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A multi-center randomized, placebo-controlled trial of mirabegron, a new beta3-adrenergic receptor agonist on left ventricular mass and diastolic function in patients with structural heart disease

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Could a repurposed drug help people at risk of heart failure?

An EU-supported project has tested if repurposing mirabegron, a drug known to activate beta3-adrenergic receptors and improve bladder muscle function, could benefit people at risk of heart failure.

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Heart failure with preserved ejection fraction (HFpEF) is when the heart’s left ventricle ejects blood effectively but can’t then achieve the suction needed to refill properly. The result is diminished cardiac output reducing oxygen supply around the body, typically felt during exertion. Treatments are mainly limited to the drugs sacubitril/valsartan, especially for patients on the lower end of ejection fraction, and SGLT2 inhibitors, recently shown to be beneficial for most patients. The BETA3_LVH project tested whether repurposing the drug mirabegron, currently used to treat bladder conditions, could also work for HFpEF. “As we had discovered that the beta3-adrenoreceptor in the bladder that mirabegron activates was also present in the heart, we wanted to know if it could protect patients from HFpEF,” explains Jean-Luc Balligand, coordinator of the EU-funded project. However, a phase II clinical trial found that administering the standard clinical dose of 50 mg of mirabegron daily, had a neutral effect both on hypertrophy (cardiac muscle thickness – a risk factor for HFpEF) and on left ventricular filling. “While we couldn’t demonstrate a role for the beta3-adrenoreceptor in our trial, we can’t yet exclude it. Crucially, we were the first to show that mirabegron is safe for patients at risk of cardiovascular disease,” adds Balligand.

The promise of beta3

Beta3 is an adrenergic receptor sensitive to stress hormones. It comprises clusters of proteins on a cell’s surface that bind to extracellular molecules, triggering signalling for specific cellular responses. Beta3 is interesting for potential treatments because it can dilate vessels and degrade fat and is expressed more in heart disease while also remaining functional in the failing heart. “Animal models have shown that beta3 protects the heart from hypertrophy and fibrosis, which both lead to heart failure,” remarks Balligand.

Clinical testing

The team’s phase II clinical trial comprised 296 adult patients recruited from 10 European hospitals, randomly assigned to receive mirabegron or a placebo over 12 months. The participants were screened for signs of cardiac hypertrophy, alongside cardiovascular risk factors. 90 % were hypertensive, 20 % diabetic, and most overweight or obese. Patients were monitored using echocardiography and cardiac magnetic resonance imaging (MRI) which image the working heart in 2D and 3D. Combined, these enabled the team to evaluate the size of the heart, including any cardiac hypertrophy, and calculate left ventricle filling, before drug treatment, then at six months and 12 months. “We also monitored the capacity of vessels to dilate, alongside changes in metabolism, such as blood sugar levels and other biomarkers, such as lipids and insulin,” adds Balligand. PET and CT scans were also used to monitor metabolic activity, especially to see how the mirabegron might influence brown/beige fat tissues. As these burn calories, they are known to reduce metabolic disease. However, no signals of activity were found, before or after treatment. “Beige/brown fat is scarce in such patients – often below PET/CT detection levels – and 50 mg of mirabegron a day was obviously not sufficient to activate it. More sensitive techniques, such as metabolomic analyses of blood samples, could be used in future trials,” says Balligand.

A step forward for safe treatments

HFpEF accounts for around 50 % of all heart failure, and repurposed drugs could be readily made available to patients most at risk. “For the first time, we established the safety of mirabegron in patients with high cardiovascular risk. These patients were typically excluded from phase III and IV clinical trials of mirabegron for urological problems, but the drug is routinely prescribed to treat overactive bladder disease in elderly patients, many with cardiovascular comorbidities,” notes Balligand.

Keywords

BETA3_LVH, cardiovascular disease, heart, metabolic, ventricle, hypertrophy, mirabegron, adrenergic receptor, beta3, blood

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