BACKGROUND: In the STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials, the GLP-1 receptor agonist semaglutide improved symptoms, physical limitations, bodyweight, and exercise function in people with obesity-related heart failure with preserved ejection fraction. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, we aimed to provide a more definitive assessment of the effects of semaglutide across a range of outcomes and to test whether these effects were consistent across key patient subgroups. METHODS: We conducted a prespecified pooled analysis of individual patient data from STEP-HFpEF and STEP-HFpEF DM, randomised, double-blind, placebo-controlled trials at 129 clinical research sites in 18 countries. In both trials, eligible participants were aged 18 years or older, had heart failure with a left ventricular ejection fraction of at least 45%, a BMI of at least 30 kg/m2, New York Heart Association class II-IV symptoms, and a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; a measure of heart failure-related symptoms and physical limitations) of less than 90 points. In STEP-HFpEF, people with diabetes or glycated haemoglobin A1c concentrations of at least 6·5% were excluded, whereas for inclusion in STEP-HFpEF DM participants had to have been diagnosed with type 2 diabetes at least 90 days before screening and to have an HbA1c of 10% or lower. In both trials, participants were randomly assigned to either 2·4 mg semaglutide once weekly or matched placebo for 52 weeks. The dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and bodyweight in all randomly assigned participants. Confirmatory secondary endpoints included change from baseline to week 52 in 6-min walk distance, a hierarchical composite endpoint (all-cause death, heart failure events, and differences in changes in KCCQ-CSS and 6-min walk distance); and C-reactive protein (CRP) concentrations. Heterogeneity in treatment effects was assessed across subgroups of interest. We assessed safety in all participants who received at least one dose of study drug. FINDINGS: Between March 19, 2021 and March 9, 2022, 529 people were randomly assigned in STEP-HFpEF, and between June 27, 2021 and Sept 2, 2022, 616 were randomly assigned in STEP-HFpEF DM. Overall, 1145 were included in our pooled analysis, 573 in the semaglutide group and 572 in the placebo group. Improvements in KCCQ-CSS and reductions in bodyweight between baseline and week 52 were significantly greater in the semaglutide group than in the placebo group (mean between-group difference for the change from baseline to week 52 in KCCQ-CSS 7·5 points [95% CI 5·3 to 9·8]; p<0·0001; mean between-group difference in bodyweight at week 52 -8·4% [-9·2 to -7·5]; p<0·0001). For the confirmatory secondary endpoints, 6-min walk distance (mean between-group difference at week 52 17·1 metres [9·2 to 25·0]) and the hierarchical composite endpoint (win ratio 1·65 [1·42 to 1·91]) were significantly improved, and CRP concentrations (treatment ratio 0·64 [0·56 to 0·72]) were significantly reduced, in the semaglutide group compared with the placebo group (p<0·0001 for all comparisons). For the dual primary endpoints, the efficacy of semaglutide was largely consistent across multiple subgroups, including those defined by age, race, sex, BMI, systolic blood pressure, baseline CRP, and left ventricular ejection fraction. 161 serious adverse events were reported in the semaglutide group compared with 301 in the placebo group. INTERPRETATION: In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide was superior to placebo in improving heart failure-related symptoms and physical limitations, and reducing bodyweight in participants with obesity-related heart failure with preserved ejection fraction. These effects were largely consistent across patient demographic and clinical characteristics. Semaglutide was well tolerated. FUNDING: Novo Nordisk.

Azienda Socio Sanitaria Territorial Papa Giovanni XXIII Bergamo Italy

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

Canadian VIGOUR Centre University of Alberta Edmonton AB Canada

Cardiology and Angiology Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

College of Health and Medicine Australian National University Canberra ACT Australia

Department of Cardiology Herlev Gentofte Hospital Hellerup Denmark; Department of Clinical Medicine University of Copenhagen Herlev Denmark

Department of Cardiology University Medical Center Groningen University of Groningen Groningen Netherlands

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

Department of Cardiovascular Medicine and Section on Geriatrics and Gerontology Wake Forest School of Medicine Winston Salem NC USA

Department of Cardiovascular Medicine Mayo Clinic Rochester MN 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 UK; National Institute for Health and Care Research Leicester Biomedical Research Centre Leicester UK

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

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

Division of Cardiovascular Sciences Faculty of Biology Medicine and Health University of Manchester Manchester UK

Heart and Vascular Centre Semmelweis University Budapest Hungary

Heart Failure and Cardiac Transplantation Johns Hopkins University Heart Failure with Preserved Ejection Fraction Program Johns Hopkins Hospital Baltimore MD USA

Heart Failure Unit Department of Cardiology Rabin Medical Center Faculty of Medicine Tel Aviv University Tel Aviv Israel

Hospital Clínico Universitario de Valencia INCLIVA Universidad de Valencia Valencia Spain; Centro de Investigación Biomédica en Red Cardiovascular Valencia Spain

Institute for Clinical and Experimental Medicine IKEM Prague Czech Republic

Instituto de Cardiologia J F Cabral Corrientes Argentina

Max Super Speciality Hospital Saket New Delhi India

Medical University of Graz Graz Austria

Novo Nordisk Søborg Denmark

School of Cardiovascular and Metabolic Health University of Glasgow Glasgow UK

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

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ClinicalTrials.gov
NCT04788511, NCT04916470