EMA Approves Semaglutide as First GLP-1 RA for Cardiovascular, Stroke-Related Benefits

According to a new announcement, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has approved an update to semaglutide’s (Rybelsus; Novo Nordisk) label, allowing the glucagon-like peptide 1 receptor agonist (GLP-1 RA) to be used to reduce cardiovascular death, heart attack, and stroke. With the decision, it becomes the first GLP-1 RA approved in the EU for type 2 diabetes with a proven cardiovascular benefit.¹

Semaglutide, marketed as Ozempic in the United States and Rybelsus in Europe, became the first and only oral GLP-1 RA approved for the treatment of type 2 diabetes in 2019. This latest indication is based on data from the phase 3 SOUL trial (NCT03914326), where treatment with the GLP-1 RA led to reduced cardiovascular death, heart attack, and stroke by 14% versus placebo, when added to standard of care, in adults with type 2 diabetes at high cardiovascular risk.

"Heart problems are the leading cause of disability and death for people living with type 2 diabetes. Therefore, treatments that also address heart problems are key to improving not only health outcomes, but also quality of life – and this approval will help do just that," Emil Kongshøj Larsen, executive vice president, International Operations at Novo Nordisk, said in a statement.¹ "This milestone makes semaglutide the only oral GLP-1 RA with proven blood glucose and body weight reduction, as well as cardiovascular benefits."

Regulatory action in the U.S. is expected later this year on whether semaglutide will gain an expanded label to cover cardiovascular risk reduction. At the same time, Novo Nordisk has sought approval for a 25 mg once-daily oral version of semaglutide for adults with obesity or overweight who also have cardiovascular disease. A decision anticipated around year’s end could make Wegovy the first oral GLP-1 RA formally cleared for long-term weight management.

READ MORE: Real-World Data Points to Greater Impact of Semaglutide Over Tirzepatide in Reducing Heart Attack, Stroke Risk

The phase 3 SOUL trial, published in the New England Journal of Medicine, comprised 9650 patients aged 50 years or older who had type 2 diabetes with a glycated hemoglobin level of 6.5 to 10.0%, and known atherosclerotic cardiovascular disease, chronic kidney disease, or both. Patients received either once-daily oral semaglutide (maximum dose, 14 mg) or placebo, in addition to standard of care, over a mean follow-up of 47.5 (±10.9) months.²

In SOUL, a primary-outcome event, a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, occurred in 12.0% of those in the oral semaglutide group compared with 13.8% in the placebo group (HR, 0.86; 95% CI, 0.77-0.96; P = .006). Secondary outcomes, which included incidence of major kidney disease events, rated on a 5-point composite outcome, did not differ between the semaglutide group and those on placebo.

In addition to outperforming placebo on primary efficacy end points, semaglutide was considered safe and well tolerated, with slightly less serious adverse events found in the GLP-1 RA group (47.9%) than placebo (50.3%). The difference between the trial groups in the incidence of gallbladder disorders, retinal disorders, and malignant neoplasms, ranged from 0.4 to 0.8 percentage points. Adverse events (AEs) that led to treatment discontinuation occurred in 15.5% of those in the semaglutide group and 11.6% of those on placebo.

GLP-1 RAs like semaglutide have been studied more in stroke-related contexts in recent years. In July, a study published in JAMA Neurology showed that GLP-1 RAs were associated with significantly lower medication use, fewer symptoms and signs, an reduced the need for procedural interventions over a 1-year follow-up period in patients with idiopathic intracranial hypertension (IIH). The trial, which tested GLP-1s lixisenatide, albiglutide, dulaglutide, semaglutide, liraglutide, and exenatide, supported the use of these medications as a management strategy for IIH.³

REFERENCES
1. EU approval makes Novo Nordisk’s oral semaglutide the first and only oral GLP-1 RA to reduce cardiovascular death, heart attack and stroke. News release. Novo Nordisk. September 15, 2025. Accessed September 15, 2025. https://www.globenewswire.com/news-release/2025/09/15/3149955/0/en/EU-approval-makes-Novo-Nordisk-s-oral-semaglutide-the-first-and-only-oral-GLP-1-RA-to-reduce-cardiovascular-death-heart-attack-and-stroke.html
2. McGuire DK, Marx N, Mulvagh SL, et al. Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes. NEJM. 2025;392;2001-2012. doi:10.1056/NEJMoa2501006
3. Sioutas GS, Mualem W, Reavey-Cantwell J, et al. GLP-1 Receptor Agonists in Idiopathic Intracranial Hypertension. JAMA Neurol. Published July 14, 2025. doi:10.1001/jamaneurol.2025.2020