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 (Semaglutide Treatment Effect in People with Obesity and HFpEF) program. Whether benefits were due to mechanical unloading or effects on HF pathobiology is uncertain. OBJECTIVES: This study sought to determine if semaglutide 2.4 mg reduced N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with obesity-related HFpEF and compare treatment responses by baseline NT-proBNP. METHODS: This was a prespecified secondary analysis of pooled data from 2 double-blind, placebo-controlled, randomized trials (STEP-HFpEF [Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity] and STEP-HFpEF DM [Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes]) testing effects of semaglutide in patients with obesity-related HFpEF. The main outcomes were change in NT-proBNP at 52 weeks and change in the dual primary endpoints of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and body weight by baseline NT-proBNP. RESULTS: In total, 1,145 patients were randomized. Semaglutide compared with placebo reduced NT-proBNP 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 NT-proBNP (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; P interaction = 0.02; baseline NT-proBNP as a continuous variable: P interaction = 0.004). Reductions in body weight were consistent across baseline NT-proBNP levels (P interaction = 0.21). CONCLUSIONS: In patients with obesity-related HFpEF, semaglutide reduced NT-proBNP. Participants with higher baseline NT-proBNP had a similar degree of weight loss but experienced larger reductions in HF-related symptoms and physical limitations with semaglutide than those with lower NT-proBNP.

Baylor Scott and White Research Institute Dallas Texas USA; Department of Medicine University of Mississippi Jackson Mississippi USA

Department of Cardiovascular Disease Saint Luke's Mid America Heart Institute University of Missouri Kansas City School of Medicine Kansas City Missouri USA

Department of Cardiovascular Medicine and Section on Geriatrics and Gerontology Wake Forest University School of Medicine Winston Salem North Carolina USA

Department of Cardiovascular Medicine Mayo Clinic Rochester Minnesota USA

Department of General Internal Medicine 3 Kawasaki Medical School Okayama Japan

Department of Noninvasive Cardiology Medical University of Lodz Lodz Poland

Diabetes Research Centre University of Leicester Leicester United Kingdom; NIHR Leicester Biomedical Research Centre Leicester United Kingdom

Division of Cardiac Surgery Li Ka Shing Knowledge Institute of St Michael's Hospital Unity Health Toronto University of Toronto Toronto Ontario Canada

Division of Cardiology Department of Medicine Northwestern University Feinberg School of Medicine Chicago Illinois USA

Division of Cardiology The Johns Hopkins University School of Medicine Baltimore Maryland USA

Institute for Clinical and Experimental Medicine Prague Czech Republic

Instituto de Cardiología de Corrientes J F Cabral Corrientes Argentina

Novo Nordisk A S Søborg Denmark

School of Cardiovascular and Metabolic Health University of Glasgow Glasgow United Kingdom

Section of Cardiology Department of Medicine Sahlgrenska University Hospital Ostra Gothenburg Sweden

University of Alberta Edmonton Alberta Canada