SOUL: Oral Semaglutide Cuts MACE by 14% in People with Type 2 Diabetes

A tablet form of semaglutide was linked to a 14% reduction in major adverse cardiovascular events (MACE), including cardiovascular death, heart attack, or stroke, at an average follow-up of four years in high-risk type 2 diabetes (T2D), offering a potential alternative to the standard-of-care injections.1

SOUL, presented at the American College of Cardiology (ACC) 2025 Annual Scientific Sessions in Chicago, was the first trial to measure the cardiovascular benefit of an oral glucagon-like peptide-1 (GLP-1 ) receptor agonist. The trial’s patient population included those individuals with T2D and atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or both.

“This study gives us confidence that people who are resistant or reluctant to take injections can still have an option for clinical benefit with this medication in the form of a tablet,” said Darren K. McGuire, MD, a professor of medicine at UT Southwestern Medical Center and Parkland Health. “Whether you take it in tablet or injection, these drugs very rapidly reduce systemic inflammation.”

Mechanisms by which GLP-1s benefit cardiovascular health are still unknown, but anti-inflammatory activity could play a role. Guideline-directed injectable forms of semaglutide require multiple self-injections, but have established cardiovascular efficacy in people with high-risk T2D, including those with ASCVD and CKD. Although their benefit is known, the need for frequent injections can be a barrier for those with a fear of needles or those who cannot use injectable medications.

The US Food and Drug Administration (FDA) initially approved oral semaglutide, marketed under Rybelsus, in September 2019 for treating adults with T2D. In 2023, the FDA approved a label update for oral semaglutide to be used in first-line treatment of patients with T2D.

Oral semaglutide has established cardiovascular safety for people with T2D and high cardiovascular risk, but the formulation’s impact on cardiovascular outcomes has not been determined. The double-blind, placebo-controlled, event-driven, superiority SOUL trial recruited 9650 patients aged 50 years and older with T2D, ASCVD, and/or CKD from 450 medical centers in 44 countries—half received daily oral semaglutide and the other half received placebo with an average follow-up of 47.5 months.

Upon analysis, McGuire and colleagues identified a primary-outcome event in 579 of 4825 participants (12.0%; incidence, 3.1 events per 100 person-years) receiving oral semaglutide, compared with 668 of 4825 participants (13.8%; incidence, 3.7 events per 100 person-years) in the placebo group (hazard ratio [HR], 0.86; 95% CI, 0.77–0.96; P =.006).

Investigators pointed to the 26% reduction in the rate of non-fatal myocardial infarction among patients taking oral semaglutide as the primary driver of the benefit on the composite primary endpoint, followed by a 12% and 7% lower rate of non-fatal strokes and cardiovascular death, respectively. No significant difference was identified in kidney function-related outcomes.

Serious adverse events were reported in nearly half (47.9%) of the oral semaglutide group and more than half (50.3%) in the placebo group (P =.02). Gastrointestinal disorders, including nausea, diarrhea, constipation, and gas, were more frequent with oral semaglutide than placebo (5.0% vs. 4.4%).

Oral semaglutide’s benefit was consistent across most prespecified analyses, including those defined according to age, sex, body mass index (BMI), a history of cardiovascular or kidney disease, eGFR, and. Noting 26.9% of patients treated with sodium-glucose transport protein 2 (SGLT2) inhibitors at baseline, McGuire and colleagues highlighted the consistent benefit of oral semaglutide.

“There’s been a huge [open] question among clinicians about whether these drugs are complementary and whether we should use one or the other or both,” McGuire added. “The results showed no significant differences in outcomes between patients who took SGLT2 inhibitors, who were likely to have more advanced disease, and those who did not, suggesting that the drugs can be safely used together and are complementary in their ability to reduce cardiovascular risk.”

Following the positive data reported from SOUL, Novo Nordisk announced plans to file for regulatory approval of a label expansion for oral semaglutide as a therapy indicated for reducing MACE risk in adults with T2D and established CVD in both the United States and the European Union.

References

1. McGuire DK, Marx N, Mulvagh SL, et al. Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes. The New England Journal of Medicine. Published online March 29, 2025. doi: 10.1056/NEJMoa2501006

2. American College of Cardiology. Oral Semaglutide Reduces Cardiovascular Events by 14% at Four Years. Press Release. March 29, 2025. Accessed March 29, 2025.

3. Collins L, Costello RA. Glucagon-Like Peptide-1 Receptor Agonists. [Updated 2024 Feb 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551568/

4. Johnson V. Oral semaglutide reduces MACE risk in people with type 2 diabetes and CVD. HCP Live. October 22, 2024. Accessed March 29, 2025. https://www.hcplive.com/view/oral-semaglutide-reduces-mace-risk-type-2-diabetes-cvd.