Oral Semaglutide Reduces Heart Failure Events in Type 2 Diabetes

Heart failure (HF) is a major complication among individuals with type 2 diabetes (T2D), contributing to increased morbidity and mortality. Although the phase 3b SOUL (NCT03914326) trial previously demonstrated that oral semaglutide reduces major adverse cardiovascular events (MACE) in T2D, its impact on HF outcomes had not been fully characterized.¹

The secondary analysis of the study, published in JAMA Internal Medicine, now reveals that oral semaglutide may offer specific benefits in reducing HF events for patients with preexisting HF.

“Strengths of these analyses include standardized data collection and centrally adjudicated HF outcomes, minimizing bias and providing a deeper understanding of the effects of oral semaglutide across specific T2D individual phenotypes,” wrote the researchers of the study.

The SOUL study is a long-term clinical trial designed to evaluate whether the oral T2D medication semaglutide can improve heart health.² Participants are randomly assigned to receive either semaglutide tablets or a placebo and must take one tablet daily on an empty stomach, avoiding food or drink for at least 30 minutes afterward. The study spans approximately 3.5 to 5 years and includes up to 25 clinic visits and one phone call with the study doctor. Women who are pregnant, breastfeeding, or planning pregnancy are not eligible to participate.

This secondary analysis included 9650 participants from the SOUL randomized clinical trial, conducted at 444 centers across 33 countries.¹ Participants were adults with T2D and established atherosclerotic cardiovascular disease or chronic kidney disease. Enrollment occurred from June 17, 2019, to March 24, 2021, with a mean (SD) follow-up of 47.5 (10.9) months.

Participants were stratified by baseline HF status: 23.1% had a history of HF, including preserved ejection fraction (10.3%), reduced ejection fraction (6.1%), or unknown subtype (6.7%).

Patients received once-daily oral semaglutide or placebo in addition to standard-of-care therapy. The prespecified primary outcome for this analysis was a composite HF end point, defined as time to first HF hospitalization, urgent HF visit, or cardiovascular death. Secondary outcomes included MACE and safety assessments, particularly serious adverse events.

Among participants with HF at baseline, oral semaglutide significantly reduced the risk of the composite HF outcome compared with placebo (HR, 0.78; 95% CI, 0.63-0.96). When analyzed by HF subtype, the risk reduction was more pronounced in those with preserved ejection fraction (HR, 0.59; 95% CI, 0.39-0.86) but not statistically significant in those with reduced ejection fraction (HR, 0.98; 95% CI, 0.70-1.38).

Conversely, participants without baseline HF experienced no meaningful risk reduction with oral semaglutide for HF events (HR, 1.01; 95% CI, 0.84-1.20; P for interaction = .06). For MACE, oral semaglutide demonstrated consistent benefit regardless of HF history: HR 0.83 (95% CI, 0.68-1.01) in patients with HF and HR 0.86 (95% CI, 0.75-0.98) in those without HF (P for interaction = .77).

Safety outcomes were comparable between groups. Among participants with HF, serious adverse events occurred in 53.8% of those on oral semaglutide vs 57.1% of those receiving placebo, supporting a favorable safety profile.

However, the researchers acknowledged limitations. This analysis is limited by its post hoc nature, although outcomes were prespecified. The trial was not powered to detect subtype-specific HF outcomes, particularly in reduced ejection fraction. Additionally, participants were largely on guideline-directed background therapy, which may limit generalizability to broader populations.

Despite these limitations, the researchers believe that the study suggests that oral semaglutide provides a meaningful reduction in HF events among people with T2D with preexisting HF, particularly those with preserved ejection fraction, without increasing serious adverse events. For patients without HF at baseline, semaglutide did not alter HF risk. These findings reinforce the potential of oral semaglutide as a targeted therapy to reduce HF burden in high-risk T2D populations.

“In this secondary analysis of the SOUL randomized clinical trial, among individuals with T2D, atherosclerotic [cardiovascular] disease, and/or chronic kidney disease, a reduction of HF events was observed with use of oral semaglutide compared with placebo in those with a history of HF, without increasing the risk of serious adverse events,” wrote the researchers.

References

1. 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

2. A heart disease study of semaglutide in patients with type 2 diabetes (SOUL). NIH. Last updated December 11, 2025. Accessed February 13, 2026. https://clinicaltrials.gov/study/NCT03914326