The BETA3LVH trial tested the hypothesis that repurposing mirabegron for the treatment of patients at risk of developing or worsening heart failure would be safe and prevent the development of cardiac hypertrophy with impairment of ventricular filling (leading to “heart failure with preserved or mildly reduced ejection fraction”).

Therefore, patients with signs of cardiac muscle hypertrophy but little or no clinical symptoms of heart failure were recruited in 8 european countries between 2016 and 2021; they were randomly assigned to take mirabegron (50 mg daily) or placebo for 12 months. Over these 12 months, they were regularly evaluated by clinical and imaging techniques to monitor functional and morphological signs of cardiac remodeling. The primary focus was the change between baseline and 12 months in ; i. left ventricular mass by cardiac magnetic resonance imaging; ii. Left ventricular filling by Doppler echocardiography. A number of additional variables were studied, e.g. exercise capacity, cardiac fibrosis, peripheral metabolism and biomarkers. A subset of patients were also examined by Positron Emission Tomography for any effect of mirabegron (versus placebo) on “brown” fat; and also by digital tonometry for any effect on endothelial function (i.e. regulating the capacity of vessels to dilate). Importantly, safety (i.e. incidence of adverse-including serious-events were carefully monitored over 12 months in the two treatment arms.

Despite the COVID-19 pandemic, the target 296 patients (calculated to yield sufficient statistical power to the trial) were randomized, of whom 147 received mirabegron and 149 received placebo. At the end of the 12 month-treatment, all patients with at least one measurement of either left ventricular mass or left ventricular filling were included in the primary analysis. The results show a neutral effect of mirabegron on both co-primary endpoints (i.e. no difference from placebo). Similarly, no difference from placebo was observed on all other endpoints. However, at the dose used, mirabegron can be considered safe, as the incidence of adverse events was similar between the two treatment arms.

The first important conclusion is that, at 50mg/day, i.e. the dose currently recommended for urological indications, mirabegron is safe in patients at high cardiovascular risk (mostly obese, hypertensive, with signs of cardiac structural remodeling). BETA3LVH is the first clinical trial testing this safety against placebo in such a high risk population.

The second conclusion from our study is that even in the placebo arm, we did not observe a worsening of cardiac hypertrophy or impairment of cardiac filling over the 12 month-observation period. This is probably due to high compliance of the patients to their standard medical care for their underlying conditions, i.e. most of them took anti-hypertensive medications that are already known to prevent cardiac hypertrophy.

The third conclusion, then, is that in the conditions of our trial, mirabegron at the standard dose of 50mg/day does not yield any additional benefit (versus placebo) over standard-of-care. But given the already potent background standard treatment, there was very little room to unveil an effect on our endpoints. Also, the abundance of the beta3 adrenergic receptor (the target of mirabegron) is known to be highest in hearts from late-stage cardiac failure. As we wanted to test the effect of mirabegron in a “prevention mode” in patients at very early stages of the disease, the dose of mirabegron used may not have been sufficient to efficiently hit its lowly-abundant targets.

Fortunately, new, more potent activators of the beta3-adrenergic receptor are coming on the market. These deserve to be tested in future clinical trials on patients with more advanced cardiac disease.

Acknowledgements: this was an academic investigator-initiated clinical trial funded by a European Commission Horizon 2020 grant and registered with ClinicalTrials.gov, NCT02599480. We thank all collaborators on the study, in the recruiting academic hospitals, core labs, coordinating and monitoring teams and biometry, and particularly all patients for their generous participation.