Combination treatment with vibegron and solifenacin for refractory non‐monosymptomatic enuresis

We read with great interest the article by Uchihara et al.1 The authors, in their retrospective study of 29 children with refractory enuresis that was unresponsive to conventional treatments, demonstrated that vibegron, a novel selected β3-adrenoreceptor agonist, may provide a promising treatment by increasing bladder capacity. In 2020, we first reported vibegron as a useful treatment option for refractory monosymptomatic nocturnal enuresis (MNE), particularly in those with constipation.2 We revealed a significantly higher proportion of patients with refractory MNE who received combination treatment with vibegron and solifenacin in the response group than in the no-response group.3 However, the efficacy of the combination treatment for refractory non-monosymptomatic nocturnal enuresis (NMNE) remains unknown. Here, we report on the effects of vibegron treatment for 3 months as an add-on therapy in children with NMNE that is refractory to solifenacin—i.e., with persistent daytime urinary incontinence (DUI) after 3 months of solifenacin. This retrospective study enrolled 21 children with refractory NMNE (median age 7.4 years) at Saitama Children's Medical Center from January 2019 to September 2022. For children with NMNE, the first step was lifestyle guidance such as regular voiding habits and a good voiding posture, and solifenacin (2.5 mg for patients weighing <25 kg, or 5 mg for patients weighing ≥25 kg; Vesicare, tablet, Astellas Pharma Inc., Tokyo, Japan) was initiated after constipation was excluded or successfully treated. However, all patients had persistent DUI and wetting nights (WN) after monotherapy with solifenacin for a median duration of 4.2 months, and subsequently received the combination treatment with vibegron (15 mg for patients weighing <25 kg, or 25 mg for patients weighing ≥25 kg; Beova, trituration tablet, Kissei Pharma Co., Nagano, Japan) and solifenacin once daily after the evening meal. The median number of DUI was significantly reduced from 13 to 6 days after the 3-month combination treatment (p < 0.05). The median of the maximum voided volume of daytime voiding was significantly increased from 6.1 to 8.7 mL/kg (p < 0.05). The proportion of patients who achieved complete response (CR) (100% reduction; n = 4) or partial response (PR) (50%–99% reduction; n = 6) in DUI was 48%. No significant differences were found in baseline characteristics between the response and the no-response groups in DUI (Table 1). The median number of WN was significantly reduced from 26 to 13 days at 3 months after the combination treatment (p < 0.001). The median of the maximum voided volume of first-morning voiding was significantly increased from 7.8 to 10.9 mL/kg (p < 0.001). The proportion of patients who achieved CR (n = 1) or PR (n = 8) in WN was 43%. A receiver operating characteristic (ROC) curve analysis showed that the proportion of patients who had <10 days/4 weeks of DUI at vibegron initiation was significantly higher in the response group than in the no-response group. The area under the ROC curve, sensitivity, and specificity were 0.87, 91.7%, and 88.9%, respectively. No severe adverse events requiring drug discontinuation were observed during the treatment period. In recent randomized controlled studies in adults with overactive bladder, combination treatment with β3-adrenoreceptor agonist and anticholinergic agent increased mean voided volume significantly with no important additional adverse effects,4 which was consistent with our study. DUI should be treated before addressing NE according to the standardization document from International Children's Continence Society.5 However, no evidence supported the delay of specific anti-enuretic therapy in children with NMNE with minor daytime symptoms. As previously reported in patients with MNE treated with desmopressin,6 older children were likely to respond to vibegron in our study. We therefore conclude that vibegron as an early add-on therapy may be suitable in older children with NMNE whose number of DUI is few after solifenacin. Yusuke Gonda and Shuichiro Fujinaga designed the study, drafted the manuscript, and were responsible for the data integrity and analysis results. Hiroki Miyano edited and reviewed the manuscript. All authors critically reviewed and approved the final manuscript. Shuichiro Fujinaga has received Grants-in-Aid for research of Saitama Children's Medical Center. The authors declare no conflict of interest. All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Research Committee and/or National Research Committee at which the study was conducted with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The ethics committee of Saitama Children's Medical Center approved this study (approval number, 2022-04-013).