Oral Semaglutide Cuts Heart Failure Events in Diabetes Patients With Prior HF: SOUL Trial Analysis
USA: Oral semaglutide may lower the risk of heart failure–related events in people with type 2 diabetes who already have heart failure, without increasing serious adverse events, a secondary analysis of the SOUL randomized clinical trial published in JAMA Internal Medicine has revealed.
Heart failure is a frequent and serious complication of type 2 diabetes, contributing substantially to cardiovascular morbidity and mortality. While glucagon-like peptide-1 receptor agonists have demonstrated cardiovascular benefits, their effects on heart failure outcomes have remained less clear. The SOUL trial previously showed that oral semaglutide reduced major adverse cardiovascular events in people with type 2 diabetes and established cardiovascular or kidney disease.
In the new analysis, Rodica Pop-Busui from the Division of Endocrinology, Diabetes and Clinical Nutrition at Oregon Health & Science University, Portland, and colleagues examined whether these benefits extended specifically to heart failure outcomes, taking baseline heart failure status into account.
This prespecified secondary analysis drew on data from the double-blind, placebo-controlled, phase 3b SOUL trial, conducted across 444 centers in 33 countries. The study enrolled adults with type 2 diabetes and atherosclerotic cardiovascular disease and/or chronic kidney disease, who were randomized to receive once-daily oral semaglutide or placebo in addition to standard care. Participants were stratified according to whether they had a history of heart failure at baseline, and outcomes were analyzed over a mean follow-up of nearly four years.
The analysis revealed the following findings:
- Of 9,650 participants, just over 23% had heart failure at baseline.
- Oral semaglutide significantly reduced the risk of composite heart failure events in participants with pre-existing heart failure.
- No significant benefit was observed in participants without heart failure at baseline.
- Although the interaction was not statistically significant, the overall effect favored semaglutide in those with heart failure.
- The reduction in heart failure events was mainly seen in patients with preserved ejection fraction.
- No clear benefit was observed in patients with reduced ejection fraction.
- Oral semaglutide reduced major adverse cardiovascular events similarly in patients with and without heart failure.
- Serious adverse events occurred at comparable rates with semaglutide and placebo, indicating good safety.
The authors note that limitations inherent to secondary analyses, including smaller subgroup sizes and reliance on investigator-reported heart failure classification, should be considered when interpreting the results.
Overall, these findings support a potential role for oral semaglutide in reducing heart failure–related events in people with type 2 diabetes and established heart failure, particularly those with preserved ejection fraction, without compromising safety.
Reference:
Pop-Busui R, Rasmussen S, Deanfield JE, et al. Oral Semaglutide and Heart Failure Outcomes in Persons With Type 2 Diabetes: A Secondary Analysis of the SOUL Randomized Clinical Trial. JAMA Intern Med. Published online February 02, 2026. doi:10.1001/jamainternmed.2025.7774
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