Semaglutide Improves Heart Failure Outcomes in SOUL Trial Secondary Analysis

The benefits of the oral semaglutide medication, initially demonstrated for managing type 2 diabetes and reducing cardiovascular events, now appear to extend to improving outcomes for patients with heart failure. A secondary analysis of the SOUL trial, published in February 2026, reveals a significant reduction in heart failure events among those taking oral semaglutide compared to placebo – a finding consistent with observations from the injectable version of the drug.

SOUL Trial: Expanding the Profile of Oral Semaglutide

The SOUL (Semaglutide Cardiovascular Outcomes Trial) was a large, international study designed to assess the impact of oral semaglutide on major adverse cardiovascular events (MACE) – a composite measure including cardiovascular death, non-fatal heart attack, and stroke – in individuals with type 2 diabetes. The initial results, published in 2025, showed a clear benefit. This recent secondary analysis, however, delves deeper, specifically examining the drug’s effect on heart failure, a frequent and serious complication of diabetes. The study, conducted across 444 centers in 33 countries, enrolled 9,650 participants between June 2019 and March 2021.

Participants in the SOUL trial had type 2 diabetes and either atherosclerotic cardiovascular disease (plaque buildup in the arteries) or chronic kidney disease. Crucially, the researchers stratified participants based on their heart failure status at the beginning of the trial – whether they had a history of heart failure or not. This allowed for a focused comparison of semaglutide’s effects in these two distinct groups. The average follow-up period was approximately 47.5 months.

Heart Failure Subtypes and Treatment Response

Approximately 23.1% of the participants had a pre-existing history of heart failure. Within this group, researchers further categorized heart failure based on ejection fraction – a measure of how well the heart pumps blood. They identified three subgroups: those with preserved ejection fraction (HFpEF, 10.3%), reduced ejection fraction (HFrEF, 6.1%), and those with an unknown ejection fraction (6.7%).

The analysis revealed a notable difference in the effect of oral semaglutide depending on whether participants had heart failure at baseline. For those with a history of heart failure, the hazard ratio (HR) for the composite heart failure outcome (hospitalization, urgent visit, or cardiovascular death) was 0.78 (95% confidence interval, 0.63-0.96). This suggests a 22% reduction in risk with semaglutide compared to placebo. However, in participants without a prior history of heart failure, the HR was 1.01 (95% CI, 0.84-1.20), indicating no significant benefit or harm. The difference between these two groups approached statistical significance (P for interaction = .06).

Further breakdown of the heart failure subgroup showed even more nuanced results. Among those with heart failure and preserved ejection fraction (HFpEF), oral semaglutide was associated with a substantial risk reduction – an HR of 0.59 (95% CI, 0.39-0.86). This translates to a nearly 41% reduction in the risk of heart failure events. For those with reduced ejection fraction (HFrEF), the HR was 0.98 (95% CI, 0.79-1.22), suggesting little to no effect.

Understanding the Implications: Beyond Glucose Control

These findings are significant because they suggest that oral semaglutide may offer benefits beyond its established role in glucose control and reducing cardiovascular risk in type 2 diabetes. Heart failure is a complex condition with substantial morbidity and mortality, and effective treatments are continually sought. The observed reduction in heart failure events, particularly in those with HFpEF, is encouraging.

It’s significant to note that this is a secondary analysis, meaning it wasn’t the primary focus of the original SOUL trial. While the results are compelling, they should be interpreted with caution. Secondary analyses are prone to finding spurious associations, and further research is needed to confirm these findings. The original SOUL trial focused on a broader range of cardiovascular outcomes, and this analysis specifically targeted heart failure events.

What Does This Imply for Patients?

These results do not mean that all patients with heart failure should immediately start taking oral semaglutide. The study population was specifically individuals with type 2 diabetes and existing cardiovascular risk factors. The findings do, however, suggest that oral semaglutide may be a particularly valuable treatment option for those with both type 2 diabetes and heart failure, especially those with preserved ejection fraction. Patients should discuss their individual risk factors and treatment options with their healthcare provider.

It’s also crucial to understand the limitations of hazard ratios. An HR of 0.78, for example, doesn’t mean that 22% of people taking semaglutide will avoid a heart failure event. It means that the risk of experiencing an event is reduced by 22% compared to those taking placebo. The absolute risk reduction will depend on the baseline risk of heart failure events in the population being treated.

The Evolving Landscape of Heart Failure Treatment

The treatment of heart failure has undergone significant advances in recent years, with the development of latest medications that target different pathways involved in the disease process. Oral semaglutide joins a growing list of therapies that may offer benefits beyond traditional heart failure medications. The potential for a single medication to address both diabetes and heart failure is particularly appealing, as these conditions often coexist.

Next Steps: Confirmatory Trials and Guideline Updates

The findings from this secondary analysis of the SOUL trial are likely to prompt further research. Dedicated clinical trials specifically designed to evaluate the effects of oral semaglutide on heart failure outcomes in a broader population are needed. These trials should include participants with and without diabetes, and should assess the long-term effects of the drug on heart failure progression, and mortality.

professional medical societies will likely review these findings as they update their guidelines for the management of heart failure. It’s possible that oral semaglutide may be incorporated into treatment recommendations for certain subgroups of patients with heart failure and type 2 diabetes. The process of guideline development is rigorous and evidence-based, ensuring that recommendations are based on the best available data.