FDA Expands Semaglutide Label to Reduce Cardiovascular Risk in Adults With Type 2 Diabetes

The FDA has expanded the label for oral semaglutide (Rybelsus; Novo Nordisk) tablets 7 mg and 14 mg to reduce the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes who are at an elevated risk.1 This includes adults without a prior heart attack or stroke, according to a Novo Nordisk news release.

This decision makes oral semaglutide the first and only oral glucagon-like peptide 1 (GLP-1) receptor agonist with an approved cardiovascular risk reduction indication. The approval was based on data from the Novo Nordisk-funded phase 3b SOUL trial (NCT03914326), which showed a 14% relative risk reduction in 3-point MACE vs placebo when oral semaglutide 14 mg was added to standard therapies.2

John B. Buse, MD, PhD, professor of medicine at the University of North Carolina (UNC) School of Medicine, director of the UNC Diabetes Care Center, and steering committee co-chair of the SOUL trial, explained that adults with diabetes are at a heightened risk of cardiovascular events and that MACE prevention goes beyond just managing blood sugar.1

“Having an oral GLP-1 therapy to help improve glycemic control was an innovation in and of itself,” Buse said. “This new indication, based on the SOUL data, marks even further advancement and showcases the versatility of semaglutide while expanding options for millions of people.”

Changes to the Label

Semaglutide tablets are now approved to reduce MACE risk in adults with diabetes. | Image Credit: Pixelcrafts - stock.adobe.com

Oral semaglutide was initially approved in 2019 as the first and only GLP-1 medicine in pill form to improve glycemic control in adults with type 2 diabetes as an adjunct to diet and exercise.3 The SOUL outcomes trial was subsequently designed to determine whether the oral formulation confers the same kind of cardiovascular benefit observed with injectable semaglutide and other agents in the GLP-1 class.2

Findings From SOUL

SOUL researchers randomized 9650 adults with type 2 diabetes and established atherosclerotic cardiovascular disease, chronic kidney disease, or both to oral semaglutide—titrated to 14 mg—or placebo on top of standard therapies and followed participants for a median of 49.5 months. The primary end point was time to first 3-point MACE, including cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke.

MACE occurred in 12% of patients receiving oral semaglutide and 13.8% receiving placebo, marking a 14% relative risk reduction (HR, 0.86; 95% CI, 0.77-0.96; P = .006). In a prespecified 3-year analysis, the absolute risk reduction was 2 percentage points (number needed to treat, 50; 95% CI, 31-125). The benefit was generally consistent across prespecified subgroups, including by age, sex, baseline kidney function, and use of background medications.

Looking at individual components, nonfatal MI was 26% less likely with semaglutide than placebo (4.0% vs 5.2%). Nonfatal stroke and cardiovascular death also decreased by 12% (3% vs 3.3%) and 7% (6.2% vs 6.6%), respectively, but these differences were not statistically significant. Confirmatory kidney outcomes also did not reach statistical significance (8.4% vs 9%).

It’s important to note a few major limitations to the SOUL trial. Beyond it being fully supported by the drug manufacturer, women and non-White patients were largely excluded. Women made up less than 30% of each study arm, and less than a quarter of patients were Asian, less than 15% were Hispanic or Latino, less than 3% were Black, and less than 1% were American Indian, Alaska Native, Native Hawaiian, or Pacific Islander.

“Type 2 diabetes is more likely to affect Black persons than White persons, and the risk of cardiovascular disease and the associated mortality are higher among women than men,” the researchers said despite the lack of Black women included in the study.

Safety and Adverse Effects of Oral Semaglutide

Serious adverse events occurred in 47.9% of participants on oral semaglutide vs 50.3% with placebo. The most common were cardiac disorders (17.8% vs 19.8%) and infections/infestations (15.0% vs 16.5%).

Gastrointestinal disorders are typical for GLP-1 receptor agonists and were more frequent with oral semaglutide than placebo (5.0% vs 4.4%). Drug discontinuation due to adverse events occurred in 15.5% of patients on oral semaglutide vs 11.6% on placebo, driven largely by gastrointestinal symptoms. Acute pancreatitis occurred in 0.4% of each group. The researchers reported no new safety signals.

“The incidence of serious adverse events was lower among participants receiving oral semaglutide than among those receiving placebo, a difference that was mostly due to the higher incidence of cardiac disorders and infections or infestations in the placebo group,” the researchers said.

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. McGuire DK, Marx N, Mulvagh SL, et al. Oral semaglutide and cardiovascular outcomes in high-risk type 2 diabetes. N Engl J Med. 2025;392(20):2001-2012. doi:10.1056/NEJMoa2501006
3. Caffrey M. FDA approves Novo Nordisk's oral semaglutide, first GLP-1 in pill form. AJMC®. September 20, 2019. Accessed October 20, 2025. https://www.ajmc.com/view/fda-approves-novo-nordisks-oral-semaglutide-first-glp1-in-pill-form