Oral GLP-1 Receptor Agonists Can Reduce Heart Failure

Heart failure is a common complication in patients with type

2 diabetes. In the double-blind, placebo-controlled, rand-

omized, multicenter phase3b clinical trial SOUL (Semaglu-

tide Cardiovascular Outcomes Trial), oral semaglutides re-

duced the risk of major adverse cardiovascular events,

consisting of cardiovascular death, nonfatal myocardial in-

farction, or non fatal stroke, in patients with type 2 diabetes.

Whether oral semaglutides also affect the severity of heart

failure was the subject of a secondary analysis of the SOUL

study.

The study participants (n = 9650), with a median age of

66 years, had type 2 diabetes and atherosclerotic cardio-

vascular disease and/or chronic kidney disease. They were

stratified according to the presence (23.1%) or absence of

heart failure at the start of the study. Among participants

with heart failure, 10.3% had heart failure with preserved

ejection fraction (HFpEF), 6.1% had heart failure with re-

duced ejection fraction, and 6.7% had an unknown subtype.

Study participants were randomly assigned to receive

either oral semaglutide or placebo once daily in addition to

their standard treatment, which could include SGLT2 in-

hibitors and mineralocorticoid receptor antagonists. The

prespecified composite heart failure outcome of interest

consisted of heart failure-related hospitalization, heart

failure-related emergency treatment, or cardiovascular

death after a median follow-up of approximately four years

(47.5 months).

The analysis showed that the risk of reaching the com-

bined heart failure endpoint was reduced by 22% in pa-

tients with preexisting heart failure receiving oral semaglu-

tides compared to the placebo group (hazard ratio [HR]:

0.78; 95% confidence interval [CI]: 0.63–0.96), especially

in patients with HFpEF. However, in patients without a his-

tory of heart failure the risk did not change (HR: 1.01; 95%

CI: 0.84–1.20). The frequency of serious adverse events in

participants with heart failure was similar between oral

semaglutide (53.8%) and placebo (57.1%).

The authors conclude that this data indicates a potential

additional benefit from oral semaglutide in reducing heart

failure-related events in patients with type 2 diabetes and

heart failure. 

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Source: Pop-Busui R et al.: Oral Semaglutide and Heart Failure Outcomes in Persons With Type 2 Diabetes: A Secondary Analysis of the SOUL Randomised Clinical Trial. JAMA Intern Med. Published online 2 February 2026. doi:10.1001/jamainternmed.2025.777

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