Current Treatment of Overactive Bladder in Patients with Diabetes and Obesity
A review and assessment of five current research studies for the efficacy in managing overactive bladder syndrome, particularly in patients with metabolic disease.
October 2019
Volume 1, Issue 8

Efficacy and Safety of Combination Pharmacotherapy for Overactive Bladder

An international team of experts examined recent trials for safety, efficacy and quality of life findings of dual oral pharmacotherapy management of overactive bladder syndrome.

European Urology. 2019; Ahead of print:

Commentary by Alexander Gomelsky, MD, and Larado Valadez, MD

Analysis of OAB Treatment with Dual Medication Therapy  

A rapid evidence assessment of four randomized controlled trials (RCTs) and three other studies was conducted to examine the efficacy of mirabegron combined with antimuscarinic therapies in individuals with overactive bladder (OAB).

In examining the outcomes of a phase 2, randomized, triple-masked, placebo- and monotherapy-controlled study, to evaluate the efficacy, dose-response relationship, safety and tolerability in patients with OAB receiving mirabegron or solifenacin succinate alone and in combination (Symphony Trial).1 The investigators randomized 1,307 adults with OAB symptoms into one of 12 treatment cohorts: five monotherapy groups (solifenacin 2.5 mg [S2.5], 5 mg [S5], or 10 mg [S10]; or mirabegron 25 mg [M25] or 50 mg [M50]), six combination groups (S2.5, S5, or S10 plus M25 or M50), and placebo.

In comparing with S5 monotherapy, all combination therapies with S5 or S10 significantly improved mean volume voided per micturition. Three combinations, S10 plus M25, S5 plus M50, and S10 plus M50, reduced micturition frequency by the end of treatment, and all combination regimens except for S2.5 plus M25 significantly reduced urgency episodes compared with S5 monotherapy. No dose-related trends in treatment-related adverse events, blood pressure, pulse rate, postvoid residual volume, electrocardiogram, or laboratory values were observed, but the incidence of constipation was slightly higher and appeared to be dose-related with combination therapies.1

On the basis of these findings, two combinations, S5 plus M25 and S5 plus M50, were assessed in phase 3 studies.2,3 The phase 3B BESIDE trial assessed S5 combined with mirabegron (M25 increased to M50 after 4 weeks) for 12 weeks, compared with 12 weeks of monotherapy with S5 or S10, in 2,174 individuals with OAB that had responded inadequately to 4 weeks of S5 monotherapy and had received mirabegron as an add-on.2

The study demonstrated superiority for S5 plus M50 over S5 monotherapy with respect to adjusted mean change from baseline to end of treatment in the mean number of urinary incontinence episodes over 24 hours (-1.80 vs -1.53, P < 0.001). The combination also showed significantly greater improvements, compared with S5 monotherapy, in MVV (28.05 vs 16.52, P < 0.001), urgency urinary incontinence episodes per 24 hours, and proportion of patients with no urinary incontinence episodes at the end of treatment (46.0% vs 37.9%, P = 0.001).

The combination proved noninferior to S10 monotherapy with respect to mean number of daily micturitions over 24 hours and the number of incontinence episodes noted in a three-day diary at the end of treatment, and it was superior to S10 monotherapy with respect to reduction in micturition frequency. A prespecified analysis found that the combination reduced the mean number of daily urinary incontinence episodes at the end of treatment to a similar extent across age groups.2

In the phase 3, SYNERGY study,  3,527 individuals diagnosed with OAB were assessed for response to treatment with S5 and M25 or S5 and M50 combinations, compared with S5, M25, or M50 monotherapies, in with OAB, including treatment-naïve patients; they were followed for 12 weeks.3

Compared with the monotherapies, treatment with the combination therapies resulted in consistently greater improvements in efficacy. The study did not meet the objective for one coprimary endpoint—change from baseline to end of treatment in the mean number of urinary incontinence episodes over 24 hours (P = 0.052 compared with M50 monotherapy), but the nominal P value for the other coprimary endpoint—change from baseline to end of therapy in mean number of micturitions over 24 hours—was 0.05 (-2.59 for S5 and M50 vs -2.20 for S5, P = 0.006); -2.59 vs -2.03 for M50, P = 0.001). S5 plus M50 also improved mean volume voided per micturition compared with S5 monotherapy (39.73 vs 30.99, = 0.005) or M50 (39.73 vs 21.99, P < 0.001).3

The proportion of patients reporting no urinary incontinence episodes at the end of treatment was also significantly higher with the combination (52.2%) than with S5 (42.9%; P =.0009) and against M50 (46.3%; P = 0.023) monotherapy. Improvements in urgency urinary incontinence, urgency episodes, and nocturia at the end of treatment were also greater with the combinations than with monotherapy. A predefined subgroup analysis found a much larger effect with combination treatment in participants who had received previous overactive bladder treatment, compared with treatment-naïve participants.3

The long-term, phase 3, SYNERGY-2 trial,4 which was initated to assess one year of treatment with S5 and M50 versus S5 or M50 monotherapy in 1,829 individuals with OAB, achieved results similar to the BESIDE trial and the SYNERGY study. The investigators reported that S5 plus M50 treatment resulted in greater improvements in urinary incontinence episodes (-2.0 vs -1.9, P = 0.002 for S5 and -1.6, P < 0.001] for M50), micturitions over 24 hours (-2.6 vs -2.2, P = 0.0004 for S5 and -2.1 with a P < 0.0001 for M50), and MVV (37.7 vs 24.9, P < 0.001 for S5, and 21.8, P < 0.001 for M50).

The authors concluded that findings from all three phase 3 trials demonstrated that combination therapies resulted in similar or greater improvements in patient-reported outcomes and health-related quality of life, compared with solifenacin or mirabegron monotherapy.

Treatment-related adverse events were mild to moderate in severity. Incidences of dry mouth, constipation, and urinary tract infections were less than 10%, and no notable differences were observed in vital signs or postvoid residual volume.

In the SYNERGY and SYNERGY-2 trials,3,4 urinary retention was reported slightly more frequently among participants receiving combination therapy, but the majority of episodes did not require catheterization.4In SYNERGY, investigators collected data on cardiovascular events but found no clinically meaningful differences in electrocardiogram parameters, QT interval prolongation, or elevated blood pressure.4Similarly, the frequency of hypertension, tachycardia, and QT interval prolongation was low and similar across treatment groups in the BESIDE study.3

The rapid evidence assessment included three other studies evaluating the clinical efficacy and safety of mirabegron combined with antimuscarinic therapy in individuals with moderate to severe OAB. In a study by Kosilov et al, 239 treatment-experienced patients with overactive bladder and incontinence showed greater improvements in urodynamic parameters and quality of life scores after six weeks’ treatment with S10 and M50 than with monotherapies, although the incidence of adverse events did not differ between groups. The incidence of adverse events, which included dry mouth, hypertension, increased heart rate, and dizziness, did not differ significantly between combination therapy and monotherapy. 

A multicenter, open-label study conducted by a Japanese team,6 enrolled 223 adults who received S2.5 or S5 for at least four weeks. The investigators found that by adding mirabegron, the participants had significantly improved clinical outcomes and more favorable patient responses to treatment. In this study,6 treatment-related adverse events, which were mild to moderate in severity, were reported in 23.3% of participants, with the most common event being constipation. There were no dose-related changes. QT interval prolongation was observed in three patients, but it was not clinically meaningful.

in small study of patients (n=30) whose OAB had responded suboptimally to four weeks of treatment with M50, the results indicated improved patient-reported outcomes after the addition of 10 mg of propiverine given for eight weeks.7 Three patients in this study reported dry mouth, but there were no reports of acute urinary retention.

In effect, the investigators of this rapid evidence assessment of recent pharmacotherapy trials concluded that 50 mg of mirabegron combined with 5 mg solifenacin proved to be the most effective and well-tolerated treatment for both treatment-naïve patients with OAB and patients whose OAB symptoms had responded inadequately to monotherapy. The combination appears to be a reliable option for patients with persistent OAB symptoms.

Expert Commentary on Use of Combination Therapy for Overactive Bladder Syndrome

This review reaches several important conclusions. First, the authors present compelling evidence that combination of mirabegron and solifenacin is associated with significant improvement in multiple objective, bladder diary variables. This is not surprising since there are abundant, randomized studies in the literature that demonstrate objective improvement in OAB patients on either anticholinergics or mirabegron, independently. 

Another noted benefit of prescribing this combination therapy—the reported outcomes may be achieved without increasing the anticholinergic load, which may be an especially welcome management approach for elderly patients. Likewise, the dry mouth, which arises as a common side effect with anticholinergic therapy, may lead to a worsening of preexisting polydipsia in diabetics. 

Also, the addition of mirabegron in patients with suboptimal improvement on solifenacin alone (ie, not in treatment-naïve patients) is associated with symptomatic improvement in this population. Finally, dose-escalation of mirabegron to 50 mg is another option that may improve symptoms without requiring escalation of anticholinergic medications dosing, which is likely to worsen preexisting bowel dysfunction in this population.

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