutide versus 50.3% with placebo.² Cardiac disorders were reported in 17.8% versus 19.8%, and infections or infestations in 15.0% versus 16.5%, respectively. Gastrointestinal disorders were more common with semaglutide (5.0% vs. 4.4%), and adverse events leading to permanent discontinuation occurred in 15.5% of participants in the semaglutide group versus 11.6% in the placebo group, mainly gastrointestinal events or infections.³

"A new benchmark has been set for future oral innovations,” Dave Moore, Novo Nordisk EVP, US operations, said. “The semaglutide molecule has consistently demonstrated robust outcomes across multiple, large-scale trials, further reinforcing the already established cardiovascular profile it delivers for patients.”¹

Oral semaglutide was initially approved in 2019 to improve glycemic control in adults with T2D in combination with diet and exercise.⁴ Novo Nordisk is the sole manufacturer of FDA-approved semaglutide medicines and continues to caution patients and clinicians about unsafe compounded or counterfeit alternatives.

The company has also submitted a supplemental application for a once-daily oral semaglutide formulation for obesity management, with a regulatory decision expected later this year.

References

1. 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. Novo Nordisk. October 17, 2025. accessed October 20, 2025. https://www.novonordisk-us.com/media/news-archive/news-details.html?id=916435

2. Halsey G. Oral Semaglutide Lowers Risk of MACE 14% in High-Risk Adults: Final Phase 3 SOUL Trial Readout. Patient Care. March 31, 2025. https://www.patientcareonline.com/view/oral-semaglutide-lowers-risk-of-mace-14-in-high-risk-adults-final-phase-3-soul-trial-readout

3. McGuire DK, Marx N, Mulvagh SL, et al. Oral semaglutide and cardiovascular outcomes in high-risk type 2 diabetes. N Engl J Med. Published online March 29, 2025. doi:10.1056/NEJMoa2501006

4. Halsey G. FDA approves first oral GLP-1 receptor agonist for T2D. Patient Care. September 20, 2019. https://www.patientcareonline.com/view/fda-approves-first-oral-glp-1-receptor-agonist-t2d