Oral Semaglutide Shows Promise in Reducing Heart Failure Events in Type 2 Diabetes

New data presented in a secondary analysis of the SOUL trial confirm the therapeutic potential of oral semaglutide in managing heart failure (HF) among individuals with type 2 diabetes (T2D) at high cardiovascular risk. The findings, published in JAMA Internal Medicine on February 2, 2026, suggest a potential benefit of the oral medication, particularly for those with heart failure with preserved ejection fraction (HFpEF).

Study Design and Participants

The SOUL trial, a randomized controlled trial, involved 9,650 patients with T2D and established atherosclerotic cardiovascular disease and/or chronic kidney disease. Participants, with a median age of approximately 66 years (28.9% female), were randomized to receive either once-daily oral semaglutide or a placebo, in addition to their standard treatment regimen. The median follow-up period spanned several years.

At the beginning of the trial, 2,229 patients (23.1%) had documented heart failure.

Key Findings: Heart Failure Risk Reduction

The analysis revealed that oral semaglutide was associated with a significant 22% reduction in the risk of a composite heart failure endpoint – encompassing hospitalization for HF, urgent consultation for HF, or cardiovascular death – in patients with pre-existing heart failure. This translated to a hazard ratio (HR) of approximately 0.78 (95% confidence interval 0.63–0.96).

Although, in patients without prior heart failure, no significant benefit was observed on this endpoint (HR ≈ 1.01; 95% CI 0.84–1.20). The interaction between baseline HF status and treatment effect showed a trend toward significance (p ≈ 0.06), but did not reach conventional statistical significance.

Subgroup Analysis: HFpEF vs. HFrEF

Further analysis categorized patients by heart failure type. Oral semaglutide demonstrated a more pronounced benefit in patients with heart failure with preserved ejection fraction (HFpEF), reducing the risk of HF-related events by approximately 40% (HR ≈ 0.59, with a 95% confidence interval that did not cross 1).

In contrast, no clear benefit was observed in patients with heart failure with reduced ejection fraction (HFrEF), with an estimated effect closer to neutral.

Cardiovascular Outcomes and Safety

Regarding major adverse cardiovascular events (MACE – cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), oral semaglutide continued to demonstrate an overall benefit consistent with the primary trial results, regardless of baseline heart failure status.

The frequency of serious adverse events was comparable between the semaglutide and placebo groups in patients with pre-existing heart failure. No new safety signals specifically related to heart failure were identified. The most common adverse effects remained gastrointestinal, consistent with other GLP-1 receptor agonists.

Study Limitations

Researchers acknowledge that this analysis is secondary to a trial primarily designed to assess MACE, not specifically heart failure events. The lack of formal statistical significance in the interaction between baseline HF status and treatment effect, and the limited sample sizes in the subgroup analyses by HF type, as well warrant cautious interpretation.

Implications and Future Research

These findings suggest that oral semaglutide may offer a valuable therapeutic option for individuals with T2D and pre-existing heart failure, particularly those with HFpEF. However, dedicated clinical trials specifically designed to investigate the effects of oral semaglutide on heart failure outcomes are needed to confirm these results and establish definitive treatment guidelines.

Sources:

• Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes – New England Journal of Medicine
• Oral Semaglutide and Heart Failure Outcomes in Persons With Type 2 Diabetes – JAMA Internal Medicine
• Oral Semaglutide and Cardiovascular Outcomes in People With Type 2 Diabetes – ClinicalTrials.gov