https://www.nejm.org/doi/full/10.1056/NEJMoa2501006
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Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes
Abstract
Background
The cardiovascular safety of oral semaglutide, a glucagon-like peptide 1 receptor agonist, has been established in persons with type 2 diabetes and high cardiovascular risk.
An assessment of the cardiovascular efficacy of oral semaglutide in persons with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both is needed.
Methods
In this double-blind, placebo-controlled, event-driven, superiority trial, we randomly assigned participants who were 50 years of age or older, had type 2 diabetes with a glycated hemoglobin level of 6.5 to 10.0%, and had known atherosclerotic cardiovascular disease, chronic kidney disease, or both to receive either once-daily oral semaglutide (maximal dose, 14 mg) or placebo, in addition to standard care.
The primary outcome was major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke), assessed in a time-to-first-event analysis. The confirmatory secondary outcomes included major kidney disease events (a five-point composite outcome).
Results
Among the 9650 participants who had undergone randomization, the mean (±SD) follow-up was 47.5±10.9 months, and the median follow-up was 49.5 months.
A primary-outcome event occurred in 579 of the 4825 participants (12.0%; incidence, 3.1 events per 100 person-years) in the oral semaglutide group, as compared with 668 of the 4825 participants (13.8%; incidence, 3.7 events per 100 person-years) in the placebo group (hazard ratio, 0.86; 95% confidence interval, 0.77 to 0.96; P=0.006).
The results for the confirmatory secondary outcomes did not differ significantly between the two groups.
The incidence of serious adverse events was 47.9% in the oral semaglutide group and 50.3% in the placebo group; the incidence of gastrointestinal disorders was 5.0% and 4.4%, respectively.
Conclusions
Among persons with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both, the use of oral semaglutide was associated with a significantly lower risk of major adverse cardiovascular events than placebo, without an increase in the incidence of serious adverse events.
Funded by Novo Nordisk; SOUL ClinicalTrials.gov number, NCT03914326.
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• Utdrag ur press release från Novo Nordisk
- Rybelsus® reduced major adverse cardiovascular events by 14% vs placebo in adults with type 2 diabetes and cardiovascular and/or chronic kidney disease in the SOUL cardiovascular outcomes trial1.
- Data were presented at the American College of Cardiology’s (ACC) Annual Scientific Session and Expo in Chicago, US, while simultaneously published today yesterday in New England Journal of Medicine2.
- Rybelsus®, the only approved oral GLP-1 medicine, demonstrated this risk reduction on top of standards of cardiovascular and diabetes care.
- Based on SOUL findings, Novo Nordisk submitted a label extension application for Rybelsus® for CV event risk reduction to the US FDA and EMA.
These new data from the phase 3b trial were featured during a late-breaking clinical trial session at the American College of Cardiology’s (ACC) Annual Scientific Session and Expo in Chicago, US and simultaneously published today in New England Journal of Medicine2.
The SOUL trial achieved its primary endpoint, demonstrating a 14% reduction in risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes and CVD and/or CKD when treated with Rybelsus® compared to placebo. Each component of MACE, being CV death, nonfatal myocardial infarction and nonfatal stroke, contributed to the risk reduction1.
“Heart attacks and strokes are the leading causes of disability and death for people with type 2 diabetes, and there is a need for new, patient-centric treatments to help manage this risk,” said Darren McGuire, MD, Distinguished Chair in Cardiovascular Science and Teaching Professor of Medicine at UT Southwestern, US, and SOUL steering committee co-chair. “The SOUL trial in adults with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) and/or CKD demonstrated significant reductions in the risk of major cardiovascular events including heart attack, stroke and CV death in those treated with oral semaglutide vs placebo. The proven cardiovascular benefit reflects a profound clinical impact for our patients who now have an oral option to improve health outcomes.”
Cardiometabolic diseases span a wide range of conditions, including cardiovascular and peripheral artery disease, type 2 diabetes and chronic kidney disease3. When combined, these conditions represent the leading cause of death globally4. Having type 2 diabetes directly increases the risk of developing interconnected cardiometabolic diseases, while also contributing to the progression of other cardiovascular risk factors5. Nearly one in three adults with type 2 diabetes have CVD6.
The overall safety profile of oral semaglutide in SOUL was consistent with that seen in previous semaglutide trials, and no new safety signals were observed. The incidence of serious adverse events (SAEs) was lower in participants receiving Rybelsus® than those receiving placebo, mostly due to the higher rate of cardiovascular events and infections in the placebo group. The most common SAEs were cardiac disorders (17.8% and 19.8%, respectively) and infections/infestations (15.0% and 16.5%, respectively) in the Rybelsus® and placebo arms1.
SOUL confirmed the well-established safety and tolerability profile of semaglutide supported by long-term safety data with more than 33 million patient years8.
Based on data from the SOUL clinical trial, Novo Nordisk submitted a label extension application for Rybelsus®, which has been accepted for review by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA. A decision is anticipated in 2025.
• About SOUL
SOUL was a multicentre, international, randomised, double-blind, parallel-group, placebo-controlled, phase 3 cardiovascular outcomes trial with 9,650 people enrolled.
It was conducted to assess the effect of oral semaglutide vs placebo on cardiovascular outcomes in people with type 2 diabetes and established CVD and/or CKD.
The SOUL trial was initiated in 2019. The key objective of SOUL was to demonstrate that oral semaglutide lowers the risk of major adverse cardiovascular events (a composite endpoint consisting of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) compared to placebo, both added to standard of care in patients with type 2 diabetes and established CVD and/or CKD9,10.
• About Rybelsus®
Rybelsus® (oral semaglutide) is a GLP-1 receptor agonist indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus to improve glycaemic control as an adjunct to diet and exercise11,12.
Rybelsus® is administered once daily and is approved for use in three therapeutic dosages: 3 mg, 7 mg and 14 mg13,14. Rybelsus® offers superior blood glucose lowering vs Januvia® and Jardiance®13,14, together with consistent weight reduction13-15 and reduction in cardiometabolic risk factors15.
Rybelsus® is currently commercially marketed in 45 countries. More than 2.1 million people with type 2 diabetes are currently being treated with Rybelsus® worldwide16.
• References
1. McGuire DK, et al. Oral presentation presented at the American College of Cardiology Congress Scientific Session & Expo 2025; 29–31 March 2025. Presentation 104-07.
2. McGuire DK., et al. N Engl J Med. 2025, New England Journal of Medicine: https://www.nejm.org/doi/full/10.1056/NEJMoa2501006
3. Reiter-Brennan C, et al. Curr Cardiol Rep. 2021;23:22.
4. World Health Organization [online]. Available at: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) Last accessed: February 2025.
5. Chakraborty S, et al. Clin Med Insights Endocrinol Diabetes. 2023;16:11795514231220780.
6. Mosenzon O, et al. Cardiovasc Diabetol. 2021;20:154
7. Marx N., et al. Circulation 2025: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.125.074545
8. Novo Nordisk data on file.
9. NCT03914326. Available at: https://clinicaltrials.gov/ct2/show/NCT03914326 Last accessed: February 2025.
10. McGuire DK, et al. Diabetes Obes Metab. 2023;25:1932–1941.
11. Rybelsus® (semaglutide) US PI. 2024 [online]. Available at: https://www.novo-pi.com/rybelsus.pdf Last accessed: March 2025.
12. Rybelsus® (semaglutide) SmPC. 2025 [online]. Available at: https://www.ema.europa.eu/en/documents/product-information/rybelsus-epar-product-information_en.pdf Last accessed: March 2025.
13. Rodbard HW, et al. Diabetes Care. 2019;42:2272–2281.
14. Rosenstock J, et al. JAMA. 2019;321:1466–1480.
15. Husain M, et al. N Engl J Med. 2019;381:841–851.
16. Novo Nordisk Data on File. IQVIA Ozempic and Rybelsus patient numbers March 2025.
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