Clinical use of the β₃ adrenoceptor agonist mirabegron in patients with overactive bladder syndrome

Abstract

Mirabegron is a β 3 adrenoceptor agonist licensed for the treatment of overactive bladder symptoms, such as urinary urgency or urgency incontinence. β 3 adrenoceptor activation causes detrusor muscle relaxation, but mirabegron may also act by binding other targets in the bladder, and it may also reduce activity in sensory nerves. Phase III clinical trials (SCORPIO, ARIES, and CAPRICORN) evaluated mirabegron at various doses, demonstrating reduction from baseline to endpoint in mean incontinence episodes and mean number of micturitions per 24 h (coprimary endpoints), along with health-related quality of life and a range of secondary measures. Efficacy was seen in many patients who had previously discontinued antimuscarinic therapy on the grounds of lack of efficacy or poor tolerability. Treatment emergent adverse effects were documented in a long-term study (TAURUS), mostly being of mild or moderate severity. The most frequent adverse effects were hypertension, dry mouth, constipation, and headache, with a lower incidence of dry mouth than for the antimuscarinic active comparator. Efficacy and safety are not substantially different in older patients. A urodynamic safety study in men showed no consistent effect on voiding function, but a small increase in postvoid residual. Use of mirabegron in combination with α-adrenergic blockers does not appear to increase adverse effects. Dose reduction is needed in people with severe renal failure, or moderate hepatic failure. Dose adjustment is not needed in relation to food intake. Ongoing research is evaluating the potential for combination therapy with antimuscarinics.

Cardiac beta3‐adrenergic receptors in the clinical arena: the end of the beginning

“…The paper by Bundgaard in this issue of the journal proposes a treatment target, the third isotype of beta‐adrenergic receptors (β3 AR) that was identified in the human myocardium >15 years ago, but only recently tested in the clinical arena thanks to the availability of a specific agonist, mirabegron. The molecule is available for clinical use in urology for the treatment of overactive bladder disease, a painful condition of frequent micturition, based on its well‐established relaxing effect on the bladder smooth muscle that expresses β3 AR . Bundgaard et al .…”

Targeting cardiac myocyte Na+-K+ pump function with β3 adrenergic agonist in rabbits and patients with severe congestive heart failure

“…Our use of mirabegron off-label in doses recommended for the approved indication might not be optimal for treatment of HF and up to 6-fold higher doses have been used in studies on overactive bladder 33,34 . There were no effects expected to be adverse in HF and consistent with this, none were apparent when patients with mostly NYHA Class II HFrEF were given the 6fold higher dose.…”

Comprehensive review of cardiovascular toxicity of drugs and related agents

“…Pharmacologically, it is a β 3 ‐agonist that can dose dependently produce tachycardia. Studies have documented hypertension associated with its use; however, causality is lacking since hypertension was observed with a similar frequency in placebo and/or comparator arms of the studies …”