On October 23, 2025, the U.S. Food and Drug Administration (FDA) expanded the label for Novo Nordisk’s oral semaglutide (Rybelsus®) to include reduction of major adverse cardiovascular events (MACE)—cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke—in adults with type 2 diabetes mellitus (T2D) and either established cardiovascular disease or high cardiovascular risk, irrespective of prior CV event history. This approval establishes oral semaglutide as the first oral GLP-1 receptor agonist with a cardiovascular indication for both primary and secondary prevention.
The decision rests on the phase 3 SOUL trial (NCT03914326), a double-blind, randomized, placebo-controlled outcomes study enrolling approximately 9,650 adults with T2D and high CV risk. Participants received oral semaglutide 14 mg daily or placebo atop standard-of-care glucose-lowering and CV risk management. The primary endpoint—time to first MACE—was reduced by 14% (HR 0.86; 95% CI 0.76–0.96; p=0.008) in the overall population, with consistent benefits in subgroups with and without prior CV events. Secondary endpoints, including CV death and all-cause mortality, showed directional improvements, though not all reached statistical significance.
Safety aligned with the known GLP-1 RA profile: gastrointestinal adverse events (nausea, vomiting, diarrhea) were most common but generally mild-to-moderate and transient. Discontinuation due to GI intolerance occurred in 8.2% of semaglutide-treated patients versus 2.1% on placebo. No new safety signals emerged; pancreatitis, medullary thyroid carcinoma, and retinopathy risks remain as class warnings. This approval broadens therapeutic access, offering an oral alternative to injectable GLP-1 RAs (e.g., subcutaneous semaglutide, dulaglutide) previously holding CV indications. Clinicians gain flexibility for patients preferring pills or with injection barriers, potentially improving adherence. The label emphasizes use as an adjunct to diet, exercise, and standard CV risk factor management; glycemic efficacy (HbA1c reduction ~1.0–1.3%) remains unchanged.
Novo Nordisk plans immediate U.S. commercial updates; global filings are underway. Analysts project incremental Rybelsus uptake in cardiology and primary care, reinforcing GLP-1 dominance in cardiorenal metabolic disease management. Long-term real-world registries will monitor adherence and outcomes in broader populations.
