Skip to main content
SpringerLink
Log in

Overactive Bladder and the β3-Adrenoceptor Agonists: Current Strategy and Future Prospects

  • Current Opinion
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Overactive bladder (OAB) is a clinical syndrome describing the symptom complex of urgency, with or without urgency incontinence, and is usually associated with frequency and nocturia. It is a common, under-diagnosed and therefore under-treated condition that can have a detrimental effect on physical functioning and psychological well-being. Initial treatment of OAB includes lifestyle advice, behavioural modifications, bladder retraining and pelvic floor muscle training, usually in combination with antimuscarinic agents. The β3-adrenoceptor agonist mirabegron is the first of a new class of drugs that are now competing with the more established antimuscarinics for the treatment of OAB. Our review focuses on the mode of action, efficacy and tolerability of mirabegron. The place of β3-adrenoceptor agonists in the treatment algorithm of OAB is discussed, considering the adverse events associated with antimuscarinics. Drug therapy tailored to different population groups appears a promising future prospect. Development of other β3-adrenoceptor agonists is expected, and combination therapy regimens might revolutionise the treatment of OAB.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Haylen BT, de Ridder D, Freeman RM, Swift SE, Berghmans B, Lee J, et al. An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Neurourol Urodyn. 2010;29:4–20.

    PubMed  Google Scholar 

  2. Irwin DE, Kopp ZS, Agatep B, Milsom I, Abrams P. Worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction. BJU Int. 2011;103:1132–9.

    Article  Google Scholar 

  3. Milsom I, Abrams P, Cardozo L, Roberts RG, Thüroff J, Wein AJ. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int. 2001;87(9):760–6.

    Article  CAS  PubMed  Google Scholar 

  4. Kelleher CJ, Cardozo LD, Khullar V, Salvatore S. A new questionnaire to assess the quality of life of urinary incontinent women. BJOG. 1997;104:1374–9.

    Article  CAS  Google Scholar 

  5. Irwin DE, Mungapen L, Milsom I, Kopp Z, Reeves P, Kelleher C. The economic impact of overactive bladder syndrome in six Western countries. BJU Int. 2009;103:202–9.

    Article  PubMed  Google Scholar 

  6. Moore K, Dumoulin C, Bradley C, Burgio K, Chambers T, Hagen S, et al. Adult Conservative Management. In: Abrams P, Cardozo L, Khoury S, Wein A, editors. Incontinence. 5th ed. Paris: Health Publication Ltd; 2013. p. 1101–228.

    Google Scholar 

  7. Andersson KE. Antimuscarinics for treatment of overactive bladder. Lancet Neurol. 2004;3:46–53.

    Article  CAS  PubMed  Google Scholar 

  8. Andersson KE. Antimuscarinic mechanisms and the overactive detrusor: an update. Eur Urol. 2011;59(3):377–86.

    Article  CAS  PubMed  Google Scholar 

  9. Chapple CR, Khullar V, Gabriel Z, Muston D, Bitoun CE, Weinstein D, et al. The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis. Eur Urol. 2008;54:543–62.

    Article  CAS  PubMed  Google Scholar 

  10. Veenboer PW, Bosch JL. Long-term adherence to antimuscarinic therapy in everyday practice: a systematic review. J Urol. 2014;191(4):1003–8.

    Article  CAS  PubMed  Google Scholar 

  11. Benner JS, Nichol MB, Rovner ES, et al. Patient-reported reasons for discontinuing overactive bladder medication. BJU Int. 2010;105:1276–82.

    Article  PubMed  Google Scholar 

  12. Chancellor MB, Migliaccio-Walle K, Bramley TJ, Chaudhari SL, Corbell C, Globe D. Long-term patterns of use and treatment failure with anticholinergic agents for overactive bladder. Clin Ther. 2013;35(11):1744–51.

    Article  CAS  PubMed  Google Scholar 

  13. Tyagi P, Thomas CA, Yoshimura N, Chancellor MB. Investigations into the presence of functional Beta1, Beta2 and Beta3-adrenoceptors in urothelium and detrusor of human bladder. Int Braz J Urol. 2009;35:76–83.

    Article  PubMed  Google Scholar 

  14. Yamaguchi O. Beta3-adrenoreceptors in human detrusor muscle. Urology. 2002;59(5 Suppl 1):25–9.

    Article  PubMed  Google Scholar 

  15. Andersson KE, Arner A. Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev. 2004;84:935–86.

    Article  CAS  PubMed  Google Scholar 

  16. Uchida H, Shishido K, Nomiya M, Yamaguchi O. Involvement of cyclic AMP-dependent and -independent mechanisms in the relaxation of rat detrusor muscle via betaadrenoceptors. Eur J Pharmacol. 2005;518:195–202.

    Article  CAS  PubMed  Google Scholar 

  17. Aizawa N, Homma Y, Igawa Y. Effects of mirabegron, a novel beta3-adrenoceptor agonist, on primary bladder afferent activity and bladder microcontractions in rats compared with the effects of oxybutynin. Eur Urol. 2012;62:1165–73.

    Article  CAS  PubMed  Google Scholar 

  18. Chapple CR, Kaplan SA, Mitcheson D, Klecka J, Cummings J, Drogendijk T, et al. Randomized double-blind, active-controlled phase 3 study to assess 12-month safety and efficacy of mirabegron, a β(3)-adrenoceptor agonist, in overactive bladder. Eur Urol. 2013;63:296–305.

    Article  CAS  PubMed  Google Scholar 

  19. Nitti VW, Auerbach S, Martin N, Calhoun A, Lee M, Herschorn S. Results of a randomized phase III trial of mirabegron in patients with overactive bladder. J Urol. 2013;189:1388–95.

    Article  CAS  PubMed  Google Scholar 

  20. Khullar V, Amarenco G, Angulo JC, Cambronero J, Høye K, Milsom I, et al. Efficacy and tolerability of mirabegron, a β(3)-adrenoceptor agonist, in patients with overactive bladder: results from a randomised European-Australian phase 3 trial. Eur Urol. 2013;63:283–95.

    Article  CAS  PubMed  Google Scholar 

  21. Herschorn S, Barkin J, Castro-Diaz D, Frankel JM, Espuna-Pons M, Gousse AE, Stölzel M, Martin N, Gunther A, Van Kerrebroeck P. A phase III, randomized, double-blind, parallel-group, placebo-controlled, multicentre study to assess the efficacy and safety of the β3 adrenoceptor agonist, mirabegron, in patients with symptoms of overactive bladder. Urology. 2013;82(2):313–20.

    Article  PubMed  Google Scholar 

  22. Yamaguchi O, Marui E, Kakizaki H, Homma Y, Igawa Y, Takeda M, Nishizawa O, Gotoh M, Yoshida M, Yokoyama O, Seki N, Ikeda Y, Ohkawa S. Phase III, randomised, double-blind, placebo-controlled study of the β3-adrenoceptor agonist mirabegron, 50 mg once daily, in Japanese patients with overactive bladder. BJU Int. 2014;113(6):951–60.

    Article  CAS  PubMed  Google Scholar 

  23. Kuo HC, Lee KS, Na Y, Sood R, Nakaji S, Kubota Y, Kuroishi K. Results of a randomized, double-blind, parallel-group, placebo- and active-controlled, multicenter study of mirabegron, a β3-adrenoceptor agonist, in patients with overactive bladder in Asia. Neurourol Urodyn. 2015;34(7):685–92.

    Article  CAS  PubMed  Google Scholar 

  24. Khullar V, Cambronero J, Angulo JC, et al. Efficacy of mirabegron in patients with and without prior antimuscarinic therapy for overactive bladder: a post hoc analysis of a randomized European-Australian Phase 3 trial. BMC Urol. 2013;13:45.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Sacco E, Bientinesi R, Tienforti D, Racioppi M, Gulino G, D’Agostino D, Vittori M, Bassi P. Discovery history and clinical development of mirabegron for the treatment of overactive bladder and urinary incontinence. Expert Opin Drug Discov. 2014;9(4):433–48.

    Article  CAS  PubMed  Google Scholar 

  26. National Institute for Health and Care Excellence. Mirabegron for treatment of overactive bladder. Technology appraisal guidance 290. 2013. http://www.nice.org.uk/guidance/ta290. Accessed 10 May 2015.

  27. Gormley EA, Lightner DJ, Faraday M, Vasavada SP. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline amendment. J Urol. 2015;193(5):1572–80.

    Article  PubMed  Google Scholar 

  28. Nazir J, Posnett J, Walker A, Odeyemi IA, Hakimi Z, Garnham A. Economic evaluation of pharmacological treatments for overactive bladder from the perspective of the UK National Health Service. J Med Econ. 2015;18(5):390–7.

    Article  PubMed  Google Scholar 

  29. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01638000. Accessed 15 May 2015.

  30. Mills EJ, Thorlund K, Ioannidis JP. Demystifying trial networks and network meta-analysis. BMJ. 2013;346:f2914.

    Article  PubMed  Google Scholar 

  31. Maman K, Aballea S, Nazir J, Desroziers K, Neine ME, Siddiqui E, Odeyemi I, Hakimi Z. Comparative efficacy and safety of medical treatments for the management of overactive bladder: a systematic literature review and mixed treatment comparison. Eur Urol. 2014;65(4):755–65.

    Article  CAS  PubMed  Google Scholar 

  32. Wagg A, Franks B, Ramos B, Berner T. Persistence and adherence with mirabegron, a new beta-3 receptor agonist versus antimuscarinics in overactive bladder: early experience in Canada. Value in Health. 2014;17(7):A471.

    Article  Google Scholar 

  33. Balachandran AA, Duckett JR. The risk and severity of developing symptomatic palpitations when prescribed mirabegron for overactive bladder. Eur J Obstet Gynecol Reprod Biol. 2015;187:60–3.

    Article  CAS  PubMed  Google Scholar 

  34. Hanna-Mitchell AT, Kashyap M, Chan WV, Andersson KE, Tannenbaum C. Pathophysiology of idiopathic overactive bladder and the success of treatment: a systematic review from ICI-RS 2013. Neurourol Urodyn. 2014;33(5):611–7.

    Article  CAS  PubMed  Google Scholar 

  35. Giarenis I, Mastoroudes H, Srikrishna S, Robinson D, Cardozo L. Is there a difference between women with or without detrusor overactivity complaining of symptoms of overactive bladder? BJU Int. 2013;112:501–7.

    Article  PubMed  Google Scholar 

  36. Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, Yu O, Crane PK, Larson EB. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015;175(3):401–7.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Fox C, Richardson K, Maidment ID, Savva GM, Matthews FE, Smithard D, Coulton S, Katona C, Boustani MA, Brayne C. Anticholinergic medication use and cognitive impairment in the older population: the medical research council cognitive function and ageing study. J Am Geriatr Soc. 2011;59(8):1477–83.

    Article  PubMed  Google Scholar 

  38. Wagg A, Cardozo L, Nitti VW, Castro-Diaz D, Auerbach S, Blauwet MB, Siddiqui E. 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(5):666–75.

    Article  PubMed  Google Scholar 

  39. Nitti VW, Rosenberg S, Mitcheson DH, He W, Fakhoury A, Martin NE. Urodynamics and safety of the β3-adrenoceptor agonist mirabegron in males with lower urinary tract symptoms and bladder outlet obstruction. J Urol. 2013;190(4):1320–7.

    Article  CAS  PubMed  Google Scholar 

  40. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02044510. Accessed 17 May 2015.

  41. Abrams P, Kelleher C, Staskin D, Rechberger T, Kay R, Martina R et al. Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study (Symphony). Eur Urol. 2015;67(3):577–88.

    Article  CAS  PubMed  Google Scholar 

  42. Yamaguchi O, Kakizaki H, Homma Y, Igawa Y, Takeda M, Nishizawa O, Gotoh M, Yoshida M, Yokoyama O, Seki N, Okitsu A, Hamada T, Kobayashi A, Kuroishi K. Safety and efficacy of mirabegron as ‘add-on’ therapy in patients with overactive bladder treated with solifenacin: a post-marketing, open-label study in Japan (MILAI study). BJU Int. 2015. doi:10.1111/bju.13068 (Epub ahead of print).

  43. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01745094. Accessed 19 May 2015.

  44. Ichihara K, Masumori N, Fukuta F, Tsukamoto T, Iwasawa A, Tanaka Y. 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(3):921–6.

    Article  CAS  PubMed  Google Scholar 

  45. Robinson D, Giarenis I, Cardozo L. The medical management of refractory overactive bladder. Maturitas. 2013;74(4):386–90.

    Article  PubMed  Google Scholar 

  46. 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(5):834–40.

    Article  CAS  PubMed  Google Scholar 

  47. Maruyama I, Goi Y, Tatemichi S, Maruyama K, Hoyano Y, Yamazaki Y, Kusama H. Bladder selectivity of the novel β3-agonist ritobegron (KUC-7483) explored by in vitro and in vivo studies in the rat. Naunyn Schmiedebergs Arch Pharmacol. 2012;385(8):845–52.

    Article  CAS  PubMed  Google Scholar 

  48. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01004315. Accessed 18 May 2015.

  49. http://www.kissei.co.jp/e_contents/relation/2010/20100702.html. Accessed 18 May 2015.

  50. Sacco E, Bientinesi R. Innovative pharmacotherapies for women with overactive bladder: where are we now and what is in the pipeline? Int Urogynecol J. 2015;26(5):629–40.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Urogynaecology, King’s College Hospital NHS Foundation Trust, Denmark Hill, London, SE5 9RS, UK

    Ilias Giarenis, Dudley Robinson & Linda Cardozo

Authors
  1. Ilias Giarenis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dudley Robinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Linda Cardozo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ilias Giarenis.

Ethics declarations

Funding

No funding was received for the conduct of this review manuscript.

Conflict of interest

Dr Giarenis has received speaker honoraria and travel expenses from Astellas. Mr Robinson has been a consultant to Allergan, Astellas, Ferring, and Pfizer and has received speaker honoraria from Allergan, Astellas, Ferring and Pfizer. Professor Cardozo has been a consultant to Allergan and Astellas and has received speaker honoraria from Astellas and Allergan. Their institution (King’s College Hospital) has received trial funding from Allergan, Astellas and Pfizer.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Giarenis, I., Robinson, D. & Cardozo, L. Overactive Bladder and the β3-Adrenoceptor Agonists: Current Strategy and Future Prospects. Drugs 75, 1707–1713 (2015). https://doi.org/10.1007/s40265-015-0456-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-015-0456-0

Keywords

Search

Navigation