FDA approves Novo Nordisk’s oral semaglutide (Rybelsus) for CV risk reduction in T2DM adults

Novo Nordisk has received FDA approval for Rybelsus for reducing the risk of major adverse cardiovascular events (MACE) such as cardiovascular (CV) death, heart attack, or stroke in adults with type 2 diabetes who are at high risk for these events, whether they've had a prior CV event or not (primary and secondary prevention). Results of the SOUL trial reinforce the clinical profile of the semaglutide molecule, which has been studied across a variety of therapeutic areas.

"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," said Dr John B Buse, Distinguished Professor of Medicine, Director of the UNC Diabetes Care Center, and Steering Committee Co-Chair of the SOUL trial. "Having an oral GLP-1 therapy to help improve glycaemic 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."

This new indication makes Rybelsus the only oral GLP-1 medicine approved to reduce the risk of MACE in adults with type 2 diabetes who are at high risk for these events. It serves for both primary prevention (reducing the risk of major adverse cardiovascular events by preventing or managing risk factors in adults who are at high risk for these events) and secondary prevention (reducing the risk of another event in people who have had a serious CV event).

The primary objective of the phase 3b SOUL trial was to evaluate the effects of oral semaglutide 14mg, in addition to standard of care, on reducing the risk of MACE in adults with type 2 diabetes at high risk for major cardiovascular events. The primary endpoint of the study was the time to first occurrence of MACE (a 3-point composite of CV death, non-fatal myocardial infarction, or nonfatal stroke). MACE events occurred in 579/4825 participants (12.0%) of the semaglutide group and 668/4825 participants (13.8%) of the placebo group (HR 0.86; 95% CI, 0.77-0.96; p=0.006). Oral semaglutide 14 mg demonstrated a statistically significant 14% relative reduction in risk of MACE at four years (2% absolute risk reduction at three years) compared with placebo. These results add to the extensive body of randomised clinical trial and real-world evidence supporting semaglutide.

"As the only FDA-approved GLP-1 therapy in a pill, now recognised for its proven cardiovascular benefits, a new benchmark has been set for future oral innovations," said Dave Moore, Executive Vice President, US Operations of Novo Nordisk. "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 was consistent with that seen in previous trials, with safety data collection focused on serious adverse events, those of special interest, and those leading to discontinuation. The most common serious adverse events (SAEs) in the oral semaglutide 14mg and placebo groups were cardiac disorders (17.8% and 19.8%, respectively) and infections/infestations (15.0% and 16.5%, respectively). SAEs were less common with oral semaglutide 14mg (47.9%) than with placebo (50.3%), although there was a higher incidence of gastrointestinal disorders with oral semaglutide 14mg (5.0% versus 4.4%). Adverse events that led to permanent discontinuation of oral semaglutide or placebo occurred in 749 participants (15.5%) in the oral semaglutide group and in 559 participants (11.6%) in the placebo group. Such events were mainly gastrointestinal disorders as well as infections or infestations.

The FDA initially approved Rybelsus in 2019 as the first and only GLP-1 medicine in pill form, along with diet and exercise, to improve glycaemic control for adults with type 2 diabetes.

Separately, Novo Nordisk has also submitted a supplemental application in the US for a once-daily oral formulation of semaglutide under the trade name Wegovy for the treatment of obesity. A decision is expected later in 2025.