Semaglutide and NTproBNP in Obesity-Related HFpEF: Insights from STEP-HFpEF Program

Background The glucagon-like peptide-1 receptor agonist, semaglutide, improved health status and reduced body weight in patients with obesity-related heart failure (HF) with preserved ejection fraction (HFpEF) in the STEP-HFpEF Program. Whether benefits were due to mechanical unloading or effects on HF pathobiology is uncertain. Objectives Determine if semaglutide 2.4 mg reduced N-terminal pro-brain natriuretic peptide (NTproBNP) in patients with obesity-related HFpEF and compare treatment responses by baseline NTproBNP. Methods Prespecified secondary analysis of pooled data from two double-blind, placebo-controlled, randomized trials (STEP-HFpEF and STEP-HFpEF DM) testing effects of semaglutide in patients with obesity-related HFpEF. The main outcomes were change in NTproBNP at 52 weeks and change in the dual primary endpoints of KCCQ-CSS and body weight by baseline NTproBNP. Results 1145 patients were randomized. Semaglutide, compared with placebo, reduced NTproBNP at 52 weeks (estimated treatment ratio 0.82 [95% CI: 0.74-; 0.91]; P = 0.0002). Improvements in health status were more pronounced in those with higher vs lower baseline NTproBNP (estimated difference: tertile 1: 4.5 points [95% CI: 0.8–8.2], tertile 2: 6.2 points [95% CI: 2.4–10.0], tertile 3: 11.9 points [95% CI: 8.1–15.7]; interaction P = 0.02; baseline NTproBNP as a continuous variable: interaction P = 0.004). Reductions in body weight were consistent across baseline NTproBNP levels (interaction P = 0.21). Conclusions In patients with obesity-related HFpEF, semaglutide reduced NTproBNP. Participants with higher baseline NTproBNP had a similar degree of weight loss but experienced larger reductions in HF-related symptoms and physical limitations with semaglutide than those with lower NTproBNP.