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Pharmacological treatment of male LUTS – how effective are silodosin, tadalafil and mirabegron in nocturia?
By Prof. Karl-Erik Andersson
One of the most common and bothersome of male lower urinary tract symptoms (LUTS) is nocturia. Bosch and Weiss (2012), reviewing the nocturia prevalence literature, analysed 43 trials and found that 11.0–35.2 % of men aged 20–40 years reported nocturia ≥1 times per night, and that 2.0–16.6 % of men had nocturia ≥2 times per night. In men >70 years of age, the corresponding rates of nocturia rose to 68.9–93.0 % and 29.0–59.3 %. The perception of bother associated with nocturia largely depends on the individual. Tikkinen et al. (2010) reported, based on a random sample of 6000 subjects aged 18-79 years, that nocturia was bothersome when the individual has to void at least 2 times per night (i.e., clinically relevant nocturia). Accepting the high number of males who have bothersome nocturia, there should be room for treatment.
Treatment of male LUTS still poses a challenge. Pharmacological treatment is usually based on non-subtype selective α1-adrenoceptor (AR) antagonists and 5α-reductase inhibitors, alone or in combination (Füllhase et al., 2014; Russo et al., 2014, Silva et al., 2014). As pointed out by Silva et al. (2014), this classical paradigm is being challenged by other drugs such as the selective α-AR antagonist, silodosin, 5-phosphodiesterase (PDE) inhibitors, and β3-AR agonists. A main question is: how effective are these ”new” treatments on nocturia? This issue has been discussed in several recent reviews (Eisenhardt et al., 2014; Oelke et al., 2014; Oelke et al., 2014a; Silva et al., 2014).
Even if α1-AR antagonists without subtype selectivity occasionally have shown significant effects on nocturia in male patients with LUTS, the effect has been inconsistent. Contributing to this may be that only rarely has nocturia been a primary end point when the effects on LUTS of drugs, including α1-AR antagonists, have been studied (Cornu et al., 2012). However, based on analysis of three placebo-controlled registration studies, Eisenhardt et al. (2014) concluded that the α1A-AR subtype-selective antagonist, silodosin, consistently and significantly improves nocturia in men with LUTS/BPH. It may be questioned why these results with silodosin appear to be more consistent than with other α1-AR antagonists - has the drug effects that separates it from other members of the class? Silodosin is the only clinically available α1-AR antagonist that exhibits relevant selectivity for the α1A-AR over α1B- (583-fold) and α1D-ARs (56-fold) (Russo et al., 2014). It is difficult to immediately link this selectivity to an effect on nocturia. After all, why should α1-AR antagonists be effective on male nocturia? It is well acknowledged that nocturia has a multifactorial etiology, but also that nocturia can be related to reduced bladder capacity, increased fluid intake and increased nocturnal diuresis (Cornu et al., 2012; Van Kerrebroeck and Andersson 2014; Oelke et al., 2014). The most likely target for the α1-AR antagonists seems to be bladder capacity. Some investigators (Boucheloche et al., 2005, but not others Nomiya et al., 2003) have found an upregulation of α1-ARs and contractile effects of α1-AR agonists in human bladders with outflow obstruction. Experimentally, it has been shown that α1-AR antagonists (silodosin and prazosin) improve storage function in rats with bladder outflow obstruction through reduction of afferent activity (Yazaki et al., 2011). Whatever the mechanism, the improvement of nocturia by silodosin (silodosin 53%, placebo 43%) was similar to that obtained with a PDE5 inhibitor, tadalafil (tadalafil 48%, placebo 41%) or with the combination of the 5α-reductase inhibitor, dutasteride and the α1A/D-AR agonist, tamsulosin (combination 48%, placebo 29%), see Oelke et al (2014).
Silodosin may be an attractive option for treatment of LUTS, but does not seem to offer any great advantages over other LUTS treatments with respect to nocturia. Its tendency to cause anejaculation is a reality that has to be considered.
PDE5 inhibitors alone can improve BPH/LUTS, including nocturia. Data integrated from four randomized, placebo-controlled, double-blind, 12-week registrational studies of tadalafil for LUTS/BPH revealed a statistically significant improvement in nocturnal frequency over placebo; however, the treatment difference was small and not considered clinically meaningful (Oelke et al., 2014a). However, combination of PDE5 inhibitor with α1-AR antagonists (silodosin, prazosin), has experimentally been shown to have a synergistic effect on LUT function (Buono et al., 2014), and there are many clinical studies suggesting that that a combination of a PDE5 inhibitor and a non-selective α1-AR antagonist can have additive effects and may provide better symptomatic control of LUTS than α1-AR antagonists alone (Gacci et al., 2014; Singh et al., 2014; Yan et al., 2014).
The selective ß3-AR agonist, mirabegron, has been shown to increase bladder capacity without interference with micturition pressure, post void residual, or voiding contraction (see e.g., Chapple et al., 2014). There are several studies evaluating the benefits of mirabegron in the male population (see Suarez et al., 2013). In OAB studies where 25-30 % of patients were male, mirabegron had a significant beneficial effect on the number of nocturnal voidings (Chapple et al., 2014). However, there seem to be no studies with nocturia as a primary endpoint. Ichihara et al. (2015) evaluated the efficacy and safety of add-on treatment with mirabegron for OAB symptoms remaining after α1-AR antagonist (tamsulosin) treatment in men with benign prostatic obstruction. The combination was effective and safe on OAB symptoms, however, the effect on night time frequency (OAB symptom score) or nocturia (IPSS) was modest.
It seems that silodosin, tadalafil, and mirabegron, all can have a beneficial effect on male nocturia. However, the overall effect of these drugs as monotherapy is not impressive. It may be that combinations may have a better effect, but convincing studies are rare. Since the target for silodosin, tadalafil, and mirabegron seems to be bladder capacity, a logical combination would be between any of these drugs and an antidiuretic (e.g., desmopressin) to also reduce nocturnal polyuria. Such studies would be desirable but seem not yet available.
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Commented by Prof. Antonella Giannantoni
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