FDA Approves Oral Semaglutide (Rybelsus) for CV Risk Reduction in Type 2 Diabetes

The US Food and Drug Administration (FDA) has approved oral semaglutide 7 mg and 14 mg (Rybelsus) for cardiovascular (CV) risk reduction in patients with type 2 diabetes (T2D) who are at high risk, irrespective of prior CV events.1

Announced by parent company Novo Nordisk on October 17, 2025, the approval is a direct result of positive results from the SOUL trial, a multicenter, international, randomized, double-blind, placebo-controlled, parallel-group phase 3b trial. Initiated in 2019, the trial also included a mean follow-up of 4 years.1

Initially approved in 2019 to improve glycemic control for adults with T2D, this oral semaglutide dose is now the only GLP-1 medication available for reducing risk of major adverse cardiovascular events (MACEs). It is administered once daily in either a 7 mg or 14 mg dose. It is prescribed in conjunction with diet and exercise to improve blood sugar in adults with T2D and to reduce MACE risk, including heart attack, stroke, or death.1

“Even in the absence of a previous heart attack or stroke, adults with [T2D] face an increased risk of cardiovascular events, underscoring the need for therapies that go beyond managing blood sugar,” John Buse, MD, PhD, distinguished professor of medicine, director of the UNC Diabetes Care Center, and Steering Committee Co-Chair of the SOUL trial, said in a statement. “Having an oral GLP-1 therapy to help improve glycemic control was an innovation in and of itself. 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.”1

The SOUL trial enrolled patients ≥50 years diagnosed with T2D who had an HbA1c of 6.5%-10% (47-86 mmol/mol). Additionally, patients were required to have at least one from among coronary heart disease, cerebrovascular disease, symptomatic peripheral artery disease, and chronic kidney disease. Patients with myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischemic attack, or heart failure classified as New York Heart Association Class IV were excluded.2

The 9650 patients enrolled in the trial were randomly assigned in a 1:1 ratio to either oral semaglutide or placebo. Both groups received 1 tablet daily for 3.5-5 years; the semaglutide group was prescribed increasing doses while placebo remained consistent throughout. The primary endpoint was time to first occurrence of MACEs.2

Ultimately, oral semaglutide 14 mg demonstrated a significant 14% relative reduction in MACE risk after 4 years, with a 2% reduction at 3 years, compared to placebo. MACEs occurred in 579/4825 participants (12%) in the semaglutide group and 668/4825 (13.8%) in placebo recipients (hazard ratio [HR], 0.86; 95% CI, 0.77-0.96; P = .006). Additionally, oral semaglutide 14 mg demonstrated a significant 14% relative risk reduction at 4 years.1

“As the only FDA-approved GLP-1 therapy in a pill, now recognized for its proven cardiovascular benefits, a new benchmark has been set for future oral innovations,” Dave Moore, executive vice president, US Operations of Novo Nordisk Inc, said in a statement. “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

References

1. Novo Nordisk, Inc. 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. PR Newswire. October 17, 2025. Accessed October 20, 2025. https://www.prnewswire.com/news-releases/fda-approves-novo-nordisks-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-302588005.html

2. Novo Nordisk, Inc. A Hear Disease Study of Semaglutide in Patients With Type 2 Diabetes (SOUL). ClinicalTrials.gov identifier: NCT03914326. Updated September 24, 2025. Accessed October 20, 2025. https://clinicaltrials.gov/study/NCT03914326