{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T06:11:27Z","timestamp":1794377487777,"version":"4.9.0"},"reference-count":15,"publisher":"American Medical Association (AMA)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Cardiol"],"published-print":{"date-parts":[[2025,6,1]]},"abstract":"\n Importance<\/jats:title>\n Excess body fat plays a pivotal role in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). HU6 is a novel, controlled metabolic accelerator that enhances mitochondrial uncoupling resulting in increased metabolism and fat-specific weight loss.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n To assess efficacy and safety of HU6 in reducing body weight, improving peak volume of oxygen consumption (VO\n 2<\/jats:sub>\n ) and body composition among patients with obesity-related HFpEF.\n <\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n The Exploratory Phase 2A, Double-Blind, Placebo-Controlled Dose Escalation Study of Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of HU6 for Subjects With Obese HFpEF (HuMAIN-HFpEF) trial was a multicenter, dose-escalation randomized clinical trial among patients with chronic stable HFpEF and obesity. Data were analyzed from July to October 2024.<\/jats:p>\n <\/jats:sec>\n \n Intervention<\/jats:title>\n HU6 treatment for 19 weeks, starting at 150 mg per day and potentially up titrated to 450 mg per day based on safety and tolerability vs placebo.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n The primary end point was change in body weight.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Of 66 participants randomized (mean [SD] age, 64.5 [12] years; 38 female [58%]; mean [SD] weight, 110.9\u2009[22.4] kg), 56 completed the trial. HU6 (vs placebo) significantly decreased weight (between-group difference, \u22122.86 kg; 95% CI, \u22124.68 to \u22121.04 kg;\n P<\/jats:italic>\n \u2009=\u2009.003), total fat mass (between-group difference, \u22122.96 kg; 95% CI, \u22124.50 to \u22121.42 kg;\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001), and percentage visceral fat (between-group difference,\u22121.3%; 95% CI, \u22122.1 to \u22120.5%;\n P<\/jats:italic>\n \u2009=\u2009.003), with no significant loss of muscle mass. There were no statistically significant changes in peak VO\n 2<\/jats:sub>\n , 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire score, high-sensitivity C-reactive protein level, N-terminal pro\u2013brain natriuretic peptide level, or diastolic function. Serious adverse events were noted in 5 participants (4 in the HU6\u2009group; 1 in the placebo\u2009group), including 1 death, all judged unrelated to treatment.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n Among patients with obesity-related HFpEF, treatment with HU6 for 19 weeks led to modest but statistically significant weight loss without significant changes in peak VO\n 2<\/jats:sub>\n . Larger trials of longer duration are warranted to determine whether longer-term administration of HU6 can improve exercise function, quality of life, and cardiovascular outcomes in this increasingly common disorder.\n <\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT05284617<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamacardio.2025.0103","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T11:00:47Z","timestamp":1741777247000},"page":"609","source":"Crossref","is-referenced-by-count":21,"title":["Novel Controlled Metabolic Accelerator for Obesity-Related HFpEF"],"prefix":"10.1001","volume":"10","author":[{"given":"Ambarish","family":"Pandey","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory D.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Medicine, Massachusetts General Brigham, Boston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry A.","family":"Borlaug","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjiv J.","family":"Shah","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Sauer","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Saint Luke\u2019s Mid America Heart Institute, Kansas City, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheldon","family":"Litwin","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Medical University of South Carolina, Charleston"},{"name":"Division of Cardiology, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kavita","family":"Sharma","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane K.","family":"Jorkasky","sequence":"additional","affiliation":[{"name":"Independent Consultant, Devon, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Tarka","sequence":"additional","affiliation":[{"name":"Independent Consultant, Phoenixville, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaharyar M.","family":"Khan","sequence":"additional","affiliation":[{"name":"Rivus Pharmaceuticals, Charlottesville, Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalane W.","family":"Kitzman","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine and Section on Geriatrics and Gerontology, Wake Forest University School of Medicine, Winston-Salem, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"10437","key":"hbr250002r1","doi-asserted-by":"publisher","first-page":"1635","DOI":"10.1016\/S0140-6736(24)00469-0","article-title":"Semaglutide vs placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomized trials.","volume":"403","author":"Butler","year":"2024","journal-title":"Lancet"},{"issue":"11","key":"hbr250002r2","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1056\/NEJMoa2032183","article-title":"Once-weekly semaglutide in adults with overweight or obesity.","volume":"384","author":"Wilding","year":"2021","journal-title":"N Engl J 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