FDA Approves Oral Semaglutide for Risk of MACE for Patients With Diabetes

The FDA approved semaglutide (Rybelsus) tablets, the only oral glucagon-like peptide-1 medication, for reducing the risk of major adverse cardiovascular events (MACE), including cardiovascular (CV) death, heart attack, or stroke for patients with type 2 diabetes (T2D) at high risk for these events, even if they have had a prior CV event.¹

"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," John B. Buse, MD, PhD, distinguished professor of medicine and director of the University of North Carolina Diabetes Care Center, said in a news release.¹ "Having an oral GLP-1 therapy to help improve glycemic 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."

The approval was based on results from the SOUL (NCT03914326) trial, which examined the oral version of the semaglutide molecule. In the study, investigators aimed to determine if semaglutide had a positive effect on heart disease, with patients receiving either the oral drug or a placebo tablet. The study is expected to last 3.5 to 5 years, and patients will have up to 25 clinic visits and 1 phone call with the study physician.²

The primary end points included the number of patients who experienced a first MACE, including CV death, nonfatal myocardial infarction, and nonfatal stroke, up to week 265. The secondary confirmatory outcomes included major kidney disease events, including renal death, onset of persistent reduction in eGFR of 50% or more, onset of persistent eGFR of less than 15 mL/Min/1.73m², and initiation of chronic renal replacement therapy, at week 265.²

From June 2019 to March 2021, 9650 patients were included in the study, with 4825 being randomly receiving semaglutide or the placebo. The mean age was 66 years, and 28.9% were women, according to the study authors. Most patients had a history of CV disease, and 42.4% had a history of chronic kidney disease. Further, 26.9% of patients were receiving SGLT2 inhibitors at baseline.³

For the primary outcome, approximately 12% of patients, or 3.1 events per 100 person-years, experienced MACE in the oral semaglutide group compared with 13.8%, or 3.7 events per 100 person-years, in the placebo group. The absolute risk reduction was 2 percentage points. Approximately 6.2% and 6.6% died from cardiovascular causes, 4% and 5.2% experienced nonfatal myocardial infarction, and 3% and 3.3% experienced a nonfatal stroke, respectively. For the secondary outcome in relation to major kidney disease, an event occurred in 8.4% of patients, or 2.1 events per 100 person-years, in the semaglutide group compared with 9%, or 2.4 events per 100 person-years. Among the components, 28.8% were kidney related, and 71.2% were deaths from cardiovascular causes.³

As for safety, the profile was consistent with previous trials, with the most common serious adverse events including cardiac disorders and infections/infestations.¹

"As the only FDA-approved GLP-1 therapy in a pill, now recognized for its proven cardiovascular benefits, a new benchmark has been set for future oral innovations," Dave Moore, executive vice president of US Operations at Novo Nordisk, said in the news release.¹ "The semaglutide molecule has consistently demonstrated robust outcomes across multiple, large-scale trials, further reinforcing the already established cardiovascular profile it delivers for patients."

READ MORE: Diabetes Resource Center

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REFERENCES

1. FDA approves Novo Nordisk’s oral semaglutide for cardiovascular (CV) risk reduction in adults with type 2 diabetes who are at high risk, including those who have not had a prior CV event. News release. Novo Nordisk. October 17, 2025. Accessed October 20, 2025. https://www.novonordisk-us.com/media/news-archive/news-details.html?id=916435

2. A heart disease study of semaglutide in patients with type 2 diabetes (SOUL). ClinicalTrials.gov identification: NCT03914326. September 24, 2025. Accessed October 20, 2025. https://clinicaltrials.gov/study/NCT03914326

3. McGuire DK, Marx N, Mulvagh SL, et al. Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes. N Engl J Med. 2025;392(20):2001-2012. doi:10.1056/NEJMoa2501006