Beta3-adrenoreceptor agonist mirabegron – a potential antiobesity drug?

KEYWORDS:

• Brown adipose tissue
• energy expenditure
• mirabegron
• obesity
• overactive bladder
• β₃-adrenoreceptor agonists

1. Introduction

Mirabegron is the first β₃-adrenoreceptor (AR) agonist which was approved for the treatment of overactive bladder (OAB) in the United States, Japan, the European Union, and Canada at a dose of 50 mg daily [1]. Three phase III clinical trials lasting 12 weeks and one carried out over 12 months confirmed its efficacy, good tolerability, and safety in patients with OAB [2]. The clinical profile of mirabegron was comparable to antimuscarinics, the most commonly prescribed drugs for the treatment of OAB, except for dry mouth which occurred five times less frequently with mirabegron.

β₃-AR agonists were investigated for over three decades primarily as potential antiobesity drugs devoid of cardiovascular adverse events (AEs) associated with administration of conventional adrenergic agonists [3]. Most of these drugs exerted favorable metabolic effects in experimental studies conducted in rodents but they failed in the clinical trials in humans due to their β₁- and β₂-AR-mediated cardiovascular AEs [3]. Recently described mirabegron-induced activation of human brown adipose tissue (BAT) by Cypess et al., however, led us to reconsider a potential role of mirabegron in weight management [4].

2. Mirabegron in the treatment of overactive bladder

Essential pharmacotherapy for OAB is represented by antimuscarinic drugs which are, however, frequently associated with AEs such as dry mouth, constipation, and blurred vision. Effects of a selective β₃-AR agonist mirabegron on bladder relaxation were discovered in 2007. Later on, mirabegron underwent multiple clinical studies aimed at the treatment of OAB [1]. Nitti et al. reported a pooled analysis of three randomized, double-blind, placebo-controlled, phase III studies for efficacy and safety of mirabegron in the treatment of OAB [2]. These 12-week studies enrolled 4622 patients who were given placebo, mirabegron (25, 50, 100 mg/day), or antimuscarinic agent tolterodine extended release (4 mg/day). Mirabegron administration was associated with significant improvements in incontinence episodes and micturition frequency [2]. The drug was well tolerated. The most common AEs (≥3%) were hypertension, nasopharyngitis, and urinary tract infections. The percentage of patients reporting hypertension as an AE was comparable in mirabegron-treated groups (7.3%) and in placebo group (7.6%). Dry mouth, a characteristic bothersome AE associated with antimuscarinic agents, was at placebo levels with mirabegron and significantly lower when compared to tolterodine. Recently, efficacy and safety of mirabegron in the treatment of OAB has been confirmed in Japanese and Asian populations and in older patients.

A 1-year randomized, double-blind, parallel-group study was conducted in 2444 patients to evaluate safety, tolerability, and efficacy of mirabegron in a dose of 50 and 100 mg/day when compared to the commonly used antimuscarinic drug tolterodine [5]. This study confirmed the sustained efficacy profile of mirabegron throughout the 12-month treatment period. For both mirabegron and tolterodine, similar reductions of micturitions, incontinence episodes, and mean volume voided per micturition were reported. Frequencies of AEs (hypertension, headache, nasopharyngitis, and urinary tract infections) over the 12 months were similar in the mirabegron-treated and tolterodine-treated groups. Dry mouth, however, occurred more frequently in response to treatment with tolterodine (8.6%) than with mirabegron (2.8% with 50 mg, 2.3% with 100 mg). A minor increase in pulse rate observed after mirabegron treatment (+0.9 bpm – a.m.; +0.4 bpm – p.m.) was lower than that observed after tolterodine (+1.5 bpm – a.m.; +1.9 bpm – p.m.). The incidence of tachycardia was also lower in the mirabegron group (3.9%) than in the tolterodine group (6.0%). Prolongation of ECG QT_c interval was observed in only 1 of the 812 patients in both mirabegron- and tolterodine-treated groups. In a separate randomized, double-blind, placebo- and active-controlled study, the proarrhythmic safety of repeat doses of mirabegron was demonstrated in healthy subjects [6]. Administration of mirabegron at the doses of 50 and 100 mg did not lead to prolongation of QT_c interval in either sex.

3. Metabolic consequences of stimulation of β₃-adrenoreceptors

β₃-ARs, discovered in the eighties, were shown to be widely expressed in adipocytes, particularly in BAT which is richly innervated by sympathetic nerves [3,7]. The BAT in adult humans is present only in small quantities in the neck, interscapular, and perirenal areas. However, due to its high thermogenic capacity (500 W/kg) associated with the expression of uncoupling protein 1 (UCP1), it could significantly influence energy balance through the cold- and diet-induced thermogenesis mediated by β₃-AR. β₃-AR agonists have been proposed as potential antiobesity drugs devoid of cardiovascular AEs associated with administration of conventional adrenergic agonists. Arch reviewed the development of β₃-AR agonists over the last 30 years [3]. Stimulation of BAT by β₃-AR agonists in rodents increases both energy expenditure and fatty acid oxidation and leads to depletion of fat stores, preservation of lean body mass, and improvement in insulin sensitivity. Drugs highly selective for human β₃-AR with a good oral bioavailability were developed but they failed in the clinic due to their β₁- and β₂-AR-mediated cardiovascular effects in humans [3].

In addition to brown adipocytes, UCP1-expressing adipocytes with thermogenic capacity also appear in the white adipose tissue (WAT) in response to cold exposure, several endogenous circulating factors originating in muscle, liver, and heart (irisin, fibroblast growth factor, natriuretic peptides), or in response to stimulation by β₃-adrenergic agonists [7]. These adipocytes interspersed within WAT, predominantly in subcutaneous fat, are named brite (‘brown in white’) or beige adipocytes. Both the amount and the activities of brown and beige adipocytes correlate with leanness in humans and may affect the development of metabolic diseases. Recently, repeated mild cold exposure of 17–19°C was proposed to increase the volume and activity of thermogenic adipose tissues and thus to treat obesity in adult humans [8].

4. Expert opinion

Lifestyle intervention represents the cornerstone of weight management. Antiobesity drugs should provide additional weight loss and improvements in cardiometabolic risks compared to that achieved by lifestyle modification alone. Currently available drugs for the long-term treatment of obesity affect energy balance particularly by reducing food intake and food reward behavior in the central nervous system or by reducing nutrient absorption in the intestine [9]. Low energy diet–induced decrease in energy expenditure is a serious barrier in achieving long-term weight loss. No antiobesity drug directly affecting adipose tissue and/or leading to increased energy expenditure has been available although the β₃-ARs as potential thermogenic substances were deeply investigated for decades [3]. In addition, these compounds induced about 50% reduction in plasma glucose in a rodent model of diabetes. Mirabegron was initially also studied as a potential antidiabetic agent. Selective activation of β₃-AR may favorably affect glucose homeostasis, energy expenditure, and body composition.

Cypess et al. recently demonstrated activation of human BAT in healthy male subjects by a selective β₃-AR agonist mirabegron applied in a single oral dose of 200 mg [4]. Increased BAT metabolic activity measured by (18)F-fluorodeoxyglucose positron emission tomography and computed tomography (PET/CT) was demonstrated particularly in the cervical–supraclavicular–axillary fat depots. Activation of BAT was associated with a simultaneous increase in the resting metabolic rate (+203 kcal/day, or +13%). However, administration of mirabegron 200 mg was also associated with increased heart rate and systolic blood pressure. Such stimulation of the cardiovascular system is due to additional binding of mirabegron to β₁-AR at the high doses. It should be further studied whether the long-term administration of the well-tolerated daily dose of 50 mg approved for the treatment of OAB would be sufficient for activation of BAT and thermogenesis. There is evidence that chronic stimulation of sympathetic nervous activity and β₃-ARs may activate BAT. In 1981, BAT was described in outdoor workers in northern Finland chronically exposed to low environmental temperatures. Van Merken Lichtenbelt et al. studied BAT activity with PET/CT and observed BAT activity in both lean and overweight/obese healthy men during cold exposure [10]. Overweight/obese subjects exhibited significantly lower BAT activity than lean subjects. In contrast, the treatment efficacy of β₃-AR agonist mirabegron for OAB in females was the same across the body mass index categories [11]. Lee et al. reported that overnight exposure of healthy volunteers to 19°C for 1 month was associated with increased BAT volume and BAT activity as well as with an increase in diet-induced thermogenesis, postprandial insulin sensitivity, and adiponectin levels [12]. PET/CT imaging revealed that the catecholamine excess in pheochromocytomas activated BAT [13]. It should be expected that also the chronic administration of β₃-AR agonist mirabegron at the doses of 50 and 100 mg may result in activation of thermogenic tissues in humans with all subsequent beneficial metabolic consequences. Nevertheless, these aspects were not studied in trials of mirabegron in the treatment of OAB.

Due to the increased blood pressure in some patients, an administration of mirabegron is contraindicated in patients with uncontrolled hypertension. Experiments in rabbits revealed that an activation of β₃-AR restores NO/redox balance, improves endothelial function, and thus exerts vascular protective effects [14]. Recently, it was shown that the mirabegron-induced urethral smooth muscle relaxation is also mediated by blockade of α₁ ARs [15]. Whether the blockade of α₁ ARs by mirabegron can exert certain favorable hemodynamic effects in humans should be further investigated.

Introduction of novel β₃-adrenergic agonists into the treatment of obesity in the future will require long-term trials on their efficacy, tolerability, and safety. It should be emphasized that weight management with antiobesity drugs should be preferred in young and middle-aged subjects to reduce the possible cardiometabolic health risks and prevent cardiometabolic diseases than in polymorbid elderly patients with established cardiovascular morbidity.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was supported by the Czech Ministry of Health [project number 00023761, Institute of Endocrinology, Prague, Czech Republic].