Novo Nordisk announced that the U.S. Food and Drug Administration (FDA) has approved Rybelsus® (oral semaglutide) for a new indication — reducing the risk of major adverse cardiovascular events (MACE) such as cardiovascular (CV) death, heart attack, or stroke in adults with type 2 diabetes at high risk for such events, regardless of whether they have had a prior CV event. This approval makes Rybelsus® the only oral GLP-1 receptor agonist with proven cardiovascular benefits for both primary and secondary prevention.
The approval is based on the results of the SOUL phase 3b trial, which reinforced the cardiovascular efficacy of oral semaglutide, further validating the clinical potential of the semaglutide molecule — already used across multiple therapeutic areas.
Dr. John B. Buse, Distinguished Professor of Medicine and Director of the UNC Diabetes Care Center, and Steering Committee Co-Chair of the SOUL trial, highlighted the broader implications of this development:
“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. 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.”
The SOUL trial evaluated the efficacy of oral semaglutide 14 mg, in addition to standard care, on MACE risk reduction in adults with type 2 diabetes at high CV risk. The study’s primary endpoint — time to first MACE (a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke) — showed a statistically significant benefit. MACE occurred in 12.0% (579/4,825) of the semaglutide group versus 13.8% (668/4,825) in the placebo group, representing a 14% relative risk reduction (HR 0.86; 95% CI, 0.77–0.96; p=0.006). This corresponds to a 2% absolute risk reduction at 3 years, demonstrating durable cardiovascular protection.
Dave Moore, Executive Vice President, U.S. Operations, Novo Nordisk Inc., said:
“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. The semaglutide molecule has consistently demonstrated robust outcomes across multiple, large-scale trials, further reinforcing the already established cardiovascular profile it delivers for patients.”
The overall safety profile of oral semaglutide 14 mg in SOUL remained consistent with previous trials. Serious adverse events (SAEs) were slightly lower with semaglutide (47.9%) compared to placebo (50.3%), though gastrointestinal disorders were somewhat higher (5.0% vs. 4.4%). The most common SAEs included cardiac disorders and infections or infestations, while gastrointestinal issues were the leading cause of treatment discontinuation.
Initially approved in 2019 to improve glycemic control in adults with type 2 diabetes alongside diet and exercise, Rybelsus® now holds a unique position as the only oral GLP-1 therapy with demonstrated cardiovascular benefit.
Separately, Novo Nordisk has submitted a supplemental U.S. application for a once-daily oral version of Wegovy® (semaglutide) for obesity management, with an FDA decision expected later this year. The company continues to take strong action against unlawful compounded and counterfeit versions of semaglutide, emphasizing patient safety and access to authentic, FDA-approved Novo Nordisk medications.
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