Clinical Utility of β₃-Adrenoreceptor Agonists for the Treatment of Overactive Bladder: A Review of the Evidence and Current Recommendations

References

• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• Ahlquist RP. A study of the adrenotropic receptors. Am J Physiol. 1948;153:586–600. doi:10.1152/ajplegacy.1948.153.3.586
   PubMed Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• Yamaguchi O, Chapple CR. Beta3-adrenoceptors in urinary bladder. Neurourol Urodyn. 2007;26:752–756. doi:10.1002/nau.20420
   PubMed Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• Keam SJ. Vibegron: first Global Approval. Drugs. 2018;78:1835–1839. doi:10.1007/s40265-018-1006-3
   PubMed Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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.
   Google Scholar
• European Medicines Agency. Betmiga prolonged-release tablets: summary of product characteristics; 2017. Available from: http://www.ema.europa.eu/. Accessed August 19, 2021.
   Google Scholar
• 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 Web of Science ®Google Scholar
• Deeks ED. Mirabegron: a review in overactive bladder syndrome. Drugs. 2018;78:833–844. doi:10.1007/s40265-018-0924-4
   PubMed Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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
   Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• Franco I. Overactive bladder in children. Nat Rev Urol. 2016;13:520–532. doi:10.1038/nrurol.2016.152
   PubMed Web of Science ®Google Scholar
• 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
   Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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
   Web of Science ®Google Scholar
• 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
   PubMedGoogle Scholar
• Eapen R, Radomski S. Review of the epidemiology of overactive bladder. Res Rep Urol. 2016;8:71–76. doi:10.2147/RRU.S102441
   PubMed Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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
   PubMedGoogle Scholar
• 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 Web of Science ®Google Scholar
• 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
   Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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 Web of Science ®Google Scholar
• 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.
   Google Scholar
• 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.
   Google Scholar