• Mikhail N Kosiborod, Mark C Petrie, Barry A Borlaug, Javed Butler, Melanie J Davies, G Kees Hovingh, Dalane W Kitzman, Daniél V Møller, Marianne B Treppendahl, Subodh Verma, Thomas J Jensen, Karoline Liisberg, Marie L Lindegaard, Walter Abhayaratna, Fozia Z Ahmed, Tuvia Ben-Gal, Vijay Chopra, Justin A Ezekowitz, Michael Fu, Hiroshi Ito, Małgorzata Lelonek, Vojtěch Melenovský, Bela Merkely, Julio Núñez, Eduardo Perna, Morten Schou, Michele Senni, Kavita Sharma, Peter van der Meer, Dirk Von Lewinski, Dennis Wolf, Sanjiv J Shah, and STEP-HFpEF DM Trial Committees and Investigators.
• From the Department of Cardiovascular Disease, Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City School of Medicine, Kansas City (M.N.K.); the School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow (M.C.P.), the Diabetes Research Centre, University of Leicester, and the NIHR Leicester Biomedical Research Centre, Leicester (M.J.D.), and the Division of Cardiovascular Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester (F.Z.A.) - all in the United Kingdom; the Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (B.A.B.); the Baylor Scott and White Research Institute, Dallas (J.B.); the Department of Medicine, University of Mississippi, Jackson (J.B.); Novo Nordisk, Søborg (G.K.H., D.V.M., M.B.T., T.J.J., K.L., M.L.L.), and the Department of Cardiology, Herlev-Gentofte Hospital, University of Copenhagen, Herlev (M. Schou) - both in Denmark; the Department of Cardiovascular Medicine and Section on Geriatrics and Gerontology, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.); the Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto (S.V.), and the University of Alberta, Edmonton (J.A.E.) - both in Canada; the College of Health and Medicine, Australian National University, Canberra, ACT, Australia (W.A.); the Heart Failure Unit, Cardiology Department, Rabin Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel (T.B.-G.); Max Super Speciality Hospital, Saket, New Delhi, India (V.C.); the Section of Cardiology, Department of Medicine, Sahlgrenska University Hospital-Östra, Gothenburg, Sweden (M.F.); the Department of General Internal Medicine 3, Kawasaki Medical School, Okayama, Japan (H.I.); the Department of Noninvasive Cardiology, Medical University of Lodz, Lodz, Poland (M.L.); the Institute for Clinical and Experimental Medicine, Prague, Czech Republic (V.M.); the Heart and Vascular Center, Semmelweis University, Budapest, Hungary (B.M.); Hospital Clínico Universitario de Valencia, INCLIVA, Universidad de Valencia, and CIBER (Centro de Investigación Biomédica en Red) Cardiovascular - both in Valencia, Spain (J.N.); Instituto de Cardiologia J.F. Cabral, Corrientes, Argentina (E.P.); ASST (Azienda Socio Sanitaria Territoriale) Papa Giovanni XXIII, Bergamo, Italy (M. Senni); the Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore (K.S.); the Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (P.M.); the Medical University of Graz, Graz, Austria (D.V.L.); Cardiology and Angiology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany (D.W.); and the Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago (S.J.S.).
• N. Engl. J. Med. 2024 Apr 18; 390 (15): 139414071394-1407.

BackgroundObesity and type 2 diabetes are prevalent in patients with heart failure with preserved ejection fraction and are characterized by a high symptom burden. No approved therapies specifically target obesity-related heart failure with preserved ejection fraction in persons with type 2 diabetes.MethodsWe randomly assigned patients who had heart failure with preserved ejection fraction, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more, and type 2 diabetes to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level.ResultsA total of 616 participants underwent randomization. The mean change in the KCCQ-CSS was 13.7 points with semaglutide and 6.4 points with placebo (estimated difference, 7.3 points; 95% confidence interval [CI], 4.1 to 10.4; P<0.001), and the mean percentage change in body weight was -9.8% with semaglutide and -3.4% with placebo (estimated difference, -6.4 percentage points; 95% CI, -7.6 to -5.2; P<0.001). The results for the confirmatory secondary end points favored semaglutide over placebo (estimated between-group difference in change in 6-minute walk distance, 14.3 m [95% CI, 3.7 to 24.9; P = 0.008]; win ratio for hierarchical composite end point, 1.58 [95% CI, 1.29 to 1.94; P<0.001]; and estimated treatment ratio for change in CRP level, 0.67 [95% CI, 0.55 to 0.80; P<0.001]). Serious adverse events were reported in 55 participants (17.7%) in the semaglutide group and 88 (28.8%) in the placebo group.ConclusionsAmong patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure-related symptoms and physical limitations and greater weight loss than placebo at 1 year. (Funded by Novo Nordisk; STEP-HFpEF DM ClinicalTrials.gov number, NCT04916470.).Copyright © 2024 Massachusetts Medical Society.

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