Oral semaglutide 14 mg demonstrated superior reduction in risk of cardiovascular events in late-breaking SOUL trial presented at the American College of Cardiology

• SOUL study showed Rybelsus^® (semaglutide) tablets 14 mg reduced the risk of major adverse cardiovascular events (MACE) by 14% (ARR 2% absolute risk reduction at 3 years) vs placebo in adults with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) and/or chronic kidney disease (CKD)¹
• Oral semaglutide 14 mg demonstrated this reduction of risk on top of standards of cardiovascular (CV) and diabetes care
• Data simultaneously published today in The New England Journal of Medicine, and based on SOUL findings, Novo Nordisk submitted a label extension application for Rybelsus^® (semaglutide) tablets 14 mg for CV event risk reduction to the FDA

PLAINSBORO, N.J., March 29, 2025 /PRNewswire/ -- Novo Nordisk today presented the full results from the SOUL cardiovascular outcomes trial investigating the effects of Rybelsus^® (semaglutide) tablets 14 mg on reducing the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes and ASCVD and/or CKD.¹ These new data from the phase 3 trial were featured during a Late-Breaking Clinical Trial session at the American College of Cardiology's (ACC) Annual Scientific Session and Expo and simultaneously published today in The New England Journal of Medicine.

The randomized, double-blind, parallel-group, placebo-controlled, event-driven CV outcomes trial which enrolled 9,650 adults with type 2 diabetes and ASCVD and/or CKD, achieved its primary endpoint, with oral semaglutide 14 mg demonstrating a 14% reduction in risk of MACE (2% absolute risk reduction at 3 years) compared to placebo (579 vs 668 events; hazard ratio: 0.86 [0.77; 0.96]; P=0.0055). The primary endpoint was time from randomization to first occurrence of a major adverse CV event (a composite of CV death, nonfatal myocardial infarction or nonfatal stroke).^1,2

"The significant reduction in risk of composite endpoint of heart attack, stroke, or death seen in the SOUL trial in adults with type 2 diabetes highlights the cardiovascular impact of oral semaglutide in adult patients with cardiometabolic conditions such as type 2 diabetes and atherosclerotic cardiovascular disease and/or chronic kidney disease," said John B. Buse, MD, PhD, Distinguished Professor of Medicine, Director of UNC Diabetes Care Center, Steering Committee Co-Chair of the SOUL trial. "Given the cardiovascular outcomes seen in SOUL, the trial represents important data for a community who may need options that also address common and serious comorbidities of type 2 diabetes, like cardiovascular disease."

Cardiometabolic diseases span a wide range of conditions, including type 2 diabetes and cardiovascular disease.³ Overall, cardiovascular disease represents the leading cause of death globally.⁴ Having type 2 diabetes directly increases the risk of developing interconnected cardiometabolic diseases, while also contributing to the progression of other cardiovascular risk factors.^5,6 Nearly one in three adults with type 2 diabetes have cardiovascular disease (CVD).⁷   

"Novo Nordisk continues to evolve its leadership beyond any one therapy area, toward a broader spectrum of cardiometabolic diseases that explores the interconnectivity of these conditions to create better outcomes for patients," said Michael Radin, MD, Executive Medical Director, Diabetes Medical Affairs at Novo Nordisk, Inc. "The SOUL data reinforce the importance of looking beyond glycemic control to explore cardiovascular disease in patients with type 2 diabetes."

The overall safety profile of oral semaglutide 14 mg in SOUL was consistent with that seen in previous trials, and no new safety signals were observed. The incidence of serious adverse events (SAEs) was lower in participants receiving oral semaglutide 14 mg 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).¹

Serious adverse events were less common with oral semaglutide 14 mg (47.9%) than with placebo (50.3%), although there was a higher incidence of gastrointestinal disorders with oral semaglutide 14 mg (5.0% versus 4.4%). Adverse events leading to permanent treatment discontinuation were more common for oral semaglutide 14 mg than placebo (749 [15.5%] and 559 [11.6%], respectively), comprising mainly gastrointestinal disorders in both arms (310 [6.4%] and 98 [2.0%], respectively). Additionally, the placebo group had 96 cases (2.0%) of infections and infestations leading to treatment discontinuation (versus 63 [1.3%] with oral semaglutide 14 mg).^1,2

Based on data from the SOUL clinical trial, Novo Nordisk submitted a label extension application for Rybelsus^® (semaglutide) tablets 14 mg which has been accepted for review by the US Food & Drug Administration (FDA). A decision is anticipated in 2025.²

About SOUL 
SOUL was a multicenter, international, randomized, double-blind, parallel-group, placebo-controlled, event-driven phase 3 cardiovascular outcomes trial with 9,650 people enrolled. It was conducted to assess the effect of oral semaglutide 14 mg vs placebo on cardiovascular outcomes in adults with type 2 diabetes and ASCVD and/or CKD. SOUL included adults aged ≥50 years with type 2 diabetes and evidence of ASCVD (coronary artery disease [CAD], cerebrovascular disease, symptomatic peripheral arterial disease [PAD]) and/or CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2). The SOUL trial was initiated in 2019 with a total duration of 5 years and 2 months.

The key objective of the SOUL trial was to demonstrate that oral semaglutide 14 mg helps lower 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 ASCVD and/or CKD.⁸

About Rybelsus^® 
Rybelsus^® (semaglutide) tablets 7 mg and 14 mg is a once daily glucagon-like peptide-1 (GLP-1) receptor agonist indicated for adults with type 2 diabetes along with diet and exercise to improve glycemic control.⁹

Only Novo Nordisk manufactures FDA-approved semaglutide medicines, like Rybelsus^®. Given the vast amount of information on knock-off or compounded semaglutide being shared in the media, it is important for healthcare professionals and patients to have the clarity and confidence in knowing what they are using has undergone rigorous review for safety, effectiveness and quality. If the label doesn't say Rybelsus^®, it's not FDA-approved. Learn more about the responsible use of semaglutide-containing medicines and the significant safety and health risks associated with compounded or knock-off "semaglutide" at semaglutide.com. 

About Novo Nordisk
Novo Nordisk is a leading global healthcare company that's been making innovative medicines to help people with diabetes lead longer, healthier lives for more than 100 years. This heritage has given us experience and capabilities that also enable us to drive change to help people defeat other serious chronic diseases such as obesity, rare blood, and endocrine disorders. We remain steadfast in our conviction that the formula for lasting success is to stay focused, think long-term, and do business in a financially, socially, and environmentally responsible way. With U.S. headquarters in New Jersey and over ten manufacturing, R&D and business locations in eight states plus Washington DC, Novo Nordisk employs approximately 10,000 people throughout the country. For more information, visit novonordisk-us.com, Facebook, Instagram, and X. 

Contacts for further information: 

References

1. McGuire DK, Poulter NR, Pop-Busui R, et al. Oral Semaglutide Reduces Cardiovascular Events in People with Type 2 Diabetes with Atherosclerotic Cardiovascular and/or Chronic Kidney Disease: Primary Results From the SOUL Randomized Trial. Oral presentation presented at the American College of Cardiology Congress Scientific Session & Expo 2025; 29-31 March 2025; McCormick Place Convention Center, Chicago, US. Presentation 104-07.
2. Data on file. Novo Nordisk, Inc.; Plainsboro, NJ.
3. Reiter-Brennan C, Dzaye O, Davis D, et al. Comprehensive care models for cardiometabolic disease. Curr Cardiol Rep. 2021;23(3):22. Published 2021 Feb 24. doi:10.1007/s11886-021-01450-1.
4. World Health Organization. Cardiovascular diseases (cvds). Accessed February 28, 2025. https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)
5. Feng X (Snow), Farej R, Dean BB, et al. CKD prevalence among patients with and without type 2 diabetes: regional differences in the United States. Kidney Medicine. 2022;4(1):100385. doi:https://doi.org/10.1016/j.xkme.2021.09.003.
6. Jankowski J, Floege J, Fliser D, Böhm M, Marx N: Cardiovascular disease in chronic kidney disease: pathophysiological insights and therapeutic options. Circulation. 2021, 143:1157-72. 10.1161/CIRCULATIONAHA.120.050686.
7. Mosenzon O, Alguwaihes A, Leon JLA, et al. CAPTURE: a multinational, cross-sectional study of cardiovascular disease prevalence in adults with type 2 diabetes across 13 countries. Cardiovasc Diabetol. 2021;20:154.
8. ClinicalTrials.gov. A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes (SOUL). Available at: https://clinicaltrials.gov/ct2/show/NCT03914326 Last accessed: February 2025.
9. Rybelsus^® (semaglutide) tablets [package insert]. Plainsboro, NJ: Novo Nordisk Inc; 2024.

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