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Randomized Controlled Trial
. 2023 Nov 1;8(11):1031-1040.
doi: 10.1001/jamacardio.2023.3003.

Repurposing the β3-Adrenergic Receptor Agonist Mirabegron in Patients With Structural Cardiac Disease: The Beta3-LVH Phase 2b Randomized Clinical Trial

Jean-Luc Balligand  1 , Dulce Brito  2   3   4 , Oana Brosteanu  5 , Barbara Casadei  6   7 , Christophe Depoix  1 , Frank Edelmann  8 , Vanessa Ferreira  9 , Gerasimos Filippatos  10 , Bernhard Gerber  1 , Damien Gruson  1 , Dirk Hasenclever  11 , Kristian Hellenkamp  12 , Ignatios Ikonomidis  10 , Bartosz Krakowiak  13 , Renaud Lhommel  1 , Masliza Mahmod  9 , Stefan Neubauer  9 , Alexandre Persu  1 , Stefan Piechnik  9 , Burkert Pieske  8 , Elisabeth Pieske-Kraigher  8 , Fausto Pinto  2   3   4 , Piotr Ponikowski  13 , Michele Senni  14 , Jean-Noël Trochu  15   16 , Nancy Van Overstraeten  1 , Rolf Wachter  12   17 , Anne-Catherine Pouleur  1
Affiliations
Randomized Controlled Trial

Repurposing the β3-Adrenergic Receptor Agonist Mirabegron in Patients With Structural Cardiac Disease: The Beta3-LVH Phase 2b Randomized Clinical Trial

Jean-Luc Balligand et al. JAMA Cardiol. .

Abstract

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 β3-adrenergic receptors (β3ARs) may represent a new target, as their activation attenuates LV remodeling.

Objective: To determine whether activation of β3ARs by repurposing a β3AR 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.

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Conflict of interest statement

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 für Herz-Kreislauf-Forschung, Deutsche Forschungsgemeinschaft, Bundesministerium für 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.

Figures

Figure 1.
Figure 1.. Trial Flow Diagram
CMR indicates cardiac magnetic resonance imaging; E/e′, ratio of peak early transmitral ventricular filling velocity to early diastolic tissue Doppler velocity; LVMI, left ventricular mass index.
Figure 2.
Figure 2.. Change in Primary Outcomes Over Time in the Mirabegron and Placebo Groups
A and B, Treatment-specific changes in left ventricular mass index (A) and E/e′ ratio (B) at postbaseline visits, deduced from the basic linear mixed model. Because the groups were randomized, the mean at baseline was not estimated separately by group. P values refer to treatment differences tested against 0.
Figure 3.
Figure 3.. Prespecified Subgroup Analyses
A and B, Results of prespecified explorative subgroup analyses for the left ventricular mass index (A) and E/e′ ratio (B) primary end points. The following subgroups were analyzed: age (≤65 or >65 years at baseline), sex, body mass index (BMI [calculated as weight in kilograms divided by height in meters squared] of ≤30 or >30 at baseline), presence of diabetes, atrial fibrillation, β-blocker use as standard treatment, and geographic region. The interaction test P value refers to the null hypothesis that the treatment effects are the same across subgroups. P values are not multiplicity adjusted.
See this image and copyright information in PMC

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