Investigating the Effects of Semaglutide on Heart Failure Related to Obesity

A recent secondary analysis of the STEP-HFpEF trial revealed promising results regarding the use of semaglutide 2.4 mg (Wegovy) in heart failure patients with moderately reduced and preserved ejection fraction (HFmrEF, HFpEF) associated with obesity. This analysis, presented by Dr. Javed Butler, showcased the consistent benefits of semaglutide in various subgroups during the Heart Failure Society of America (HFSA) meeting and in the Journal of the American College of Cardiology. Notably, semaglutide demonstrated significant improvements in quality of life measures and body weight loss, indicating a potential shift in the management strategies of obesity-related HFpEF.

Semaglutide showed a positive impact on the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, with an average increase of 5.0 points in patients with an ejection fraction (EF) of 45-49%, 9.8 points in those with an EF of 50-59%, and 7.4 points in individuals with an EF of ≥60%. Interestingly, there was no significant interaction observed, suggesting that semaglutide’s benefits remain consistent across these subgroups. Additionally, the drug demonstrated a significant reduction in body weight compared to placebo, reaching 7.6 percentage points in patients with an EF of 45-49%, 10.6 percentage points in those with an EF of 50-59%, and 11.9 percentage points in individuals with an EF of ≥60%. These findings imply that semaglutide may offer effective treatments for HFpEF related to obesity.

The overall positive results from the STEP-HFpEF trial, combined with the outcomes of this secondary analysis, suggest a potential paradigm shift in the management of obesity-related HFpEF. The authors of an accompanying editorial highlight that semaglutide, along with other emerging incretin-based therapeutics and weight/metabolism-oriented approaches, could play a central role in obesity-related HFpEF management strategies. This proposed shift could significantly impact the treatment options available for this prevalent, debilitating, and deadly phenotype of HFpEF.

Interestingly, the effects of semaglutide on HFpEF patients with varying EFs resemble the treatment effects observed with SGLT2 inhibitors. While other medications, such as beta-blockers and angiotensin system inhibitors, show diminished efficacy with higher EFs, semaglutide’s consistency throughout the EF range ≥45% raises questions about the drug’s pharmacological action beyond weight loss. This opens up possibilities for exploring its potential benefits in non-obese patients and other types of heart failure. However, if the benefits are solely attributable to weight loss, further research into diet, exercise, and other pharmacological therapies would be necessary.

One of the most intriguing findings from the secondary analysis was the consistent decrease in NT-proBNP levels with semaglutide across all EF categories. This result aligns with a diet-induced weight loss trial and highlights semaglutide’s potential mechanism of action, which extends beyond weight loss alone. Dr. Butler suggests that semaglutide may have additional pharmacological actions that benefit heart failure patients. Understanding these mechanisms could further enhance its applicability and efficacy in patients with various heart failure conditions.

The results of the STEP-HFpEF trial offer vital reassurances regarding the safety of semaglutide, even in patients with below-normal EF ranges. Previous studies with exenatide had suggested potential harm in heart failure patients with reduced EF. However, semaglutide demonstrated better safety profiles than placebo across the different LVEF groups. While further studies are needed, the treatment benefits observed at an LVEF


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