Oral Semaglutide and Heart Failure Outcomes in Persons With Type 2 Diabetes

Pop-Busui R, Rasmussen S, Deanfield JE, Buse JB, Marx N, Mulvagh SL, Inzucchi SE, Mann JF, Emerson SS, Poulter NR, Engelmann MD, Hovingh GK, Tanggaard KB, Birkenfeld AL, Connelly KA, Haluzik M, Cavender MA, Kellerer M, Jhund PS, Gregersen S, Nielsen OW, Lam CS, McGuire DK (2026)

Publication Type: Journal article

Publication year: 2026

Journal

DOI: 10.1001/jamainternmed.2025.7774

Abstract

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.

Involved external institutions

Oregon Health and Science University (OSHU) United States (USA) (US) Novo Nordisk A/S Denmark (DK) University College London (UCL) United Kingdom (GB) University of North Carolina at Chapel Hill United States (USA) (US) Universitätsklinikum Aachen (UKA) Germany (DE) Dalhousie University Canada (CA) Yale University United States (USA) (US) KfH Kuratorium für Dialyse und Nierentransplantation e.V. Germany (DE) Imperial College London / The Imperial College of Science, Technology and Medicine United Kingdom (GB) Universitätsklinikum Tübingen Germany (DE) St. Michael's Hospital Canada (CA) Institute for Clinical and Experimental Medicine (IKEM) Czech Republic (CZ) Marienhospital Stuttgart Germany (DE) University of Glasgow United Kingdom (GB) Aarhus University Denmark (DK) National University of Singapore (NUS) Singapore (SG) University of Texas Southwestern Medical Center (UT Southwestern) United States (USA) (US)

How to cite

APA:

Pop-Busui, R., Rasmussen, S., Deanfield, J.E., Buse, J.B., Marx, N., Mulvagh, S.L.,... McGuire, D.K. (2026). Oral Semaglutide and Heart Failure Outcomes in Persons With Type 2 Diabetes. JAMA Internal Medicine. https://doi.org/10.1001/jamainternmed.2025.7774

MLA:

Pop-Busui, Rodica, et al. "Oral Semaglutide and Heart Failure Outcomes in Persons With Type 2 Diabetes." JAMA Internal Medicine (2026).

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