Overactive bladder (OAB) is characterized by symptoms of urinary urgency, frequency, and nocturia with or without urgency incontinence in the absence of a lower urinary tract infection [1]. OAB is a common multifactorial health disorder that is associated with detrimental effects on quality of life and a considerable economic burden [2]. The prevalence of OAB is high, with 12%–16% of adults in Europe, the United States, and Asia affected by this symptomatic syndrome [3].

Antimuscarinic agents are the mainstay of oral pharmacotherapy for OAB, but long-term treatment is limited by their insufficient efficacy and antimuscarinic agent-associated adverse events (AEs). In clinical practice, antimuscarinics are often initially prescribed; however, increasing the dose may exacerbate antimuscarinic AEs, such as constipation and dry mouth, and result in treatment discontinuation [4]. The efficacy of β3-adrenergics, which are associated with a new safety profile that differs from that of antimuscarinics, has been shown [5]. Mirabegron is a selective β3-adrenoceptor (AR) agonist [6] that is the drug of first choice for OAB. Given that β3-adrenergics and anticholinergics have distinct mechanisms of action, the combination of both drugs is a possible option and has been tested in several clinical trials [7,8].

We performed a meta-analysis to evaluate the safety and efficacy of the combination of solifenacin (5 or 10 mg) plus mirabegron (50 mg) compared with solifenacin (5 or 10 mg) monotherapy (the most widely used doses in clinical practice) for OAB treatment.

OAB is one of the most frequent lower urinary tract symptoms (LUTS) in both genders and is associated with significant bothersome symptoms and a poorer quality of life [17]. In many cases, no underlying cause is found, and the case of OAB is considered idiopathic [18]. Pharmacological therapy is widely used for OAB treatment. The 2 main classes of drugs used are antimuscarinics and the newer β3-AR agonists [19]. Combining 2 oral pharmacotherapies with distinct modes of action and proven efficacy may improve OAB symptoms without exacerbating the burden of anticholinergic or β3-AR agonists, which can obviate the need for dose escalation or more invasive interventions [20].

This systematic review and quantitative meta-analysis summarized the evidence from RCTs regarding the efficacy and safety of mirabegron (50 mg per day) add-on therapy to solifenacin (5 or 10 mg per day) for OAB treatment. Our study demonstrated that the combination therapy was superior to solifenacin alone (5 or 10 mg per day) in improving the mean number of micturitions per 24 hours, the mean number of episodes of incontinence per 24 hours, the mean volume voided per micturition, and the mean number of urgency episodes per 24 hours. Two RCTs [13,14] evaluating the mean number of nocturia episodes, mean number of pads per 24 hours, and the Patient Perception of Bladder Condition score showed that adding mirabegron therapy to solifenacin was superior to solifenacin alone for improving OAB symptoms. One RCT [15] demonstrated that the postvoid residual bladder capacity, detrusor compliance, and maximum bladder capacity values significantly changed in the combination group. Overall, the combination therapy resulted in more pronounced improvements in multiple parameters. The findings indicate that combination therapy may be more useful than monotherapy for patients seeking additional symptomatic improvement.

Yamaguchi et al. [21] reported the results of the MILAI study, which was an open-label phase IV trial that demonstrated the effects of mirabegron as an add-on therapy in patients in whom OAB was treated with solifenacin. The authors discovered that the addition of mirabegron to solifenacin resulted in only mild to moderate AEs and had promising results in terms of efficacy. Imamura et al. [22] found that the different mechanisms of action of mirabegron and solifenacin were synergistic in inhibiting cold stress-induced detrusor overactivity in spontaneously hypertensive rats. Therefore, the combination of mirabegron and solifenacin offered significant improvements over single-drug treatment and lacked serious side effects in patients with cold stress-exacerbated LUTS.

When urine is stored, the binding of acetylcholine in the bladder activates afferent nerves to the muscarinic receptors (MRs) [23]. MR antagonists can effectively suppress the activation of the afferent nerves by blocking MRs. Additionally, MR antagonists may desensitize the bladder afferent nerves [24]. In contrast, β3-AR agonists stimulate the release of nitric monoxide (NO) by the urothelium [25] by binding to receptors within the urothelium. NO suppresses the activation of the afferent nerves, and β3-AR activation has an inhibitory effect on bladder afferent activity. Moreover, the combination of antimuscarinic and β3-AR agonist agents was found to inhibit part of the Rho kinase pathway in vitro [26]. As a result, the combination of mirabegron and solifenacin may effectively improve bladder function during the storage phase by inhibiting afferent nerve activation.

The safety data included in this meta-analysis suggest that the combination of mirabegron and solifenacin is well tolerated. Measures of adverse reactions, such as discontinuations due to AEs and common TEAEs, were similar in the combination group and the solifenacin-only group. This result demonstrates the safety of mirabegron add-on therapy to solifenacin for OAB treatment. Dry mouth, which was the most frequently reported AE with antimuscarinics [27] and a common reason for treatment discontinuation [4], did not show a different pattern of incidence in the combination versus solifenacin-only groups. The vital signs, electrocardiogram parameters, and postvoid residual volume in the combination group showed no synergistic effects beyond those known from either monotherapy. Therefore, mirabegron (50 mg per day) add-on therapy to solifenacin (5 or 10 mg per day) seems to offer a good balance between side effects and efficacy.

This meta-analysis included only double-blind RCTs. The quality of the individual studies in the meta-analysis was high based on the quality assessment scale that we developed. Nevertheless, few studies were included. The long-term safety, efficacy, and persistence of combination therapy cannot be extrapolated from this article, and the present analysis excluded data from unpublished studies. These factors may contribute to bias. Although the combination of either 5 mg or 10 mg of solifenacin with 50 mg of mirabegron was found to be effective, the impacts of add-on treatment over monotherapy according to solifenacin dosage (5 mg vs. 10 mg) might be different. In this regard, it would be preferable to show that there was no difference in the efficacy and safety according to the solifenacin dosage. However, such a comparison could not be conducted because of small number of RCTs that were included. More high-quality trials with larger sample sizes should further investigate the efficacy and safety of mirabegron add-on therapy to solifenacin for OAB. Furthermore, cost is an important factor, particularly for older adults who may have high out-of-pocket costs associated with these drugs.

This meta-analysis indicates that mirabegron add-on therapy to solifenacin provides a satisfactory therapeutic effect for OAB symptoms without increasing the risk of side effects.