USA: Insights from the STEP-HFpEF program showed the efficacy of semaglutide in reducing N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with obesity-related heart failure (HF) with preserved ejection fraction (HFpEF).
Participants with higher baseline NT-proBNP showed comparable weight loss. Still, they had greater reductions in heart failure-related symptoms and physical limitations with semaglutide compared to those with lower NT-proBNP levels," the researchers reported in the Journal of the American College of Cardiology.

The findings indicate that the heart failure benefits of semaglutide are likely not solely due to mechanical unloading associated with weight loss; rather, they also encompass a range of weight loss-independent, disease-modifying effects.
Semaglutide, a glucagon-like peptide-1 receptor agonist, is reported to improve health status and reduce body weight in patients with obesity-related HFpEF in the STEP-HFpEF (Semaglutide Treatment Effect in People with Obesity and HFpEF) program. It remains unclear whether the benefits resulted from mechanical unloading or effects on heart failure pathobiology. Therefore, Barry A. Borlaug, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA, and colleagues sought to determine if semaglutide 2.4 mg reduced NT-proBNP in patients with obesity-related HFpEF and compare treatment responses by baseline NT-proBNP.
For this purpose, they conducted a prespecified secondary analysis of pooled data from 2 double-blind, placebo-controlled, randomized trials (STEP-HFpEF and STEP-HFpEF DM) testing semaglutide effects in patients with obesity-related HFpEF. A total of 1,145 patients were randomized.
The primary outcomes included changes in NT-proBNP at 52 weeks and alterations in the dual primary endpoints of the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and body weight based on baseline NT-proBNP levels.
The study led to the following findings:
Compared to a placebo, semaglutide reduced NT-proBNP at 52 weeks (estimated treatment ratio: 0.82).
Improvements in health status were more pronounced in those with higher vs lower baseline NT-proBNP (estimated difference: tertile 1: 4.5 points; tertile 2: 6.2 points; tertile 3: 11.9 points; baseline NT-proBNP as a continuous variable).
Reductions in body weight were consistent across baseline NT-proBNP levels.
In conclusion, semaglutide significantly reduced NT-proBNP levels in patients with obesity-related HFpEF in the STEP-HFpEF program. Participants with higher baseline NT-proBNP showed similar weight loss but greater reductions in heart failure-related symptoms and physical limitations compared to those with lower NT-proBNP. This suggests disease-modifying effects of semaglutide and supports the need for outcome trials of incretin-based therapies in HFpEF.
Limitations included the absence of cardiac imaging through echocardiography or cardiac magnetic resonance imaging for all participants, which would have enabled an assessment of semaglutide's effects on cardiac structure and function. An echocardiographic substudy was conducted, with plans to report these findings. Additionally, the enrollment of non-White patients was insufficient, restricting the generalizability of the results.
Reference:
Petrie, M. C., Borlaug, B. A., Butler, J., Davies, M. J., Kitzman, D. W., Shah, S. J., Verma, S., Jensen, T. J., Einfeldt, M. N., Liisberg, K., Perna, E., Sharma, K., Ezekowitz, J. A., Fu, M., Melenovský, V., Ito, H., Lelonek, M., & Kosiborod, M. N. (2024). Semaglutide and NT-proBNP in Obesity-Related HFpEF: Insights From the STEP-HFpEF Program. Journal of the American College of Cardiology, 84(1), 27-40. https://doi.org/10.1016/j.jacc.2024.04.022