Mirabegron has failed to prevent the progression of structural heart disease to more advance stages, according to results of the Beta3-LVH trial presented today at the American Heart Association Scientific Sessions 2022 in Chicago, US and online.1 The research was conducted by a consortium of European partners including the European Society of Cardiology (ESC).

Mirabegron is a beta-3 adrenergic receptor agonist currently used for the treatment of overactive bladder disease. Beta3-LVH was the first large clinical trial to evaluate the effects of a standard therapeutic dose of mirabegron on left ventricular mass and diastolic function in patients with left ventricular hypertrophy.

Although the trial was neutral for the primary endpoint, it did meet the objective of demonstrating safety of the clinically used dose of mirabegron in patients with cardiovascular risk factors,” said study author Professor Jean-Luc Balligand of the University of Louvain, Brussels, Belgium. “The majority of patients in the trial had hypertension and were obese, while nearly a fifth had type 2 diabetes and 8% had atrial fibrillation. The incidence of adverse events with mirabegron over 12 months was minimal and did not differ from placebo.”

It is estimated that 2–3% of adults in developed countries have heart failure, of which up to half have preserved left ventricular ejection fraction.2 Left ventricular hypertrophy and fibrosis contribute to the onset and progression of heart failure with preserved ejection fraction. There are currently no established therapies to prevent the progression of cardiac hypertrophy and reduce the incidence of heart failure with preserved ejection fraction. In preclinical studies, activation of beta-3 adrenergic receptors protected from adverse cardiovascular tissue remodelling.

This European multicentre phase IIb trial enrolled 296 patients with left ventricular hypertrophy (i.e. increased left ventricular mass index [LVMi] or increased wall thickening) by echocardiography and no or mild heart failure symptoms (up to New York Heart Association [NYHA] class II). Participants were randomly assigned to receive mirabegron (n=147) or placebo (n=149) for 12 months. The co-primary endpoints were LVMi by cardiac magnetic resonance imaging (MRI) and left ventricular diastolic function (assessed by the E/e’ ratio) at 12 months.  Secondary endpoints included indicators of myocardial remodelling and function, namely cardiac fibrosis and left atrial volume index (both by cardiac MRI), maximal exercise capacity (peak VO2 max) and laboratory markers (including NT-pro-BNP, glycaemic control and high-sensitivity troponin T).

The average age of participants was 63 years and 77% were men. At baseline, the mean (pooled; standard error of the mean [SEM]) LVMi was 59.6 (0.69) g/m2, and E/e’ was 9.51 (0.18). The baseline and covariates adjusted difference between mirabegron and placebo in LVMi at 12 months was +1.3 g/m2 (95% confidence interval [CI]: -0.15; 2.74; p=0.079); and in E/e’ at 12 months was -0.15 (95% CI: -0.69; 0.4; p=0.6), which did not reach the pre-defined statistical significance level.

Mirabegron had no effect on any of the secondary outcomes, except for a small decrease in plasma high-sensitivity troponin T at 12 months (p<0.01).

Professor Balligand said: “Patients in the trial had high cardiovascular risk profiles but no, or mild, symptoms and were well treated with standard of care therapies. There was therefore little room to unveil any improvement with mirabegron compared to placebo, particularly on a relatively short time scale. In addition, expression of the beta-3 receptor in the heart increases during the later stages of heart failure, meaning that expression was likely low in our study population, and we used just the standard dose of the drug. A small pilot study previously found that one week of 300 mg mirabegron/day was beneficial in heart failure patients with NYHA class III to IV, so high expression of the receptor and a high dose of the agonist.”

He concluded:

Future studies should include patients with more advanced heart failure for longer time periods, and either a higher dose of mirabegron or a newer, more potent, beta-3 agonist such as vibegron.”