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Repurposing the β(3)-Adrenergic Receptor Agonist Mirabegron in Patients With Structural Cardiac Disease: The Beta3-LVH Phase 2b Randomized Clinical Trial

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 β(3)-adrenergic receptors (β3ARs) may represen...

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Autores principales: Balligand, Jean-Luc, Brito, Dulce, Brosteanu, Oana, Casadei, Barbara, Depoix, Christophe, Edelmann, Frank, Ferreira, Vanessa, Filippatos, Gerasimos, Gerber, Bernhard, Gruson, Damien, Hasenclever, Dirk, Hellenkamp, Kristian, Ikonomidis, Ignatios, Krakowiak, Bartosz, Lhommel, Renaud, Mahmod, Masliza, Neubauer, Stefan, Persu, Alexandre, Piechnik, Stefan, Pieske, Burkert, Pieske-Kraigher, Elisabeth, Pinto, Fausto, Ponikowski, Piotr, Senni, Michele, Trochu, Jean-Noël, Van Overstraeten, Nancy, Wachter, Rolf, Pouleur, Anne-Catherine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Medical Association 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10512168/
https://www.ncbi.nlm.nih.gov/pubmed/37728907
http://dx.doi.org/10.1001/jamacardio.2023.3003
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author Balligand, Jean-Luc
Brito, Dulce
Brosteanu, Oana
Casadei, Barbara
Depoix, Christophe
Edelmann, Frank
Ferreira, Vanessa
Filippatos, Gerasimos
Gerber, Bernhard
Gruson, Damien
Hasenclever, Dirk
Hellenkamp, Kristian
Ikonomidis, Ignatios
Krakowiak, Bartosz
Lhommel, Renaud
Mahmod, Masliza
Neubauer, Stefan
Persu, Alexandre
Piechnik, Stefan
Pieske, Burkert
Pieske-Kraigher, Elisabeth
Pinto, Fausto
Ponikowski, Piotr
Senni, Michele
Trochu, Jean-Noël
Van Overstraeten, Nancy
Wachter, Rolf
Pouleur, Anne-Catherine
author_facet Balligand, Jean-Luc
Brito, Dulce
Brosteanu, Oana
Casadei, Barbara
Depoix, Christophe
Edelmann, Frank
Ferreira, Vanessa
Filippatos, Gerasimos
Gerber, Bernhard
Gruson, Damien
Hasenclever, Dirk
Hellenkamp, Kristian
Ikonomidis, Ignatios
Krakowiak, Bartosz
Lhommel, Renaud
Mahmod, Masliza
Neubauer, Stefan
Persu, Alexandre
Piechnik, Stefan
Pieske, Burkert
Pieske-Kraigher, Elisabeth
Pinto, Fausto
Ponikowski, Piotr
Senni, Michele
Trochu, Jean-Noël
Van Overstraeten, Nancy
Wachter, Rolf
Pouleur, Anne-Catherine
author_sort Balligand, Jean-Luc
collection PubMed
description 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 β(3)-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/m(2) for women or ≥115 g/m(2) 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/m(2) 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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spelling pubmed-105121682023-09-22 Repurposing the β(3)-Adrenergic Receptor Agonist Mirabegron in Patients With Structural Cardiac Disease: The Beta3-LVH Phase 2b Randomized Clinical Trial Balligand, Jean-Luc Brito, Dulce Brosteanu, Oana Casadei, Barbara Depoix, Christophe Edelmann, Frank Ferreira, Vanessa Filippatos, Gerasimos Gerber, Bernhard Gruson, Damien Hasenclever, Dirk Hellenkamp, Kristian Ikonomidis, Ignatios Krakowiak, Bartosz Lhommel, Renaud Mahmod, Masliza Neubauer, Stefan Persu, Alexandre Piechnik, Stefan Pieske, Burkert Pieske-Kraigher, Elisabeth Pinto, Fausto Ponikowski, Piotr Senni, Michele Trochu, Jean-Noël Van Overstraeten, Nancy Wachter, Rolf Pouleur, Anne-Catherine JAMA Cardiol Original Investigation 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 β(3)-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/m(2) for women or ≥115 g/m(2) 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/m(2) 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 American Medical Association 2023-09-20 2023-11 /pmc/articles/PMC10512168/ /pubmed/37728907 http://dx.doi.org/10.1001/jamacardio.2023.3003 Text en Copyright 2023 Balligand JL et al. JAMA Cardiology. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the CC-BY License.
spellingShingle Original Investigation
Balligand, Jean-Luc
Brito, Dulce
Brosteanu, Oana
Casadei, Barbara
Depoix, Christophe
Edelmann, Frank
Ferreira, Vanessa
Filippatos, Gerasimos
Gerber, Bernhard
Gruson, Damien
Hasenclever, Dirk
Hellenkamp, Kristian
Ikonomidis, Ignatios
Krakowiak, Bartosz
Lhommel, Renaud
Mahmod, Masliza
Neubauer, Stefan
Persu, Alexandre
Piechnik, Stefan
Pieske, Burkert
Pieske-Kraigher, Elisabeth
Pinto, Fausto
Ponikowski, Piotr
Senni, Michele
Trochu, Jean-Noël
Van Overstraeten, Nancy
Wachter, Rolf
Pouleur, Anne-Catherine
Repurposing the β(3)-Adrenergic Receptor Agonist Mirabegron in Patients With Structural Cardiac Disease: The Beta3-LVH Phase 2b Randomized Clinical Trial
title Repurposing the β(3)-Adrenergic Receptor Agonist Mirabegron in Patients With Structural Cardiac Disease: The Beta3-LVH Phase 2b Randomized Clinical Trial
title_full Repurposing the β(3)-Adrenergic Receptor Agonist Mirabegron in Patients With Structural Cardiac Disease: The Beta3-LVH Phase 2b Randomized Clinical Trial
title_fullStr Repurposing the β(3)-Adrenergic Receptor Agonist Mirabegron in Patients With Structural Cardiac Disease: The Beta3-LVH Phase 2b Randomized Clinical Trial
title_full_unstemmed Repurposing the β(3)-Adrenergic Receptor Agonist Mirabegron in Patients With Structural Cardiac Disease: The Beta3-LVH Phase 2b Randomized Clinical Trial
title_short Repurposing the β(3)-Adrenergic Receptor Agonist Mirabegron in Patients With Structural Cardiac Disease: The Beta3-LVH Phase 2b Randomized Clinical Trial
title_sort repurposing the β(3)-adrenergic receptor agonist mirabegron in patients with structural cardiac disease: the beta3-lvh phase 2b randomized clinical trial
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10512168/
https://www.ncbi.nlm.nih.gov/pubmed/37728907
http://dx.doi.org/10.1001/jamacardio.2023.3003
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