Benign prostatic hyperplasia (BPH) is one of the common diseases among elderly men, that causes various lower urinary tract symptoms (LUTS). Tadalafil, a phosphodiesterase type 5 inhibitor (PDE5i), is one of the standard treatment options for BPH. It relieves voiding and storage symptoms via a variety of mechanisms, including up-regulation of the NO/cGMP pathway, down-regulation of the Rho-kinase pathway, modulation of autonomic nervous system overactivity, improvement of blood flow, and reduction of prostatic inflammation. However, it is not elucidated for which patients tadalafil is effective. We previously demonstrated that tadalafil improved ischemia and reduced inflammation in the prostate of OLETF rat, a type 2 diabetes model with severe obesity, more significantly than in control LETO rat [Ref. 1]. Thereafter, we made a hypothesis that tadalafil is effective for BPH patients with metabolic syndrome.

The analysis of clinical data was approved by the Ethics Committee of our institution. The BPH patients who received tadalafil treatment from January 2018 to December 2022 in our institution were enrolled in the study. We retrospectively examined the timing of treatment change for evaluating the efficacy of tadalafil therapy. Treatment change includes the following events: additions or changes of an anticholinergic agent, cholinergic agent, beta-3 adrenergic agonists, 5 alpha-reductase inhibitors, and surgical treatment. 
The time to treatment change was compared between high and low body mass index (BMI), with or without diabetes mellitus (DM), hypertension (HT), and dyslipidemia (DL), by log-rank test. The Cox proportional hazards regression analyses were performed to clarify the relative factors associated with the time to treatment change. All statistical analyses were carried out using EZR, and p-values <0.05 were considered significant.

The 102 patients participated. We divided the group into patients with BMI less than 20 (n=19) and those with BMI greater than 20 (n=83). The median time to treatment change was significantly shorter in the patients with low BMI than in the patients with high BMI (17.0 and 26.0 months respectively; p=0.026) (Fig.1-A). 
   Next, we evaluated the relationship between the time to treatment change and having comorbidities of DL, DM, and HT. The median time to treatment change treatment was significantly shorter in the no-DL group than DL group (22 vs. 32 months, p=0.046, Fig. 1-B). The median time to treatment change tended to be shorter in the no-DM group than DM group (22 vs. 29 months, p=0.161, Fig. 1-C). The median time to treatment change tended to be shorter in the no-HT group than the HT group (22 months vs. 26 months, p=0.507, Fig. 1-D). 
   We next divided the group into patients with at least two of the four factors (BMI more than 20, DL, DM, and HT) and those with less than two. The median time to treatment change treatment was significantly shorter in the group with less than 2 factors than those with at least two (16 vs. 27 months, p=0.018, Fig. 1-E). 
   The Cox proportional hazards regression analyses were carried out to evaluate the factors contributing to the efficacy of tadalafil. In multivariate analyses, BMI to be more than 20 was a factor significantly associated with the long usage of tadalafil treatment (hazard ratio=0.523; 95%CI, 0.295 to 0.947; p=0.032, Fig. 2).

The present study indicated that tadalafil might potentially be effective for patients with more than 2 factors of metabolic syndrome. We supposed these responders have different mechanisms of the response for tadalafil. Patients with metabolic syndrome would have some problems with their vessels, and it is widely known that tadalafil has the effect to improve pelvic blood flow. Taken together them, we supposed the patients with metabolic syndrome could receive more benefits from tadalafil than the patients without it in terms of the improvement of pelvic blood flow. 
In the multivariate analyses, BMI less than 20 was significantly associated with poor response to tadalafil treatment. The patients with BMI less than 20 were considered to be skinny people. It was speculated that the volume of skeletal muscle might be associated with drug metabolisms. Tadalafil is activated by CYP3A4 in the liver and skeletal muscle-derived IL-6 regulated liver metabolism [Ref. 2]. Skinny patients have less skeletal muscle than patients with non-skinny patients and have lower activity of tadalafil. Further studies are required to prove our hypothesis.

Tadalafil treatment tended to be effective for patients with metabolic syndrome with high BMI and having comorbidities of DM, DL, and HT.

Kobayashi H, Zha X, Nagase K, et al. Phosphodiesterase 5 inhibitor suppresses prostate weight increase in type 2 diabetic rats. Life Sci. 2022;298:120504.
Knudsen JG, Joensen E, Bertholdt L, et al. Skeletal muscle IL-6 and regulation of liver metabolism during high-fat diet and exercise training. Physiological Reports. 2016;4(9):e12788.