In the SOUL trial of 9,650 diabetic patients, oral semaglutide reduced the composite heart failure outcome by 22% in those with existing heart failure, with a remarkable 41% reduction specifically in patients with preserved ejection fraction.
41% HFpEF reductionOral semaglutide reduced heart failure events by 41% in patients with preserved ejection fraction — a type of heart failure that has long lacked effective treatments
What the researchers found
Among 9,650 participants with T2D and atherosclerotic CVD and/or CKD (median follow-up 47.5 months), 2,229 (23.1%) had heart failure at baseline. In participants with HF, oral semaglutide reduced the composite HF outcome (HF hospitalization, urgent HF visit, or CV death) by 22% (HR 0.78; 95% CI: 0.63-0.96). No significant benefit was seen in participants without HF (HR 1.01; 95% CI: 0.84-1.20).
The most striking subgroup result: patients with HF with preserved ejection fraction (HFpEF) showed a 41% reduction (HR 0.59; 95% CI: 0.39-0.86), while those with reduced ejection fraction (HFrEF) showed no significant benefit (HR 0.98; 95% CI: 0.70-1.38). MACE reduction with semaglutide was consistent regardless of HF status (HR 0.83 in HF; HR 0.86 in no HF). Serious adverse events were similar between semaglutide and placebo in the HF population.
Why it matters
Heart failure with preserved ejection fraction (HFpEF) affects millions and has been called the greatest unmet need in cardiovascular medicine — very few treatments have shown clear benefit. This analysis of the SOUL trial shows oral semaglutide reduces HFpEF events by 41%, which is among the largest treatment effects ever seen for this condition. Combined with the consistent MACE reduction, this positions oral semaglutide as potentially transformative for diabetic patients with heart failure.
How the study worked
Secondary analysis of the SOUL randomized clinical trial — a double-blind, placebo-controlled, event-driven phase 3b trial conducted at 444 centers in 33 countries. 9,650 participants with T2D and atherosclerotic CVD and/or CKD were randomized to once-daily oral semaglutide or placebo added to standard care. Participants were stratified by baseline HF status (2,229 with HF, 7,421 without). The prespecified composite HF outcome included time to first HF hospitalization, urgent HF visit, or cardiovascular death. Median follow-up was 47.5 months.
What this study cannot tell us
This is a secondary (post-hoc) analysis of a trial not primarily designed to study heart failure outcomes. The HF subgroups, particularly HFpEF (n=991) and HFrEF (n=592), are relatively small for definitive subgroup conclusions. The interaction p-value for HF vs no-HF (p=0.06) did not reach conventional significance. The unknown HF subtype group (646 patients) complicates interpretation. Dedicated prospective trials in HFpEF populations would be needed to confirm these findings.
How to read the evidence
This is a secondary analysis of a large, well-conducted randomized controlled trial (SOUL, n=9,650, phase 3b). While the parent trial is high-quality, the heart failure analysis was not the primary endpoint, and subgroup findings (HFpEF vs HFrEF) should be considered hypothesis-generating pending dedicated trials.
When this study was published
Published in 2026 in JAMA Internal Medicine, this is a very current analysis from one of the most important cardiovascular outcome trials for GLP-1 drugs. The SOUL trial's long follow-up (nearly 4 years median) provides more durable evidence than earlier trials.
The bigger picture
The SOUL trial joins SELECT, SUSTAIN-6, and PIONEER 6 as landmark evidence that GLP-1 receptor agonists provide cardiovascular benefits beyond glucose control. The HFpEF finding is particularly groundbreaking because this common condition has long been resistant to treatment. If confirmed in dedicated HFpEF trials, oral semaglutide could become one of the few evidence-based treatments for this condition — and it's a pill rather than an injection, which dramatically improves patient accessibility and adherence.
Questions still open
- Will a dedicated randomized trial of semaglutide in HFpEF patients confirm the 41% event reduction seen in this secondary analysis?
- Why does semaglutide appear to benefit HFpEF but not HFrEF — is this related to differences in obesity prevalence and metabolic dysfunction between subtypes?
- Could the oral formulation's continuous daily dosing provide advantages over weekly injectable semaglutide for heart failure management?
Common questions
What is heart failure with preserved ejection fraction, and why is it hard to treat?
Is oral semaglutide now recommended for heart failure?
Read the original research
Oral Semaglutide and Heart Failure Outcomes in Persons With Type 2 Diabetes: A Secondary Analysis of the SOUL Randomized Clinical Trial.
JAMA internal medicine
Citation
Pop-Busui, Rodica; Rasmussen, Søren; Deanfield, John E; Buse, John B; Marx, Nikolaus; Mulvagh, Sharon L; Inzucchi, Silvio E; Mann, Johannes F E; Emerson, Scott S; Poulter, Neil R; Engelmann, Mads D M; Hovingh, G Kees; Bayer Tanggaard, Katrine; Birkenfeld, Andreas L; Connelly, Kim A; Haluzik, Martin; Cavender, Matthew A; Kellerer, Monika; Jhund, Pardeep S; Gregersen, Søren; Nielsen, Olav Wendelboe; Lam, Carolyn S P; McGuire, Darren K. (2026). Oral Semaglutide and Heart Failure Outcomes in Persons With Type 2 Diabetes: A Secondary Analysis of the SOUL Randomized Clinical Trial.. JAMA internal medicine. https://doi.org/10.1001/jamainternmed.2025.7774