PMID- 37728907 OWN - NLM STAT- MEDLINE DCOM- 20231114 LR - 20240320 IS - 2380-6591 (Electronic) IS - 2380-6583 (Print) VI - 8 IP - 11 DP - 2023 Nov 1 TI - Repurposing the beta3-Adrenergic Receptor Agonist Mirabegron in Patients With Structural Cardiac Disease: The Beta3-LVH Phase 2b Randomized Clinical Trial. PG - 1031-1040 LID - 10.1001/jamacardio.2023.3003 [doi] AB - IMPORTANCE: Left ventricular (LV) hypertrophy contributes to the onset and progression of heart failure (HF), particularly for patients with pre-HF (stage B) for whom no treatment has yet proven effective to prevent transition to overt HF (stage C). The beta3-adrenergic receptors (beta3ARs) may represent a new target, as their activation attenuates LV remodeling. OBJECTIVE: To determine whether activation of beta3ARs by repurposing a beta3AR agonist, mirabegron, is safe and effective in preventing progression of LV hypertrophy and diastolic dysfunction among patients with pre- or mild HF. DESIGN, SETTING, AND PARTICIPANTS: The Beta3-LVH prospective, triple-blind, placebo-controlled phase 2b randomized clinical trial enrolled patients between September 12, 2016, and February 26, 2021, with a follow-up of 12 months. The trial was conducted at 10 academic hospitals in 8 countries across Europe (Germany, Poland, France, Belgium, Italy, Portugal, Greece, and the UK). Patients aged 18 years or older with or without HF symptoms (maximum New York Heart Association class II) were screened for the presence of LV hypertrophy (increased LV mass index [LVMI] of >/=95 g/m2 for women or >/=115 g/m2 for men) or maximum wall thickness of 13 mm or greater using echocardiography. Data analysis was performed in August 2022. INTERVENTION: Participants were randomly assigned (1:1) to mirabegron (50 mg/d) or placebo, stratified by the presence of atrial fibrillation and/or type 2 diabetes, for 12 months. MAIN OUTCOMES AND MEASURES: The primary end points were LVMI determined using cardiac magnetic resonance imaging and LV diastolic function (early diastolic tissue Doppler velocity [E/e'] ratio assessed using Doppler echocardiography) at 12 months. Patients with at least 1 valid measurement of either primary end point were included in the primary analysis. Safety was assessed for all patients who received at least 1 dose of study medication. RESULTS: Of the 380 patients screened, 296 were enrolled in the trial. There were 147 patients randomized to mirabegron (116 men [79%]; mean [SD] age, 64.0 [10.2] years) and 149 to placebo (112 men [75%]; mean [SD] age, 62.2 [10.9] years). All patients were included in the primary intention-to-treat analysis. At 12 months, the baseline and covariate-adjusted differences between groups included a 1.3-g/m2 increase in LVMI (95% CI, -0.15 to 2.74; P = .08) and a -0.15 decrease in E/e' (95% CI, -0.69 to 0.4; P = .60). A total of 213 adverse events (AEs) occurred in 82 mirabegron-treated patients (including 31 serious AEs in 19 patients) and 215 AEs occurred in 88 placebo-treated patients (including 30 serious AEs in 22 patients). No deaths occurred during the trial. CONCLUSIONS: In this study, mirabegron therapy had a neutral effect on LV mass or diastolic function over 12 months among patients who had structural heart disease with no or mild HF symptoms. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02599480. FAU - Balligand, Jean-Luc AU - Balligand JL AD - Institut de Recherche Experimentale et Clinique, Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain, Brussels, Belgium. FAU - Brito, Dulce AU - Brito D AD - Department of Cardiology, Centro Hospitalar Universitario Lisboa Norte, Lisboa, Portugal. AD - Centro Academico de Medicina de Lisboa, Universidade de Lisboa, Lisboa, Portugal. AD - Faculdade de Medicina, Centro Cardiovascular, Universidade de Lisboa, Lisboa, Portugal. FAU - Brosteanu, Oana AU - Brosteanu O AD - Clinical Trial Centre Leipzig, Universitat Leipzig, Leipzig, Germany. FAU - Casadei, Barbara AU - Casadei B AD - Division of Cardiovascular Medicine, Radcliffe Department of Medicine, British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, United Kingdom. AD - National Institute of Health Research Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, United Kingdom. FAU - Depoix, Christophe AU - Depoix C AD - Institut de Recherche Experimentale et Clinique, Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain, Brussels, Belgium. FAU - Edelmann, Frank AU - Edelmann F AD - Department of Cardiology, German Centre for Cardiovascular Research, Charite University Campus Virchow, Berlin, Germany. FAU - Ferreira, Vanessa AU - Ferreira V AD - Radcliffe Department of Medicine, Oxford Centre for Clinical Magnetic Resonance Research, University of Oxford, Oxford, United Kingdom. FAU - Filippatos, Gerasimos AU - Filippatos G AD - Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece. FAU - Gerber, Bernhard AU - Gerber B AD - Institut de Recherche Experimentale et Clinique, Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain, Brussels, Belgium. FAU - Gruson, Damien AU - Gruson D AD - Institut de Recherche Experimentale et Clinique, Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain, Brussels, Belgium. FAU - Hasenclever, Dirk AU - Hasenclever D AD - Institute for Medical Informatics, Statistics, and Epidemiology, Universitat Leipzig, Leipzig, Germany. FAU - Hellenkamp, Kristian AU - Hellenkamp K AD - Department of Cardiology and Pneumology, German Centre for Cardiovascular Research, Universitatsmedizin Gottingen, Gottingen, Germany. FAU - Ikonomidis, Ignatios AU - Ikonomidis I AD - Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece. FAU - Krakowiak, Bartosz AU - Krakowiak B AD - Department of Cardiology, Centre for Heart Diseases, Clinical Military Hospital, Wroclaw Medical University, Wroclaw, Poland. FAU - Lhommel, Renaud AU - Lhommel R AD - Institut de Recherche Experimentale et Clinique, Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain, Brussels, Belgium. FAU - Mahmod, Masliza AU - Mahmod M AD - Radcliffe Department of Medicine, Oxford Centre for Clinical Magnetic Resonance Research, University of Oxford, Oxford, United Kingdom. FAU - Neubauer, Stefan AU - Neubauer S AD - Radcliffe Department of Medicine, Oxford Centre for Clinical Magnetic Resonance Research, University of Oxford, Oxford, United Kingdom. FAU - Persu, Alexandre AU - Persu A AD - Institut de Recherche Experimentale et Clinique, Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain, Brussels, Belgium. FAU - Piechnik, Stefan AU - Piechnik S AD - Radcliffe Department of Medicine, Oxford Centre for Clinical Magnetic Resonance Research, University of Oxford, Oxford, United Kingdom. FAU - Pieske, Burkert AU - Pieske B AD - Department of Cardiology, German Centre for Cardiovascular Research, Charite University Campus Virchow, Berlin, Germany. FAU - Pieske-Kraigher, Elisabeth AU - Pieske-Kraigher E AD - Department of Cardiology, German Centre for Cardiovascular Research, Charite University Campus Virchow, Berlin, Germany. FAU - Pinto, Fausto AU - Pinto F AD - Department of Cardiology, Centro Hospitalar Universitario Lisboa Norte, Lisboa, Portugal. AD - Centro Academico de Medicina de Lisboa, Universidade de Lisboa, Lisboa, Portugal. AD - Faculdade de Medicina, Centro Cardiovascular, Universidade de Lisboa, Lisboa, Portugal. FAU - Ponikowski, Piotr AU - Ponikowski P AD - Department of Cardiology, Centre for Heart Diseases, Clinical Military Hospital, Wroclaw Medical University, Wroclaw, Poland. FAU - Senni, Michele AU - Senni M AD - Department of Cardiology, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, University of Milano-Bicocca, Bergamo, Italy. FAU - Trochu, Jean-Noel AU - Trochu JN AD - Institut du Thorax, Centre National de la Recherche Scientifique, Nantes Universite, Nantes, France. AD - L'Institut National de la Sante et de la Recherche Medicale, Centre Hospitalier Universitaire de Nantes, Nantes Universite, Nantes, France. FAU - Van Overstraeten, Nancy AU - Van Overstraeten N AD - Institut de Recherche Experimentale et Clinique, Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain, Brussels, Belgium. FAU - Wachter, Rolf AU - Wachter R AD - Department of Cardiology and Pneumology, German Centre for Cardiovascular Research, Universitatsmedizin Gottingen, Gottingen, Germany. AD - Department of Cardiology, University Hospital Leipzig, Leipzig, Germany. FAU - Pouleur, Anne-Catherine AU - Pouleur AC AD - Institut de Recherche Experimentale et Clinique, Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain, Brussels, Belgium. LA - eng SI - ClinicalTrials.gov/NCT02599480 GR - CH/12/3/29609/BHF_/British Heart Foundation/United Kingdom PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - United States TA - JAMA Cardiol JT - JAMA cardiology JID - 101676033 RN - 0 (Adrenergic Agonists) RN - MVR3JL3B2V (mirabegron) SB - IM MH - Female MH - Humans MH - Male MH - Middle Aged MH - Adrenergic Agonists/therapeutic use MH - *Diabetes Mellitus, Type 2 MH - *Heart Failure/drug therapy MH - Hypertrophy, Left Ventricular MH - Prospective Studies MH - Aged PMC - PMC10512168 COIS- Conflict of Interest Disclosures: Dr Balligand reported receiving grants from the European Commission during the conduct of the study, grants from Novartis and Daiichi-Sankyo outside the submitted work, and consulting fees from Amgen, Novartis, and Daiichi-Sankyo outside the submitted work. Dr Balligand also reported being a minor shareholder of Spinovit srl and serving as a board member for the Wallonia Health and Biotech Cluster, Biowin, and the AstraZeneca Foundation. Dr Casadei reported receiving grants from the British Heart Foundation and the UK National Institute for Health and Care Research (NIHR); in-kind clinical trial support from IRhythm; speaking fees from the Menarini Foundation; and expert fees from the Fondation Leducq, German Centre for Cardiovascular Research, and UK Medical Research Council outside the submitted work. Dr Ferreira reported receiving grants from the British Heart Foundation and the NIHR Oxford Biomedical Research Centre during the conduct of the study. Dr Ferreira also reported having patents licensed to Oxford University Innovation (WO/2020/161481, WO/2021/044153, and WO/2020/234570) outside the submitted work. Dr Filippatos reported serving as a European Commission committee member and receiving lecture and/or expert fees from Bayer, Boehringer Ingelheim, Medtronic, Vifor, Amgen, Servier, Impulse Dynamics, and Novartis during the conduct of the study. Dr Gerber reported receiving lecture fees from Servier and serving on a Bristol Myers Squibb advisory board outside the submitted work. Dr Hasenclever reported receiving grants from the European Commission Horizon 2020 Framework Programme during the conduct of the study. Dr Hellenkamp reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Springer Medizin Verlag, and Deutsche Gezellshaft Kardiologie and travel support from Abbott and Bayer outside the submitted work. Dr Ikonomidis reported receiving lecture fees from Novartis, AstraZeneca, Abbott, Boehringer Ingelheim, Novo Nordisk, and Bayer outside the submitted work. Dr Krakowiak reported receiving grants from the European Union during the conduct of the study and personal fees from Boehringer Ingelheim, American Regent, Ionis Pharmaceuticals, Corvia Medical, V-Wave, Novo Nordisk, Applied Therapeutics, AstraZeneca, NewAmsterdam Pharma BV, Servier, and Janssen-Cilag outside the submitted work. Dr Lhommel reported receiving grants from the European Commission during the conduct of the study and consulting fees from GE Healthcare and Advanced Accelerator Applications (a Novartis company) outside the submitted work. Dr Piechnik reported receiving grants from the European Commission during the conduct of the study, nonfinancial support from Siemens outside the submitted work, and grants from the British Heart Foundation Oxford Center of Research Excellence outside the submitted work. Dr Piechnik also had a patent (US20120078084A1) licensed to Siemens. Dr Pieske reported receiving consulting and/or lecture fees or congress sponsorship from Bayer, MSD, Novartis, Boehringer Ingelheim, AstraZeneca, Daiichi-Sankyo, Boston Scientific, Edwards, and Bristol Myers Squibb outside the submitted work. Dr Pieske also reported serving on advisory boards of Novartis, Bayer, and MSD and being a minor shareholder of Imaging Clinical Trials Services (ICTS) GmbH. Dr Pieske-Kraigher reported being a shareholder of ICTS GmbH. Dr Pinto reported serving on the Vifor advisory board and as president of the World Heart Federation (2021-2022). Dr Senni reported receiving consulting and lecture fees from Novartis, Bayer, Merck, MSD, Vifor, AstraZeneca, Abbott, Boehringer Ingelheim, and Novo Nordisk outside the submitted work. Dr Trochu reported receiving grants from the European Commission Horizon 2020 Framework Programme during the conduct of the study. Dr Trochu also reported receiving consulting fees from Bayer, Bristol Myers Squibb, Abbott, AstraZeneca, and Novartis; lecture fees from Boehringer Ingelheim and Vifor; and congress travel sponsorship from Corvia outside the submitted work. Dr Van Overstraeten reported receiving grants from the European Commission Horizon 2020 Framework Programme during the conduct of the study. Dr Van Overstraeten also reported receiving personal fees from and had a patent licensed to Spinovit srl outside the submitted work. Dr Wachter reported receiving grants from the European Union during the conduct of the study. Dr Wachter also reported receiving grants from Deutsches Zentrum fur Herz-Kreislauf-Forschung, Deutsche Forschungsgemeinschaft, Bundesministerium fur Bildung und Forschung, and Medtronic; and consulting and/or lecture fees from Bayer, CVRx, Medtronic, Servier, Novartis, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Pharmacosmos, and Daiichi-Sankyo outside the submitted work. Dr Pouleur reported receiving grants from the European Commission Horizon 2020 Framework Programme during the conduct of the study and consulting and/or speaker fees from AstraZeneca, Bayer, Boehringer Ingelheim, Vifor, Pfizer, and Janssen outside the submitted work. No other disclosures were reported. EDAT- 2023/09/20 18:42 MHDA- 2023/11/09 06:42 PMCR- 2023/09/20 CRDT- 2023/09/20 12:03 PHST- 2023/11/09 06:42 [medline] PHST- 2023/09/20 18:42 [pubmed] PHST- 2023/09/20 12:03 [entrez] PHST- 2023/09/20 00:00 [pmc-release] AID - 2809846 [pii] AID - hoi230043 [pii] AID - 10.1001/jamacardio.2023.3003 [doi] PST - ppublish SO - JAMA Cardiol. 2023 Nov 1;8(11):1031-1040. doi: 10.1001/jamacardio.2023.3003.