Oral Semaglutide Reduces Heart Failure Events in Type 2 Diabetes Patients With Prior HF

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.

This secondary analysis included 9,650 participants from the SOUL randomized clinical trial, conducted at 444 centers across 33 countries. Participants were adults with type 2 diabetes and established atherosclerotic cardiovascular disease or chronic kidney disease. Enrollment occurred from June 17, 2019, to March 24, 2021, with a mean follow-up of 47.5 months. Of the participants, just over 23% had heart failure at baseline.

Participants were stratified by baseline heart failure status: 23.1% had a history of heart failure, 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 heart failure end point, defined as time to first heart failure hospitalization, urgent heart failure visit, or cardiovascular death.

Among participants with heart failure at baseline, oral semaglutide significantly reduced the risk of the composite heart failure outcome compared with placebo (HR, 0.78; 95% CI, 0.63-0.96). When analyzed by heart failure 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 heart failure experienced no meaningful risk reduction with oral semaglutide for heart failure events (HR, 1.01; 95% CI, 0.84-1.20; P for interaction = .06). Although the interaction was not statistically significant, the overall effect favored semaglutide in those with heart failure.

For major adverse cardiovascular events, oral semaglutide demonstrated consistent benefit regardless of heart failure history: HR 0.83 (95% CI, 0.68-1.01) in patients with heart failure and HR 0.86 (95% CI, 0.75-0.98) in those without heart failure (P for interaction = .77).

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

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 heart failure outcomes, particularly in reduced ejection fraction. Additionally, participants were largely on guideline-directed background therapy, which may limit generalizability to broader populations.

The SOUL study is a long-term clinical trial designed to evaluate whether the oral type 2 diabetes medication semaglutide can improve heart health. 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.

"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.

"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.