Bladder hypertrophy can occur as part of several conditions including bladder outlet obstruction or experimental diabetes. β-Adrenoceptor (β-AR) stimulation can have anti-hypertrophic effects in several tissues, and knock-out of β3-AR leads to bladder hypertrophy in mice [1]. Therefore, we designed the animal equivalent of a phase III study to determine whether treatment with the β3-AR agonist mirabegron can reverse diabetes-associated bladder hypertrophy in rats.

Our study fulfilled the criteria of the animal equivalent of a phase III study, i.e., was based on a prespecified protocol including statistical analysis plan, had a defined primary outcome parameter (bladder weight), was powered to detect an at least 30% reduction in bladder weight, was randomized, and investigators were blinded to group allocation. 
10-13 week-old female Sprague Dawley rats were randomized to receive streptozotocin (STZ; 50 mg/kg i.p.) or vehicle to induce a model of type I diabetes. Two weeks later, each group was randomized to receive mirabegron (10 mg/kg/day by oral gavage) or vehicle for another two weeks. More than 70 studies showed that diabetes associated bladder hypertrophy has fully developed at this time of treatment initiation [2]. This design was chosen to reflect the clinical reality of a delayed diagnosis of diabetes, with already fully established bladder hypertrophy.
Data are means ± SD of 17-20 rats. Mirabegron-associated changes in bladder weight (diabetic vs. diabetic + mirabegron goup) were analyzed by unpaired t-tests not assuming a similar SD across groups (Welch’s test).

STZ induced the expected increase in blood glucose from 107 ± 8 to 502 ± 94 mg/dl and increase in bladder weight from 83 ± 12 to 171 ± 37 mg, but neither was affected by concomitant treatment with mirabegron (model validation; Figure 1). Treatment with mirabegron did not affect bladder weight or bladder/body weight ratio in the diabetic (primary outcome parameter) or in the euglycemic rats (exploratory secondary outcome; Figure 1). Thus, the null hypothesis that mirabegron does not change diabetes-associated bladder hypertrophy was not rejected (p = 0.7027 in a Welch’s test).

Applying the animal equivalent of a phase III pivotal study to a translationally relevant setting (developed bladder hypertrophy), our findings do not support the idea that a β3-AR agonist reverses bladder hypertrophy.

We conclude that a 2-week treatment with 10 mg/kg/day mirabegron does reverse diabetes-associated bladder hypertrophy in rats. Whether this also applies to other causes of bladder hypertrophy, remains to be tested.

Kayki-Mutlu G., Ferrero K., Arioglu-Inan, E, Michel M.C., Koch W. (2022) Uncovering a role of ß3-adrenoceptors in control of bladder size. Eur Urol 79 (S1): S17
Arioglu-Inan E., Ellenbroek J.H., Michel M.C. (2018) Neurourol Urodyn 37: 1212-1219