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Background: The majority of patients with heart failure with preserved ejection fraction (HFpEF) have the obesity phenotype, but no therapies specifically targeting obesity in HFpEF exist., Objectives: The aim of this study was to describe the design and baseline characteristics of 2 trials of semaglutide, a glucagon-like peptide-1 receptor agonist, in patients with the obesity HFpEF phenotype: STEP-HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF; NCT04788511) and STEP-HFpEF DM (Semaglutide Treatment Effect in People with obesity and HFpEF and type 2 diabetes; NCT04916470)., Methods: Both STEP-HFpEF and STEP-HFpEF DM are international multicenter, double-blind, placebo-controlled trials that randomized adults with HFpEF and a body mass index ≥30 kg/m 2 to once-weekly semaglutide at a dose of 2.4 mg or placebo. Participants were eligible if they had a left ventricular ejection fraction (LVEF) ≥45%; NYHA functional class II to IV; a Kansas City Cardiomyopathy Questionnaire (KCCQ)-Clinical Summary Score (CSS) <90 points; and ≥1 of the following: elevated filling pressures, elevated natriuretic peptides plus structural echocardiographic abnormalities, recent heart failure hospitalization plus ongoing diuretic use, and/or structural abnormalities. The dual primary endpoints are the 52-week change in the KCCQ-CSS and body weight., Results: In STEP-HFpEF and STEP-HFpEF DM (N = 529 and N = 617, respectively), nearly half were women, and most had severe obesity (median body mass index of 37 kg/m 2 ) with typical features of HFpEF (median LVEF of 57%, frequent comorbidities, and elevated natriuretic peptides). Most participants received diuretic agents and renin-angiotensin blockers at baseline, and approximately one-third were on mineralocorticoid receptor antagonists. Sodium-glucose cotransporter-2 inhibitor use was rare in STEP-HFpEF but not in STEP HFpEF DM (32%). Patients in both trials had marked symptomatic and functional impairments (KCCQ-CSS ∼59 points, 6-minute walking distance ∼300 m)., Conclusions: In total, STEP-HFpEF program randomized 1,146 participants with the obesity phenotype of HFpEF and will determine whether semaglutide improves symptoms, physical limitations, and exercise function in addition to weight loss in this vulnerable group., Competing Interests: Funding Support and Author Disclosures The STEP-HFpEF and STEP-HFpEF DM trials were funded by Novo Nordisk. Dr Kosiborod served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received research grants from AstraZeneca and Boehringer Ingelheim; holds stocks in Artera Health and Saghmos Therapeutics; has received honorarium from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has received other research support from AstraZeneca. Dr Abildstrøm is employed by Novo Nordisk; and has shares in Novo Nordisk. Dr Borlaug has received research support from the National Institutes of Health and the United States Department of Defense; has received research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations; and is named inventor (U.S. patent number 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Butler is a consultant to Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Roche, Sequana, SQ Innovation, 3live, and Vifor. Dr Christensen is employed by Novo Nordisk; and has shares in Novo Nordisk. Dr Davies has acted as a consultant, advisory board member, and speaker for Boehringer Ingelheim, Lilly, Novo Nordisk, and Sanofi; is an advisory board member and speaker for AstraZeneca; is an advisory board member for Pfizer, Medtronic, and ShouTi Pharma Inc; is a speaker for Novartis, Sanofi, and Amgen; and has received grants in support of investigator and investigator-initiated trials from AstraZeneca, Sanofi-Aventis, Eli Lilly, Boehringer Ingelheim, Janssen, and Novo Nordisk. Dr Hovingh is employed by Novo Nordisk and The Amsterdam University Medical Center; and has shares in Novo Nordisk. Dr Kitzman has served as a paid consultant for Novo Nordisk; and his institution has received grant awards from Novo Nordisk. Dr Lindegaard is employed by Novo Nordisk; and has shares in Novo Nordisk. Dr Møller is employed by Novo Nordisk; and has shares in Novo Nordisk. Dr Shah has been supported by research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423); and reports receiving consulting fees from Abbott, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, Metabolic Flux, MyoKardia, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Treppendahl is employed by Novo Nordisk; and has shares in Novo Nordisk. Dr Verma has received speaking honoraria and/or consulting fees from Abbott, AstraZeneca, Bayer, Boehringer-Ingelheim, Novo Nordisk, Novartis, Merck, PhaseBio, HLS Therapeutics, Amarin, Eli Lilly, Janssen, Pfizer, TIMI, and Canadian Medical and Surgical Knowledge Translation Research Group. Dr Petrie has received research grants or consultancy fees from SQ Innovations, AstraZeneca, Roche, Boehringer Ingelheim, Pharmacosmos, Eli Lilly, Napp Pharmaceuticals, Novartis, and Novo Nordisk; has served on committees for AbbVie, Akero, Alnylam, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Resverlogix, Teikoku, New Amsterdam, and Novo Nordisk; and is director of Global Clinical Trial Partners., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)