A secondary analysis of the SOUL trial, published in JAMA Internal Medicine, found that daily oral semaglutide reduced serious heart-failure–related events in people with type 2 diabetes. The benefit was most pronounced among participants with heart failure with preserved ejection fraction (HFpEF), a subtype that has proven difficult to treat.
Trial overview
SOUL was a large randomized clinical trial comparing once-daily oral semaglutide with placebo in people with type 2 diabetes. The main trial previously showed a reduction in major adverse cardiovascular events (MACE: myocardial infarction, stroke, or cardiovascular death). This secondary analysis specifically examined heart failure outcomes.
Participants averaged 66 years old and 29% were female. About one-quarter of participants (2,229 people) had preexisting heart failure at baseline. Of those with heart failure, 44% were classified as HFpEF, 27% as heart failure with reduced ejection fraction (HFrEF), and 29% were unclassified. Mean follow-up was roughly four years.
Key findings
– Among participants with preexisting heart failure, oral semaglutide reduced the risk of serious heart failure–related outcomes (hospitalization for heart failure or heart-failure–related death) by 22% versus placebo.
– The effect was concentrated in the HFpEF subgroup, which experienced a 41% lower risk of those serious outcomes.
– No statistically significant benefit was observed in participants with HFrEF or in those without heart failure at baseline.
Safety
The analysis found no new safety concerns: rates of serious adverse events were similar between the semaglutide and placebo groups. As an oral option, semaglutide may be easier for some patients to take than injectable GLP-1 receptor agonists.
Clinical interpretation and expert perspective
Cardiology and heart-failure experts described the results as confirmatory and encouraging. Observers noted the findings strengthen the case for GLP-1–based therapies in patients with HFpEF—especially when obesity and diabetes are present—and suggested that additional evidence could support broader payer coverage. The results are seen as clinically meaningful because proven treatments for HFpEF remain limited.
Why HFpEF may benefit
HFpEF is characterized by preserved left-ventricular ejection fraction (typically ≥50%) combined with impaired ventricular filling due to stiffness. It is a heterogeneous syndrome often driven or worsened by conditions such as obesity, hypertension, diabetes, atrial fibrillation, and chronic kidney disease. Therapies that improve glycemic control and produce weight loss, such as semaglutide, may therefore reduce HFpEF risk or severity by targeting these underlying contributors.
Related evidence
Other trials with incretin-based drugs have suggested heart-failure benefits. For example, SUMMIT reported a strong reduction in heart-failure events with the dual GIP/GLP-1 agonist tirzepatide in people with HFpEF, and STEP-HFpEF DM showed symptom and functional improvement with semaglutide in patients who have HFpEF and diabetes. Most prior cardiovascular outcome data for GLP-1 agents came from injectable formulations; SOUL provides large randomized evidence specifically for an oral GLP-1.
Limitations and next steps
These heart-failure results come from a secondary analysis rather than a trial prospectively powered for heart-failure endpoints. Subgroup findings (HFpEF versus HFrEF) should therefore be interpreted cautiously. Further research is needed to confirm which patient subgroups derive the most benefit, to compare oral GLP-1s directly with other heart-failure therapies, and to clarify long-term outcomes and cost-effectiveness. If replicated, oral semaglutide could become a convenient pharmacologic option for people with type 2 diabetes and HFpEF, with potential implications for clinical practice and insurance coverage.
Public-health context
Heart failure imposes a large and growing economic burden: U.S. costs already exceed $30 billion annually and are projected to rise substantially. More than one in five people with type 2 diabetes have heart failure, and that prevalence is increasing, highlighting the importance of interventions that reduce heart-failure events in this population.
