Semaglutide 2.4 mg (Wegovy) has demonstrated notable improvements in outcomes for patients with moderately reduced and preserved ejection fraction in heart failure (HFmrEF, HFpEF) related to obesity. This compelling information was revealed through a prespecified secondary analysis of the STEP-HFpEF trial. According to Javed Butler, MD, MPH, MBA, of the Baylor Scott and White Research Institute in Dallas, the benefits of semaglutide were consistent across various subgroups. These findings were presented at the esteemed Heart Failure Society of America (HFSA) meeting and published in the Journal of the American College of Cardiology.
One key aspect evaluated in the trial was the impact of semaglutide on quality of life. The analysis revealed a significant improvement in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score among patients with different ejection fractions. Semaglutide outperformed placebo by a margin of 5.0 points for patients with an ejection fraction of 45-49%, 9.8 points for those with an ejection fraction of 50-59%, and 7.4 points for individuals with an ejection fraction of 60% or greater. It is essential to highlight that no significant interaction was observed (P=0.56). This means that semaglutide consistently enhances quality of life across the range of ejection fractions.
Another crucial primary endpoint assessed in the STEP-HFpEF trial was the impact of semaglutide on body weight loss. The results exhibited a considerable reduction in body weight compared to the placebo group. Semaglutide demonstrated a significant weight loss of 7.6 percentage points for patients with an ejection fraction of 45-49%, 10.6 percentage points for those with an ejection fraction of 50-59%, and 11.9 percentage points for individuals with an ejection fraction of 60% or greater (P=0.08 for interaction). This substantial weight loss effect is a valuable asset in addressing obesity-related heart failure and further supports the potential role of semaglutide in managing HFpEF.
An accompanying editorial penned by Muthiah Vaduganathan, MD, MPH, and John W. Ostrominski, MD, highlighted the significance of these findings. They suggested that semaglutide, along with other emerging incretin-based therapies and weight/metabolism-oriented approaches, could play a pivotal role in obesity-related HFpEF management. Obesity-related HFpEF represents one of the most common and potentially dangerous phenotypes of HFpEF. The authors noted that traditional treatments like beta-blockers, renin-angiotensin system inhibitors, and angiotensin receptor-neprilysin inhibitors may lose efficacy as ejection fraction increases. However, semaglutide, a GLP-1 receptor agonist, has demonstrated consistent treatment effects across a wide range of ejection fractions. This paradigm shift in treatment strategies has the potential to revolutionize the management of obesity-related heart failure.
During the HFSA late-breaking trial session, discussant John McMurray, MD, PhD, explored the underlying mechanisms of semaglutide’s benefits. While weight loss appears to be a significant factor, McMurray questioned whether the drug possesses additional pharmacological actions that contribute to its efficacy. If semaglutide exhibits other beneficial actions beyond weight loss, it could hold promise for non-obese patients and individuals with different forms of heart failure. Further research is needed to explore potential diet and exercise interventions and the efficacy of other pharmacological therapies, such as novel oral GLP-1 receptor agonists orforglipron, dual GIP/GLP-1 receptor agonist tirzepatide (Mounjaro), and the novel triple GIP/GLP-1/glucagon receptor agonist retatrutide.
One intriguing finding from the STEP-HFpEF secondary analysis was the decrease in NT-proBNP levels, which was consistent across ejection fraction categories. Similar findings were observed in a diet-induced weight loss trial involving a comparable patient population. In contrast, other studies have shown an increase in natriuretic peptide levels in patients undergoing bariatric surgery. This observation sheds light on the potential mechanism of action of semaglutide beyond weight loss. The significance of these findings resides in their implications for a broader understanding of the drug’s therapeutic effects.
The results of the STEP-HFpEF trial offer vital reassurance regarding the safety of semaglutide in heart failure patients with reduced ejection fraction. Previous data on the GLP-1 receptor agonist exenatide (Byetta) had raised concerns about potential harm in HF with reduced ejection fraction. However, the safety profile of semaglutide in the trial was notably favorable compared to placebo across all ejection fraction groups. Additionally, the trial tentatively supports the concept of a more general, LVEF-independent, obesity-related heart failure phenotype that can be favorably modified using incretin-based therapies. While further research is necessary to establish definitive evidence, this finding opens the door to new possibilities in managing heart failure associated with obesity.
The emergence of semaglutide as a therapeutic option in obesity-related heart failure represents a significant breakthrough. The STEP-HFpEF trial’s results, combined with the consistent improvements seen in quality of life and weight loss across various ejection fractions, highlight the potential of semaglutide and other incretin-based therapies in managing HFpEF. These findings challenge traditional treatment approaches and provide a fresh perspective on addressing obesity-related heart failure. Further research will undoubtedly delve deeper into the mechanisms of action and explore the possibilities of semaglutide in diverse patient populations beyond those with obesity-related heart failure. As we continue to uncover the potential of semaglutide, it is clear that we are taking a significant step toward transforming the management of heart failure.
Leave a Reply