This nonsystematic review provides a summary of current evidence on the use of β3-adrenoreceptor agonists (β3-ARAs) for the treatment for lower urinary tract symptoms. Soon after their discovery in 1989, β3-ARs were identified as a predominant adrenoreceptor subtype in the human urinary bladder. Although it is widely believed that β3-ARAs cause detrusor relaxation, the effect on bladder afferent signaling likely plays an important role in their mechanism of action as well. In 2011 and 2012, mirabegron was approved for clinical use in overactive bladder (OAB) patients. Pooled analysis of data from prospective randomized studies on >60,000 OAB patients showed that when compared to placebo, mirabegron was superior with respect to reducing the frequency, number, and severity of urgency episodes, number of incontinence episodes and increasing dry rate, but not in reduction of nocturia episodes. The only side effect showing significantly higher incidence than placebo was nasopharyngitis. Mirabegron is approved for OAB treatment in all age-groups and in pediatric patients with neurogenic bladder. Vibegron is another β3-ARA approved for OAB treatment in the US and Japan. Several large, multicenter, double-blind, randomized trials have documented statistically significant superiority of vibegron over placebo on all efficacy end points. Other β3-ARAs are being developed; however, to date none has been introduced to clinical use. All β3-ARAs provide efficacy similar to anticholinergics. They have a favorable safety profile and are well tolerated. Due to their different mechanisms of action, combination of β3-ARAs with anticholinergic compounds allows for increased efficacy.

Biomedical Laboratory University of Southern Denmark Odense Denmark

Department of Surgical Studies Medical Faculty Ostrava University Ostrava Czech Republic

Department of Urology Odense University Hospital Odense Denmark

Department of Urology University Hospital Ostrava Czech Republic

Research Unit of Urology Department of Clinical Research University of Southern Denmark Odense Denmark

See more in PubMed

Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn. 2002;21:167–178. doi:10.1002/nau.10052 PubMed DOI

Irwin DE, Milsom I, Hunskaar S, et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol. 2006;50:1306–1314. doi:10.1016/j.eururo.2006.09.019 PubMed DOI

Milsom I, Abrams P, Cardozo L, et al. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int. 2001;87:760–766. doi:10.1046/j.1464-410x.2001.02228.x PubMed DOI

de Groat WC, Griffiths D, Yoshimura N. Neural control of the lower urinary tract. Compr Physiol. 2015;5:327–396. doi:10.1002/cphy.c130056 PubMed DOI PMC

Ahlquist RP. A study of the adrenotropic receptors. Am J Physiol. 1948;153:586–600. doi:10.1152/ajplegacy.1948.153.3.586 PubMed DOI

Emorine LJ, Marullo S, Briend-Sutren MM, et al. Molecular characterization of the human beta 3-adrenergic receptor. Science. 1989;245:1118–1121. doi:10.1126/science.2570461 PubMed DOI

Michel MC, Vrydag W. Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol. 2006;147(Suppl 2):S88–119. doi:10.1038/sj.bjp.0706619 PubMed DOI PMC

Nomiya M, Yamaguchi O. A quantitative analysis of mRNA expression of alpha 1 and beta-adrenoceptor subtypes and their functional roles in human normal and obstructed bladders. J Urol. 2003;170:649–653. doi:10.1097/01.ju.0000067621.62736.7c PubMed DOI

Yamaguchi O, Chapple CR. Beta3-adrenoceptors in urinary bladder. Neurourol Urodyn. 2007;26:752–756. doi:10.1002/nau.20420 PubMed DOI

Cernecka H, Kersten K, Maarsingh H, et al. β3-adrenoceptor-mediated relaxation of rat and human urinary bladder: roles of BKCa channels and Rho kinase. Naunyn Schmiedebergs Arch Pharmacol. 2015;388:749–759. doi:10.1007/s00210-015-1128-z PubMed DOI PMC

Andersson KE. Antimuscarinic mechanisms and the overactive detrusor: an update. Eur Urol. 2011;59:377–386. doi:10.1016/j.eururo.2010.11.040 PubMed DOI

Andersson KE, Arner A. Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev. 2004;84:935–986. doi:10.1152/physrev.00038.2003 PubMed DOI

Petkov GV, Nelson MT. Differential regulation of Ca2+-activated K+ channels by beta-adrenoceptors in Guinea pig urinary bladder smooth muscle. Am J Physiol Cell Physiol. 2005;288:C1255–1263. doi:10.1152/ajpcell.00381.2004 PubMed DOI

Aizawa N, Homma Y, Igawa Y. Effects of mirabegron, a novel β3-adrenoceptor agonist, on primary bladder afferent activity and bladder microcontractions in rats compared with the effects of oxybutynin. Eur Urol. 2012;62(6):1165–1173. doi:10.1016/j.eururo.2012.08.056 PubMed DOI

Igawa Y, Aizawa N, Michel MC. β3 -Adrenoceptors in the normal and diseased urinary bladder-What are the open questions? Br J Pharmacol. 2019;176:2525–2538. doi:10.1111/bph.14658 PubMed DOI PMC

Michel MC, Sand C. Effect of pre-contraction on β-adrenoceptor-mediated relaxation of rat urinary bladder. World J Urol. 2009;27:711–715. doi:10.1007/s00345-009-0416-y PubMed DOI PMC

Sawada N, Nomiya M, Hood B, et al. Protective effect of a β3-adrenoceptor agonist on bladder function in a rat model of chronic bladder ischemia. Eur Urol. 2013;64:664–671. doi:10.1016/j.eururo.2013.06.043 PubMed DOI

Tyagi P, Tyagi V. Mirabegron, a β3-adrenoceptor agonist for the potential treatment of urinary frequency, urinary incontinence or urgency associated with overactive bladder. IDrugs. 2010;13:713–722. PubMed

Keam SJ. Vibegron: first Global Approval. Drugs. 2018;78:1835–1839. doi:10.1007/s40265-018-1006-3 PubMed DOI

Ohlstein EH, von Keitz A, Michel MC. A multicenter, double-blind, randomized, placebo-controlled trial of the β3-adrenoceptor agonist solabegron for overactive bladder. Eur Urol. 2012;62:834–840. doi:10.1016/j.eururo.2012.05.053 PubMed DOI

Michel MC. ß-adrenergic receptor subtypes in the urinary tract. In: Andresson KE, Michel MC, editors. Handbook of Experimental Pharmacology Vol. 202: Urinary Tract. Berlin Heidelberg: Springer; 2011:307–318. PubMed

European Medicines Agency. Betmiga prolonged-release tablets: summary of product characteristics; 2017. Available from: http://www.ema.europa.eu/. Accessed August 19, 2021.

Krauwinkel W, van Dijk J, Schaddelee M, et al. Pharmacokinetic properties of mirabegron, a β3-adrenoceptor agonist: results from two phase I, randomized, multiple-dose studies in healthy young and elderly men and women. Clin Ther. 2012;34:2144–2160. doi:10.1016/j.clinthera.2012.09.010 PubMed DOI

Deeks ED. Mirabegron: a review in overactive bladder syndrome. Drugs. 2018;78:833–844. doi:10.1007/s40265-018-0924-4 PubMed DOI

Freeman R, Foley S, Rosa Arias J, et al. Mirabegron improves quality-of-life, treatment satisfaction, and persistence in patients with overactive bladder: a multi-center, non-interventional, real-world, 12-month study. Curr Med Res Opin. 2018;34:785–793. doi:10.1080/03007995.2017.1419170 PubMed DOI

Kelleher C, Hakimi Z, Zur R, et al. Efficacy and tolerability of mirabegron compared with antimuscarinic monotherapy or combination therapies for overactive bladder: a systematic review and network meta-analysis. Eur Urol. 2018;74:324–333. doi:10.1016/j.eururo.2018.03.020 PubMed DOI

Ko KJ, Choo MS, Chang YS, et al. A multicenter prospective study for overactive bladder patient treatment satisfaction with mirabegron after being unsatisfied with antimuscarinic therapy (FAVOR study). Neurourol Urodyn. 2020;39:2417–2424. doi:10.1002/nau.24505 PubMed DOI

Yamaguchi O, Ikeda Y, Ohkawa S. Phase III study to assess long-term (52-week) safety and efficacy of mirabegron, a β3 -adrenoceptor agonist, in Japanese patients with overactive bladder. Low Urin Tract Symptoms. 2017;9:38–45. doi:10.1111/luts.12107 PubMed DOI

Tubaro A, Batista JE, Nitti VW, et al. Efficacy and safety of daily mirabegron 50 mg in male patients with overactive bladder: a critical analysis of five phase III studies. Ther Adv Urol. 2017;9:137–154. doi:10.1177/1756287217702797 PubMed DOI PMC

Shin DG, Kim HW, Yoon SJ, et al. Mirabegron as a treatment for overactive bladder symptoms in men (MIRACLE study): efficacy and safety results from a multicenter, randomized, double-blind, placebo-controlled, parallel comparison phase IV study. Neurourol Urodyn. 2019;38:295–304. doi:10.1002/nau.23852 PubMed DOI

Carlson KV, Rovner ES, Nair KV, et al. Persistence with mirabegron or antimuscarinic treatment for overactive bladder syndrome: findings from the PERSPECTIVE registry study. Low Urin Tract Symptoms. 2021;13:425–434. doi:10.1111/luts.12382 PubMed DOI PMC

De Nunzio C, Brucker B, Bschleipfer T, et al. Beyond antimuscarinics: a review of pharmacological and interventional options for overactive bladder management in men. Eur Urol. 2021;79:492–504. doi:10.1016/j.eururo.2020.12.032 PubMed DOI

Vasudeva P, Prasad V, Yadav S, et al. Efficacy and safety of mirabegron for the treatment of neurogenic detrusor overactivity resulting from traumatic spinal cord injury: a prospective study. Neurourol Urodyn. 2021;40:666–671. doi:10.1002/nau.24604 PubMed DOI

Krhut J, Borovička V, Bílková K, et al. Efficacy and safety of mirabegron for the treatment of neurogenic detrusor overactivity - Prospective, randomized, double-blind, placebo-controlled study. Neurourol Urodyn. 2018;37:2226–2233. doi:10.1002/nau.23566 PubMed DOI

Welk B, Hickling D, McKibbon M, et al. A pilot randomized-controlled trial of the urodynamic efficacy of mirabegron for patients with neurogenic lower urinary tract dysfunction. Neurourol Urodyn. 2018;37:2810–2817. doi:10.1002/nau.23774 PubMed DOI

Glykas I, Fragkoulis C, Mitsikostas DD, et al. B3 agonists or anticholinergics in the treatment of the lower urinary tract dysfunction in patients with multiple sclerosis? - A randomized study. World J Urol. 2021;39:3049–3056. doi:10.1007/s00345-020-03555-8 PubMed DOI

Brucker BM, Jericevic D, Rude T, et al. Mirabegron versus solifenacin in multiple sclerosis patients with overactive bladder symptoms: a prospective comparative nonrandomized study. Urology. 2020;145:94–99. doi:10.1016/j.urology.2020.08.008 PubMed DOI

Gubbiotti M, Conte A, Di Stasi SM, et al. Feasibility of mirabegron in the treatment of overactive bladder in patients affected by Parkinson’s disease: a pilot study. Ther Adv Neurol Disord. 2019;12:1756286419843458. doi:10.1177/1756286419843458 PubMed DOI PMC

Cho SY, Jeong SJ, Lee S, et al. Mirabegron for treatment of overactive bladder symptoms in patients with Parkinson’s disease: a double-blind, randomized placebo-controlled trial (Parkinson’s Disease Overactive bladder Mirabegron, PaDoMi Study). Neurourol Urodyn. 2021;40:286–294. doi:10.1002/nau.24552 PubMed DOI

Asche CV, Kim J, Kulkarni AS, et al. Presence of central nervous system, cardiovascular and overall co-morbidity burden in patients with overactive bladder disorder in a real-world setting. BJU Int. 2012;109(4):572–580. doi:10.1111/j.1464-410X.2011.10436.x PubMed DOI

Hines LE, Murphy JE. Potentially harmful drug-drug interactions in the elderly: a review. Am J Geriatr Pharmacother. 2011;9(6):364–377. doi:10.1016/j.amjopharm.2011.10.004 PubMed DOI

Rutman MP, Horn JR, Newman DK, et al. Overactive bladder prescribing considerations: the role of polypharmacy, anticholinergic burden, and CYP2D6 drug‒drug interactions. Clin Drug Investig. 2021;41(4):293–302. doi:10.1007/s40261-021-01020-x PubMed DOI PMC

Herschorn S, Staskin D, Schermer CR, et al. Safety and tolerability results from the PILLAR study: a phase IV, double-blind, randomized, placebo-controlled study of mirabegron in patients ≥ 65 years with overactive bladder-wet. Drugs Aging. 2020;37:665–676. doi:10.1007/s40266-020-00783-w PubMed DOI PMC

Wagg A, Cardozo L, Nitti VW, et al. The efficacy and tolerability of the β3-adrenoceptor agonist mirabegron for the treatment of symptoms of overactive bladder in older patients. Age Ageing. 2014;43:666–675. doi:10.1093/ageing/afu017 PubMed DOI

Lozano-Ortega G, Walker DR, Johnston K, et al. Comparative safety and efficacy of treatments for overactive bladder among older adults: a network meta-analysis. Drugs Aging. 2020;37:801–816. doi:10.1007/s40266-020-00792-9 PubMed DOI PMC

Franco I. Overactive bladder in children. Nat Rev Urol. 2016;13:520–532. doi:10.1038/nrurol.2016.152 PubMed DOI

Rittig S, Baka-Ostrowska M, Tøndel C, et al. The pharmacokinetics, safety, and tolerability of mirabegron in children and adolescents with neurogenic detrusor overactivity or idiopathic overactive bladder and development of a population pharmacokinetic model-based pediatric dose estimation. J Pediatr Urol. 2020;16:31.e1–31.e10. doi:10.1016/j.jpurol.2019.10.009 PubMed DOI

Blais AS, Nadeau G, Moore K, et al. Prospective pilot study of mirabegron in pediatric patients with overactive bladder. Eur Urol. 2016;70:9–13. doi:10.1016/j.eururo.2016.02.007 PubMed DOI

Kim SC, Park M, Chae C, et al. Efficacy and tolerability of mirabegron compared with solifenacin for children with idiopathic overactive bladder: a preliminary study. Investig Clin Urol. 2021;62:317–323. doi:10.4111/icu.20200380 PubMed DOI PMC

Baka-Ostrowska M, Bolong DT, Persu C, et al. Efficacy and safety of mirabegron in children and adolescents with neurogenic detrusor overactivity: an open-label, Phase 3, dose-titration study. Neurourol Urodyn. 2021;40:1490–1499. doi:10.1002/nau.24657 PubMed DOI PMC

Rutledge EC, Hernandez N, Gonzalez RR. Contemporary landmark trials update in the management of idiopathic overactive bladder. Curr Bladder Dysfunct Rep. 2020;15:377–385. doi:10.1007/s11884-020-00617-w DOI

Gibson W, MacDiarmid S, Huang M, et al. Treating overactive bladder in older patients with a combination of mirabegron and solifenacin: a prespecified analysis from the BESIDE study. Eur Urol Focus. 2017;3(6):629–638. doi:10.1016/j.euf.2017.08.008 PubMed DOI

Eapen R, Radomski S. Review of the epidemiology of overactive bladder. Res Rep Urol. 2016;8:71–76. doi:10.2147/RRU.S102441 PubMed DOI PMC

Kaplan SA, Herschorn S, McVary KT, et al. Efficacy and safety of mirabegron versus placebo add-on therapy in men with overactive bladder symptoms receiving tamsulosin for underlying benign prostatic hyperplasia: a randomized, phase 4 study (PLUS). J Urol. 2020;203:1163–1171. doi:10.1097/JU.0000000000000738 PubMed DOI

Kakizaki H, Lee KS, Yamamoto O, et al. Mirabegron add-on therapy to tamsulosin for the treatment of overactive bladder in men with lower urinary tract symptoms: a randomized, placebo-controlled study (MATCH). Eur Urol Focus. 2020;6:729–737. doi:10.1016/j.euf.2019.10.019 PubMed DOI

Ichihara K, Masumori N, Fukuta F, et al. A randomized controlled study of the efficacy of tamsulosin monotherapy and its combination with mirabegron for overactive bladder induced by benign prostatic obstruction. J Urol. 2015;193:921–926. doi:10.1016/j.juro.2014.09.091 PubMed DOI

Hou J, Xu F, Du H, et al. Adverse events associated with mirabegron 50mg versus placebo: a systematic review and meta-analysis. Prog Urol. 2021;31:SS1166–2. doi:10.1016/j.purol.2021.05.005 PubMed DOI

Nitti VW, Rosenberg S, Mitcheson DH, et al. Urodynamics and safety of the β 3 -adrenoceptor agonist mirabegron in males with lower urinary tract symptoms and bladder outlet obstruction. J Urol. 2013;190:1320–1327. doi:10.1016/j.juro.2013.05.062 PubMed DOI

Moss MC, Rezan T, Karaman UR, et al. Treatment of concomitant OAB and BPH. Curr Urol Rep. 2017;18:1. doi:10.1007/s11934-017-0649-z PubMed DOI

Sager C, Sanmartino M, Burek C, et al. Efficacy and safety of Mirabegron as adjuvant treatment in children with refractory neurogenic bladder dysfunction. J Pediatr Urol. 2020;16:655.e1–655.e6. doi:10.1016/j.jpurol.2020.07.020 PubMed DOI

Krhut J, Wohlfahrt P, Pudich J, et al. Cardiovascular safety of mirabegron in individuals treated for spinal cord injury- or multiple sclerosis-induced neurogenic detrusor overactivity. Int Urol Nephrol. 2021;53:1089–1095. doi:10.1007/s11255-020-02774-7 PubMed DOI

Griebling TL, Campbell NL, Mangel J, et al. Effect of mirabegron on cognitive function in elderly patients with overactive bladder: MoCA results from a phase 4 randomized, placebo-controlled study (PILLAR). BMC Geriatr. 2020;20:109. doi:10.1186/s12877-020-1474-7 PubMed DOI PMC

Phiri K, Hallas J, Linder M, et al. A study of cancer occurrence in users of mirabegron and antimuscarinic treatments for overactive bladder. Curr Med Res Opin. 2021;37:867–877. doi:10.1080/03007995.2021.1891035 PubMed DOI

Krhut J, Martan A, Zachoval R, et al. Is it possible to cure the symptoms of the overactive bladder in women? Int Urol Nephrol. 2018;50:433–439. doi:10.1007/s11255-017-1777-6 PubMed DOI

Ali M, Grogan S, Powell S, et al. Qualitative analysis of factors influencing patient persistence and adherence to prescribed overactive bladder medication in UK primary care. Adv Ther. 2019;36:3110–3122. doi:10.1007/s12325-019-01098-y PubMed DOI PMC

Mitcheson HD, Samanta S, Muldowney K, et al. Vibegron (RVT-901/MK-4618/KRP-114V) administered once daily as monotherapy or concomitantly with tolterodine in patients with an overactive bladder: a multicenter, phase iib, randomized, double-blind, controlled trial. Eur Urol. 2019;75:274–282. doi:10.1016/j.eururo.2018.10.006 PubMed DOI

Staskin D, Frankel J, Varano S, et al. International phase III, randomized, double-blind, placebo and active controlled study to evaluate the safety and efficacy of vibegron in patients with symptoms of overactive bladder: EMPOWUR. J Urol. 2020;204:316–324. doi:10.1097/JU.0000000000000807 PubMed DOI

Staskin D, Frankel J, Varano S, et al. Once-daily vibegron 75 mg for overactive bladder: long-term safety and efficacy from a double-blind extension study of the international phase 3 trial (EMPOWUR). J Urol. 2021;205:1421–1429. doi:10.1097/JU.0000000000001574 PubMed DOI

Su S, Liang L, Lin J, et al. Systematic review and meta-analysis of the efficacy and safety of vibegron vs antimuscarinic monotherapy for overactive bladder. Medicine. 2021;100(5):e23171. doi:10.1097/MD.0000000000023171 PubMed DOI PMC

Varano S, Staskin D, Frankel J, et al. Efficacy and safety of once-daily vibegron for treatment of overactive bladder in patients aged ≥65 and ≥75 years: subpopulation analysis from the EMPOWUR randomized, international, phase III study. Drugs Aging. 2021;38:137–146. doi:10.1007/s40266-020-00829-z PubMed DOI PMC

Lightner DJ, Gomelsky A, Souter L, et al. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline amendment 2019. J Urol. 2019;202:558–563. doi:10.1097/JU.0000000000000309 PubMed DOI

Harding CK, Lapitan MC, Arlandis S, et al. EAU Guidelines on Management of Non-Neurogenic Female Lower Urinary Tract Symptoms (LUTS). Arnhem, The Netherlands: EAU Guidelines Office; 2021.

Gravas S, Cornu JN, Gacci M, et al. EAU Guidelines on Management of Non-Neurogenic Male Lower Urinary Tract Symptoms (LUTS), Incl. Benign Prostatic Obstruction (BPO). Arnhem, The Netherlands: EAU Guidelines Office; 2021.