Oral semaglutide reduced the risk of the composite heart failure outcome compared with placebo in patients with type 2 diabetes and a history of heart failure (HR 0.78; 95% CI 0.63-0.96).
RCT (n=9,650)
double-blind
randomized
Yes
Does once-daily oral semaglutide reduce the composite of HF hospitalization, urgent HF visit, or CV death in patients with type 2 diabetes and atherosclerotic cardiovascular disease and/or chronic kidney disease?
Oral semaglutide significantly reduces the risk of heart failure events in patients with type 2 diabetes and a history of heart failure, particularly those with preserved ejection fraction.
Effect estimate: HR 0.78 (95% CI 0.63-0.96)
Importance Heart failure (HF) is a common complication of type 2 diabetes (T2D). Oral semaglutide reduced the risk of major adverse cardiovascular (CV) events (MACE; comprising CV death, nonfatal myocardial infarction, or nonfatal stroke) in people with T2D in the SOUL trial, but the impact on HF outcomes in these participants is unknown. Objective To evaluate the effect of oral semaglutide on HF events, MACE, and safety among participants with or without HF at baseline. Design, Setting, and Participants This is a secondary analysis of the double-blind, placebo-controlled, event-driven, phase 3b SOUL randomized clinical trial, which was conducted at 444 centers in 33 countries. Participants were enrolled from June 17, 2019, to March 24, 2021, and had T2D and atherosclerotic CV disease and/or chronic kidney disease, stratified according to the presence or absence of HF history at baseline. Data were analyzed from December 2024 to August 2025. Intervention Once-daily oral semaglutide or placebo in addition to standard of care. Main Outcomes and Measures Prespecified composite HF outcome (time to first occurrence of HF hospitalization, urgent HF visit, or CV death). Results Overall, 9650 participants (median IQR age, 66.0 61.0-72.0 years; 2790 28.9% female) were randomized, with a mean (SD) follow-up of 47.5 (10.9) months. Of these participants, 2229 (23.1%) had HF history (991 10.3% with preserved ejection fraction, 592 6.1% with reduced ejection fraction, and 646 6.7% with unknown subtype). For participants with HF at baseline, the hazard ratio (HR) for risk of the composite HF outcome with oral semaglutide vs placebo was 0.78 (95% CI, 0.63-0.96) and was 1.01 (95% CI, 0.84-1.20) in those without HF at baseline ( P for interaction = .06). Among participants with HF, the HR was 0.59 (95% CI, 0.39-0.86) in those with preserved ejection fraction and 0.98 (95% CI, 0.70-1.38) in those with reduced ejection fraction. There was no heterogeneity in the risk reduction of MACE with oral semaglutide in participants with HF history (HR, 0.83; 95% CI, 0.68-1.01) or without HF history (HR, 0.86; 95% CI, 0.75-0.98) ( P for interaction = .77). Serious adverse event occurrence among participants with HF was similar with oral semaglutide (594 53.8%) and placebo (642 57.1%). Conclusions and Relevance In this secondary analysis of the SOUL randomized clinical trial, among individuals with T2D, atherosclerotic CV 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. These data support the potential benefit of oral semaglutide in reducing HF events in people with T2D and HF. Trial Registration ClinicalTrials.gov Identifier: NCT03914326
OHSU press release and ACC-related coverage amplified in past 14 days; strong social media shares among cardiologists and endocrinologists; ties into growing GLP-1 buzz with quantified risk reduction driving clinical interest.
Pop-Busui et al. (2026) conducted an RCT in Type 2 diabetes and atherosclerotic cardiovascular disease and/or chronic kidney disease (n=9,650). Oral semaglutide vs. Placebo was evaluated on Composite HF outcome (time to first occurrence of HF hospitalization, urgent HF visit, or CV death) (HR 0.78, 95% CI 0.63-0.96). Oral semaglutide reduced the risk of the composite heart failure outcome compared with placebo in patients with type 2 diabetes and a history of heart failure (HR 0.78; 95% CI 0.63-0.96).