ORAL semaglutide is associated with a reduced risk of heart failure events in people with type 2 diabetes and pre-existing heart failure, according to a secondary analysis of the SOUL randomised clinical trial.
Heart Failure and Diabetes: A High-Risk Overlap
While glucagon-like peptide-1 receptor agonists are well established for reducing major adverse cardiovascular events, their role in heart failure outcomes has remained less clear. The SOUL trial previously demonstrated cardiovascular benefit with oral semaglutide in people with type 2 diabetes and atherosclerotic cardiovascular disease or chronic kidney disease. This secondary analysis examined whether those benefits extended to heart failure outcomes and whether effects differed according to baseline heart failure status.
Reduced Heart Failure Events in Patients With Existing HF
Among more than 9,600 participants, nearly one quarter had a history of heart failure at baseline. In this subgroup, oral semaglutide was associated with a significantly lower risk of the composite heart failure outcome, including heart failure hospitalisation, urgent heart failure visits, or cardiovascular death. In contrast, no reduction in heart failure events was observed among participants without heart failure at baseline. This divergence suggests that semaglutide’s heart failure benefit may be specific to patients with established disease rather than preventative in those without prior heart failure.
Greater Benefit in Preserved Ejection Fraction
When heart failure subtypes were examined, the reduction in heart failure events appeared more pronounced in participants with preserved ejection fraction compared with those with reduced ejection fraction. Although not all subgroup analyses reached statistical significance, the findings align with growing evidence that GLP-1 receptor agonists may be particularly relevant in heart failure with preserved ejection fraction, a condition with limited treatment options. Importantly, the reduction in heart failure events did not come at the expense of safety, with similar rates of serious adverse events observed between semaglutide and placebo groups.
Cardiovascular Outcomes Remain Consistent
The effect of oral semaglutide on major adverse cardiovascular events was consistent regardless of heart failure status at baseline. This suggests that the observed heart failure benefit in patients with established disease complements, rather than replaces, the broader cardiovascular protection already associated with semaglutide therapy.
Clinical Implications for High-Risk Patients
These findings support the use of oral semaglutide in people with type 2 diabetes and existing heart failure to reduce heart failure-related events, without increasing safety concerns. While further studies are needed to clarify mechanisms and subtype-specific effects, the results reinforce the expanding role of GLP-1 receptor agonists in cardiometabolic disease management.
Reference
Pop-Busui R et al. Oral semaglutide and heart failure outcomes in persons with type 2 diabetes: a secondary analysis of the SOUL randomized clinical trial. JAMA Intern Med.2026;DOI:10.1001/jamainternmed.2025.7774.
