To our knowledge, this meta-analysis is the first to evaluate the efficacy and safety of silodosin for the treatment of BPH. BPH is the most important cause of LUTS in males, and 50% of men with BPH complain about LUTS.19
Male LUTS can be classified into three categories, including voiding (hesitancy, slow stream, intermittency, incomplete emptying), storage (frequency, urgency, nocturia, urge urinary incontinence) and postmicturition (postvoid dribbling).20
Moreover, both the voiding and storage symptoms have a significant impact on the overall QoL.21
To date, alpha1
-adrenergic receptor antagonists are one of the most common treatments for BPH due to LUTS. Silodosin is a new alpha1A
-blocker and has been approved by the US Food and Drug Administration for the treatment of BPH since October 2008.22
However, the efficacy and safety of silodosin were unclear. Therefore, we combined subject searching with random searching to obtain relevant articles and used meta-analysis to evaluate the efficacy and safety of silodosin for the treatment of LUTS/BPH. In our study, we found that compared with placebo, silodosin can significantly improve the IPSS, QoL score and Qmax
. Among the adverse effects, ejaculation disorder was the most common adverse effect (21.9% versus 0.8%, respectively). Moreover, compared with 0.2 mg tamsulosin, silodosin can significantly improve the IPSS, QoL score and Qmax
. However, the incidence of ejaculation disorder was higher.
In this meta-analysis, the results indicate that silodosin was better than placebo and not inferior to tamsulosin, which was verified by the reduction in total IPSS. The difference in the change in the total IPSS between the silodosin and tamsulosin groups was −1.4 (95% CI: −2.11–0.18, respectively). Therefore, 8 mg silodosin is considered to be at least as effective as 0.2 mg tamsulosin, the recommended dosage regimen in Asian countries. Moreover, with respect to subjective symptoms, silodosin was effective in reducing not only the voiding symptoms but also the storage symptoms. In addition, the change in the QoL score from baseline was significantly different between the silodosin group and the placebo or 0.2 mg tamsulosin group.
-ARs are a family of G protein-coupled receptors. The binding of norepinephrine and epinephrine induces phospholipase C activation, leading to the generation of secondary messengers, including inositol triphosphate and diacylglycerol. Finally, this binding induces an increase in the intracellular calcium levels and smooth muscle contraction.23
As is well known, prostate contraction is the main cause of LUTS due to BPH and is predominantly mediated by alpha1A
Therefore, the blockage of alpha1A
-AR induces prostatic and urethral smooth muscle relaxation and may improve the voiding symptoms. Yokoyama et al.26
demonstrated that the selective alpha1A
-blocker silodosin exerts inhibitory effects on detrusor overactivity by modulating C-fibre afferent activity using animal models. Consequently, alpha1A
-blockade can improve the storage symptoms.
Wilt and colleagues9
assessed the efficacy and safety of tamsulosin for the treatment of BPH. In the tamsulosin studies, 14 studies involving 4122 subjects were included; in these studies, the placebo-controlled study duration lasted less than 13 weeks, and the mean age of the subjects was 64 years. The pooled results showed that the weighted mean differences for the mean change from baseline for the Boyarsky symptom score for the 0.4 mg and 0.8 mg doses of tamsulosin relative to placebo were −1.1 and −1.6 points, respectively. The weighted mean differences for the mean change from baseline in peak urine flow were 1.1 and 1.1 ml s−1
for 0.4 and 0.8 mg, respectively. In the included studies, our pooled results showed that the MD for the mean change from baseline for IPSS for the 8 mg dose of silodosin relative to placebo was −2.78 points. The MD for the mean change from baseline in the peak urine flow was 1.17 ml s−1
for 8 mg silodosin. Moreover, we also assessed the efficacy and safety of silodosin for the treatment of BPH compared with tamsulosin. The pooled results indicated that the MD for the mean change from baseline in the IPSS, peak urine flow and QoL score were −1.14 points, −0.85 ml s−1
and −0.26 points, respectively.
In these studies,14,15,18
the most commonly reported adverse reaction for silodosin was ejaculation disorder. Compared with 0.2 mg tamsulosin, the incidence of ejaculation disorder was higher (18% vs.
4%) in this meta-analysis. Similarly, Chapple et al.16
reported that the frequency of ‘ejaculation disorder' was 14.2% in the silodosin treatment group, which was also significantly higher compared with 2.1% in the 0.4 mg tamsulosin treatment group. However, Song et al.27
reported that the overall incidence of ejaculatory dysfunction was 13.4% after 12 weeks of 0.2 mg tamsulosin treatment. Retrograde ejaculation is caused by smooth muscle relaxation in the prostate, urethra, bladder neck and vas deferens. The alpha1A
-AR is mainly expressed in the bladder neck, vas deferens and seminal vesicles.23
Moreover, Moriyama et al.28
showed that the alpha1A
-AR subtype mediates human vas deferens contraction. Therefore, this adverse effect is explained by the high alpha1A
-AR subtype selectivity of silodosin. Moreover, Homma et al.29
performed a post hoc
analysis of the data from a randomized, double-blind, placebo-controlled clinical trial of silodosin in Japan and found that ejaculation disorder caused by selective alpha1A
-blockers was associated with very large improvements in the lower urinary tract symptoms. The silodosin subgroup with ejaculation failure experienced a greater reduction in the total IPSS than the silodosin subgroup without ejaculation impairment and the placebo subgroup (−11.8 vs.
−5.3, respectively). However, there was no difference in the discontinuation rates between the silodosin subgroup with ejaculation disorder and the silodosin subgroup without ejaculation disorder. Thus, ejaculation disorder may be a predictor of the efficacy of the alpha1
Akiyama et al.30
demonstrated that silodosin did not induce any negative cardiovascular effects in patients with BPH in male decerebrate dogs. Tatemichi et al.31
indicated that silodosin did not affect blood pressure, heart rate or electrocardiogram in conscious dogs with voiding dysfunction. A recent RCT16
suggested that compared with tamsulosin or placebo, silodosin showed no significant differences in the supine systolic blood pressure, diastolic blood pressure and heart rate. Alpha1B
-ARs have been demonstrated to mediate both blood vessel contraction and baroreceptor-induced inotropic effects.32,33,34
Moreover, tamsulosin has a higher selectivity for the alpha1B
-AR than silodosin, and thus, the decrease in blood pressure induced by tamsulosin may be mediated by its blocking action on the alpha1B
-AR participating in blood vessel contraction and baroreceptor-induced inotropic effects.13,24
Therefore, the lack of cardiovascular side effects may be a major advantage of silodosin.
Our meta-analysis had several limitations. First, all included studies are of moderate quality.35
Second, the durations of all the included studies were short (only 12 weeks). Third, in this meta-analysis, the dose of tamsulosin was 0.2 mg and the dosage regimen of silodosin was 4 mg twice a day, which is commonly used in Asia, but the used dose of tamsulosin is 0.4 mg and the dosage regimen of silodosin is 8 mg once daily in Europe and the United States. These limitations might not allow for a reliable conclusion. Therefore, the findings of this review require a more efficient performance of higher-quality, long-term randomized controlled trials to verify and explore the efficacy and safety of silodosin. In particular, studies that compare 8 mg silodosin with 0.4 mg tamsulosin are needed in the future.