The US Food and Drug Administration (FDA) has approved a label expansion for Novo Nordisk’s oral semaglutide, marketed as Rybelsus.
The approval allows for the drug’s use to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes who are also at high risk for heart disease. This decision positions it not only as a treatment for blood sugar control but also as a preventive cardiovascular agent for a broad patient population.
Clinical Evidence
The FDA’s approval for cardiovascular risk reduction was based on the findings from the Phase IIIb SOUL trial (NCT03914326). The study was designed to evaluate the effects of a 14 mg dose of Rybelsus on cardiovascular outcomes.
The trial enrolled 9,650 adults with type 2 diabetes who were at high risk for major cardiovascular events. All participants continued to receive standard-of-care treatment, with one group also receiving Rybelsus and the other a placebo.
The study’s primary endpoint was the time to the first occurrence of a Major Adverse Cardiovascular Event (MACE), defined as a composite of three serious outcomes: cardiovascular death, non-fatal heart attack (myocardial infarction), or non-fatal stroke.
Over the course of the trial, MACE events occurred in 12% participants in the Rybelsus group, compared to 13.8% in the placebo group. In practical terms, this means that treatment with Rybelsus 14 mg demonstrated a statistically significant 14% relative reduction in the risk of experiencing a MACE compared to placebo at four years.
The SOUL trial also provided a comprehensive look at the safety profile of Rybelsus in this specific patient population. Overall, the safety data were found to be consistent with what has been observed in previous clinical trials for the drug.
Notably, the incidence of serious adverse events was lower in the Rybelsus group (47.9%) than in the placebo group (50.3%). The most common categories of SAEs in both groups were cardiac disorders and infections/infestations, which were reported less frequently in the Rybelsus group.
Furthermore, adverse events leading to permanent discontinuation of the study product were more common with Rybelsus (15.5%) than with placebo (11.6%). According to the data, these discontinuations were mainly attributable to gastrointestinal disorders, a known class effect for GLP-1 receptor agonists, as well as infections.
Obesity Landscape
The company markets several formulations of the semaglutide molecule, which now serve as the cornerstone of its strategy. For type 2 diabetes, this includes the injectable Ozempic and the oral Rybelsus. For weight management, it offers the higher-dose injectable Wegovy. The sales and popularity of Ozempic, along with its weight loss counterpart Wegovy (semaglutide), have allowed Novo Nordisk to generate DKK290.4 billion ($40.3 billion) in revenue in 2024.
This new cardiovascular indication for Rybelsus provides a strategic expansion, allowing the company to leverage the benefits of its GLP-1 platform across multiple therapeutic areas and formulations.
Novo Nordisk’s weight loss drugs, Wegovy (semaglutide) and Saxenda (liraglutide), raking in DKK65.1 billion ($9 billion) in sales in 2024. However, it has received stiff competition from Eli Lilly’s dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist Zepbound (tirzepatide), which generated $4.9 billion in sales in 2024.
The Danish company has made multiple moves to expand its diabetes, obesity, and cardiovascular offerings, including a $2.2 billion deal with Septerna to discover, develop, and commercialize oral small molecule medicines for these indications.
