Budi Iman Santoso

Introduction
• Overactive bladder (OAB) : A syndrome of urinary urgency, often with urinary
frequency and nocturia, in the absence of local pathological factors (International
Continence Society)

• OAB is a common condition,and prevalence increases with age (7-27% in men, and
9–43% in women)

• Some OAB patients complains of urgency urinary incontinence (UUI) and/or stress
incontinence (SUI), especially women
• OAB is a non-life-threatening condition, but it greatly affect quality of life!
• Social functions: work, physical exercise, sleep, and sexual function

• Many people do not seek treatment due to embarrassment or ignorance

• Urgency  key symptom in diagnosing OAB

• Nocturia is the most bothersome symptoms in OAB  Related to decrease in sleep

quality and health-related quality of life, and also related to depression in the elderly
population
Pathophysiology of OAB
1. Neurogenic theory: reduction in the inhibitory neural impulses and increase in
the afferent impulses from the bladder trigger the voiding reflex
2. Myogenic theory: the detrusor muscle becomes more sensitive to cholinergic
stimulation leading to increased spontaneous activity
3. Autonomous bladder theory: alteration or exacerbation of phasic activity is
generated by muscarinic stimulation
4. Afferent signaling theory: spontaneous bladder contractions during filling result
in increased afferent output and hence the awareness of bladder filling
Treatment of OAB
(AUA/SUFU Guideline)

1. First-Line Treatments: Behavioral Therapies

• Weight loss exercise
• Bladder training
• Pelvic floor muscle training (Kegel, etc)
• Fluid management

2. Second-Line Treatments: Pharmacologic Management

• Oral β3-adrenoceptor agonists
• Oral anti-muscarinics
 Pharmacologic Agents
• Antimuscarinic (Solifenacin): block acetylcholine from binding to muscarinic receptors.
• Systematic anticholinergic adverse effects: dry eyes, dry mouth and constipation  low
compliance
• Muscarinic receptor subtypes M2 and M3, targeted by solifenacin, are the predominant
subtypes in the detrusor muscle

• β3-adrenoceptoragonists (Mirabegron) mimics sympathetic activity. Stimulates the β3-

adrenoceptors on the detrusor muscle  bladder relaxation during the filling stage.
• Adverse Effects: Increased blood pressure, nasopharyngitis, UTI, headache, dizziness and
urinary retention
 Mirabegron: Clinical Considerations
• First b3-adrenoceptor agonist approved for OAB
• Once-daily oral administration
• Reduces the frequency of micturition, incontinence and urgency
• Improves HR-QOL
• Sustains these improvements over 52 weeks’ therapy
• Generally well tolerated
Pharmacology of Mirabegron
• The beta-adrenoceptors are distributed in adipose tissue, heart, vascular systems
and the bladder.

• The β3 subtype was identified in 1989  the predominate adrenoceptor in the

bladder
• Direct stimulation  detrusor relaxation in humans  increase
bladder capacity.

• Mirabegron has a particular affinity for β3 adrenoceptors and improves the

storage capacity of the bladder with little effect on the contractile ability of the
bladder
Pharmacology of Mirabegron (2)
• Rapidly absorbed after oral administration, has a tmax of 3–4 hours, half-life of 40
hours and a bioavailability of 35% at the 50 mg dose

• Mirabegron: highly lipophilic and is metabolized in liver by cytochrome p450

• Minimum effect on commonly used drugs such as: oral contraceptive pill, warfarin,
metformin, digoxin and solifenacin.
 Results From Mirabegron RCTs

Thiagamoorthy G, Kotes S, Zacche M, Cardozo L. The efficacy and tolerability of mirabegron, a β3 adrenoceptor agonist, in
patients with symptoms of overactive bladder. Ther Adv Urol 2016, Vol. 8(1) 38–46
 BLOSSOM
• statistically significant improvement in mean voids per 24 hours when compared with
placebo (p⩽0.01)
• significant improvements in mean volume per void and mean number of episodes of
urinary incontinence for mirabegron

DRAGON
• Primary endpoint: change in the mean number of voids per 24 hours from baseline to
end of treatment.
• This was not statistically significant in the mirabegron 25mg group, but was in the 50,
100, and 200mg OD groups with

Thiagamoorthy G, Kotes S, Zacche M, Cardozo L. The efficacy and tolerability of mirabegron, a β3 adrenoceptor agonist, in
patients with symptoms of overactive bladder. Ther Adv Urol 2016, Vol. 8(1) 38–46
 SCORPIO
• Statistically significant improvements in all primary and secondary endpoints in both
mirabegron doses (50 and 100 mg) compared with placebo (p⩽0.05).
• Tolterodine was not significantly different

CAPRICORN
• Coprimary outcome: change from baseline to end of treatment at 12 weeks with regard
to the mean number of incontinence episodes per 24 hours and mean number of voids
per 24 hours
• Both mirabegron groups (25 and 50 mg)  statistically significant improvements in the
coprimary endpoints compared with placebo

Thiagamoorthy G, Kotes S, Zacche M, Cardozo L. The efficacy and tolerability of mirabegron, a β3 adrenoceptor agonist, in
patients with symptoms of overactive bladder. Ther Adv Urol 2016, Vol. 8(1) 38–46
 PERSISTENCE
“Treatment persistence requires an acceptable balance between tolerability and efficacy .”
– Wagg et al. BJU International 20121
Mirabegron is associated with the highest number of days on therapy compared to antimuscarinics2
• Patients treated with Mirabegron persisted on treatment for significantly longer than antimuscarinics 3
• The median time to treatment discontinuation with Betmiga (169 days) was significantly longer vs other antimuscarinics (range 30–78
days)3

References: 1. Wagg A, Compion G, Fahey A, Siddiqui E. Persistence with prescribed antimuscarinic therapy for overactive bladder: a UK experience. BJU Int 2012;110:1767-1274. 2. Wagg A, Franks B, Ramos B, Berner T. Persistence and adherence with
the new beta-3 receptor agonist, mirabegron, versus antimuscarinics in overactive bladder: Early experience in Canada. Can Urol Assoc J 2015;9:343-50. doi: 10.5489/cuaj.3098. 3. Chapple CR, Nazir J, Hakimi Z, et al. Persistence and Adherence with
Mirabegron versus Antimuscarinic Agents in Patients with Overactive Bladder: A Retrospective Observational Study in UK Clinical Practice. Eur Urol 2017;72:389-399.
 Mirabegron impact on sexual dysfunction

• FSFI (Female Sexual Function Index) Total Score significantly improved in 42/50 patients
(84%) from 18.9 ± 4.3 to 21.8 ± 4.5 (p < 0.0001).

Gubbiotti M, et al. The impact of Mirabegron on sexual function in women with idiopathic overactive bladder. BMC Urology
(2019) 19:7
Conclusion
• Mirabegron is a safe, effective and well-tolerated new class of drug

• Tolerability profile of mirabegron offers  improve patients’ adherence with treatment

for OAB as dry mouth is often the reason cited for stopping antimuscarinic
treatment

• Mirabegron has consistently demonstrated its efficacy and tolerability in phase III
RCTs

• Need head-to-head comparison between mirabegron and other anticholinergic drugs