Research Summary

Oral Semaglutide Associated With Fewer Heart Failure Events in Type 2 Diabetes

Edited by:
Kate Young

Key Highlights

  • In a secondary analysis of the SOUL randomized clinical trial, oral semaglutide lowered the risk of a composite heart failure (HF) outcome in participants with type 2 diabetes who had heart failure at baseline.
  • No corresponding reduction was seen in participants without baseline HF.
  • The apparent benefit was driven largely by participants with HFpEF, while no clear benefit was shown in HFrEF.
  • Serious adverse event rates were similar between oral semaglutide and placebo in participants with baseline HF.

In a secondary analysis of the SOUL randomized clinical trial published in JAMA Internal Medicine, oral semaglutide was associated with a lower risk of the prespecified composite heart failure outcome in adults with type 2 diabetes and baseline heart failure, compared with placebo. The composite endpoint included heart failure (HF) hospitalization, urgent HF visit, or cardiovascular death.

The study evaluated whether the cardiovascular effects of oral semaglutide differed by HF status at study entry. Overall, the signal for benefit appeared confined to participants with established HF at baseline rather than those without known HF.

SOUL was a double-blind, randomized, placebo-controlled, event-driven phase 3b trial conducted at 444 centers in 33 countries. Participants were adults aged 50 years or older with type 2 diabetes and atherosclerotic cardiovascular disease and/or chronic kidney disease, and they were assigned to once-daily oral semaglutide up to 14 mg or placebo on top of standard care. Enrollment ran from June 17, 2019, to March 24, 2021.

This secondary analysis included 9,650 randomized participants, with a mean follow-up of 47.5 months. At baseline, 2,229 participants (23.1%) had a history of HF, including 991 with HFpEF, 592 with HFrEF, and 646 with unknown subtype. Researchers analyzed outcomes by baseline HF status and HF subtype using Cox proportional hazards models; analyses were not adjusted for multiplicity.

Study Findings

Among participants with HF at baseline, the composite HF outcome occurred in 157 of 1,105 patients (14.2%) treated with oral semaglutide and 200 of 1,124 patients (17.8%) given placebo, for a hazard ratio of 0.78 (95% CI, 0.63-0.96). Among participants without HF at baseline, the corresponding hazard ratio was 1.01 (95% CI, 0.84-1.20), with a P value for interaction of .06.

Within HF subtypes, the hazard ratio for the composite HF outcome was 0.59 (95% CI, 0.39-0.86) in HFpEF and 0.98 (95% CI, 0.70-1.38) in HFrEF. For major adverse cardiovascular events, there was no heterogeneity by baseline HF status: hazard ratios were 0.83 (95% CI, 0.68-1.01) in those with HF and 0.86 (95% CI, 0.75-0.98) in those without HF. Serious adverse events in the baseline HF group occurred in 53.8% of the oral semaglutide group and 57.1% of the placebo group. These findings are reported from the study analysis only.

Clinical Implications

According to the study authors, these findings support a potential role for oral semaglutide in reducing HF events in people with type 2 diabetes, atherosclerotic cardiovascular disease and/or chronic kidney disease, and established HF, particularly HFpEF. They also stated that the observed benefit was not accompanied by an increase in serious adverse events.

The authors noted several limitations. As a secondary analysis, some subgroup sample sizes were small, limiting power to detect differences within or between subgroups, and the HF outcome analyses were not adjusted for multiple comparisons. They also reported that HF subtype classification relied on investigator-reported data rather than standardized clinical assessment, and nearly 30% of participants with HF could not be further subtyped.

Expert Commentary

“In this secondary analysis of the SOUL randomized clinical trial among individuals with T2D and ASCVD and/or CKD, we observed a reduction in the composite risk of HF hospitalization, urgent HF visit, or CV death in those with a history of HF receiving oral semaglutide compared with placebo, despite a high baseline use of SGLT2 inhibitors and MRAs, and without increasing the risk of SAEs. These benefits were attributed mostly to those with HFpEF, with no indication of compromised safety in HFrEF,” the researchers concluded.

Reference
Pop-Busui R, Rasmussen S, Deanfield JE, 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;186(4):426-436. doi:10.1001/jamainternmed.2025.7774.