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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.

Literature

Bosch JL, Weiss JP (2012). The prevalence and causes of nocturia. J Urol 189:S86–S92

Tikkinen KA, Johnson TM 2nd, Tammela TL, Sintonen H, Huakka J, Huhtala H, Auvinen A (2010). Nocturia frequency, bother, and quality of life: how often is too often? A population based study in Finland. Eur Urol 57:488–496

Füllhase C, Soler R, Gratzke C. New strategies in treating male lower urinary tract symptoms. Curr Opin Urol. 2014 Jan;24(1):29-35.

Russo A, La Croce G, Capogrosso P, Ventimiglia E, Colicchia M, Serino A, Mirone V, Damiano R, Montorsi F, Salonia A. Latest pharmacotherapy options for benign prostatic hyperplasia. Expert Opin Pharmacother. 2014 Nov;15(16):2319-28

Silva J, Silva CM, Cruz F. Current medical treatment of lower urinary tract symptoms/BPH: do we have a standard? Curr Opin Urol. 2014 Jan;24(1):21-8

Eisenhardt A, Schneider T, Cruz F, Oelke M. Consistent and significant improvement of nighttime voiding frequency (nocturia) with silodosin in men with LUTS suggestive of BPH: pooled analysis of three randomized, placebo-controlled, double-blind phase III studies. World J Urol. 2014 Oct;32(5):1119-25.

Oelke M, Adler E, Marschall-Kehrel D, Herrmann TR, Berges R. Nocturia: state of the art and critical analysis of current assessment and treatment strategies. World J Urol. 2014 Oct;32(5):1109-17.

Oelke M, Weiss JP, Mamoulakis C, Cox D, Ruff D, Viktrup L. Effects of tadalafil on nighttime voiding (nocturia) in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a post hoc analysis of pooled data from four randomized, placebo-controlled clinical studies. World J Urol. 2014a Oct;32(5):1127-32

Cornu JN, Abrams P, Chapple CR, Dmochowski RR, Lemack GE, Michel MC, Tubaro A, Madersbacher S. A contemporary assessment of nocturia: definition, epidemiology, pathophysiology, and management--a systematic review and meta-analysis. Eur Urol. 2012 Nov;62(5):877-90.

Van Kerrebroeck P, Andersson KE. Terminology, epidemiology, etiology, and pathophysiology of nocturia. Neurourol Urodyn. 2014 Apr;33 Suppl 1:S2-5.

Bouchelouche K, Andersen L, Alvarez S, Nordling J, Bouchelouche P. Increased contractile response to phenylephrine in detrusor of patients with bladder outlet obstruction: effect of the alpha1A and alpha1D-adrenergic receptor antagonist tamsulosin. J Urol. 2005 Feb;173(2):657-61.

Nomiya M, Yamaguchi O. A quantitative analysis of mRNA expression of alpha 1 and beta-adrenoceptor subtypes and their functional roles in human normal and obstructed bladders. J Urol. 2003 Aug;170(2 Pt 1):649-53.

Yazaki J, Aikawa K, Shishido K, Yanagida T, Nomiya M, Ishibashi K, Haga N, Yamaguchi O. Alpha1-adrenoceptor antagonists improve bladder storage function through reduction of afferent activity in rats with bladder outlet obstruction. Neurourol Urodyn. 2011 Mar;30(3):461-7

Buono R, Briganti A, Freschi M, Villa L, La Croce G, Moschini M, Benigni F, Castiglione F, Montorsi F, Hedlund P. Silodosin and tadalafil have synergistic inhibitory effects on nerve-mediated contractions of human and rat isolated prostates. Eur J Pharmacol. 2014 Dec 5;744:42-51.

Gacci M, Ficarra V, Sebastianelli A, Corona G, Serni S, Shariat SF, Maggi M, Zattoni F, Carini M, Novara G. Impact of medical treatments for male lower urinary tract symptoms due to benign prostatic hyperplasia on ejaculatory function: a systematic review and meta-analysis. J Sex Med. 2014 Jun;11(6):1554-66.

Singh DV, Mete UK, Mandal AK, Singh SK. A comparative randomized prospective study to evaluate efficacy and safety of combination of tamsulosin and tadalafil vs. tamsulosin or tadalafil alone in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. J Sex Med. 2014 Jan;11(1):187-96

Yan H, Zong H, Cui Y, Li N, Zhang Y. The efficacy of PDE5 inhibitors alone or in combination with alpha-blockers for the treatment of erectile dysfunction and lower urinary tract symptoms due to benign prostatic hyperplasia: a systematic review and meta-analysis. J Sex Med. 2014 Jun;11(6):1539-45.

Chapple CR, Cardozo L, Nitti VW, Siddiqui E, Michel MC. Mirabegron in overactive bladder: a review of efficacy, safety, and tolerability. Neurourol Urodyn. 2014 Jan;33(1):17-30. Suarez O, Osborn D, Kaufman M, Reynolds WS, Dmochowski R. Mirabegron for male lower urinary tract symptoms. Curr Urol Rep. 2013 Dec;14(6):580-4

Ichihara K, Masumori N, Fukuta F, Tsukamoto T, Iwasawa A, Tanaka Y. A randomized controlled study of the efficacy of tamsulosin monotherapy and its combination with mirabegron for overactive bladder induced by benign prostatic obstruction. J Urol. 2015 Mar;193(3):921-6


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