The U.S. Food and Drug Administration (FDA) has approved Novo Nordisk’s oral semaglutide therapy Rybelsus to lower the risk of major adverse cardiovascular events (MACE) in adults with Type 2 diabetes who are at increased risk of such complications. The decision extends the cardiovascular indication previously granted to Novo’s injectable semaglutide products, Ozempic and Wegovy.
The expanded approval covers Rybelsus tablets in 7 mg and 14 mg doses for reducing the likelihood of cardiovascular death, heart attack, or stroke. This approval comes five weeks after the European Medicines Agency (EMA) granted a similar expansion for the same patient population.
Novo Nordisk stated that the FDA’s decision provides a new treatment option for patients who prefer an oral therapy over injectables. Dave Moore, head of Novo Nordisk’s U.S. operations, described the decision as a milestone for oral GLP-1 therapies, stating, “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.” Moore added that semaglutide has consistently shown strong results across multiple large-scale studies, reinforcing its cardiovascular efficacy profile.
The FDA’s approval was supported by results from a phase 3 clinical trial involving 9,650 adults with Type 2 diabetes and either established cardiovascular disease or chronic kidney disease. The trial’s primary objective was to measure the time to first occurrence of a MACE event, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
Results showed that patients taking the 14 mg dose of Rybelsus experienced a 14% reduction in the risk of MACE compared to those receiving a placebo. Over a four-year follow-up, MACE events occurred in 12% of patients in the Rybelsus group versus 13.8% in the placebo group.
Discontinuation due to adverse events was reported in 15.5% of participants taking Rybelsus and 11.6% of those on placebo. Most of these discontinuations were related to gastrointestinal side effects.
While Rybelsus remains less prominent than Novo Nordisk’s top-selling injectable products Ozempic and Wegovy, it generated 11.3 billion Danish kroner ($1.7 billion) in sales during the first half of this year. The drug initially received FDA approval in 2019 for adults with Type 2 diabetes who were not meeting their A1C targets with other treatments. In 2023, the agency expanded its use as a first-line treatment for the condition. Novo Nordisk is also evaluating Rybelsus in trials to assess its potential in lowering the risk of heart failure.
Ozempic and Wegovy obtained their MACE approvals in 2024 and 2020, respectively. Meanwhile, Eli Lilly, Novo’s main competitor in the GLP-1 market, has yet to receive a similar approval for its dual-action tirzepatide therapies. Lilly is testing its obesity drug Zepbound in the phase 3 Surmount-MMO study and recently presented phase 3 data showing Mounjaro’s non-inferiority to Trulicity in reducing cardiovascular risk. Despite analysts labeling the results as modest, Lilly plans to seek Mounjaro’s approval for MACE reduction by the end of the year.
The FDA’s latest decision positions Rybelsus as the first oral GLP-1 receptor agonist with an approved cardiovascular benefit, marking an expansion of therapeutic options for patients managing both diabetes and cardiovascular risk.
The FDA’s approval of Rybelsus for cardiovascular risk reduction has broader implications beyond diabetes management. It reflects a growing trend in regulatory strategy, where the FDA emphasizes treatments that address multiple comorbidities in chronic conditions. This aligns with global health priorities set by organizations such as the American Diabetes Association and the World Health Organization, both of which highlight cardiovascular disease as the leading cause of death in people with Type 2 diabetes.
For clinicians, this FDA milestone reinforces the importance of individualized therapy. Oral semaglutide may be especially beneficial for newly diagnosed patients or those hesitant to start injectable medications. Endocrinologists note that the convenience of oral dosing could lead to earlier intervention, better compliance, and ultimately fewer hospitalizations due to cardiovascular events.
