Context
Several preclinical reports, randomized controlled trials, systematic reviews, and posthoc analyses corroborate the role of phosphodiesterase type 5 inhibitors (PDE5-Is) in the treatment of men with lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE).
Objective
Update of the latest evidence on the mechanisms of action, evaluate the current meta-analyses, and emphasize the results of pooled data analyses of PDE5-Is in LUTS/BPE.
Evidence acquisition
Literature analysis of basic researches on PDE5-Is, systematic literature search in PubMed and Scopus until May 2015 on reviews of trials on PDE5-Is, and collection of pooled data available on tadalafil 5 mg.
Evidence synthesis
Latest evidences on the pathophysiology of LUTS/BPE has provided the rationale for use of PDE5-Is: (1) improvement of LUT oxygenation, (2) smooth muscle relaxation, (3) negative regulation of proliferation and transdifferentiation of LUT stroma, (4) reduction of bladder afferent nerve activity, and (5) down-regulation of prostate inflammation are the proven mechanisms of action of PDE5-Is. Data from eight systematic reviews demonstrated that PDE5-Is allow to improve LUTS (International Prostate Symptom Score mean difference vs placebo: 2.35–4.21) and erectile function (International Index of Erectile Function mean difference vs placebo: 2.25–5.66), with negligible change in flow rate (Qmax mean difference vs placebo: 0.01–1.43). Pooled data analyses revealed that tadalafil 5 mg once daily allows the clinically-meaningful improvement of LUTS and nocturnal voiding frequency independent of both erectile dysfunction severity and improvement.
Conclusions
PDE5-Is are safe and effective in improving both LUTS and erectile function in appropriately selected men with LUTS/BPE. Data on the reduction of disease progression, long-term outcomes, and cost-effectiveness analyses are still lacking.
Patient summary
We reviewed recent literature on phosphodiesterase type 5 inhibitors in men with lower urinary tract symptoms associated with prostatic enlargement. We found evidence to confirm that phosphodiesterase type 5 inhibitors are a valid treatment option for men affected by bothersome urinary symptoms with or without erectile dysfunction.
Lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE) and erectile dysfunction (ED) are both highly prevalent in elderly men [1]
The aim of this review is to provide an update on the current knowledge on the potential mechanisms of action of PDE5-Is on LUTS/BPE, critically analyze systematic reviews and relevant data from the current literature on the clinical use of all PDE5-Is, and report the latest evidence on pooled-data analyses of tadalafil once daily to provide a definite rationale for the clinical use of tadalafil for the treatment of LUTS/BPE.
The pathways mediating the activity of PDE5-Is: LUTS have a multifactorial pathophysiology and have been discussed extensively [7]
The role of the bladder in male LUTS has been emphasized [9]
In the pathophysiology of LUTS, the NO/cyclic guanosine monophosphate (cGMP) (NO/cGMP) signaling pathway is believed to play a central role. Since NO signaling occurs via stimulation of soluble guanylate cyclase producing cGMP, it is reasonable to assume that the level of cGMP in different LUT tissues can influence their ability to generate LUTS. One way of modulating cGMP levels is to selectively inhibit cGMP degradation, and it is generally believed that all effects of PDE5Is are mediated by selective inhibition of the degradation of cyclic GMP.
Mechanism of action of PDE5-Is: In several animal species, including humans, the entire LUT expresses PDE5, with a relatively higher abundance within the bladder [16]
Although it is well established that PDE5 is expressed and biologically active in LUT, its functional role is still a matter of debate. Clinical studies demonstrated that its inhibition, through all the aforementioned PDE5-Is, resulted in amelioration of LUTS. Several mechanisms of action of PDE5-Is in LUTS have been hypothesized.
Immunohistochemical studies indicate that PDE5 is localized in the endothelial and smooth muscle cells of the LUT blood vessels [17]
Several in vitro studies have demonstrated that PDE5-Is can relax isolated prostate and bladder neck strips [27]
In the human prostate [17]
The NO/cGMP signaling pathway is likely to have a significant role in the innervation of the LUT. In human, neuronal NO synthase and guanylate cyclase are expressed in the uroepithelium, in neural fibers of the bladder neck and prostatic urethra, and in afferent nerves and interstitial cells, respectively [35]
Emerging evidences indicate that metabolic derangements, clustered in the metabolic syndrome (MetS) construct, may have a role in BPH pathophysiology. Within MetS, visceral obesity and dyslipidemia are the major predictors of an enlarged prostate size [3]
A systematic literature search in PubMed and Scopus was performed until May 2015, to identify systematic reviews of randomized controlled trial (RCTs), including the following MeSH terms: phosphodiesterase type 5 inhibitor and tadalafil PLUS urinary symptoms OR lower urinary tract symptoms OR benign prostatic hyperplasia OR prostate. We included only systematic reviews of RCTs comparing PDE5-Is treatment with different oral therapies or placebos for LUTS/BPH, while we excluded reviews of RTCs without PDE5-Is, nonclinical trials with PDE5-Is, or nonsystematic review. A total of eight papers were analyzed (Fig. 1; Table 1).
Table 1 Characteristics of the studies included in the review
a Significant improvement versus placebo.
b PDE5-Is + ABs versus ABs alone.
c Significant improvement versus ABs alone.
d PDE5-Is nonspecified.
* p = 0.04 for Tadalafil 5 mg.
ABs = alpha-blockers; BPH = benign prostatic hyperplasia; diff. = difference; ED = erectile dysfunction; IIEF = International Index Of Erectile Function; IPSS = International Prostatic Symptom Score; MRAs = muscarinic receptor antagonists; O = other PDE5-Is; PDE5-Is = phosphodiesterase 5 inhibitors; PLA = placebo; P.ts = patients; Qmax = maximum flow rate at uroflowmetry; S = sildenafil; T = tadalafil;. V = vardenafil; 5ARIs = 5a-reductase inhibitors.
Moreover, we selected more clinically relevant data from current literature on the clinical use of all PDE5-Is, including all post-hoc pooled data analyses (Table 2), with a nonsystematic approach (studies published only as abstract or presented without abstract and reports from meetings and studies not published in English were not considered for this review).
Table 2 Summary of posthoc pooled-data analyses of patients treated with tadalafil 5 mg once daily versus placebo for lower urinary tract symptoms/benign prostatic enlargement
Publication | No. of patients (n) |
Follow up (wk) |
Main findings | |
---|---|---|---|---|
Tadalafil | Placebo | |||
Oelke et al., 2015 [47] J.C. Nickel, G.B. Brock, S. Herschorn, R. Dickson, C. Henneges, L. Viktrup. Proportion of tadalafil-treated patients with clinically meaningful improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia. BJU Int. 2015;115:815-821 Crossref |
742 | 735 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from baseline to endpoint in significantly more patients with tadalafil (69.1%) vs placebo (54.8%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from baseline to endpoint in significantly more patients with tadalafil (59.8%) vs placebo (43.7%; p < 0.001) • 59.8% (50.2%) and 79.3% (72.5%) of the responders had ≥3 (≥25%) IPSS point improvement already after wk 1 and wk 4, respectively |
Nickel et al., 2015 [48] M. Oelke, B. Wiese, R. Berges. Nocturia and its impact on health related quality of life and health care seeking behavior in German community-dwelling men aged 50 years or older. World J Urol. 2014;32:1155-1162 Crossref |
752 | 747 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from randomization to endpoint in significantly more patients with tadalafil (71.1%) vs placebo (56.0%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from randomization to endpoint in significantly more patients with tadalafil (61.7%) vs placebo (45.5%; p < 0.001) • 38.5% (22.4%) of patients with tadalafil and 41.0% (23.3%) of patients with placebo had ≥3 (≥25%) IPSS point improvement during the placebo run-in phase |
Oelke et al., 2014 [50] H. Porst, C.G. Roehrborn, R.J. Secrest, A. Esler, L. Viktrup. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia and on erectile dysfunction in sexually active men with both conditions: analyses of pooled data from four randomized, placebo-controlled tadalafil clinical studies. J Sex Med. 2013;10:2044-2052 Crossref |
752 | 748 | 12 | Effects of tadalafil on nocturia (nocturnal voiding frequency): • for men with ≥1 nocturia episode at baseline, reduction with tadalafil (–0.5) was significantly greater than with placebo at study end (–0.4; LS mean change –0.2, p = 0.002) • for men with ≥2 nocturia episodes at baseline, reduction with tadalafil (–0.8) was significantly greater than with placebo at study end (–0.6; LS mean change –0.2, p = 0.003) • tadalafil (placebo) treatment resulted in reduction of ≥1 nocturia episodes in 47.5% (41.3%) of patients |
Porst et al., 2013 [51] G.B. Brock, K.T. McVary, C.G. Roehrborn, et al. Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: integrated data analyses from 4 placebo controlled clinical studies. J Urol. 2014;191:405-411 Crossref |
505 | 521 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • analysis only of men who were sexually active at baseline • significant improvement of total IPSS with tadalafil (–6.0) vs placebo (–3.6; p < 0.001) from baseline to study end • significant improvement of IIEF-EF with tadalafil (+6.4) vs placebo (+1.4, p < 0.001) from baseline to study end • similar IPSS improvements in men with ED vs without ED: no significant impact of ED severity on LUTS (IPSS) outcome |
Brock et al., 2014 [52] H. Porst, M. Oelke, E.R. Goldfischer, et al. Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational, randomized, placebo-controlled clinical studies. Urology. 2013;82:667-673 Crossref |
752 | 744 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • similar LUTS (IPSS) improvement with tadalafil vs placebo in men without ED (–5.4 vs –2.2, p = 0.0007) compared with men with ED (–5.9 vs –2.3, p < 0.0001); ED subgroup interaction not significant • bidirectional path analysis for sexually-active men (n = 1250) only: 92.5% of the total effects of tadalafil on LUTS/BPH via direct effect on LUTS and 7.5% via indirect effects by IIEF-EF domain improvement |
Porst et al., 2013 [53] O. Nishizawa, M. Yoshida, M. Takeda, et al. Tadalafil 5 mg once daily for the treatment of Asian men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: analyses of data pooled from three randomized, double-blind, placebo-controlled studies. Int J Urol. 2015;22:378-384 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in different patient subgroups: • improvements in IPSS and BPH-Impact Index in all patient subgroups identical (investigated patient parameters: age, symptom severity, serum testosterone concentration, prostate volume, previous α–blocker or PDE5-inhibitor use, arterial hypertension, diabetes mellitus, cardio-vascular diseases) • no baseline item was identified to predict a favorable or unfavorable treatment outcome |
Nishizawa et al., 2015 [54] C. Vlachopoulos, M. Oelke, M. Maggi, et al. Impact of cardiovascular risk factors and related comorbid conditions on the treatment response to tadalafil once-daily in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: an integrated analysis of four randomized, double-blind, placebo-controlled clinical trials. Int J Clin Pract. 2015;69:1496-1507 |
601 | 598 | 12 | Effects of tadalafil on LUTS/BPH in different subgroups of Asian patients: • analysis of Japanese, Korean, or Taiwanese men • significant improvements in total IPSS (tadalafil vs placebo) at wk 4 (–3.69 vs –2.47), wk 8 (–4.72 vs –3.43), and wk 12 (–5.32 vs –3.79), each p < 0.001 • additionally, significant improvements at wk 4, wk 8, and wk 12 for IPSS storage and IPSS voiding subscores as well as for IPSS-QoL • older patients (≥65 yr) showed significantly lower IPSS improvement than younger patients (<65 yr); otherwise, no significant impact of any other baseline item on LUTS improvement |
Vlachopoulos et al., 2015 [55] C.G. Roehrborn, C. Chapple, M. Oelke, D. Cox, A. Esler, L. Viktrup. Effects of tadalafil once-daily on maximum urinary flow rate in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. J Urol. 2014;191:1045-1050 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in patients with cardio-vascular risk factors and therapy: • subanalysis of comorbid, cardio-vascular diseases on LUTS/BPH outcome • no significant differences in efficacy of tadalafil vs placebo for various cardio-vascular diseases/comorbidities • but patients with >1 antihypertensive drugs have significantly lower IPSS improvement compared with men taking ≤1 drug • use of diuretics resulted in significantly lower IPSS improvement compared to men taking other antihypertensives or no drugs |
Roehrborn et al., 2014 [56] D.V. Singh, U.K. Mete, A.K. Mandal, S.K. Singh. 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;11:187-196 Crossref |
752 (612a) |
748 (585a) |
12 | Effects of tadalafil on uroflow (maximum urinary flow rate): • in total study population, patients with tadalafil had significantly greater Qmax improvement (mean +1.1 ml/s) compared with patients with placebo (mean +0.4 ml/s; p = 0.003) • significant Qmax improvement in the total study population was mainly driven by effects in patients who voided 250–450 ml (p = 0.011) and had a baseline Qmax 10–15 ml/s (p = 0.044) |
a With valid measurement.
BPH = benign prostatic enlargement; ED = erectile dysfunction; IPSS = International Prostate Symptom Score; LUTS = lower urinary tract symptoms; PDE5 = phosphodiesterase type 5; QoL = quality of life.
Efficacy: In the first systematic review on PDE5-Is for LUTS secondary to BPH published in literature, Laydner et al [38]
In the first meta-regression analysis on PDE5-Is alone or in combination with α-blockers, Gacci et al [2]
In a subset analysis on tadalafil based on data extrapolated from a systematic review on all PDE5-Is, Gacci et al [42]
Safety: In the review from Liu et al [39]
The first meta-analysis of AEs due to PDE5-Is reported that flushing, gastro-esophageal reflux, headache, and dyspepsia had the higher risk of occurrence (odds ratio: 4.88; 2.21; 1.88; 1.85; respectively). Moreover, regarding the overall tolerability of the association between PDE5-Is and α-blockers, Gacci et al [42]
In a recent review on tadalafil once daily, the Authors underlined the good safety profile with a relative risk of AEs from tadalafil similar to those reported with vardenafil or sildenafil (2.27 vs 1.86 vs 1.22, respectively); overall, the occurrence of AEs reported was very similar to that reported with all PDE5-Is versus placebo: 16.0% versus 6.0% [42]
Clinically-meaningful symptom improvement: Clinically-meaningful LUTS improvement is defined as a decrease of ≥3 points or ≥25% reduction of total IPSS [45]
Similar post-hoc analyses were done in 1499 patients treated with tadalafil 5 mg once daily or placebo [47]
Nocturia: Nocturia, defined as one or more voids per night, is one of the most prevalent and bothersome single urinary symptoms in community-dwelling men or patients with LUTS/BPH and the main reason for physician consultations [48]
Tadalafil for men with or without ED: The majority of the randomized, placebo-controlled tadalafil trials included patients with ED (approximately 60–70% of trial participants). Pooled data analyses evaluated whether symptom improvement was related to baseline ED status or ED improvement during tadalafil treatment [50]
Other baseline characteristics: The impact of several patient characteristics was evaluated in 1500 pooled patients with LUTS/BPH with regard to symptom improvement and adverse events, including age (≤65 vs >65 yr), symptom severity (IPSS < 20 vs ≥ 20), testosterone concentration (<300 ng/dl vs ≥300 ng/dl), prostate-specific antigen-predicted prostate volume (<40 ml vs ≥40 ml), previous α-blockers use (yes vs no), previous PDE5 inhibitor use (yes vs no), arterial hypertension (yes vs no), diabetes mellitus (yes vs no), and cardiovascular disease (yes vs no) [52]
Finally, an integrated analysis on 1371 patients, demonstrated that tadalafil 5 mg once daily for 12 wk allowed to achieve a very small, but statistically significant increase in Qmax versus the placebo (median: 1.1 ml/s vs 0.4 ml/s) [55]
Tadalafil has been also proposed in combination with alpha blockers or 5-alpha reductase inhibitors. In a prospective randomized study on 133 men with LUTS/BPH treated with tamsulsoin plus tadalafil versus tamsulosin or tadalafil alone, combination therapy was more effective than monotherapy for ED (%IIEF change from baseline: 60.2 vs 39.3 and 46.0 respectively) with similar improvement for urinary symptoms (% IPSS change from baseline: 53.9 vs 50.9 and 33.5), with a good safety profile [56]
Regarding the impact of tadalafil on sexual activity of men with ED and LUTS due to BPH tadalafil, Giuliano et al [58]
There is a large body of scientific evidence supporting the role of the NO-cGMP pathway including PDE5I in: (1) regulation of the tone of the smooth muscle fibers of the prostate, urethra, and bladder neck and in a lesser extent of the bladder (relaxant effect), (2) control of the arterial supply of the LUT (vasodilatory effect), and (3) modulation of the micturition reflex via the afferent bladder innervation (decrease in the afferent signaling). PDE5-Is may also downregulate inflammatory processes in LUT and exert antiproliferative effects.
Several meta-analyses demonstrated that PDE5-Is are effective in improving LUTS and erectile function compared with placebo. The combination of PDE5-Is with α-blockers induce a small, but statistically significant improvement of maximum flow rate as compared with α-blockers alone, in addition to the positive effect on micturition and sexual activity. PDE5-Is alone or in combination with α-blockers are well tolerated: flushing, gastroesophageal reflux, headache, and dyspepsia are the most common treatment-associated AEs.
Tadalafil 5 mg once daily achieves an improvement of clinically-meaningful urinary symptoms and nocturnal voiding frequency compared with placebo. Furthermore, the effects on LUTS are independent of ED severity at baseline and ED improvement.
Data on the long-term effects prostate size, reduction of disease progression, or prostate cancer prevalence related to the use of PDE5-Is are not available; long-term outcomes and cost-effectiveness analyses are needed.
Author contributions: Mauro Gacci had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Gacci, Giuliano.
Acquisition of data: Gacci, Giuliano, Andersson, Maggi, Oelke.
Analysis and interpretation of data: Gacci, Andersson, Chapple, Maggi, Mirone, Oelke, Porst, Roehrborn, Stief, Giuliano.
Drafting of the manuscript: Gacci, Giuliano, Andersson, Maggi, Oelke.
Critical revision of the manuscript for important intellectual content: Chapple, Mirone, Porst, Roehrborn, Stief.
Statistical analysis: Gacci.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Giuliano.
Other: None.
Financial disclosures: Mauro Gacci certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Gacci: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Pierre Fabre; Andersson: Consultancy and Advisory Boards for Allergan, Astellas, Ferring; Chapple: Consultant, Researcher and Speaker for Allergan, Astellas, Medtronic and Recordati. Consultant and speaker for Lilly. Researcher and speaker for ONO and Pfizer. Speaker for Ranbaxy; Maggi: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Intercept, Menarini; Mirone: consultant, speaker, and/or trial participant for Eli Lilly Italia, Menarini, Zambon, Recordati, GSK, Bracco; Oelke: consultant, speaker, and/or trial participant for Bayer Healthcare, Eli Lilly and Company, and Pfizer; Porst: consultant, speaker for Eli Lilly and Compani, Menarini Group and Sanofi; CRoehrborn: has financial interests and/or other relationships with Eli Lilly and Company, and with Allergan, Afferent Pharmaceuticals, Auxiliary Medical Services, Cancer and Leukemia Group B Clinical Trial Group, GlaxoSmithKline, New England Research Institutes, NeoTract, National Institute of Diabetes and Digestive and Kidney Diseases, Protox, Southwest Oncology Group, Urologix, VA Corporate Studies, and Watson Pharmaceuticals. Giuliano: consultant for Lilly, Sanofi, Pfizer.
Funding/Support and role of the sponsor: None.
Lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE) and erectile dysfunction (ED) are both highly prevalent in elderly men [1]
The aim of this review is to provide an update on the current knowledge on the potential mechanisms of action of PDE5-Is on LUTS/BPE, critically analyze systematic reviews and relevant data from the current literature on the clinical use of all PDE5-Is, and report the latest evidence on pooled-data analyses of tadalafil once daily to provide a definite rationale for the clinical use of tadalafil for the treatment of LUTS/BPE.
The pathways mediating the activity of PDE5-Is: LUTS have a multifactorial pathophysiology and have been discussed extensively [7]
The role of the bladder in male LUTS has been emphasized [9]
In the pathophysiology of LUTS, the NO/cyclic guanosine monophosphate (cGMP) (NO/cGMP) signaling pathway is believed to play a central role. Since NO signaling occurs via stimulation of soluble guanylate cyclase producing cGMP, it is reasonable to assume that the level of cGMP in different LUT tissues can influence their ability to generate LUTS. One way of modulating cGMP levels is to selectively inhibit cGMP degradation, and it is generally believed that all effects of PDE5Is are mediated by selective inhibition of the degradation of cyclic GMP.
Mechanism of action of PDE5-Is: In several animal species, including humans, the entire LUT expresses PDE5, with a relatively higher abundance within the bladder [16]
Although it is well established that PDE5 is expressed and biologically active in LUT, its functional role is still a matter of debate. Clinical studies demonstrated that its inhibition, through all the aforementioned PDE5-Is, resulted in amelioration of LUTS. Several mechanisms of action of PDE5-Is in LUTS have been hypothesized.
Immunohistochemical studies indicate that PDE5 is localized in the endothelial and smooth muscle cells of the LUT blood vessels [17]
Several in vitro studies have demonstrated that PDE5-Is can relax isolated prostate and bladder neck strips [27]
In the human prostate [17]
The NO/cGMP signaling pathway is likely to have a significant role in the innervation of the LUT. In human, neuronal NO synthase and guanylate cyclase are expressed in the uroepithelium, in neural fibers of the bladder neck and prostatic urethra, and in afferent nerves and interstitial cells, respectively [35]
Emerging evidences indicate that metabolic derangements, clustered in the metabolic syndrome (MetS) construct, may have a role in BPH pathophysiology. Within MetS, visceral obesity and dyslipidemia are the major predictors of an enlarged prostate size [3]
A systematic literature search in PubMed and Scopus was performed until May 2015, to identify systematic reviews of randomized controlled trial (RCTs), including the following MeSH terms: phosphodiesterase type 5 inhibitor and tadalafil PLUS urinary symptoms OR lower urinary tract symptoms OR benign prostatic hyperplasia OR prostate. We included only systematic reviews of RCTs comparing PDE5-Is treatment with different oral therapies or placebos for LUTS/BPH, while we excluded reviews of RTCs without PDE5-Is, nonclinical trials with PDE5-Is, or nonsystematic review. A total of eight papers were analyzed (Fig. 1; Table 1).
Table 1 Characteristics of the studies included in the review
a Significant improvement versus placebo.
b PDE5-Is + ABs versus ABs alone.
c Significant improvement versus ABs alone.
d PDE5-Is nonspecified.
* p = 0.04 for Tadalafil 5 mg.
ABs = alpha-blockers; BPH = benign prostatic hyperplasia; diff. = difference; ED = erectile dysfunction; IIEF = International Index Of Erectile Function; IPSS = International Prostatic Symptom Score; MRAs = muscarinic receptor antagonists; O = other PDE5-Is; PDE5-Is = phosphodiesterase 5 inhibitors; PLA = placebo; P.ts = patients; Qmax = maximum flow rate at uroflowmetry; S = sildenafil; T = tadalafil;. V = vardenafil; 5ARIs = 5a-reductase inhibitors.
Moreover, we selected more clinically relevant data from current literature on the clinical use of all PDE5-Is, including all post-hoc pooled data analyses (Table 2), with a nonsystematic approach (studies published only as abstract or presented without abstract and reports from meetings and studies not published in English were not considered for this review).
Table 2 Summary of posthoc pooled-data analyses of patients treated with tadalafil 5 mg once daily versus placebo for lower urinary tract symptoms/benign prostatic enlargement
Publication | No. of patients (n) |
Follow up (wk) |
Main findings | |
---|---|---|---|---|
Tadalafil | Placebo | |||
Oelke et al., 2015 [47] J.C. Nickel, G.B. Brock, S. Herschorn, R. Dickson, C. Henneges, L. Viktrup. Proportion of tadalafil-treated patients with clinically meaningful improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia. BJU Int. 2015;115:815-821 Crossref |
742 | 735 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from baseline to endpoint in significantly more patients with tadalafil (69.1%) vs placebo (54.8%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from baseline to endpoint in significantly more patients with tadalafil (59.8%) vs placebo (43.7%; p < 0.001) • 59.8% (50.2%) and 79.3% (72.5%) of the responders had ≥3 (≥25%) IPSS point improvement already after wk 1 and wk 4, respectively |
Nickel et al., 2015 [48] M. Oelke, B. Wiese, R. Berges. Nocturia and its impact on health related quality of life and health care seeking behavior in German community-dwelling men aged 50 years or older. World J Urol. 2014;32:1155-1162 Crossref |
752 | 747 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from randomization to endpoint in significantly more patients with tadalafil (71.1%) vs placebo (56.0%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from randomization to endpoint in significantly more patients with tadalafil (61.7%) vs placebo (45.5%; p < 0.001) • 38.5% (22.4%) of patients with tadalafil and 41.0% (23.3%) of patients with placebo had ≥3 (≥25%) IPSS point improvement during the placebo run-in phase |
Oelke et al., 2014 [50] H. Porst, C.G. Roehrborn, R.J. Secrest, A. Esler, L. Viktrup. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia and on erectile dysfunction in sexually active men with both conditions: analyses of pooled data from four randomized, placebo-controlled tadalafil clinical studies. J Sex Med. 2013;10:2044-2052 Crossref |
752 | 748 | 12 | Effects of tadalafil on nocturia (nocturnal voiding frequency): • for men with ≥1 nocturia episode at baseline, reduction with tadalafil (–0.5) was significantly greater than with placebo at study end (–0.4; LS mean change –0.2, p = 0.002) • for men with ≥2 nocturia episodes at baseline, reduction with tadalafil (–0.8) was significantly greater than with placebo at study end (–0.6; LS mean change –0.2, p = 0.003) • tadalafil (placebo) treatment resulted in reduction of ≥1 nocturia episodes in 47.5% (41.3%) of patients |
Porst et al., 2013 [51] G.B. Brock, K.T. McVary, C.G. Roehrborn, et al. Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: integrated data analyses from 4 placebo controlled clinical studies. J Urol. 2014;191:405-411 Crossref |
505 | 521 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • analysis only of men who were sexually active at baseline • significant improvement of total IPSS with tadalafil (–6.0) vs placebo (–3.6; p < 0.001) from baseline to study end • significant improvement of IIEF-EF with tadalafil (+6.4) vs placebo (+1.4, p < 0.001) from baseline to study end • similar IPSS improvements in men with ED vs without ED: no significant impact of ED severity on LUTS (IPSS) outcome |
Brock et al., 2014 [52] H. Porst, M. Oelke, E.R. Goldfischer, et al. Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational, randomized, placebo-controlled clinical studies. Urology. 2013;82:667-673 Crossref |
752 | 744 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • similar LUTS (IPSS) improvement with tadalafil vs placebo in men without ED (–5.4 vs –2.2, p = 0.0007) compared with men with ED (–5.9 vs –2.3, p < 0.0001); ED subgroup interaction not significant • bidirectional path analysis for sexually-active men (n = 1250) only: 92.5% of the total effects of tadalafil on LUTS/BPH via direct effect on LUTS and 7.5% via indirect effects by IIEF-EF domain improvement |
Porst et al., 2013 [53] O. Nishizawa, M. Yoshida, M. Takeda, et al. Tadalafil 5 mg once daily for the treatment of Asian men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: analyses of data pooled from three randomized, double-blind, placebo-controlled studies. Int J Urol. 2015;22:378-384 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in different patient subgroups: • improvements in IPSS and BPH-Impact Index in all patient subgroups identical (investigated patient parameters: age, symptom severity, serum testosterone concentration, prostate volume, previous α–blocker or PDE5-inhibitor use, arterial hypertension, diabetes mellitus, cardio-vascular diseases) • no baseline item was identified to predict a favorable or unfavorable treatment outcome |
Nishizawa et al., 2015 [54] C. Vlachopoulos, M. Oelke, M. Maggi, et al. Impact of cardiovascular risk factors and related comorbid conditions on the treatment response to tadalafil once-daily in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: an integrated analysis of four randomized, double-blind, placebo-controlled clinical trials. Int J Clin Pract. 2015;69:1496-1507 |
601 | 598 | 12 | Effects of tadalafil on LUTS/BPH in different subgroups of Asian patients: • analysis of Japanese, Korean, or Taiwanese men • significant improvements in total IPSS (tadalafil vs placebo) at wk 4 (–3.69 vs –2.47), wk 8 (–4.72 vs –3.43), and wk 12 (–5.32 vs –3.79), each p < 0.001 • additionally, significant improvements at wk 4, wk 8, and wk 12 for IPSS storage and IPSS voiding subscores as well as for IPSS-QoL • older patients (≥65 yr) showed significantly lower IPSS improvement than younger patients (<65 yr); otherwise, no significant impact of any other baseline item on LUTS improvement |
Vlachopoulos et al., 2015 [55] C.G. Roehrborn, C. Chapple, M. Oelke, D. Cox, A. Esler, L. Viktrup. Effects of tadalafil once-daily on maximum urinary flow rate in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. J Urol. 2014;191:1045-1050 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in patients with cardio-vascular risk factors and therapy: • subanalysis of comorbid, cardio-vascular diseases on LUTS/BPH outcome • no significant differences in efficacy of tadalafil vs placebo for various cardio-vascular diseases/comorbidities • but patients with >1 antihypertensive drugs have significantly lower IPSS improvement compared with men taking ≤1 drug • use of diuretics resulted in significantly lower IPSS improvement compared to men taking other antihypertensives or no drugs |
Roehrborn et al., 2014 [56] D.V. Singh, U.K. Mete, A.K. Mandal, S.K. Singh. 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;11:187-196 Crossref |
752 (612a) |
748 (585a) |
12 | Effects of tadalafil on uroflow (maximum urinary flow rate): • in total study population, patients with tadalafil had significantly greater Qmax improvement (mean +1.1 ml/s) compared with patients with placebo (mean +0.4 ml/s; p = 0.003) • significant Qmax improvement in the total study population was mainly driven by effects in patients who voided 250–450 ml (p = 0.011) and had a baseline Qmax 10–15 ml/s (p = 0.044) |
a With valid measurement.
BPH = benign prostatic enlargement; ED = erectile dysfunction; IPSS = International Prostate Symptom Score; LUTS = lower urinary tract symptoms; PDE5 = phosphodiesterase type 5; QoL = quality of life.
Efficacy: In the first systematic review on PDE5-Is for LUTS secondary to BPH published in literature, Laydner et al [38]
In the first meta-regression analysis on PDE5-Is alone or in combination with α-blockers, Gacci et al [2]
In a subset analysis on tadalafil based on data extrapolated from a systematic review on all PDE5-Is, Gacci et al [42]
Safety: In the review from Liu et al [39]
The first meta-analysis of AEs due to PDE5-Is reported that flushing, gastro-esophageal reflux, headache, and dyspepsia had the higher risk of occurrence (odds ratio: 4.88; 2.21; 1.88; 1.85; respectively). Moreover, regarding the overall tolerability of the association between PDE5-Is and α-blockers, Gacci et al [42]
In a recent review on tadalafil once daily, the Authors underlined the good safety profile with a relative risk of AEs from tadalafil similar to those reported with vardenafil or sildenafil (2.27 vs 1.86 vs 1.22, respectively); overall, the occurrence of AEs reported was very similar to that reported with all PDE5-Is versus placebo: 16.0% versus 6.0% [42]
Clinically-meaningful symptom improvement: Clinically-meaningful LUTS improvement is defined as a decrease of ≥3 points or ≥25% reduction of total IPSS [45]
Similar post-hoc analyses were done in 1499 patients treated with tadalafil 5 mg once daily or placebo [47]
Nocturia: Nocturia, defined as one or more voids per night, is one of the most prevalent and bothersome single urinary symptoms in community-dwelling men or patients with LUTS/BPH and the main reason for physician consultations [48]
Tadalafil for men with or without ED: The majority of the randomized, placebo-controlled tadalafil trials included patients with ED (approximately 60–70% of trial participants). Pooled data analyses evaluated whether symptom improvement was related to baseline ED status or ED improvement during tadalafil treatment [50]
Other baseline characteristics: The impact of several patient characteristics was evaluated in 1500 pooled patients with LUTS/BPH with regard to symptom improvement and adverse events, including age (≤65 vs >65 yr), symptom severity (IPSS < 20 vs ≥ 20), testosterone concentration (<300 ng/dl vs ≥300 ng/dl), prostate-specific antigen-predicted prostate volume (<40 ml vs ≥40 ml), previous α-blockers use (yes vs no), previous PDE5 inhibitor use (yes vs no), arterial hypertension (yes vs no), diabetes mellitus (yes vs no), and cardiovascular disease (yes vs no) [52]
Finally, an integrated analysis on 1371 patients, demonstrated that tadalafil 5 mg once daily for 12 wk allowed to achieve a very small, but statistically significant increase in Qmax versus the placebo (median: 1.1 ml/s vs 0.4 ml/s) [55]
Tadalafil has been also proposed in combination with alpha blockers or 5-alpha reductase inhibitors. In a prospective randomized study on 133 men with LUTS/BPH treated with tamsulsoin plus tadalafil versus tamsulosin or tadalafil alone, combination therapy was more effective than monotherapy for ED (%IIEF change from baseline: 60.2 vs 39.3 and 46.0 respectively) with similar improvement for urinary symptoms (% IPSS change from baseline: 53.9 vs 50.9 and 33.5), with a good safety profile [56]
Regarding the impact of tadalafil on sexual activity of men with ED and LUTS due to BPH tadalafil, Giuliano et al [58]
There is a large body of scientific evidence supporting the role of the NO-cGMP pathway including PDE5I in: (1) regulation of the tone of the smooth muscle fibers of the prostate, urethra, and bladder neck and in a lesser extent of the bladder (relaxant effect), (2) control of the arterial supply of the LUT (vasodilatory effect), and (3) modulation of the micturition reflex via the afferent bladder innervation (decrease in the afferent signaling). PDE5-Is may also downregulate inflammatory processes in LUT and exert antiproliferative effects.
Several meta-analyses demonstrated that PDE5-Is are effective in improving LUTS and erectile function compared with placebo. The combination of PDE5-Is with α-blockers induce a small, but statistically significant improvement of maximum flow rate as compared with α-blockers alone, in addition to the positive effect on micturition and sexual activity. PDE5-Is alone or in combination with α-blockers are well tolerated: flushing, gastroesophageal reflux, headache, and dyspepsia are the most common treatment-associated AEs.
Tadalafil 5 mg once daily achieves an improvement of clinically-meaningful urinary symptoms and nocturnal voiding frequency compared with placebo. Furthermore, the effects on LUTS are independent of ED severity at baseline and ED improvement.
Data on the long-term effects prostate size, reduction of disease progression, or prostate cancer prevalence related to the use of PDE5-Is are not available; long-term outcomes and cost-effectiveness analyses are needed.
Author contributions: Mauro Gacci had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Gacci, Giuliano.
Acquisition of data: Gacci, Giuliano, Andersson, Maggi, Oelke.
Analysis and interpretation of data: Gacci, Andersson, Chapple, Maggi, Mirone, Oelke, Porst, Roehrborn, Stief, Giuliano.
Drafting of the manuscript: Gacci, Giuliano, Andersson, Maggi, Oelke.
Critical revision of the manuscript for important intellectual content: Chapple, Mirone, Porst, Roehrborn, Stief.
Statistical analysis: Gacci.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Giuliano.
Other: None.
Financial disclosures: Mauro Gacci certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Gacci: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Pierre Fabre; Andersson: Consultancy and Advisory Boards for Allergan, Astellas, Ferring; Chapple: Consultant, Researcher and Speaker for Allergan, Astellas, Medtronic and Recordati. Consultant and speaker for Lilly. Researcher and speaker for ONO and Pfizer. Speaker for Ranbaxy; Maggi: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Intercept, Menarini; Mirone: consultant, speaker, and/or trial participant for Eli Lilly Italia, Menarini, Zambon, Recordati, GSK, Bracco; Oelke: consultant, speaker, and/or trial participant for Bayer Healthcare, Eli Lilly and Company, and Pfizer; Porst: consultant, speaker for Eli Lilly and Compani, Menarini Group and Sanofi; CRoehrborn: has financial interests and/or other relationships with Eli Lilly and Company, and with Allergan, Afferent Pharmaceuticals, Auxiliary Medical Services, Cancer and Leukemia Group B Clinical Trial Group, GlaxoSmithKline, New England Research Institutes, NeoTract, National Institute of Diabetes and Digestive and Kidney Diseases, Protox, Southwest Oncology Group, Urologix, VA Corporate Studies, and Watson Pharmaceuticals. Giuliano: consultant for Lilly, Sanofi, Pfizer.
Funding/Support and role of the sponsor: None.
Lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE) and erectile dysfunction (ED) are both highly prevalent in elderly men [1]
The aim of this review is to provide an update on the current knowledge on the potential mechanisms of action of PDE5-Is on LUTS/BPE, critically analyze systematic reviews and relevant data from the current literature on the clinical use of all PDE5-Is, and report the latest evidence on pooled-data analyses of tadalafil once daily to provide a definite rationale for the clinical use of tadalafil for the treatment of LUTS/BPE.
The pathways mediating the activity of PDE5-Is: LUTS have a multifactorial pathophysiology and have been discussed extensively [7]
The role of the bladder in male LUTS has been emphasized [9]
In the pathophysiology of LUTS, the NO/cyclic guanosine monophosphate (cGMP) (NO/cGMP) signaling pathway is believed to play a central role. Since NO signaling occurs via stimulation of soluble guanylate cyclase producing cGMP, it is reasonable to assume that the level of cGMP in different LUT tissues can influence their ability to generate LUTS. One way of modulating cGMP levels is to selectively inhibit cGMP degradation, and it is generally believed that all effects of PDE5Is are mediated by selective inhibition of the degradation of cyclic GMP.
Mechanism of action of PDE5-Is: In several animal species, including humans, the entire LUT expresses PDE5, with a relatively higher abundance within the bladder [16]
Although it is well established that PDE5 is expressed and biologically active in LUT, its functional role is still a matter of debate. Clinical studies demonstrated that its inhibition, through all the aforementioned PDE5-Is, resulted in amelioration of LUTS. Several mechanisms of action of PDE5-Is in LUTS have been hypothesized.
Immunohistochemical studies indicate that PDE5 is localized in the endothelial and smooth muscle cells of the LUT blood vessels [17]
Several in vitro studies have demonstrated that PDE5-Is can relax isolated prostate and bladder neck strips [27]
In the human prostate [17]
The NO/cGMP signaling pathway is likely to have a significant role in the innervation of the LUT. In human, neuronal NO synthase and guanylate cyclase are expressed in the uroepithelium, in neural fibers of the bladder neck and prostatic urethra, and in afferent nerves and interstitial cells, respectively [35]
Emerging evidences indicate that metabolic derangements, clustered in the metabolic syndrome (MetS) construct, may have a role in BPH pathophysiology. Within MetS, visceral obesity and dyslipidemia are the major predictors of an enlarged prostate size [3]
A systematic literature search in PubMed and Scopus was performed until May 2015, to identify systematic reviews of randomized controlled trial (RCTs), including the following MeSH terms: phosphodiesterase type 5 inhibitor and tadalafil PLUS urinary symptoms OR lower urinary tract symptoms OR benign prostatic hyperplasia OR prostate. We included only systematic reviews of RCTs comparing PDE5-Is treatment with different oral therapies or placebos for LUTS/BPH, while we excluded reviews of RTCs without PDE5-Is, nonclinical trials with PDE5-Is, or nonsystematic review. A total of eight papers were analyzed (Fig. 1; Table 1).
Table 1 Characteristics of the studies included in the review
a Significant improvement versus placebo.
b PDE5-Is + ABs versus ABs alone.
c Significant improvement versus ABs alone.
d PDE5-Is nonspecified.
* p = 0.04 for Tadalafil 5 mg.
ABs = alpha-blockers; BPH = benign prostatic hyperplasia; diff. = difference; ED = erectile dysfunction; IIEF = International Index Of Erectile Function; IPSS = International Prostatic Symptom Score; MRAs = muscarinic receptor antagonists; O = other PDE5-Is; PDE5-Is = phosphodiesterase 5 inhibitors; PLA = placebo; P.ts = patients; Qmax = maximum flow rate at uroflowmetry; S = sildenafil; T = tadalafil;. V = vardenafil; 5ARIs = 5a-reductase inhibitors.
Moreover, we selected more clinically relevant data from current literature on the clinical use of all PDE5-Is, including all post-hoc pooled data analyses (Table 2), with a nonsystematic approach (studies published only as abstract or presented without abstract and reports from meetings and studies not published in English were not considered for this review).
Table 2 Summary of posthoc pooled-data analyses of patients treated with tadalafil 5 mg once daily versus placebo for lower urinary tract symptoms/benign prostatic enlargement
Publication | No. of patients (n) |
Follow up (wk) |
Main findings | |
---|---|---|---|---|
Tadalafil | Placebo | |||
Oelke et al., 2015 [47] J.C. Nickel, G.B. Brock, S. Herschorn, R. Dickson, C. Henneges, L. Viktrup. Proportion of tadalafil-treated patients with clinically meaningful improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia. BJU Int. 2015;115:815-821 Crossref |
742 | 735 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from baseline to endpoint in significantly more patients with tadalafil (69.1%) vs placebo (54.8%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from baseline to endpoint in significantly more patients with tadalafil (59.8%) vs placebo (43.7%; p < 0.001) • 59.8% (50.2%) and 79.3% (72.5%) of the responders had ≥3 (≥25%) IPSS point improvement already after wk 1 and wk 4, respectively |
Nickel et al., 2015 [48] M. Oelke, B. Wiese, R. Berges. Nocturia and its impact on health related quality of life and health care seeking behavior in German community-dwelling men aged 50 years or older. World J Urol. 2014;32:1155-1162 Crossref |
752 | 747 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from randomization to endpoint in significantly more patients with tadalafil (71.1%) vs placebo (56.0%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from randomization to endpoint in significantly more patients with tadalafil (61.7%) vs placebo (45.5%; p < 0.001) • 38.5% (22.4%) of patients with tadalafil and 41.0% (23.3%) of patients with placebo had ≥3 (≥25%) IPSS point improvement during the placebo run-in phase |
Oelke et al., 2014 [50] H. Porst, C.G. Roehrborn, R.J. Secrest, A. Esler, L. Viktrup. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia and on erectile dysfunction in sexually active men with both conditions: analyses of pooled data from four randomized, placebo-controlled tadalafil clinical studies. J Sex Med. 2013;10:2044-2052 Crossref |
752 | 748 | 12 | Effects of tadalafil on nocturia (nocturnal voiding frequency): • for men with ≥1 nocturia episode at baseline, reduction with tadalafil (–0.5) was significantly greater than with placebo at study end (–0.4; LS mean change –0.2, p = 0.002) • for men with ≥2 nocturia episodes at baseline, reduction with tadalafil (–0.8) was significantly greater than with placebo at study end (–0.6; LS mean change –0.2, p = 0.003) • tadalafil (placebo) treatment resulted in reduction of ≥1 nocturia episodes in 47.5% (41.3%) of patients |
Porst et al., 2013 [51] G.B. Brock, K.T. McVary, C.G. Roehrborn, et al. Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: integrated data analyses from 4 placebo controlled clinical studies. J Urol. 2014;191:405-411 Crossref |
505 | 521 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • analysis only of men who were sexually active at baseline • significant improvement of total IPSS with tadalafil (–6.0) vs placebo (–3.6; p < 0.001) from baseline to study end • significant improvement of IIEF-EF with tadalafil (+6.4) vs placebo (+1.4, p < 0.001) from baseline to study end • similar IPSS improvements in men with ED vs without ED: no significant impact of ED severity on LUTS (IPSS) outcome |
Brock et al., 2014 [52] H. Porst, M. Oelke, E.R. Goldfischer, et al. Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational, randomized, placebo-controlled clinical studies. Urology. 2013;82:667-673 Crossref |
752 | 744 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • similar LUTS (IPSS) improvement with tadalafil vs placebo in men without ED (–5.4 vs –2.2, p = 0.0007) compared with men with ED (–5.9 vs –2.3, p < 0.0001); ED subgroup interaction not significant • bidirectional path analysis for sexually-active men (n = 1250) only: 92.5% of the total effects of tadalafil on LUTS/BPH via direct effect on LUTS and 7.5% via indirect effects by IIEF-EF domain improvement |
Porst et al., 2013 [53] O. Nishizawa, M. Yoshida, M. Takeda, et al. Tadalafil 5 mg once daily for the treatment of Asian men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: analyses of data pooled from three randomized, double-blind, placebo-controlled studies. Int J Urol. 2015;22:378-384 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in different patient subgroups: • improvements in IPSS and BPH-Impact Index in all patient subgroups identical (investigated patient parameters: age, symptom severity, serum testosterone concentration, prostate volume, previous α–blocker or PDE5-inhibitor use, arterial hypertension, diabetes mellitus, cardio-vascular diseases) • no baseline item was identified to predict a favorable or unfavorable treatment outcome |
Nishizawa et al., 2015 [54] C. Vlachopoulos, M. Oelke, M. Maggi, et al. Impact of cardiovascular risk factors and related comorbid conditions on the treatment response to tadalafil once-daily in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: an integrated analysis of four randomized, double-blind, placebo-controlled clinical trials. Int J Clin Pract. 2015;69:1496-1507 |
601 | 598 | 12 | Effects of tadalafil on LUTS/BPH in different subgroups of Asian patients: • analysis of Japanese, Korean, or Taiwanese men • significant improvements in total IPSS (tadalafil vs placebo) at wk 4 (–3.69 vs –2.47), wk 8 (–4.72 vs –3.43), and wk 12 (–5.32 vs –3.79), each p < 0.001 • additionally, significant improvements at wk 4, wk 8, and wk 12 for IPSS storage and IPSS voiding subscores as well as for IPSS-QoL • older patients (≥65 yr) showed significantly lower IPSS improvement than younger patients (<65 yr); otherwise, no significant impact of any other baseline item on LUTS improvement |
Vlachopoulos et al., 2015 [55] C.G. Roehrborn, C. Chapple, M. Oelke, D. Cox, A. Esler, L. Viktrup. Effects of tadalafil once-daily on maximum urinary flow rate in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. J Urol. 2014;191:1045-1050 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in patients with cardio-vascular risk factors and therapy: • subanalysis of comorbid, cardio-vascular diseases on LUTS/BPH outcome • no significant differences in efficacy of tadalafil vs placebo for various cardio-vascular diseases/comorbidities • but patients with >1 antihypertensive drugs have significantly lower IPSS improvement compared with men taking ≤1 drug • use of diuretics resulted in significantly lower IPSS improvement compared to men taking other antihypertensives or no drugs |
Roehrborn et al., 2014 [56] D.V. Singh, U.K. Mete, A.K. Mandal, S.K. Singh. 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;11:187-196 Crossref |
752 (612a) |
748 (585a) |
12 | Effects of tadalafil on uroflow (maximum urinary flow rate): • in total study population, patients with tadalafil had significantly greater Qmax improvement (mean +1.1 ml/s) compared with patients with placebo (mean +0.4 ml/s; p = 0.003) • significant Qmax improvement in the total study population was mainly driven by effects in patients who voided 250–450 ml (p = 0.011) and had a baseline Qmax 10–15 ml/s (p = 0.044) |
a With valid measurement.
BPH = benign prostatic enlargement; ED = erectile dysfunction; IPSS = International Prostate Symptom Score; LUTS = lower urinary tract symptoms; PDE5 = phosphodiesterase type 5; QoL = quality of life.
Efficacy: In the first systematic review on PDE5-Is for LUTS secondary to BPH published in literature, Laydner et al [38]
In the first meta-regression analysis on PDE5-Is alone or in combination with α-blockers, Gacci et al [2]
In a subset analysis on tadalafil based on data extrapolated from a systematic review on all PDE5-Is, Gacci et al [42]
Safety: In the review from Liu et al [39]
The first meta-analysis of AEs due to PDE5-Is reported that flushing, gastro-esophageal reflux, headache, and dyspepsia had the higher risk of occurrence (odds ratio: 4.88; 2.21; 1.88; 1.85; respectively). Moreover, regarding the overall tolerability of the association between PDE5-Is and α-blockers, Gacci et al [42]
In a recent review on tadalafil once daily, the Authors underlined the good safety profile with a relative risk of AEs from tadalafil similar to those reported with vardenafil or sildenafil (2.27 vs 1.86 vs 1.22, respectively); overall, the occurrence of AEs reported was very similar to that reported with all PDE5-Is versus placebo: 16.0% versus 6.0% [42]
Clinically-meaningful symptom improvement: Clinically-meaningful LUTS improvement is defined as a decrease of ≥3 points or ≥25% reduction of total IPSS [45]
Similar post-hoc analyses were done in 1499 patients treated with tadalafil 5 mg once daily or placebo [47]
Nocturia: Nocturia, defined as one or more voids per night, is one of the most prevalent and bothersome single urinary symptoms in community-dwelling men or patients with LUTS/BPH and the main reason for physician consultations [48]
Tadalafil for men with or without ED: The majority of the randomized, placebo-controlled tadalafil trials included patients with ED (approximately 60–70% of trial participants). Pooled data analyses evaluated whether symptom improvement was related to baseline ED status or ED improvement during tadalafil treatment [50]
Other baseline characteristics: The impact of several patient characteristics was evaluated in 1500 pooled patients with LUTS/BPH with regard to symptom improvement and adverse events, including age (≤65 vs >65 yr), symptom severity (IPSS < 20 vs ≥ 20), testosterone concentration (<300 ng/dl vs ≥300 ng/dl), prostate-specific antigen-predicted prostate volume (<40 ml vs ≥40 ml), previous α-blockers use (yes vs no), previous PDE5 inhibitor use (yes vs no), arterial hypertension (yes vs no), diabetes mellitus (yes vs no), and cardiovascular disease (yes vs no) [52]
Finally, an integrated analysis on 1371 patients, demonstrated that tadalafil 5 mg once daily for 12 wk allowed to achieve a very small, but statistically significant increase in Qmax versus the placebo (median: 1.1 ml/s vs 0.4 ml/s) [55]
Tadalafil has been also proposed in combination with alpha blockers or 5-alpha reductase inhibitors. In a prospective randomized study on 133 men with LUTS/BPH treated with tamsulsoin plus tadalafil versus tamsulosin or tadalafil alone, combination therapy was more effective than monotherapy for ED (%IIEF change from baseline: 60.2 vs 39.3 and 46.0 respectively) with similar improvement for urinary symptoms (% IPSS change from baseline: 53.9 vs 50.9 and 33.5), with a good safety profile [56]
Regarding the impact of tadalafil on sexual activity of men with ED and LUTS due to BPH tadalafil, Giuliano et al [58]
There is a large body of scientific evidence supporting the role of the NO-cGMP pathway including PDE5I in: (1) regulation of the tone of the smooth muscle fibers of the prostate, urethra, and bladder neck and in a lesser extent of the bladder (relaxant effect), (2) control of the arterial supply of the LUT (vasodilatory effect), and (3) modulation of the micturition reflex via the afferent bladder innervation (decrease in the afferent signaling). PDE5-Is may also downregulate inflammatory processes in LUT and exert antiproliferative effects.
Several meta-analyses demonstrated that PDE5-Is are effective in improving LUTS and erectile function compared with placebo. The combination of PDE5-Is with α-blockers induce a small, but statistically significant improvement of maximum flow rate as compared with α-blockers alone, in addition to the positive effect on micturition and sexual activity. PDE5-Is alone or in combination with α-blockers are well tolerated: flushing, gastroesophageal reflux, headache, and dyspepsia are the most common treatment-associated AEs.
Tadalafil 5 mg once daily achieves an improvement of clinically-meaningful urinary symptoms and nocturnal voiding frequency compared with placebo. Furthermore, the effects on LUTS are independent of ED severity at baseline and ED improvement.
Data on the long-term effects prostate size, reduction of disease progression, or prostate cancer prevalence related to the use of PDE5-Is are not available; long-term outcomes and cost-effectiveness analyses are needed.
Author contributions: Mauro Gacci had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Gacci, Giuliano.
Acquisition of data: Gacci, Giuliano, Andersson, Maggi, Oelke.
Analysis and interpretation of data: Gacci, Andersson, Chapple, Maggi, Mirone, Oelke, Porst, Roehrborn, Stief, Giuliano.
Drafting of the manuscript: Gacci, Giuliano, Andersson, Maggi, Oelke.
Critical revision of the manuscript for important intellectual content: Chapple, Mirone, Porst, Roehrborn, Stief.
Statistical analysis: Gacci.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Giuliano.
Other: None.
Financial disclosures: Mauro Gacci certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Gacci: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Pierre Fabre; Andersson: Consultancy and Advisory Boards for Allergan, Astellas, Ferring; Chapple: Consultant, Researcher and Speaker for Allergan, Astellas, Medtronic and Recordati. Consultant and speaker for Lilly. Researcher and speaker for ONO and Pfizer. Speaker for Ranbaxy; Maggi: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Intercept, Menarini; Mirone: consultant, speaker, and/or trial participant for Eli Lilly Italia, Menarini, Zambon, Recordati, GSK, Bracco; Oelke: consultant, speaker, and/or trial participant for Bayer Healthcare, Eli Lilly and Company, and Pfizer; Porst: consultant, speaker for Eli Lilly and Compani, Menarini Group and Sanofi; CRoehrborn: has financial interests and/or other relationships with Eli Lilly and Company, and with Allergan, Afferent Pharmaceuticals, Auxiliary Medical Services, Cancer and Leukemia Group B Clinical Trial Group, GlaxoSmithKline, New England Research Institutes, NeoTract, National Institute of Diabetes and Digestive and Kidney Diseases, Protox, Southwest Oncology Group, Urologix, VA Corporate Studies, and Watson Pharmaceuticals. Giuliano: consultant for Lilly, Sanofi, Pfizer.
Funding/Support and role of the sponsor: None.
Lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE) and erectile dysfunction (ED) are both highly prevalent in elderly men [1]
The aim of this review is to provide an update on the current knowledge on the potential mechanisms of action of PDE5-Is on LUTS/BPE, critically analyze systematic reviews and relevant data from the current literature on the clinical use of all PDE5-Is, and report the latest evidence on pooled-data analyses of tadalafil once daily to provide a definite rationale for the clinical use of tadalafil for the treatment of LUTS/BPE.
The pathways mediating the activity of PDE5-Is: LUTS have a multifactorial pathophysiology and have been discussed extensively [7]
The role of the bladder in male LUTS has been emphasized [9]
In the pathophysiology of LUTS, the NO/cyclic guanosine monophosphate (cGMP) (NO/cGMP) signaling pathway is believed to play a central role. Since NO signaling occurs via stimulation of soluble guanylate cyclase producing cGMP, it is reasonable to assume that the level of cGMP in different LUT tissues can influence their ability to generate LUTS. One way of modulating cGMP levels is to selectively inhibit cGMP degradation, and it is generally believed that all effects of PDE5Is are mediated by selective inhibition of the degradation of cyclic GMP.
Mechanism of action of PDE5-Is: In several animal species, including humans, the entire LUT expresses PDE5, with a relatively higher abundance within the bladder [16]
Although it is well established that PDE5 is expressed and biologically active in LUT, its functional role is still a matter of debate. Clinical studies demonstrated that its inhibition, through all the aforementioned PDE5-Is, resulted in amelioration of LUTS. Several mechanisms of action of PDE5-Is in LUTS have been hypothesized.
Immunohistochemical studies indicate that PDE5 is localized in the endothelial and smooth muscle cells of the LUT blood vessels [17]
Several in vitro studies have demonstrated that PDE5-Is can relax isolated prostate and bladder neck strips [27]
In the human prostate [17]
The NO/cGMP signaling pathway is likely to have a significant role in the innervation of the LUT. In human, neuronal NO synthase and guanylate cyclase are expressed in the uroepithelium, in neural fibers of the bladder neck and prostatic urethra, and in afferent nerves and interstitial cells, respectively [35]
Emerging evidences indicate that metabolic derangements, clustered in the metabolic syndrome (MetS) construct, may have a role in BPH pathophysiology. Within MetS, visceral obesity and dyslipidemia are the major predictors of an enlarged prostate size [3]
A systematic literature search in PubMed and Scopus was performed until May 2015, to identify systematic reviews of randomized controlled trial (RCTs), including the following MeSH terms: phosphodiesterase type 5 inhibitor and tadalafil PLUS urinary symptoms OR lower urinary tract symptoms OR benign prostatic hyperplasia OR prostate. We included only systematic reviews of RCTs comparing PDE5-Is treatment with different oral therapies or placebos for LUTS/BPH, while we excluded reviews of RTCs without PDE5-Is, nonclinical trials with PDE5-Is, or nonsystematic review. A total of eight papers were analyzed (Fig. 1; Table 1).
Table 1 Characteristics of the studies included in the review
a Significant improvement versus placebo.
b PDE5-Is + ABs versus ABs alone.
c Significant improvement versus ABs alone.
d PDE5-Is nonspecified.
* p = 0.04 for Tadalafil 5 mg.
ABs = alpha-blockers; BPH = benign prostatic hyperplasia; diff. = difference; ED = erectile dysfunction; IIEF = International Index Of Erectile Function; IPSS = International Prostatic Symptom Score; MRAs = muscarinic receptor antagonists; O = other PDE5-Is; PDE5-Is = phosphodiesterase 5 inhibitors; PLA = placebo; P.ts = patients; Qmax = maximum flow rate at uroflowmetry; S = sildenafil; T = tadalafil;. V = vardenafil; 5ARIs = 5a-reductase inhibitors.
Moreover, we selected more clinically relevant data from current literature on the clinical use of all PDE5-Is, including all post-hoc pooled data analyses (Table 2), with a nonsystematic approach (studies published only as abstract or presented without abstract and reports from meetings and studies not published in English were not considered for this review).
Table 2 Summary of posthoc pooled-data analyses of patients treated with tadalafil 5 mg once daily versus placebo for lower urinary tract symptoms/benign prostatic enlargement
Publication | No. of patients (n) |
Follow up (wk) |
Main findings | |
---|---|---|---|---|
Tadalafil | Placebo | |||
Oelke et al., 2015 [47] J.C. Nickel, G.B. Brock, S. Herschorn, R. Dickson, C. Henneges, L. Viktrup. Proportion of tadalafil-treated patients with clinically meaningful improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia. BJU Int. 2015;115:815-821 Crossref |
742 | 735 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from baseline to endpoint in significantly more patients with tadalafil (69.1%) vs placebo (54.8%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from baseline to endpoint in significantly more patients with tadalafil (59.8%) vs placebo (43.7%; p < 0.001) • 59.8% (50.2%) and 79.3% (72.5%) of the responders had ≥3 (≥25%) IPSS point improvement already after wk 1 and wk 4, respectively |
Nickel et al., 2015 [48] M. Oelke, B. Wiese, R. Berges. Nocturia and its impact on health related quality of life and health care seeking behavior in German community-dwelling men aged 50 years or older. World J Urol. 2014;32:1155-1162 Crossref |
752 | 747 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from randomization to endpoint in significantly more patients with tadalafil (71.1%) vs placebo (56.0%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from randomization to endpoint in significantly more patients with tadalafil (61.7%) vs placebo (45.5%; p < 0.001) • 38.5% (22.4%) of patients with tadalafil and 41.0% (23.3%) of patients with placebo had ≥3 (≥25%) IPSS point improvement during the placebo run-in phase |
Oelke et al., 2014 [50] H. Porst, C.G. Roehrborn, R.J. Secrest, A. Esler, L. Viktrup. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia and on erectile dysfunction in sexually active men with both conditions: analyses of pooled data from four randomized, placebo-controlled tadalafil clinical studies. J Sex Med. 2013;10:2044-2052 Crossref |
752 | 748 | 12 | Effects of tadalafil on nocturia (nocturnal voiding frequency): • for men with ≥1 nocturia episode at baseline, reduction with tadalafil (–0.5) was significantly greater than with placebo at study end (–0.4; LS mean change –0.2, p = 0.002) • for men with ≥2 nocturia episodes at baseline, reduction with tadalafil (–0.8) was significantly greater than with placebo at study end (–0.6; LS mean change –0.2, p = 0.003) • tadalafil (placebo) treatment resulted in reduction of ≥1 nocturia episodes in 47.5% (41.3%) of patients |
Porst et al., 2013 [51] G.B. Brock, K.T. McVary, C.G. Roehrborn, et al. Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: integrated data analyses from 4 placebo controlled clinical studies. J Urol. 2014;191:405-411 Crossref |
505 | 521 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • analysis only of men who were sexually active at baseline • significant improvement of total IPSS with tadalafil (–6.0) vs placebo (–3.6; p < 0.001) from baseline to study end • significant improvement of IIEF-EF with tadalafil (+6.4) vs placebo (+1.4, p < 0.001) from baseline to study end • similar IPSS improvements in men with ED vs without ED: no significant impact of ED severity on LUTS (IPSS) outcome |
Brock et al., 2014 [52] H. Porst, M. Oelke, E.R. Goldfischer, et al. Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational, randomized, placebo-controlled clinical studies. Urology. 2013;82:667-673 Crossref |
752 | 744 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • similar LUTS (IPSS) improvement with tadalafil vs placebo in men without ED (–5.4 vs –2.2, p = 0.0007) compared with men with ED (–5.9 vs –2.3, p < 0.0001); ED subgroup interaction not significant • bidirectional path analysis for sexually-active men (n = 1250) only: 92.5% of the total effects of tadalafil on LUTS/BPH via direct effect on LUTS and 7.5% via indirect effects by IIEF-EF domain improvement |
Porst et al., 2013 [53] O. Nishizawa, M. Yoshida, M. Takeda, et al. Tadalafil 5 mg once daily for the treatment of Asian men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: analyses of data pooled from three randomized, double-blind, placebo-controlled studies. Int J Urol. 2015;22:378-384 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in different patient subgroups: • improvements in IPSS and BPH-Impact Index in all patient subgroups identical (investigated patient parameters: age, symptom severity, serum testosterone concentration, prostate volume, previous α–blocker or PDE5-inhibitor use, arterial hypertension, diabetes mellitus, cardio-vascular diseases) • no baseline item was identified to predict a favorable or unfavorable treatment outcome |
Nishizawa et al., 2015 [54] C. Vlachopoulos, M. Oelke, M. Maggi, et al. Impact of cardiovascular risk factors and related comorbid conditions on the treatment response to tadalafil once-daily in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: an integrated analysis of four randomized, double-blind, placebo-controlled clinical trials. Int J Clin Pract. 2015;69:1496-1507 |
601 | 598 | 12 | Effects of tadalafil on LUTS/BPH in different subgroups of Asian patients: • analysis of Japanese, Korean, or Taiwanese men • significant improvements in total IPSS (tadalafil vs placebo) at wk 4 (–3.69 vs –2.47), wk 8 (–4.72 vs –3.43), and wk 12 (–5.32 vs –3.79), each p < 0.001 • additionally, significant improvements at wk 4, wk 8, and wk 12 for IPSS storage and IPSS voiding subscores as well as for IPSS-QoL • older patients (≥65 yr) showed significantly lower IPSS improvement than younger patients (<65 yr); otherwise, no significant impact of any other baseline item on LUTS improvement |
Vlachopoulos et al., 2015 [55] C.G. Roehrborn, C. Chapple, M. Oelke, D. Cox, A. Esler, L. Viktrup. Effects of tadalafil once-daily on maximum urinary flow rate in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. J Urol. 2014;191:1045-1050 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in patients with cardio-vascular risk factors and therapy: • subanalysis of comorbid, cardio-vascular diseases on LUTS/BPH outcome • no significant differences in efficacy of tadalafil vs placebo for various cardio-vascular diseases/comorbidities • but patients with >1 antihypertensive drugs have significantly lower IPSS improvement compared with men taking ≤1 drug • use of diuretics resulted in significantly lower IPSS improvement compared to men taking other antihypertensives or no drugs |
Roehrborn et al., 2014 [56] D.V. Singh, U.K. Mete, A.K. Mandal, S.K. Singh. 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;11:187-196 Crossref |
752 (612a) |
748 (585a) |
12 | Effects of tadalafil on uroflow (maximum urinary flow rate): • in total study population, patients with tadalafil had significantly greater Qmax improvement (mean +1.1 ml/s) compared with patients with placebo (mean +0.4 ml/s; p = 0.003) • significant Qmax improvement in the total study population was mainly driven by effects in patients who voided 250–450 ml (p = 0.011) and had a baseline Qmax 10–15 ml/s (p = 0.044) |
a With valid measurement.
BPH = benign prostatic enlargement; ED = erectile dysfunction; IPSS = International Prostate Symptom Score; LUTS = lower urinary tract symptoms; PDE5 = phosphodiesterase type 5; QoL = quality of life.
Efficacy: In the first systematic review on PDE5-Is for LUTS secondary to BPH published in literature, Laydner et al [38]
In the first meta-regression analysis on PDE5-Is alone or in combination with α-blockers, Gacci et al [2]
In a subset analysis on tadalafil based on data extrapolated from a systematic review on all PDE5-Is, Gacci et al [42]
Safety: In the review from Liu et al [39]
The first meta-analysis of AEs due to PDE5-Is reported that flushing, gastro-esophageal reflux, headache, and dyspepsia had the higher risk of occurrence (odds ratio: 4.88; 2.21; 1.88; 1.85; respectively). Moreover, regarding the overall tolerability of the association between PDE5-Is and α-blockers, Gacci et al [42]
In a recent review on tadalafil once daily, the Authors underlined the good safety profile with a relative risk of AEs from tadalafil similar to those reported with vardenafil or sildenafil (2.27 vs 1.86 vs 1.22, respectively); overall, the occurrence of AEs reported was very similar to that reported with all PDE5-Is versus placebo: 16.0% versus 6.0% [42]
Clinically-meaningful symptom improvement: Clinically-meaningful LUTS improvement is defined as a decrease of ≥3 points or ≥25% reduction of total IPSS [45]
Similar post-hoc analyses were done in 1499 patients treated with tadalafil 5 mg once daily or placebo [47]
Nocturia: Nocturia, defined as one or more voids per night, is one of the most prevalent and bothersome single urinary symptoms in community-dwelling men or patients with LUTS/BPH and the main reason for physician consultations [48]
Tadalafil for men with or without ED: The majority of the randomized, placebo-controlled tadalafil trials included patients with ED (approximately 60–70% of trial participants). Pooled data analyses evaluated whether symptom improvement was related to baseline ED status or ED improvement during tadalafil treatment [50]
Other baseline characteristics: The impact of several patient characteristics was evaluated in 1500 pooled patients with LUTS/BPH with regard to symptom improvement and adverse events, including age (≤65 vs >65 yr), symptom severity (IPSS < 20 vs ≥ 20), testosterone concentration (<300 ng/dl vs ≥300 ng/dl), prostate-specific antigen-predicted prostate volume (<40 ml vs ≥40 ml), previous α-blockers use (yes vs no), previous PDE5 inhibitor use (yes vs no), arterial hypertension (yes vs no), diabetes mellitus (yes vs no), and cardiovascular disease (yes vs no) [52]
Finally, an integrated analysis on 1371 patients, demonstrated that tadalafil 5 mg once daily for 12 wk allowed to achieve a very small, but statistically significant increase in Qmax versus the placebo (median: 1.1 ml/s vs 0.4 ml/s) [55]
Tadalafil has been also proposed in combination with alpha blockers or 5-alpha reductase inhibitors. In a prospective randomized study on 133 men with LUTS/BPH treated with tamsulsoin plus tadalafil versus tamsulosin or tadalafil alone, combination therapy was more effective than monotherapy for ED (%IIEF change from baseline: 60.2 vs 39.3 and 46.0 respectively) with similar improvement for urinary symptoms (% IPSS change from baseline: 53.9 vs 50.9 and 33.5), with a good safety profile [56]
Regarding the impact of tadalafil on sexual activity of men with ED and LUTS due to BPH tadalafil, Giuliano et al [58]
There is a large body of scientific evidence supporting the role of the NO-cGMP pathway including PDE5I in: (1) regulation of the tone of the smooth muscle fibers of the prostate, urethra, and bladder neck and in a lesser extent of the bladder (relaxant effect), (2) control of the arterial supply of the LUT (vasodilatory effect), and (3) modulation of the micturition reflex via the afferent bladder innervation (decrease in the afferent signaling). PDE5-Is may also downregulate inflammatory processes in LUT and exert antiproliferative effects.
Several meta-analyses demonstrated that PDE5-Is are effective in improving LUTS and erectile function compared with placebo. The combination of PDE5-Is with α-blockers induce a small, but statistically significant improvement of maximum flow rate as compared with α-blockers alone, in addition to the positive effect on micturition and sexual activity. PDE5-Is alone or in combination with α-blockers are well tolerated: flushing, gastroesophageal reflux, headache, and dyspepsia are the most common treatment-associated AEs.
Tadalafil 5 mg once daily achieves an improvement of clinically-meaningful urinary symptoms and nocturnal voiding frequency compared with placebo. Furthermore, the effects on LUTS are independent of ED severity at baseline and ED improvement.
Data on the long-term effects prostate size, reduction of disease progression, or prostate cancer prevalence related to the use of PDE5-Is are not available; long-term outcomes and cost-effectiveness analyses are needed.
Author contributions: Mauro Gacci had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Gacci, Giuliano.
Acquisition of data: Gacci, Giuliano, Andersson, Maggi, Oelke.
Analysis and interpretation of data: Gacci, Andersson, Chapple, Maggi, Mirone, Oelke, Porst, Roehrborn, Stief, Giuliano.
Drafting of the manuscript: Gacci, Giuliano, Andersson, Maggi, Oelke.
Critical revision of the manuscript for important intellectual content: Chapple, Mirone, Porst, Roehrborn, Stief.
Statistical analysis: Gacci.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Giuliano.
Other: None.
Financial disclosures: Mauro Gacci certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Gacci: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Pierre Fabre; Andersson: Consultancy and Advisory Boards for Allergan, Astellas, Ferring; Chapple: Consultant, Researcher and Speaker for Allergan, Astellas, Medtronic and Recordati. Consultant and speaker for Lilly. Researcher and speaker for ONO and Pfizer. Speaker for Ranbaxy; Maggi: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Intercept, Menarini; Mirone: consultant, speaker, and/or trial participant for Eli Lilly Italia, Menarini, Zambon, Recordati, GSK, Bracco; Oelke: consultant, speaker, and/or trial participant for Bayer Healthcare, Eli Lilly and Company, and Pfizer; Porst: consultant, speaker for Eli Lilly and Compani, Menarini Group and Sanofi; CRoehrborn: has financial interests and/or other relationships with Eli Lilly and Company, and with Allergan, Afferent Pharmaceuticals, Auxiliary Medical Services, Cancer and Leukemia Group B Clinical Trial Group, GlaxoSmithKline, New England Research Institutes, NeoTract, National Institute of Diabetes and Digestive and Kidney Diseases, Protox, Southwest Oncology Group, Urologix, VA Corporate Studies, and Watson Pharmaceuticals. Giuliano: consultant for Lilly, Sanofi, Pfizer.
Funding/Support and role of the sponsor: None.
Lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE) and erectile dysfunction (ED) are both highly prevalent in elderly men [1]
The aim of this review is to provide an update on the current knowledge on the potential mechanisms of action of PDE5-Is on LUTS/BPE, critically analyze systematic reviews and relevant data from the current literature on the clinical use of all PDE5-Is, and report the latest evidence on pooled-data analyses of tadalafil once daily to provide a definite rationale for the clinical use of tadalafil for the treatment of LUTS/BPE.
The pathways mediating the activity of PDE5-Is: LUTS have a multifactorial pathophysiology and have been discussed extensively [7]
The role of the bladder in male LUTS has been emphasized [9]
In the pathophysiology of LUTS, the NO/cyclic guanosine monophosphate (cGMP) (NO/cGMP) signaling pathway is believed to play a central role. Since NO signaling occurs via stimulation of soluble guanylate cyclase producing cGMP, it is reasonable to assume that the level of cGMP in different LUT tissues can influence their ability to generate LUTS. One way of modulating cGMP levels is to selectively inhibit cGMP degradation, and it is generally believed that all effects of PDE5Is are mediated by selective inhibition of the degradation of cyclic GMP.
Mechanism of action of PDE5-Is: In several animal species, including humans, the entire LUT expresses PDE5, with a relatively higher abundance within the bladder [16]
Although it is well established that PDE5 is expressed and biologically active in LUT, its functional role is still a matter of debate. Clinical studies demonstrated that its inhibition, through all the aforementioned PDE5-Is, resulted in amelioration of LUTS. Several mechanisms of action of PDE5-Is in LUTS have been hypothesized.
Immunohistochemical studies indicate that PDE5 is localized in the endothelial and smooth muscle cells of the LUT blood vessels [17]
Several in vitro studies have demonstrated that PDE5-Is can relax isolated prostate and bladder neck strips [27]
In the human prostate [17]
The NO/cGMP signaling pathway is likely to have a significant role in the innervation of the LUT. In human, neuronal NO synthase and guanylate cyclase are expressed in the uroepithelium, in neural fibers of the bladder neck and prostatic urethra, and in afferent nerves and interstitial cells, respectively [35]
Emerging evidences indicate that metabolic derangements, clustered in the metabolic syndrome (MetS) construct, may have a role in BPH pathophysiology. Within MetS, visceral obesity and dyslipidemia are the major predictors of an enlarged prostate size [3]
A systematic literature search in PubMed and Scopus was performed until May 2015, to identify systematic reviews of randomized controlled trial (RCTs), including the following MeSH terms: phosphodiesterase type 5 inhibitor and tadalafil PLUS urinary symptoms OR lower urinary tract symptoms OR benign prostatic hyperplasia OR prostate. We included only systematic reviews of RCTs comparing PDE5-Is treatment with different oral therapies or placebos for LUTS/BPH, while we excluded reviews of RTCs without PDE5-Is, nonclinical trials with PDE5-Is, or nonsystematic review. A total of eight papers were analyzed (Fig. 1; Table 1).
Table 1 Characteristics of the studies included in the review
a Significant improvement versus placebo.
b PDE5-Is + ABs versus ABs alone.
c Significant improvement versus ABs alone.
d PDE5-Is nonspecified.
* p = 0.04 for Tadalafil 5 mg.
ABs = alpha-blockers; BPH = benign prostatic hyperplasia; diff. = difference; ED = erectile dysfunction; IIEF = International Index Of Erectile Function; IPSS = International Prostatic Symptom Score; MRAs = muscarinic receptor antagonists; O = other PDE5-Is; PDE5-Is = phosphodiesterase 5 inhibitors; PLA = placebo; P.ts = patients; Qmax = maximum flow rate at uroflowmetry; S = sildenafil; T = tadalafil;. V = vardenafil; 5ARIs = 5a-reductase inhibitors.
Moreover, we selected more clinically relevant data from current literature on the clinical use of all PDE5-Is, including all post-hoc pooled data analyses (Table 2), with a nonsystematic approach (studies published only as abstract or presented without abstract and reports from meetings and studies not published in English were not considered for this review).
Table 2 Summary of posthoc pooled-data analyses of patients treated with tadalafil 5 mg once daily versus placebo for lower urinary tract symptoms/benign prostatic enlargement
Publication | No. of patients (n) |
Follow up (wk) |
Main findings | |
---|---|---|---|---|
Tadalafil | Placebo | |||
Oelke et al., 2015 [47] J.C. Nickel, G.B. Brock, S. Herschorn, R. Dickson, C. Henneges, L. Viktrup. Proportion of tadalafil-treated patients with clinically meaningful improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia. BJU Int. 2015;115:815-821 Crossref |
742 | 735 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from baseline to endpoint in significantly more patients with tadalafil (69.1%) vs placebo (54.8%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from baseline to endpoint in significantly more patients with tadalafil (59.8%) vs placebo (43.7%; p < 0.001) • 59.8% (50.2%) and 79.3% (72.5%) of the responders had ≥3 (≥25%) IPSS point improvement already after wk 1 and wk 4, respectively |
Nickel et al., 2015 [48] M. Oelke, B. Wiese, R. Berges. Nocturia and its impact on health related quality of life and health care seeking behavior in German community-dwelling men aged 50 years or older. World J Urol. 2014;32:1155-1162 Crossref |
752 | 747 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from randomization to endpoint in significantly more patients with tadalafil (71.1%) vs placebo (56.0%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from randomization to endpoint in significantly more patients with tadalafil (61.7%) vs placebo (45.5%; p < 0.001) • 38.5% (22.4%) of patients with tadalafil and 41.0% (23.3%) of patients with placebo had ≥3 (≥25%) IPSS point improvement during the placebo run-in phase |
Oelke et al., 2014 [50] H. Porst, C.G. Roehrborn, R.J. Secrest, A. Esler, L. Viktrup. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia and on erectile dysfunction in sexually active men with both conditions: analyses of pooled data from four randomized, placebo-controlled tadalafil clinical studies. J Sex Med. 2013;10:2044-2052 Crossref |
752 | 748 | 12 | Effects of tadalafil on nocturia (nocturnal voiding frequency): • for men with ≥1 nocturia episode at baseline, reduction with tadalafil (–0.5) was significantly greater than with placebo at study end (–0.4; LS mean change –0.2, p = 0.002) • for men with ≥2 nocturia episodes at baseline, reduction with tadalafil (–0.8) was significantly greater than with placebo at study end (–0.6; LS mean change –0.2, p = 0.003) • tadalafil (placebo) treatment resulted in reduction of ≥1 nocturia episodes in 47.5% (41.3%) of patients |
Porst et al., 2013 [51] G.B. Brock, K.T. McVary, C.G. Roehrborn, et al. Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: integrated data analyses from 4 placebo controlled clinical studies. J Urol. 2014;191:405-411 Crossref |
505 | 521 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • analysis only of men who were sexually active at baseline • significant improvement of total IPSS with tadalafil (–6.0) vs placebo (–3.6; p < 0.001) from baseline to study end • significant improvement of IIEF-EF with tadalafil (+6.4) vs placebo (+1.4, p < 0.001) from baseline to study end • similar IPSS improvements in men with ED vs without ED: no significant impact of ED severity on LUTS (IPSS) outcome |
Brock et al., 2014 [52] H. Porst, M. Oelke, E.R. Goldfischer, et al. Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational, randomized, placebo-controlled clinical studies. Urology. 2013;82:667-673 Crossref |
752 | 744 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • similar LUTS (IPSS) improvement with tadalafil vs placebo in men without ED (–5.4 vs –2.2, p = 0.0007) compared with men with ED (–5.9 vs –2.3, p < 0.0001); ED subgroup interaction not significant • bidirectional path analysis for sexually-active men (n = 1250) only: 92.5% of the total effects of tadalafil on LUTS/BPH via direct effect on LUTS and 7.5% via indirect effects by IIEF-EF domain improvement |
Porst et al., 2013 [53] O. Nishizawa, M. Yoshida, M. Takeda, et al. Tadalafil 5 mg once daily for the treatment of Asian men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: analyses of data pooled from three randomized, double-blind, placebo-controlled studies. Int J Urol. 2015;22:378-384 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in different patient subgroups: • improvements in IPSS and BPH-Impact Index in all patient subgroups identical (investigated patient parameters: age, symptom severity, serum testosterone concentration, prostate volume, previous α–blocker or PDE5-inhibitor use, arterial hypertension, diabetes mellitus, cardio-vascular diseases) • no baseline item was identified to predict a favorable or unfavorable treatment outcome |
Nishizawa et al., 2015 [54] C. Vlachopoulos, M. Oelke, M. Maggi, et al. Impact of cardiovascular risk factors and related comorbid conditions on the treatment response to tadalafil once-daily in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: an integrated analysis of four randomized, double-blind, placebo-controlled clinical trials. Int J Clin Pract. 2015;69:1496-1507 |
601 | 598 | 12 | Effects of tadalafil on LUTS/BPH in different subgroups of Asian patients: • analysis of Japanese, Korean, or Taiwanese men • significant improvements in total IPSS (tadalafil vs placebo) at wk 4 (–3.69 vs –2.47), wk 8 (–4.72 vs –3.43), and wk 12 (–5.32 vs –3.79), each p < 0.001 • additionally, significant improvements at wk 4, wk 8, and wk 12 for IPSS storage and IPSS voiding subscores as well as for IPSS-QoL • older patients (≥65 yr) showed significantly lower IPSS improvement than younger patients (<65 yr); otherwise, no significant impact of any other baseline item on LUTS improvement |
Vlachopoulos et al., 2015 [55] C.G. Roehrborn, C. Chapple, M. Oelke, D. Cox, A. Esler, L. Viktrup. Effects of tadalafil once-daily on maximum urinary flow rate in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. J Urol. 2014;191:1045-1050 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in patients with cardio-vascular risk factors and therapy: • subanalysis of comorbid, cardio-vascular diseases on LUTS/BPH outcome • no significant differences in efficacy of tadalafil vs placebo for various cardio-vascular diseases/comorbidities • but patients with >1 antihypertensive drugs have significantly lower IPSS improvement compared with men taking ≤1 drug • use of diuretics resulted in significantly lower IPSS improvement compared to men taking other antihypertensives or no drugs |
Roehrborn et al., 2014 [56] D.V. Singh, U.K. Mete, A.K. Mandal, S.K. Singh. 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;11:187-196 Crossref |
752 (612a) |
748 (585a) |
12 | Effects of tadalafil on uroflow (maximum urinary flow rate): • in total study population, patients with tadalafil had significantly greater Qmax improvement (mean +1.1 ml/s) compared with patients with placebo (mean +0.4 ml/s; p = 0.003) • significant Qmax improvement in the total study population was mainly driven by effects in patients who voided 250–450 ml (p = 0.011) and had a baseline Qmax 10–15 ml/s (p = 0.044) |
a With valid measurement.
BPH = benign prostatic enlargement; ED = erectile dysfunction; IPSS = International Prostate Symptom Score; LUTS = lower urinary tract symptoms; PDE5 = phosphodiesterase type 5; QoL = quality of life.
Efficacy: In the first systematic review on PDE5-Is for LUTS secondary to BPH published in literature, Laydner et al [38]
In the first meta-regression analysis on PDE5-Is alone or in combination with α-blockers, Gacci et al [2]
In a subset analysis on tadalafil based on data extrapolated from a systematic review on all PDE5-Is, Gacci et al [42]
Safety: In the review from Liu et al [39]
The first meta-analysis of AEs due to PDE5-Is reported that flushing, gastro-esophageal reflux, headache, and dyspepsia had the higher risk of occurrence (odds ratio: 4.88; 2.21; 1.88; 1.85; respectively). Moreover, regarding the overall tolerability of the association between PDE5-Is and α-blockers, Gacci et al [42]
In a recent review on tadalafil once daily, the Authors underlined the good safety profile with a relative risk of AEs from tadalafil similar to those reported with vardenafil or sildenafil (2.27 vs 1.86 vs 1.22, respectively); overall, the occurrence of AEs reported was very similar to that reported with all PDE5-Is versus placebo: 16.0% versus 6.0% [42]
Clinically-meaningful symptom improvement: Clinically-meaningful LUTS improvement is defined as a decrease of ≥3 points or ≥25% reduction of total IPSS [45]
Similar post-hoc analyses were done in 1499 patients treated with tadalafil 5 mg once daily or placebo [47]
Nocturia: Nocturia, defined as one or more voids per night, is one of the most prevalent and bothersome single urinary symptoms in community-dwelling men or patients with LUTS/BPH and the main reason for physician consultations [48]
Tadalafil for men with or without ED: The majority of the randomized, placebo-controlled tadalafil trials included patients with ED (approximately 60–70% of trial participants). Pooled data analyses evaluated whether symptom improvement was related to baseline ED status or ED improvement during tadalafil treatment [50]
Other baseline characteristics: The impact of several patient characteristics was evaluated in 1500 pooled patients with LUTS/BPH with regard to symptom improvement and adverse events, including age (≤65 vs >65 yr), symptom severity (IPSS < 20 vs ≥ 20), testosterone concentration (<300 ng/dl vs ≥300 ng/dl), prostate-specific antigen-predicted prostate volume (<40 ml vs ≥40 ml), previous α-blockers use (yes vs no), previous PDE5 inhibitor use (yes vs no), arterial hypertension (yes vs no), diabetes mellitus (yes vs no), and cardiovascular disease (yes vs no) [52]
Finally, an integrated analysis on 1371 patients, demonstrated that tadalafil 5 mg once daily for 12 wk allowed to achieve a very small, but statistically significant increase in Qmax versus the placebo (median: 1.1 ml/s vs 0.4 ml/s) [55]
Tadalafil has been also proposed in combination with alpha blockers or 5-alpha reductase inhibitors. In a prospective randomized study on 133 men with LUTS/BPH treated with tamsulsoin plus tadalafil versus tamsulosin or tadalafil alone, combination therapy was more effective than monotherapy for ED (%IIEF change from baseline: 60.2 vs 39.3 and 46.0 respectively) with similar improvement for urinary symptoms (% IPSS change from baseline: 53.9 vs 50.9 and 33.5), with a good safety profile [56]
Regarding the impact of tadalafil on sexual activity of men with ED and LUTS due to BPH tadalafil, Giuliano et al [58]
There is a large body of scientific evidence supporting the role of the NO-cGMP pathway including PDE5I in: (1) regulation of the tone of the smooth muscle fibers of the prostate, urethra, and bladder neck and in a lesser extent of the bladder (relaxant effect), (2) control of the arterial supply of the LUT (vasodilatory effect), and (3) modulation of the micturition reflex via the afferent bladder innervation (decrease in the afferent signaling). PDE5-Is may also downregulate inflammatory processes in LUT and exert antiproliferative effects.
Several meta-analyses demonstrated that PDE5-Is are effective in improving LUTS and erectile function compared with placebo. The combination of PDE5-Is with α-blockers induce a small, but statistically significant improvement of maximum flow rate as compared with α-blockers alone, in addition to the positive effect on micturition and sexual activity. PDE5-Is alone or in combination with α-blockers are well tolerated: flushing, gastroesophageal reflux, headache, and dyspepsia are the most common treatment-associated AEs.
Tadalafil 5 mg once daily achieves an improvement of clinically-meaningful urinary symptoms and nocturnal voiding frequency compared with placebo. Furthermore, the effects on LUTS are independent of ED severity at baseline and ED improvement.
Data on the long-term effects prostate size, reduction of disease progression, or prostate cancer prevalence related to the use of PDE5-Is are not available; long-term outcomes and cost-effectiveness analyses are needed.
Author contributions: Mauro Gacci had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Gacci, Giuliano.
Acquisition of data: Gacci, Giuliano, Andersson, Maggi, Oelke.
Analysis and interpretation of data: Gacci, Andersson, Chapple, Maggi, Mirone, Oelke, Porst, Roehrborn, Stief, Giuliano.
Drafting of the manuscript: Gacci, Giuliano, Andersson, Maggi, Oelke.
Critical revision of the manuscript for important intellectual content: Chapple, Mirone, Porst, Roehrborn, Stief.
Statistical analysis: Gacci.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Giuliano.
Other: None.
Financial disclosures: Mauro Gacci certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Gacci: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Pierre Fabre; Andersson: Consultancy and Advisory Boards for Allergan, Astellas, Ferring; Chapple: Consultant, Researcher and Speaker for Allergan, Astellas, Medtronic and Recordati. Consultant and speaker for Lilly. Researcher and speaker for ONO and Pfizer. Speaker for Ranbaxy; Maggi: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Intercept, Menarini; Mirone: consultant, speaker, and/or trial participant for Eli Lilly Italia, Menarini, Zambon, Recordati, GSK, Bracco; Oelke: consultant, speaker, and/or trial participant for Bayer Healthcare, Eli Lilly and Company, and Pfizer; Porst: consultant, speaker for Eli Lilly and Compani, Menarini Group and Sanofi; CRoehrborn: has financial interests and/or other relationships with Eli Lilly and Company, and with Allergan, Afferent Pharmaceuticals, Auxiliary Medical Services, Cancer and Leukemia Group B Clinical Trial Group, GlaxoSmithKline, New England Research Institutes, NeoTract, National Institute of Diabetes and Digestive and Kidney Diseases, Protox, Southwest Oncology Group, Urologix, VA Corporate Studies, and Watson Pharmaceuticals. Giuliano: consultant for Lilly, Sanofi, Pfizer.
Funding/Support and role of the sponsor: None.
Lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE) and erectile dysfunction (ED) are both highly prevalent in elderly men [1]
The aim of this review is to provide an update on the current knowledge on the potential mechanisms of action of PDE5-Is on LUTS/BPE, critically analyze systematic reviews and relevant data from the current literature on the clinical use of all PDE5-Is, and report the latest evidence on pooled-data analyses of tadalafil once daily to provide a definite rationale for the clinical use of tadalafil for the treatment of LUTS/BPE.
The pathways mediating the activity of PDE5-Is: LUTS have a multifactorial pathophysiology and have been discussed extensively [7]
The role of the bladder in male LUTS has been emphasized [9]
In the pathophysiology of LUTS, the NO/cyclic guanosine monophosphate (cGMP) (NO/cGMP) signaling pathway is believed to play a central role. Since NO signaling occurs via stimulation of soluble guanylate cyclase producing cGMP, it is reasonable to assume that the level of cGMP in different LUT tissues can influence their ability to generate LUTS. One way of modulating cGMP levels is to selectively inhibit cGMP degradation, and it is generally believed that all effects of PDE5Is are mediated by selective inhibition of the degradation of cyclic GMP.
Mechanism of action of PDE5-Is: In several animal species, including humans, the entire LUT expresses PDE5, with a relatively higher abundance within the bladder [16]
Although it is well established that PDE5 is expressed and biologically active in LUT, its functional role is still a matter of debate. Clinical studies demonstrated that its inhibition, through all the aforementioned PDE5-Is, resulted in amelioration of LUTS. Several mechanisms of action of PDE5-Is in LUTS have been hypothesized.
Immunohistochemical studies indicate that PDE5 is localized in the endothelial and smooth muscle cells of the LUT blood vessels [17]
Several in vitro studies have demonstrated that PDE5-Is can relax isolated prostate and bladder neck strips [27]
In the human prostate [17]
The NO/cGMP signaling pathway is likely to have a significant role in the innervation of the LUT. In human, neuronal NO synthase and guanylate cyclase are expressed in the uroepithelium, in neural fibers of the bladder neck and prostatic urethra, and in afferent nerves and interstitial cells, respectively [35]
Emerging evidences indicate that metabolic derangements, clustered in the metabolic syndrome (MetS) construct, may have a role in BPH pathophysiology. Within MetS, visceral obesity and dyslipidemia are the major predictors of an enlarged prostate size [3]
A systematic literature search in PubMed and Scopus was performed until May 2015, to identify systematic reviews of randomized controlled trial (RCTs), including the following MeSH terms: phosphodiesterase type 5 inhibitor and tadalafil PLUS urinary symptoms OR lower urinary tract symptoms OR benign prostatic hyperplasia OR prostate. We included only systematic reviews of RCTs comparing PDE5-Is treatment with different oral therapies or placebos for LUTS/BPH, while we excluded reviews of RTCs without PDE5-Is, nonclinical trials with PDE5-Is, or nonsystematic review. A total of eight papers were analyzed (Fig. 1; Table 1).
Table 1 Characteristics of the studies included in the review
a Significant improvement versus placebo.
b PDE5-Is + ABs versus ABs alone.
c Significant improvement versus ABs alone.
d PDE5-Is nonspecified.
* p = 0.04 for Tadalafil 5 mg.
ABs = alpha-blockers; BPH = benign prostatic hyperplasia; diff. = difference; ED = erectile dysfunction; IIEF = International Index Of Erectile Function; IPSS = International Prostatic Symptom Score; MRAs = muscarinic receptor antagonists; O = other PDE5-Is; PDE5-Is = phosphodiesterase 5 inhibitors; PLA = placebo; P.ts = patients; Qmax = maximum flow rate at uroflowmetry; S = sildenafil; T = tadalafil;. V = vardenafil; 5ARIs = 5a-reductase inhibitors.
Moreover, we selected more clinically relevant data from current literature on the clinical use of all PDE5-Is, including all post-hoc pooled data analyses (Table 2), with a nonsystematic approach (studies published only as abstract or presented without abstract and reports from meetings and studies not published in English were not considered for this review).
Table 2 Summary of posthoc pooled-data analyses of patients treated with tadalafil 5 mg once daily versus placebo for lower urinary tract symptoms/benign prostatic enlargement
Publication | No. of patients (n) |
Follow up (wk) |
Main findings | |
---|---|---|---|---|
Tadalafil | Placebo | |||
Oelke et al., 2015 [47] J.C. Nickel, G.B. Brock, S. Herschorn, R. Dickson, C. Henneges, L. Viktrup. Proportion of tadalafil-treated patients with clinically meaningful improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia. BJU Int. 2015;115:815-821 Crossref |
742 | 735 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from baseline to endpoint in significantly more patients with tadalafil (69.1%) vs placebo (54.8%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from baseline to endpoint in significantly more patients with tadalafil (59.8%) vs placebo (43.7%; p < 0.001) • 59.8% (50.2%) and 79.3% (72.5%) of the responders had ≥3 (≥25%) IPSS point improvement already after wk 1 and wk 4, respectively |
Nickel et al., 2015 [48] M. Oelke, B. Wiese, R. Berges. Nocturia and its impact on health related quality of life and health care seeking behavior in German community-dwelling men aged 50 years or older. World J Urol. 2014;32:1155-1162 Crossref |
752 | 747 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from randomization to endpoint in significantly more patients with tadalafil (71.1%) vs placebo (56.0%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from randomization to endpoint in significantly more patients with tadalafil (61.7%) vs placebo (45.5%; p < 0.001) • 38.5% (22.4%) of patients with tadalafil and 41.0% (23.3%) of patients with placebo had ≥3 (≥25%) IPSS point improvement during the placebo run-in phase |
Oelke et al., 2014 [50] H. Porst, C.G. Roehrborn, R.J. Secrest, A. Esler, L. Viktrup. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia and on erectile dysfunction in sexually active men with both conditions: analyses of pooled data from four randomized, placebo-controlled tadalafil clinical studies. J Sex Med. 2013;10:2044-2052 Crossref |
752 | 748 | 12 | Effects of tadalafil on nocturia (nocturnal voiding frequency): • for men with ≥1 nocturia episode at baseline, reduction with tadalafil (–0.5) was significantly greater than with placebo at study end (–0.4; LS mean change –0.2, p = 0.002) • for men with ≥2 nocturia episodes at baseline, reduction with tadalafil (–0.8) was significantly greater than with placebo at study end (–0.6; LS mean change –0.2, p = 0.003) • tadalafil (placebo) treatment resulted in reduction of ≥1 nocturia episodes in 47.5% (41.3%) of patients |
Porst et al., 2013 [51] G.B. Brock, K.T. McVary, C.G. Roehrborn, et al. Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: integrated data analyses from 4 placebo controlled clinical studies. J Urol. 2014;191:405-411 Crossref |
505 | 521 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • analysis only of men who were sexually active at baseline • significant improvement of total IPSS with tadalafil (–6.0) vs placebo (–3.6; p < 0.001) from baseline to study end • significant improvement of IIEF-EF with tadalafil (+6.4) vs placebo (+1.4, p < 0.001) from baseline to study end • similar IPSS improvements in men with ED vs without ED: no significant impact of ED severity on LUTS (IPSS) outcome |
Brock et al., 2014 [52] H. Porst, M. Oelke, E.R. Goldfischer, et al. Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational, randomized, placebo-controlled clinical studies. Urology. 2013;82:667-673 Crossref |
752 | 744 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • similar LUTS (IPSS) improvement with tadalafil vs placebo in men without ED (–5.4 vs –2.2, p = 0.0007) compared with men with ED (–5.9 vs –2.3, p < 0.0001); ED subgroup interaction not significant • bidirectional path analysis for sexually-active men (n = 1250) only: 92.5% of the total effects of tadalafil on LUTS/BPH via direct effect on LUTS and 7.5% via indirect effects by IIEF-EF domain improvement |
Porst et al., 2013 [53] O. Nishizawa, M. Yoshida, M. Takeda, et al. Tadalafil 5 mg once daily for the treatment of Asian men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: analyses of data pooled from three randomized, double-blind, placebo-controlled studies. Int J Urol. 2015;22:378-384 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in different patient subgroups: • improvements in IPSS and BPH-Impact Index in all patient subgroups identical (investigated patient parameters: age, symptom severity, serum testosterone concentration, prostate volume, previous α–blocker or PDE5-inhibitor use, arterial hypertension, diabetes mellitus, cardio-vascular diseases) • no baseline item was identified to predict a favorable or unfavorable treatment outcome |
Nishizawa et al., 2015 [54] C. Vlachopoulos, M. Oelke, M. Maggi, et al. Impact of cardiovascular risk factors and related comorbid conditions on the treatment response to tadalafil once-daily in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: an integrated analysis of four randomized, double-blind, placebo-controlled clinical trials. Int J Clin Pract. 2015;69:1496-1507 |
601 | 598 | 12 | Effects of tadalafil on LUTS/BPH in different subgroups of Asian patients: • analysis of Japanese, Korean, or Taiwanese men • significant improvements in total IPSS (tadalafil vs placebo) at wk 4 (–3.69 vs –2.47), wk 8 (–4.72 vs –3.43), and wk 12 (–5.32 vs –3.79), each p < 0.001 • additionally, significant improvements at wk 4, wk 8, and wk 12 for IPSS storage and IPSS voiding subscores as well as for IPSS-QoL • older patients (≥65 yr) showed significantly lower IPSS improvement than younger patients (<65 yr); otherwise, no significant impact of any other baseline item on LUTS improvement |
Vlachopoulos et al., 2015 [55] C.G. Roehrborn, C. Chapple, M. Oelke, D. Cox, A. Esler, L. Viktrup. Effects of tadalafil once-daily on maximum urinary flow rate in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. J Urol. 2014;191:1045-1050 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in patients with cardio-vascular risk factors and therapy: • subanalysis of comorbid, cardio-vascular diseases on LUTS/BPH outcome • no significant differences in efficacy of tadalafil vs placebo for various cardio-vascular diseases/comorbidities • but patients with >1 antihypertensive drugs have significantly lower IPSS improvement compared with men taking ≤1 drug • use of diuretics resulted in significantly lower IPSS improvement compared to men taking other antihypertensives or no drugs |
Roehrborn et al., 2014 [56] D.V. Singh, U.K. Mete, A.K. Mandal, S.K. Singh. 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;11:187-196 Crossref |
752 (612a) |
748 (585a) |
12 | Effects of tadalafil on uroflow (maximum urinary flow rate): • in total study population, patients with tadalafil had significantly greater Qmax improvement (mean +1.1 ml/s) compared with patients with placebo (mean +0.4 ml/s; p = 0.003) • significant Qmax improvement in the total study population was mainly driven by effects in patients who voided 250–450 ml (p = 0.011) and had a baseline Qmax 10–15 ml/s (p = 0.044) |
a With valid measurement.
BPH = benign prostatic enlargement; ED = erectile dysfunction; IPSS = International Prostate Symptom Score; LUTS = lower urinary tract symptoms; PDE5 = phosphodiesterase type 5; QoL = quality of life.
Efficacy: In the first systematic review on PDE5-Is for LUTS secondary to BPH published in literature, Laydner et al [38]
In the first meta-regression analysis on PDE5-Is alone or in combination with α-blockers, Gacci et al [2]
In a subset analysis on tadalafil based on data extrapolated from a systematic review on all PDE5-Is, Gacci et al [42]
Safety: In the review from Liu et al [39]
The first meta-analysis of AEs due to PDE5-Is reported that flushing, gastro-esophageal reflux, headache, and dyspepsia had the higher risk of occurrence (odds ratio: 4.88; 2.21; 1.88; 1.85; respectively). Moreover, regarding the overall tolerability of the association between PDE5-Is and α-blockers, Gacci et al [42]
In a recent review on tadalafil once daily, the Authors underlined the good safety profile with a relative risk of AEs from tadalafil similar to those reported with vardenafil or sildenafil (2.27 vs 1.86 vs 1.22, respectively); overall, the occurrence of AEs reported was very similar to that reported with all PDE5-Is versus placebo: 16.0% versus 6.0% [42]
Clinically-meaningful symptom improvement: Clinically-meaningful LUTS improvement is defined as a decrease of ≥3 points or ≥25% reduction of total IPSS [45]
Similar post-hoc analyses were done in 1499 patients treated with tadalafil 5 mg once daily or placebo [47]
Nocturia: Nocturia, defined as one or more voids per night, is one of the most prevalent and bothersome single urinary symptoms in community-dwelling men or patients with LUTS/BPH and the main reason for physician consultations [48]
Tadalafil for men with or without ED: The majority of the randomized, placebo-controlled tadalafil trials included patients with ED (approximately 60–70% of trial participants). Pooled data analyses evaluated whether symptom improvement was related to baseline ED status or ED improvement during tadalafil treatment [50]
Other baseline characteristics: The impact of several patient characteristics was evaluated in 1500 pooled patients with LUTS/BPH with regard to symptom improvement and adverse events, including age (≤65 vs >65 yr), symptom severity (IPSS < 20 vs ≥ 20), testosterone concentration (<300 ng/dl vs ≥300 ng/dl), prostate-specific antigen-predicted prostate volume (<40 ml vs ≥40 ml), previous α-blockers use (yes vs no), previous PDE5 inhibitor use (yes vs no), arterial hypertension (yes vs no), diabetes mellitus (yes vs no), and cardiovascular disease (yes vs no) [52]
Finally, an integrated analysis on 1371 patients, demonstrated that tadalafil 5 mg once daily for 12 wk allowed to achieve a very small, but statistically significant increase in Qmax versus the placebo (median: 1.1 ml/s vs 0.4 ml/s) [55]
Tadalafil has been also proposed in combination with alpha blockers or 5-alpha reductase inhibitors. In a prospective randomized study on 133 men with LUTS/BPH treated with tamsulsoin plus tadalafil versus tamsulosin or tadalafil alone, combination therapy was more effective than monotherapy for ED (%IIEF change from baseline: 60.2 vs 39.3 and 46.0 respectively) with similar improvement for urinary symptoms (% IPSS change from baseline: 53.9 vs 50.9 and 33.5), with a good safety profile [56]
Regarding the impact of tadalafil on sexual activity of men with ED and LUTS due to BPH tadalafil, Giuliano et al [58]
There is a large body of scientific evidence supporting the role of the NO-cGMP pathway including PDE5I in: (1) regulation of the tone of the smooth muscle fibers of the prostate, urethra, and bladder neck and in a lesser extent of the bladder (relaxant effect), (2) control of the arterial supply of the LUT (vasodilatory effect), and (3) modulation of the micturition reflex via the afferent bladder innervation (decrease in the afferent signaling). PDE5-Is may also downregulate inflammatory processes in LUT and exert antiproliferative effects.
Several meta-analyses demonstrated that PDE5-Is are effective in improving LUTS and erectile function compared with placebo. The combination of PDE5-Is with α-blockers induce a small, but statistically significant improvement of maximum flow rate as compared with α-blockers alone, in addition to the positive effect on micturition and sexual activity. PDE5-Is alone or in combination with α-blockers are well tolerated: flushing, gastroesophageal reflux, headache, and dyspepsia are the most common treatment-associated AEs.
Tadalafil 5 mg once daily achieves an improvement of clinically-meaningful urinary symptoms and nocturnal voiding frequency compared with placebo. Furthermore, the effects on LUTS are independent of ED severity at baseline and ED improvement.
Data on the long-term effects prostate size, reduction of disease progression, or prostate cancer prevalence related to the use of PDE5-Is are not available; long-term outcomes and cost-effectiveness analyses are needed.
Author contributions: Mauro Gacci had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Gacci, Giuliano.
Acquisition of data: Gacci, Giuliano, Andersson, Maggi, Oelke.
Analysis and interpretation of data: Gacci, Andersson, Chapple, Maggi, Mirone, Oelke, Porst, Roehrborn, Stief, Giuliano.
Drafting of the manuscript: Gacci, Giuliano, Andersson, Maggi, Oelke.
Critical revision of the manuscript for important intellectual content: Chapple, Mirone, Porst, Roehrborn, Stief.
Statistical analysis: Gacci.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Giuliano.
Other: None.
Financial disclosures: Mauro Gacci certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Gacci: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Pierre Fabre; Andersson: Consultancy and Advisory Boards for Allergan, Astellas, Ferring; Chapple: Consultant, Researcher and Speaker for Allergan, Astellas, Medtronic and Recordati. Consultant and speaker for Lilly. Researcher and speaker for ONO and Pfizer. Speaker for Ranbaxy; Maggi: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Intercept, Menarini; Mirone: consultant, speaker, and/or trial participant for Eli Lilly Italia, Menarini, Zambon, Recordati, GSK, Bracco; Oelke: consultant, speaker, and/or trial participant for Bayer Healthcare, Eli Lilly and Company, and Pfizer; Porst: consultant, speaker for Eli Lilly and Compani, Menarini Group and Sanofi; CRoehrborn: has financial interests and/or other relationships with Eli Lilly and Company, and with Allergan, Afferent Pharmaceuticals, Auxiliary Medical Services, Cancer and Leukemia Group B Clinical Trial Group, GlaxoSmithKline, New England Research Institutes, NeoTract, National Institute of Diabetes and Digestive and Kidney Diseases, Protox, Southwest Oncology Group, Urologix, VA Corporate Studies, and Watson Pharmaceuticals. Giuliano: consultant for Lilly, Sanofi, Pfizer.
Funding/Support and role of the sponsor: None.
Lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE) and erectile dysfunction (ED) are both highly prevalent in elderly men [1]
The aim of this review is to provide an update on the current knowledge on the potential mechanisms of action of PDE5-Is on LUTS/BPE, critically analyze systematic reviews and relevant data from the current literature on the clinical use of all PDE5-Is, and report the latest evidence on pooled-data analyses of tadalafil once daily to provide a definite rationale for the clinical use of tadalafil for the treatment of LUTS/BPE.
The pathways mediating the activity of PDE5-Is: LUTS have a multifactorial pathophysiology and have been discussed extensively [7]
The role of the bladder in male LUTS has been emphasized [9]
In the pathophysiology of LUTS, the NO/cyclic guanosine monophosphate (cGMP) (NO/cGMP) signaling pathway is believed to play a central role. Since NO signaling occurs via stimulation of soluble guanylate cyclase producing cGMP, it is reasonable to assume that the level of cGMP in different LUT tissues can influence their ability to generate LUTS. One way of modulating cGMP levels is to selectively inhibit cGMP degradation, and it is generally believed that all effects of PDE5Is are mediated by selective inhibition of the degradation of cyclic GMP.
Mechanism of action of PDE5-Is: In several animal species, including humans, the entire LUT expresses PDE5, with a relatively higher abundance within the bladder [16]
Although it is well established that PDE5 is expressed and biologically active in LUT, its functional role is still a matter of debate. Clinical studies demonstrated that its inhibition, through all the aforementioned PDE5-Is, resulted in amelioration of LUTS. Several mechanisms of action of PDE5-Is in LUTS have been hypothesized.
Immunohistochemical studies indicate that PDE5 is localized in the endothelial and smooth muscle cells of the LUT blood vessels [17]
Several in vitro studies have demonstrated that PDE5-Is can relax isolated prostate and bladder neck strips [27]
In the human prostate [17]
The NO/cGMP signaling pathway is likely to have a significant role in the innervation of the LUT. In human, neuronal NO synthase and guanylate cyclase are expressed in the uroepithelium, in neural fibers of the bladder neck and prostatic urethra, and in afferent nerves and interstitial cells, respectively [35]
Emerging evidences indicate that metabolic derangements, clustered in the metabolic syndrome (MetS) construct, may have a role in BPH pathophysiology. Within MetS, visceral obesity and dyslipidemia are the major predictors of an enlarged prostate size [3]
A systematic literature search in PubMed and Scopus was performed until May 2015, to identify systematic reviews of randomized controlled trial (RCTs), including the following MeSH terms: phosphodiesterase type 5 inhibitor and tadalafil PLUS urinary symptoms OR lower urinary tract symptoms OR benign prostatic hyperplasia OR prostate. We included only systematic reviews of RCTs comparing PDE5-Is treatment with different oral therapies or placebos for LUTS/BPH, while we excluded reviews of RTCs without PDE5-Is, nonclinical trials with PDE5-Is, or nonsystematic review. A total of eight papers were analyzed (Fig. 1; Table 1).
Table 1 Characteristics of the studies included in the review
a Significant improvement versus placebo.
b PDE5-Is + ABs versus ABs alone.
c Significant improvement versus ABs alone.
d PDE5-Is nonspecified.
* p = 0.04 for Tadalafil 5 mg.
ABs = alpha-blockers; BPH = benign prostatic hyperplasia; diff. = difference; ED = erectile dysfunction; IIEF = International Index Of Erectile Function; IPSS = International Prostatic Symptom Score; MRAs = muscarinic receptor antagonists; O = other PDE5-Is; PDE5-Is = phosphodiesterase 5 inhibitors; PLA = placebo; P.ts = patients; Qmax = maximum flow rate at uroflowmetry; S = sildenafil; T = tadalafil;. V = vardenafil; 5ARIs = 5a-reductase inhibitors.
Moreover, we selected more clinically relevant data from current literature on the clinical use of all PDE5-Is, including all post-hoc pooled data analyses (Table 2), with a nonsystematic approach (studies published only as abstract or presented without abstract and reports from meetings and studies not published in English were not considered for this review).
Table 2 Summary of posthoc pooled-data analyses of patients treated with tadalafil 5 mg once daily versus placebo for lower urinary tract symptoms/benign prostatic enlargement
Publication | No. of patients (n) |
Follow up (wk) |
Main findings | |
---|---|---|---|---|
Tadalafil | Placebo | |||
Oelke et al., 2015 [47] J.C. Nickel, G.B. Brock, S. Herschorn, R. Dickson, C. Henneges, L. Viktrup. Proportion of tadalafil-treated patients with clinically meaningful improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia. BJU Int. 2015;115:815-821 Crossref |
742 | 735 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from baseline to endpoint in significantly more patients with tadalafil (69.1%) vs placebo (54.8%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from baseline to endpoint in significantly more patients with tadalafil (59.8%) vs placebo (43.7%; p < 0.001) • 59.8% (50.2%) and 79.3% (72.5%) of the responders had ≥3 (≥25%) IPSS point improvement already after wk 1 and wk 4, respectively |
Nickel et al., 2015 [48] M. Oelke, B. Wiese, R. Berges. Nocturia and its impact on health related quality of life and health care seeking behavior in German community-dwelling men aged 50 years or older. World J Urol. 2014;32:1155-1162 Crossref |
752 | 747 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from randomization to endpoint in significantly more patients with tadalafil (71.1%) vs placebo (56.0%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from randomization to endpoint in significantly more patients with tadalafil (61.7%) vs placebo (45.5%; p < 0.001) • 38.5% (22.4%) of patients with tadalafil and 41.0% (23.3%) of patients with placebo had ≥3 (≥25%) IPSS point improvement during the placebo run-in phase |
Oelke et al., 2014 [50] H. Porst, C.G. Roehrborn, R.J. Secrest, A. Esler, L. Viktrup. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia and on erectile dysfunction in sexually active men with both conditions: analyses of pooled data from four randomized, placebo-controlled tadalafil clinical studies. J Sex Med. 2013;10:2044-2052 Crossref |
752 | 748 | 12 | Effects of tadalafil on nocturia (nocturnal voiding frequency): • for men with ≥1 nocturia episode at baseline, reduction with tadalafil (–0.5) was significantly greater than with placebo at study end (–0.4; LS mean change –0.2, p = 0.002) • for men with ≥2 nocturia episodes at baseline, reduction with tadalafil (–0.8) was significantly greater than with placebo at study end (–0.6; LS mean change –0.2, p = 0.003) • tadalafil (placebo) treatment resulted in reduction of ≥1 nocturia episodes in 47.5% (41.3%) of patients |
Porst et al., 2013 [51] G.B. Brock, K.T. McVary, C.G. Roehrborn, et al. Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: integrated data analyses from 4 placebo controlled clinical studies. J Urol. 2014;191:405-411 Crossref |
505 | 521 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • analysis only of men who were sexually active at baseline • significant improvement of total IPSS with tadalafil (–6.0) vs placebo (–3.6; p < 0.001) from baseline to study end • significant improvement of IIEF-EF with tadalafil (+6.4) vs placebo (+1.4, p < 0.001) from baseline to study end • similar IPSS improvements in men with ED vs without ED: no significant impact of ED severity on LUTS (IPSS) outcome |
Brock et al., 2014 [52] H. Porst, M. Oelke, E.R. Goldfischer, et al. Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational, randomized, placebo-controlled clinical studies. Urology. 2013;82:667-673 Crossref |
752 | 744 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • similar LUTS (IPSS) improvement with tadalafil vs placebo in men without ED (–5.4 vs –2.2, p = 0.0007) compared with men with ED (–5.9 vs –2.3, p < 0.0001); ED subgroup interaction not significant • bidirectional path analysis for sexually-active men (n = 1250) only: 92.5% of the total effects of tadalafil on LUTS/BPH via direct effect on LUTS and 7.5% via indirect effects by IIEF-EF domain improvement |
Porst et al., 2013 [53] O. Nishizawa, M. Yoshida, M. Takeda, et al. Tadalafil 5 mg once daily for the treatment of Asian men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: analyses of data pooled from three randomized, double-blind, placebo-controlled studies. Int J Urol. 2015;22:378-384 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in different patient subgroups: • improvements in IPSS and BPH-Impact Index in all patient subgroups identical (investigated patient parameters: age, symptom severity, serum testosterone concentration, prostate volume, previous α–blocker or PDE5-inhibitor use, arterial hypertension, diabetes mellitus, cardio-vascular diseases) • no baseline item was identified to predict a favorable or unfavorable treatment outcome |
Nishizawa et al., 2015 [54] C. Vlachopoulos, M. Oelke, M. Maggi, et al. Impact of cardiovascular risk factors and related comorbid conditions on the treatment response to tadalafil once-daily in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: an integrated analysis of four randomized, double-blind, placebo-controlled clinical trials. Int J Clin Pract. 2015;69:1496-1507 |
601 | 598 | 12 | Effects of tadalafil on LUTS/BPH in different subgroups of Asian patients: • analysis of Japanese, Korean, or Taiwanese men • significant improvements in total IPSS (tadalafil vs placebo) at wk 4 (–3.69 vs –2.47), wk 8 (–4.72 vs –3.43), and wk 12 (–5.32 vs –3.79), each p < 0.001 • additionally, significant improvements at wk 4, wk 8, and wk 12 for IPSS storage and IPSS voiding subscores as well as for IPSS-QoL • older patients (≥65 yr) showed significantly lower IPSS improvement than younger patients (<65 yr); otherwise, no significant impact of any other baseline item on LUTS improvement |
Vlachopoulos et al., 2015 [55] C.G. Roehrborn, C. Chapple, M. Oelke, D. Cox, A. Esler, L. Viktrup. Effects of tadalafil once-daily on maximum urinary flow rate in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. J Urol. 2014;191:1045-1050 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in patients with cardio-vascular risk factors and therapy: • subanalysis of comorbid, cardio-vascular diseases on LUTS/BPH outcome • no significant differences in efficacy of tadalafil vs placebo for various cardio-vascular diseases/comorbidities • but patients with >1 antihypertensive drugs have significantly lower IPSS improvement compared with men taking ≤1 drug • use of diuretics resulted in significantly lower IPSS improvement compared to men taking other antihypertensives or no drugs |
Roehrborn et al., 2014 [56] D.V. Singh, U.K. Mete, A.K. Mandal, S.K. Singh. 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;11:187-196 Crossref |
752 (612a) |
748 (585a) |
12 | Effects of tadalafil on uroflow (maximum urinary flow rate): • in total study population, patients with tadalafil had significantly greater Qmax improvement (mean +1.1 ml/s) compared with patients with placebo (mean +0.4 ml/s; p = 0.003) • significant Qmax improvement in the total study population was mainly driven by effects in patients who voided 250–450 ml (p = 0.011) and had a baseline Qmax 10–15 ml/s (p = 0.044) |
a With valid measurement.
BPH = benign prostatic enlargement; ED = erectile dysfunction; IPSS = International Prostate Symptom Score; LUTS = lower urinary tract symptoms; PDE5 = phosphodiesterase type 5; QoL = quality of life.
Efficacy: In the first systematic review on PDE5-Is for LUTS secondary to BPH published in literature, Laydner et al [38]
In the first meta-regression analysis on PDE5-Is alone or in combination with α-blockers, Gacci et al [2]
In a subset analysis on tadalafil based on data extrapolated from a systematic review on all PDE5-Is, Gacci et al [42]
Safety: In the review from Liu et al [39]
The first meta-analysis of AEs due to PDE5-Is reported that flushing, gastro-esophageal reflux, headache, and dyspepsia had the higher risk of occurrence (odds ratio: 4.88; 2.21; 1.88; 1.85; respectively). Moreover, regarding the overall tolerability of the association between PDE5-Is and α-blockers, Gacci et al [42]
In a recent review on tadalafil once daily, the Authors underlined the good safety profile with a relative risk of AEs from tadalafil similar to those reported with vardenafil or sildenafil (2.27 vs 1.86 vs 1.22, respectively); overall, the occurrence of AEs reported was very similar to that reported with all PDE5-Is versus placebo: 16.0% versus 6.0% [42]
Clinically-meaningful symptom improvement: Clinically-meaningful LUTS improvement is defined as a decrease of ≥3 points or ≥25% reduction of total IPSS [45]
Similar post-hoc analyses were done in 1499 patients treated with tadalafil 5 mg once daily or placebo [47]
Nocturia: Nocturia, defined as one or more voids per night, is one of the most prevalent and bothersome single urinary symptoms in community-dwelling men or patients with LUTS/BPH and the main reason for physician consultations [48]
Tadalafil for men with or without ED: The majority of the randomized, placebo-controlled tadalafil trials included patients with ED (approximately 60–70% of trial participants). Pooled data analyses evaluated whether symptom improvement was related to baseline ED status or ED improvement during tadalafil treatment [50]
Other baseline characteristics: The impact of several patient characteristics was evaluated in 1500 pooled patients with LUTS/BPH with regard to symptom improvement and adverse events, including age (≤65 vs >65 yr), symptom severity (IPSS < 20 vs ≥ 20), testosterone concentration (<300 ng/dl vs ≥300 ng/dl), prostate-specific antigen-predicted prostate volume (<40 ml vs ≥40 ml), previous α-blockers use (yes vs no), previous PDE5 inhibitor use (yes vs no), arterial hypertension (yes vs no), diabetes mellitus (yes vs no), and cardiovascular disease (yes vs no) [52]
Finally, an integrated analysis on 1371 patients, demonstrated that tadalafil 5 mg once daily for 12 wk allowed to achieve a very small, but statistically significant increase in Qmax versus the placebo (median: 1.1 ml/s vs 0.4 ml/s) [55]
Tadalafil has been also proposed in combination with alpha blockers or 5-alpha reductase inhibitors. In a prospective randomized study on 133 men with LUTS/BPH treated with tamsulsoin plus tadalafil versus tamsulosin or tadalafil alone, combination therapy was more effective than monotherapy for ED (%IIEF change from baseline: 60.2 vs 39.3 and 46.0 respectively) with similar improvement for urinary symptoms (% IPSS change from baseline: 53.9 vs 50.9 and 33.5), with a good safety profile [56]
Regarding the impact of tadalafil on sexual activity of men with ED and LUTS due to BPH tadalafil, Giuliano et al [58]
There is a large body of scientific evidence supporting the role of the NO-cGMP pathway including PDE5I in: (1) regulation of the tone of the smooth muscle fibers of the prostate, urethra, and bladder neck and in a lesser extent of the bladder (relaxant effect), (2) control of the arterial supply of the LUT (vasodilatory effect), and (3) modulation of the micturition reflex via the afferent bladder innervation (decrease in the afferent signaling). PDE5-Is may also downregulate inflammatory processes in LUT and exert antiproliferative effects.
Several meta-analyses demonstrated that PDE5-Is are effective in improving LUTS and erectile function compared with placebo. The combination of PDE5-Is with α-blockers induce a small, but statistically significant improvement of maximum flow rate as compared with α-blockers alone, in addition to the positive effect on micturition and sexual activity. PDE5-Is alone or in combination with α-blockers are well tolerated: flushing, gastroesophageal reflux, headache, and dyspepsia are the most common treatment-associated AEs.
Tadalafil 5 mg once daily achieves an improvement of clinically-meaningful urinary symptoms and nocturnal voiding frequency compared with placebo. Furthermore, the effects on LUTS are independent of ED severity at baseline and ED improvement.
Data on the long-term effects prostate size, reduction of disease progression, or prostate cancer prevalence related to the use of PDE5-Is are not available; long-term outcomes and cost-effectiveness analyses are needed.
Author contributions: Mauro Gacci had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Gacci, Giuliano.
Acquisition of data: Gacci, Giuliano, Andersson, Maggi, Oelke.
Analysis and interpretation of data: Gacci, Andersson, Chapple, Maggi, Mirone, Oelke, Porst, Roehrborn, Stief, Giuliano.
Drafting of the manuscript: Gacci, Giuliano, Andersson, Maggi, Oelke.
Critical revision of the manuscript for important intellectual content: Chapple, Mirone, Porst, Roehrborn, Stief.
Statistical analysis: Gacci.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Giuliano.
Other: None.
Financial disclosures: Mauro Gacci certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Gacci: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Pierre Fabre; Andersson: Consultancy and Advisory Boards for Allergan, Astellas, Ferring; Chapple: Consultant, Researcher and Speaker for Allergan, Astellas, Medtronic and Recordati. Consultant and speaker for Lilly. Researcher and speaker for ONO and Pfizer. Speaker for Ranbaxy; Maggi: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Intercept, Menarini; Mirone: consultant, speaker, and/or trial participant for Eli Lilly Italia, Menarini, Zambon, Recordati, GSK, Bracco; Oelke: consultant, speaker, and/or trial participant for Bayer Healthcare, Eli Lilly and Company, and Pfizer; Porst: consultant, speaker for Eli Lilly and Compani, Menarini Group and Sanofi; CRoehrborn: has financial interests and/or other relationships with Eli Lilly and Company, and with Allergan, Afferent Pharmaceuticals, Auxiliary Medical Services, Cancer and Leukemia Group B Clinical Trial Group, GlaxoSmithKline, New England Research Institutes, NeoTract, National Institute of Diabetes and Digestive and Kidney Diseases, Protox, Southwest Oncology Group, Urologix, VA Corporate Studies, and Watson Pharmaceuticals. Giuliano: consultant for Lilly, Sanofi, Pfizer.
Funding/Support and role of the sponsor: None.
Lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE) and erectile dysfunction (ED) are both highly prevalent in elderly men [1]
The aim of this review is to provide an update on the current knowledge on the potential mechanisms of action of PDE5-Is on LUTS/BPE, critically analyze systematic reviews and relevant data from the current literature on the clinical use of all PDE5-Is, and report the latest evidence on pooled-data analyses of tadalafil once daily to provide a definite rationale for the clinical use of tadalafil for the treatment of LUTS/BPE.
The pathways mediating the activity of PDE5-Is: LUTS have a multifactorial pathophysiology and have been discussed extensively [7]
The role of the bladder in male LUTS has been emphasized [9]
In the pathophysiology of LUTS, the NO/cyclic guanosine monophosphate (cGMP) (NO/cGMP) signaling pathway is believed to play a central role. Since NO signaling occurs via stimulation of soluble guanylate cyclase producing cGMP, it is reasonable to assume that the level of cGMP in different LUT tissues can influence their ability to generate LUTS. One way of modulating cGMP levels is to selectively inhibit cGMP degradation, and it is generally believed that all effects of PDE5Is are mediated by selective inhibition of the degradation of cyclic GMP.
Mechanism of action of PDE5-Is: In several animal species, including humans, the entire LUT expresses PDE5, with a relatively higher abundance within the bladder [16]
Although it is well established that PDE5 is expressed and biologically active in LUT, its functional role is still a matter of debate. Clinical studies demonstrated that its inhibition, through all the aforementioned PDE5-Is, resulted in amelioration of LUTS. Several mechanisms of action of PDE5-Is in LUTS have been hypothesized.
Immunohistochemical studies indicate that PDE5 is localized in the endothelial and smooth muscle cells of the LUT blood vessels [17]
Several in vitro studies have demonstrated that PDE5-Is can relax isolated prostate and bladder neck strips [27]
In the human prostate [17]
The NO/cGMP signaling pathway is likely to have a significant role in the innervation of the LUT. In human, neuronal NO synthase and guanylate cyclase are expressed in the uroepithelium, in neural fibers of the bladder neck and prostatic urethra, and in afferent nerves and interstitial cells, respectively [35]
Emerging evidences indicate that metabolic derangements, clustered in the metabolic syndrome (MetS) construct, may have a role in BPH pathophysiology. Within MetS, visceral obesity and dyslipidemia are the major predictors of an enlarged prostate size [3]
A systematic literature search in PubMed and Scopus was performed until May 2015, to identify systematic reviews of randomized controlled trial (RCTs), including the following MeSH terms: phosphodiesterase type 5 inhibitor and tadalafil PLUS urinary symptoms OR lower urinary tract symptoms OR benign prostatic hyperplasia OR prostate. We included only systematic reviews of RCTs comparing PDE5-Is treatment with different oral therapies or placebos for LUTS/BPH, while we excluded reviews of RTCs without PDE5-Is, nonclinical trials with PDE5-Is, or nonsystematic review. A total of eight papers were analyzed (Fig. 1; Table 1).
Table 1 Characteristics of the studies included in the review
a Significant improvement versus placebo.
b PDE5-Is + ABs versus ABs alone.
c Significant improvement versus ABs alone.
d PDE5-Is nonspecified.
* p = 0.04 for Tadalafil 5 mg.
ABs = alpha-blockers; BPH = benign prostatic hyperplasia; diff. = difference; ED = erectile dysfunction; IIEF = International Index Of Erectile Function; IPSS = International Prostatic Symptom Score; MRAs = muscarinic receptor antagonists; O = other PDE5-Is; PDE5-Is = phosphodiesterase 5 inhibitors; PLA = placebo; P.ts = patients; Qmax = maximum flow rate at uroflowmetry; S = sildenafil; T = tadalafil;. V = vardenafil; 5ARIs = 5a-reductase inhibitors.
Moreover, we selected more clinically relevant data from current literature on the clinical use of all PDE5-Is, including all post-hoc pooled data analyses (Table 2), with a nonsystematic approach (studies published only as abstract or presented without abstract and reports from meetings and studies not published in English were not considered for this review).
Table 2 Summary of posthoc pooled-data analyses of patients treated with tadalafil 5 mg once daily versus placebo for lower urinary tract symptoms/benign prostatic enlargement
Publication | No. of patients (n) |
Follow up (wk) |
Main findings | |
---|---|---|---|---|
Tadalafil | Placebo | |||
Oelke et al., 2015 [47] J.C. Nickel, G.B. Brock, S. Herschorn, R. Dickson, C. Henneges, L. Viktrup. Proportion of tadalafil-treated patients with clinically meaningful improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia. BJU Int. 2015;115:815-821 Crossref |
742 | 735 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from baseline to endpoint in significantly more patients with tadalafil (69.1%) vs placebo (54.8%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from baseline to endpoint in significantly more patients with tadalafil (59.8%) vs placebo (43.7%; p < 0.001) • 59.8% (50.2%) and 79.3% (72.5%) of the responders had ≥3 (≥25%) IPSS point improvement already after wk 1 and wk 4, respectively |
Nickel et al., 2015 [48] M. Oelke, B. Wiese, R. Berges. Nocturia and its impact on health related quality of life and health care seeking behavior in German community-dwelling men aged 50 years or older. World J Urol. 2014;32:1155-1162 Crossref |
752 | 747 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from randomization to endpoint in significantly more patients with tadalafil (71.1%) vs placebo (56.0%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from randomization to endpoint in significantly more patients with tadalafil (61.7%) vs placebo (45.5%; p < 0.001) • 38.5% (22.4%) of patients with tadalafil and 41.0% (23.3%) of patients with placebo had ≥3 (≥25%) IPSS point improvement during the placebo run-in phase |
Oelke et al., 2014 [50] H. Porst, C.G. Roehrborn, R.J. Secrest, A. Esler, L. Viktrup. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia and on erectile dysfunction in sexually active men with both conditions: analyses of pooled data from four randomized, placebo-controlled tadalafil clinical studies. J Sex Med. 2013;10:2044-2052 Crossref |
752 | 748 | 12 | Effects of tadalafil on nocturia (nocturnal voiding frequency): • for men with ≥1 nocturia episode at baseline, reduction with tadalafil (–0.5) was significantly greater than with placebo at study end (–0.4; LS mean change –0.2, p = 0.002) • for men with ≥2 nocturia episodes at baseline, reduction with tadalafil (–0.8) was significantly greater than with placebo at study end (–0.6; LS mean change –0.2, p = 0.003) • tadalafil (placebo) treatment resulted in reduction of ≥1 nocturia episodes in 47.5% (41.3%) of patients |
Porst et al., 2013 [51] G.B. Brock, K.T. McVary, C.G. Roehrborn, et al. Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: integrated data analyses from 4 placebo controlled clinical studies. J Urol. 2014;191:405-411 Crossref |
505 | 521 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • analysis only of men who were sexually active at baseline • significant improvement of total IPSS with tadalafil (–6.0) vs placebo (–3.6; p < 0.001) from baseline to study end • significant improvement of IIEF-EF with tadalafil (+6.4) vs placebo (+1.4, p < 0.001) from baseline to study end • similar IPSS improvements in men with ED vs without ED: no significant impact of ED severity on LUTS (IPSS) outcome |
Brock et al., 2014 [52] H. Porst, M. Oelke, E.R. Goldfischer, et al. Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational, randomized, placebo-controlled clinical studies. Urology. 2013;82:667-673 Crossref |
752 | 744 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • similar LUTS (IPSS) improvement with tadalafil vs placebo in men without ED (–5.4 vs –2.2, p = 0.0007) compared with men with ED (–5.9 vs –2.3, p < 0.0001); ED subgroup interaction not significant • bidirectional path analysis for sexually-active men (n = 1250) only: 92.5% of the total effects of tadalafil on LUTS/BPH via direct effect on LUTS and 7.5% via indirect effects by IIEF-EF domain improvement |
Porst et al., 2013 [53] O. Nishizawa, M. Yoshida, M. Takeda, et al. Tadalafil 5 mg once daily for the treatment of Asian men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: analyses of data pooled from three randomized, double-blind, placebo-controlled studies. Int J Urol. 2015;22:378-384 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in different patient subgroups: • improvements in IPSS and BPH-Impact Index in all patient subgroups identical (investigated patient parameters: age, symptom severity, serum testosterone concentration, prostate volume, previous α–blocker or PDE5-inhibitor use, arterial hypertension, diabetes mellitus, cardio-vascular diseases) • no baseline item was identified to predict a favorable or unfavorable treatment outcome |
Nishizawa et al., 2015 [54] C. Vlachopoulos, M. Oelke, M. Maggi, et al. Impact of cardiovascular risk factors and related comorbid conditions on the treatment response to tadalafil once-daily in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: an integrated analysis of four randomized, double-blind, placebo-controlled clinical trials. Int J Clin Pract. 2015;69:1496-1507 |
601 | 598 | 12 | Effects of tadalafil on LUTS/BPH in different subgroups of Asian patients: • analysis of Japanese, Korean, or Taiwanese men • significant improvements in total IPSS (tadalafil vs placebo) at wk 4 (–3.69 vs –2.47), wk 8 (–4.72 vs –3.43), and wk 12 (–5.32 vs –3.79), each p < 0.001 • additionally, significant improvements at wk 4, wk 8, and wk 12 for IPSS storage and IPSS voiding subscores as well as for IPSS-QoL • older patients (≥65 yr) showed significantly lower IPSS improvement than younger patients (<65 yr); otherwise, no significant impact of any other baseline item on LUTS improvement |
Vlachopoulos et al., 2015 [55] C.G. Roehrborn, C. Chapple, M. Oelke, D. Cox, A. Esler, L. Viktrup. Effects of tadalafil once-daily on maximum urinary flow rate in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. J Urol. 2014;191:1045-1050 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in patients with cardio-vascular risk factors and therapy: • subanalysis of comorbid, cardio-vascular diseases on LUTS/BPH outcome • no significant differences in efficacy of tadalafil vs placebo for various cardio-vascular diseases/comorbidities • but patients with >1 antihypertensive drugs have significantly lower IPSS improvement compared with men taking ≤1 drug • use of diuretics resulted in significantly lower IPSS improvement compared to men taking other antihypertensives or no drugs |
Roehrborn et al., 2014 [56] D.V. Singh, U.K. Mete, A.K. Mandal, S.K. Singh. 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;11:187-196 Crossref |
752 (612a) |
748 (585a) |
12 | Effects of tadalafil on uroflow (maximum urinary flow rate): • in total study population, patients with tadalafil had significantly greater Qmax improvement (mean +1.1 ml/s) compared with patients with placebo (mean +0.4 ml/s; p = 0.003) • significant Qmax improvement in the total study population was mainly driven by effects in patients who voided 250–450 ml (p = 0.011) and had a baseline Qmax 10–15 ml/s (p = 0.044) |
a With valid measurement.
BPH = benign prostatic enlargement; ED = erectile dysfunction; IPSS = International Prostate Symptom Score; LUTS = lower urinary tract symptoms; PDE5 = phosphodiesterase type 5; QoL = quality of life.
Efficacy: In the first systematic review on PDE5-Is for LUTS secondary to BPH published in literature, Laydner et al [38]
In the first meta-regression analysis on PDE5-Is alone or in combination with α-blockers, Gacci et al [2]
In a subset analysis on tadalafil based on data extrapolated from a systematic review on all PDE5-Is, Gacci et al [42]
Safety: In the review from Liu et al [39]
The first meta-analysis of AEs due to PDE5-Is reported that flushing, gastro-esophageal reflux, headache, and dyspepsia had the higher risk of occurrence (odds ratio: 4.88; 2.21; 1.88; 1.85; respectively). Moreover, regarding the overall tolerability of the association between PDE5-Is and α-blockers, Gacci et al [42]
In a recent review on tadalafil once daily, the Authors underlined the good safety profile with a relative risk of AEs from tadalafil similar to those reported with vardenafil or sildenafil (2.27 vs 1.86 vs 1.22, respectively); overall, the occurrence of AEs reported was very similar to that reported with all PDE5-Is versus placebo: 16.0% versus 6.0% [42]
Clinically-meaningful symptom improvement: Clinically-meaningful LUTS improvement is defined as a decrease of ≥3 points or ≥25% reduction of total IPSS [45]
Similar post-hoc analyses were done in 1499 patients treated with tadalafil 5 mg once daily or placebo [47]
Nocturia: Nocturia, defined as one or more voids per night, is one of the most prevalent and bothersome single urinary symptoms in community-dwelling men or patients with LUTS/BPH and the main reason for physician consultations [48]
Tadalafil for men with or without ED: The majority of the randomized, placebo-controlled tadalafil trials included patients with ED (approximately 60–70% of trial participants). Pooled data analyses evaluated whether symptom improvement was related to baseline ED status or ED improvement during tadalafil treatment [50]
Other baseline characteristics: The impact of several patient characteristics was evaluated in 1500 pooled patients with LUTS/BPH with regard to symptom improvement and adverse events, including age (≤65 vs >65 yr), symptom severity (IPSS < 20 vs ≥ 20), testosterone concentration (<300 ng/dl vs ≥300 ng/dl), prostate-specific antigen-predicted prostate volume (<40 ml vs ≥40 ml), previous α-blockers use (yes vs no), previous PDE5 inhibitor use (yes vs no), arterial hypertension (yes vs no), diabetes mellitus (yes vs no), and cardiovascular disease (yes vs no) [52]
Finally, an integrated analysis on 1371 patients, demonstrated that tadalafil 5 mg once daily for 12 wk allowed to achieve a very small, but statistically significant increase in Qmax versus the placebo (median: 1.1 ml/s vs 0.4 ml/s) [55]
Tadalafil has been also proposed in combination with alpha blockers or 5-alpha reductase inhibitors. In a prospective randomized study on 133 men with LUTS/BPH treated with tamsulsoin plus tadalafil versus tamsulosin or tadalafil alone, combination therapy was more effective than monotherapy for ED (%IIEF change from baseline: 60.2 vs 39.3 and 46.0 respectively) with similar improvement for urinary symptoms (% IPSS change from baseline: 53.9 vs 50.9 and 33.5), with a good safety profile [56]
Regarding the impact of tadalafil on sexual activity of men with ED and LUTS due to BPH tadalafil, Giuliano et al [58]
There is a large body of scientific evidence supporting the role of the NO-cGMP pathway including PDE5I in: (1) regulation of the tone of the smooth muscle fibers of the prostate, urethra, and bladder neck and in a lesser extent of the bladder (relaxant effect), (2) control of the arterial supply of the LUT (vasodilatory effect), and (3) modulation of the micturition reflex via the afferent bladder innervation (decrease in the afferent signaling). PDE5-Is may also downregulate inflammatory processes in LUT and exert antiproliferative effects.
Several meta-analyses demonstrated that PDE5-Is are effective in improving LUTS and erectile function compared with placebo. The combination of PDE5-Is with α-blockers induce a small, but statistically significant improvement of maximum flow rate as compared with α-blockers alone, in addition to the positive effect on micturition and sexual activity. PDE5-Is alone or in combination with α-blockers are well tolerated: flushing, gastroesophageal reflux, headache, and dyspepsia are the most common treatment-associated AEs.
Tadalafil 5 mg once daily achieves an improvement of clinically-meaningful urinary symptoms and nocturnal voiding frequency compared with placebo. Furthermore, the effects on LUTS are independent of ED severity at baseline and ED improvement.
Data on the long-term effects prostate size, reduction of disease progression, or prostate cancer prevalence related to the use of PDE5-Is are not available; long-term outcomes and cost-effectiveness analyses are needed.
Author contributions: Mauro Gacci had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Gacci, Giuliano.
Acquisition of data: Gacci, Giuliano, Andersson, Maggi, Oelke.
Analysis and interpretation of data: Gacci, Andersson, Chapple, Maggi, Mirone, Oelke, Porst, Roehrborn, Stief, Giuliano.
Drafting of the manuscript: Gacci, Giuliano, Andersson, Maggi, Oelke.
Critical revision of the manuscript for important intellectual content: Chapple, Mirone, Porst, Roehrborn, Stief.
Statistical analysis: Gacci.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Giuliano.
Other: None.
Financial disclosures: Mauro Gacci certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Gacci: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Pierre Fabre; Andersson: Consultancy and Advisory Boards for Allergan, Astellas, Ferring; Chapple: Consultant, Researcher and Speaker for Allergan, Astellas, Medtronic and Recordati. Consultant and speaker for Lilly. Researcher and speaker for ONO and Pfizer. Speaker for Ranbaxy; Maggi: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Intercept, Menarini; Mirone: consultant, speaker, and/or trial participant for Eli Lilly Italia, Menarini, Zambon, Recordati, GSK, Bracco; Oelke: consultant, speaker, and/or trial participant for Bayer Healthcare, Eli Lilly and Company, and Pfizer; Porst: consultant, speaker for Eli Lilly and Compani, Menarini Group and Sanofi; CRoehrborn: has financial interests and/or other relationships with Eli Lilly and Company, and with Allergan, Afferent Pharmaceuticals, Auxiliary Medical Services, Cancer and Leukemia Group B Clinical Trial Group, GlaxoSmithKline, New England Research Institutes, NeoTract, National Institute of Diabetes and Digestive and Kidney Diseases, Protox, Southwest Oncology Group, Urologix, VA Corporate Studies, and Watson Pharmaceuticals. Giuliano: consultant for Lilly, Sanofi, Pfizer.
Funding/Support and role of the sponsor: None.
Lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE) and erectile dysfunction (ED) are both highly prevalent in elderly men [1]
The aim of this review is to provide an update on the current knowledge on the potential mechanisms of action of PDE5-Is on LUTS/BPE, critically analyze systematic reviews and relevant data from the current literature on the clinical use of all PDE5-Is, and report the latest evidence on pooled-data analyses of tadalafil once daily to provide a definite rationale for the clinical use of tadalafil for the treatment of LUTS/BPE.
The pathways mediating the activity of PDE5-Is: LUTS have a multifactorial pathophysiology and have been discussed extensively [7]
The role of the bladder in male LUTS has been emphasized [9]
In the pathophysiology of LUTS, the NO/cyclic guanosine monophosphate (cGMP) (NO/cGMP) signaling pathway is believed to play a central role. Since NO signaling occurs via stimulation of soluble guanylate cyclase producing cGMP, it is reasonable to assume that the level of cGMP in different LUT tissues can influence their ability to generate LUTS. One way of modulating cGMP levels is to selectively inhibit cGMP degradation, and it is generally believed that all effects of PDE5Is are mediated by selective inhibition of the degradation of cyclic GMP.
Mechanism of action of PDE5-Is: In several animal species, including humans, the entire LUT expresses PDE5, with a relatively higher abundance within the bladder [16]
Although it is well established that PDE5 is expressed and biologically active in LUT, its functional role is still a matter of debate. Clinical studies demonstrated that its inhibition, through all the aforementioned PDE5-Is, resulted in amelioration of LUTS. Several mechanisms of action of PDE5-Is in LUTS have been hypothesized.
Immunohistochemical studies indicate that PDE5 is localized in the endothelial and smooth muscle cells of the LUT blood vessels [17]
Several in vitro studies have demonstrated that PDE5-Is can relax isolated prostate and bladder neck strips [27]
In the human prostate [17]
The NO/cGMP signaling pathway is likely to have a significant role in the innervation of the LUT. In human, neuronal NO synthase and guanylate cyclase are expressed in the uroepithelium, in neural fibers of the bladder neck and prostatic urethra, and in afferent nerves and interstitial cells, respectively [35]
Emerging evidences indicate that metabolic derangements, clustered in the metabolic syndrome (MetS) construct, may have a role in BPH pathophysiology. Within MetS, visceral obesity and dyslipidemia are the major predictors of an enlarged prostate size [3]
A systematic literature search in PubMed and Scopus was performed until May 2015, to identify systematic reviews of randomized controlled trial (RCTs), including the following MeSH terms: phosphodiesterase type 5 inhibitor and tadalafil PLUS urinary symptoms OR lower urinary tract symptoms OR benign prostatic hyperplasia OR prostate. We included only systematic reviews of RCTs comparing PDE5-Is treatment with different oral therapies or placebos for LUTS/BPH, while we excluded reviews of RTCs without PDE5-Is, nonclinical trials with PDE5-Is, or nonsystematic review. A total of eight papers were analyzed (Fig. 1; Table 1).
Table 1 Characteristics of the studies included in the review
a Significant improvement versus placebo.
b PDE5-Is + ABs versus ABs alone.
c Significant improvement versus ABs alone.
d PDE5-Is nonspecified.
* p = 0.04 for Tadalafil 5 mg.
ABs = alpha-blockers; BPH = benign prostatic hyperplasia; diff. = difference; ED = erectile dysfunction; IIEF = International Index Of Erectile Function; IPSS = International Prostatic Symptom Score; MRAs = muscarinic receptor antagonists; O = other PDE5-Is; PDE5-Is = phosphodiesterase 5 inhibitors; PLA = placebo; P.ts = patients; Qmax = maximum flow rate at uroflowmetry; S = sildenafil; T = tadalafil;. V = vardenafil; 5ARIs = 5a-reductase inhibitors.
Moreover, we selected more clinically relevant data from current literature on the clinical use of all PDE5-Is, including all post-hoc pooled data analyses (Table 2), with a nonsystematic approach (studies published only as abstract or presented without abstract and reports from meetings and studies not published in English were not considered for this review).
Table 2 Summary of posthoc pooled-data analyses of patients treated with tadalafil 5 mg once daily versus placebo for lower urinary tract symptoms/benign prostatic enlargement
Publication | No. of patients (n) |
Follow up (wk) |
Main findings | |
---|---|---|---|---|
Tadalafil | Placebo | |||
Oelke et al., 2015 [47] J.C. Nickel, G.B. Brock, S. Herschorn, R. Dickson, C. Henneges, L. Viktrup. Proportion of tadalafil-treated patients with clinically meaningful improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia. BJU Int. 2015;115:815-821 Crossref |
742 | 735 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from baseline to endpoint in significantly more patients with tadalafil (69.1%) vs placebo (54.8%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from baseline to endpoint in significantly more patients with tadalafil (59.8%) vs placebo (43.7%; p < 0.001) • 59.8% (50.2%) and 79.3% (72.5%) of the responders had ≥3 (≥25%) IPSS point improvement already after wk 1 and wk 4, respectively |
Nickel et al., 2015 [48] M. Oelke, B. Wiese, R. Berges. Nocturia and its impact on health related quality of life and health care seeking behavior in German community-dwelling men aged 50 years or older. World J Urol. 2014;32:1155-1162 Crossref |
752 | 747 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from randomization to endpoint in significantly more patients with tadalafil (71.1%) vs placebo (56.0%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from randomization to endpoint in significantly more patients with tadalafil (61.7%) vs placebo (45.5%; p < 0.001) • 38.5% (22.4%) of patients with tadalafil and 41.0% (23.3%) of patients with placebo had ≥3 (≥25%) IPSS point improvement during the placebo run-in phase |
Oelke et al., 2014 [50] H. Porst, C.G. Roehrborn, R.J. Secrest, A. Esler, L. Viktrup. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia and on erectile dysfunction in sexually active men with both conditions: analyses of pooled data from four randomized, placebo-controlled tadalafil clinical studies. J Sex Med. 2013;10:2044-2052 Crossref |
752 | 748 | 12 | Effects of tadalafil on nocturia (nocturnal voiding frequency): • for men with ≥1 nocturia episode at baseline, reduction with tadalafil (–0.5) was significantly greater than with placebo at study end (–0.4; LS mean change –0.2, p = 0.002) • for men with ≥2 nocturia episodes at baseline, reduction with tadalafil (–0.8) was significantly greater than with placebo at study end (–0.6; LS mean change –0.2, p = 0.003) • tadalafil (placebo) treatment resulted in reduction of ≥1 nocturia episodes in 47.5% (41.3%) of patients |
Porst et al., 2013 [51] G.B. Brock, K.T. McVary, C.G. Roehrborn, et al. Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: integrated data analyses from 4 placebo controlled clinical studies. J Urol. 2014;191:405-411 Crossref |
505 | 521 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • analysis only of men who were sexually active at baseline • significant improvement of total IPSS with tadalafil (–6.0) vs placebo (–3.6; p < 0.001) from baseline to study end • significant improvement of IIEF-EF with tadalafil (+6.4) vs placebo (+1.4, p < 0.001) from baseline to study end • similar IPSS improvements in men with ED vs without ED: no significant impact of ED severity on LUTS (IPSS) outcome |
Brock et al., 2014 [52] H. Porst, M. Oelke, E.R. Goldfischer, et al. Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational, randomized, placebo-controlled clinical studies. Urology. 2013;82:667-673 Crossref |
752 | 744 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • similar LUTS (IPSS) improvement with tadalafil vs placebo in men without ED (–5.4 vs –2.2, p = 0.0007) compared with men with ED (–5.9 vs –2.3, p < 0.0001); ED subgroup interaction not significant • bidirectional path analysis for sexually-active men (n = 1250) only: 92.5% of the total effects of tadalafil on LUTS/BPH via direct effect on LUTS and 7.5% via indirect effects by IIEF-EF domain improvement |
Porst et al., 2013 [53] O. Nishizawa, M. Yoshida, M. Takeda, et al. Tadalafil 5 mg once daily for the treatment of Asian men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: analyses of data pooled from three randomized, double-blind, placebo-controlled studies. Int J Urol. 2015;22:378-384 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in different patient subgroups: • improvements in IPSS and BPH-Impact Index in all patient subgroups identical (investigated patient parameters: age, symptom severity, serum testosterone concentration, prostate volume, previous α–blocker or PDE5-inhibitor use, arterial hypertension, diabetes mellitus, cardio-vascular diseases) • no baseline item was identified to predict a favorable or unfavorable treatment outcome |
Nishizawa et al., 2015 [54] C. Vlachopoulos, M. Oelke, M. Maggi, et al. Impact of cardiovascular risk factors and related comorbid conditions on the treatment response to tadalafil once-daily in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: an integrated analysis of four randomized, double-blind, placebo-controlled clinical trials. Int J Clin Pract. 2015;69:1496-1507 |
601 | 598 | 12 | Effects of tadalafil on LUTS/BPH in different subgroups of Asian patients: • analysis of Japanese, Korean, or Taiwanese men • significant improvements in total IPSS (tadalafil vs placebo) at wk 4 (–3.69 vs –2.47), wk 8 (–4.72 vs –3.43), and wk 12 (–5.32 vs –3.79), each p < 0.001 • additionally, significant improvements at wk 4, wk 8, and wk 12 for IPSS storage and IPSS voiding subscores as well as for IPSS-QoL • older patients (≥65 yr) showed significantly lower IPSS improvement than younger patients (<65 yr); otherwise, no significant impact of any other baseline item on LUTS improvement |
Vlachopoulos et al., 2015 [55] C.G. Roehrborn, C. Chapple, M. Oelke, D. Cox, A. Esler, L. Viktrup. Effects of tadalafil once-daily on maximum urinary flow rate in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. J Urol. 2014;191:1045-1050 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in patients with cardio-vascular risk factors and therapy: • subanalysis of comorbid, cardio-vascular diseases on LUTS/BPH outcome • no significant differences in efficacy of tadalafil vs placebo for various cardio-vascular diseases/comorbidities • but patients with >1 antihypertensive drugs have significantly lower IPSS improvement compared with men taking ≤1 drug • use of diuretics resulted in significantly lower IPSS improvement compared to men taking other antihypertensives or no drugs |
Roehrborn et al., 2014 [56] D.V. Singh, U.K. Mete, A.K. Mandal, S.K. Singh. 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;11:187-196 Crossref |
752 (612a) |
748 (585a) |
12 | Effects of tadalafil on uroflow (maximum urinary flow rate): • in total study population, patients with tadalafil had significantly greater Qmax improvement (mean +1.1 ml/s) compared with patients with placebo (mean +0.4 ml/s; p = 0.003) • significant Qmax improvement in the total study population was mainly driven by effects in patients who voided 250–450 ml (p = 0.011) and had a baseline Qmax 10–15 ml/s (p = 0.044) |
a With valid measurement.
BPH = benign prostatic enlargement; ED = erectile dysfunction; IPSS = International Prostate Symptom Score; LUTS = lower urinary tract symptoms; PDE5 = phosphodiesterase type 5; QoL = quality of life.
Efficacy: In the first systematic review on PDE5-Is for LUTS secondary to BPH published in literature, Laydner et al [38]
In the first meta-regression analysis on PDE5-Is alone or in combination with α-blockers, Gacci et al [2]
In a subset analysis on tadalafil based on data extrapolated from a systematic review on all PDE5-Is, Gacci et al [42]
Safety: In the review from Liu et al [39]
The first meta-analysis of AEs due to PDE5-Is reported that flushing, gastro-esophageal reflux, headache, and dyspepsia had the higher risk of occurrence (odds ratio: 4.88; 2.21; 1.88; 1.85; respectively). Moreover, regarding the overall tolerability of the association between PDE5-Is and α-blockers, Gacci et al [42]
In a recent review on tadalafil once daily, the Authors underlined the good safety profile with a relative risk of AEs from tadalafil similar to those reported with vardenafil or sildenafil (2.27 vs 1.86 vs 1.22, respectively); overall, the occurrence of AEs reported was very similar to that reported with all PDE5-Is versus placebo: 16.0% versus 6.0% [42]
Clinically-meaningful symptom improvement: Clinically-meaningful LUTS improvement is defined as a decrease of ≥3 points or ≥25% reduction of total IPSS [45]
Similar post-hoc analyses were done in 1499 patients treated with tadalafil 5 mg once daily or placebo [47]
Nocturia: Nocturia, defined as one or more voids per night, is one of the most prevalent and bothersome single urinary symptoms in community-dwelling men or patients with LUTS/BPH and the main reason for physician consultations [48]
Tadalafil for men with or without ED: The majority of the randomized, placebo-controlled tadalafil trials included patients with ED (approximately 60–70% of trial participants). Pooled data analyses evaluated whether symptom improvement was related to baseline ED status or ED improvement during tadalafil treatment [50]
Other baseline characteristics: The impact of several patient characteristics was evaluated in 1500 pooled patients with LUTS/BPH with regard to symptom improvement and adverse events, including age (≤65 vs >65 yr), symptom severity (IPSS < 20 vs ≥ 20), testosterone concentration (<300 ng/dl vs ≥300 ng/dl), prostate-specific antigen-predicted prostate volume (<40 ml vs ≥40 ml), previous α-blockers use (yes vs no), previous PDE5 inhibitor use (yes vs no), arterial hypertension (yes vs no), diabetes mellitus (yes vs no), and cardiovascular disease (yes vs no) [52]
Finally, an integrated analysis on 1371 patients, demonstrated that tadalafil 5 mg once daily for 12 wk allowed to achieve a very small, but statistically significant increase in Qmax versus the placebo (median: 1.1 ml/s vs 0.4 ml/s) [55]
Tadalafil has been also proposed in combination with alpha blockers or 5-alpha reductase inhibitors. In a prospective randomized study on 133 men with LUTS/BPH treated with tamsulsoin plus tadalafil versus tamsulosin or tadalafil alone, combination therapy was more effective than monotherapy for ED (%IIEF change from baseline: 60.2 vs 39.3 and 46.0 respectively) with similar improvement for urinary symptoms (% IPSS change from baseline: 53.9 vs 50.9 and 33.5), with a good safety profile [56]
Regarding the impact of tadalafil on sexual activity of men with ED and LUTS due to BPH tadalafil, Giuliano et al [58]
There is a large body of scientific evidence supporting the role of the NO-cGMP pathway including PDE5I in: (1) regulation of the tone of the smooth muscle fibers of the prostate, urethra, and bladder neck and in a lesser extent of the bladder (relaxant effect), (2) control of the arterial supply of the LUT (vasodilatory effect), and (3) modulation of the micturition reflex via the afferent bladder innervation (decrease in the afferent signaling). PDE5-Is may also downregulate inflammatory processes in LUT and exert antiproliferative effects.
Several meta-analyses demonstrated that PDE5-Is are effective in improving LUTS and erectile function compared with placebo. The combination of PDE5-Is with α-blockers induce a small, but statistically significant improvement of maximum flow rate as compared with α-blockers alone, in addition to the positive effect on micturition and sexual activity. PDE5-Is alone or in combination with α-blockers are well tolerated: flushing, gastroesophageal reflux, headache, and dyspepsia are the most common treatment-associated AEs.
Tadalafil 5 mg once daily achieves an improvement of clinically-meaningful urinary symptoms and nocturnal voiding frequency compared with placebo. Furthermore, the effects on LUTS are independent of ED severity at baseline and ED improvement.
Data on the long-term effects prostate size, reduction of disease progression, or prostate cancer prevalence related to the use of PDE5-Is are not available; long-term outcomes and cost-effectiveness analyses are needed.
Author contributions: Mauro Gacci had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Gacci, Giuliano.
Acquisition of data: Gacci, Giuliano, Andersson, Maggi, Oelke.
Analysis and interpretation of data: Gacci, Andersson, Chapple, Maggi, Mirone, Oelke, Porst, Roehrborn, Stief, Giuliano.
Drafting of the manuscript: Gacci, Giuliano, Andersson, Maggi, Oelke.
Critical revision of the manuscript for important intellectual content: Chapple, Mirone, Porst, Roehrborn, Stief.
Statistical analysis: Gacci.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Giuliano.
Other: None.
Financial disclosures: Mauro Gacci certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Gacci: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Pierre Fabre; Andersson: Consultancy and Advisory Boards for Allergan, Astellas, Ferring; Chapple: Consultant, Researcher and Speaker for Allergan, Astellas, Medtronic and Recordati. Consultant and speaker for Lilly. Researcher and speaker for ONO and Pfizer. Speaker for Ranbaxy; Maggi: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Intercept, Menarini; Mirone: consultant, speaker, and/or trial participant for Eli Lilly Italia, Menarini, Zambon, Recordati, GSK, Bracco; Oelke: consultant, speaker, and/or trial participant for Bayer Healthcare, Eli Lilly and Company, and Pfizer; Porst: consultant, speaker for Eli Lilly and Compani, Menarini Group and Sanofi; CRoehrborn: has financial interests and/or other relationships with Eli Lilly and Company, and with Allergan, Afferent Pharmaceuticals, Auxiliary Medical Services, Cancer and Leukemia Group B Clinical Trial Group, GlaxoSmithKline, New England Research Institutes, NeoTract, National Institute of Diabetes and Digestive and Kidney Diseases, Protox, Southwest Oncology Group, Urologix, VA Corporate Studies, and Watson Pharmaceuticals. Giuliano: consultant for Lilly, Sanofi, Pfizer.
Funding/Support and role of the sponsor: None.
Lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE) and erectile dysfunction (ED) are both highly prevalent in elderly men [1]
The aim of this review is to provide an update on the current knowledge on the potential mechanisms of action of PDE5-Is on LUTS/BPE, critically analyze systematic reviews and relevant data from the current literature on the clinical use of all PDE5-Is, and report the latest evidence on pooled-data analyses of tadalafil once daily to provide a definite rationale for the clinical use of tadalafil for the treatment of LUTS/BPE.
The pathways mediating the activity of PDE5-Is: LUTS have a multifactorial pathophysiology and have been discussed extensively [7]
The role of the bladder in male LUTS has been emphasized [9]
In the pathophysiology of LUTS, the NO/cyclic guanosine monophosphate (cGMP) (NO/cGMP) signaling pathway is believed to play a central role. Since NO signaling occurs via stimulation of soluble guanylate cyclase producing cGMP, it is reasonable to assume that the level of cGMP in different LUT tissues can influence their ability to generate LUTS. One way of modulating cGMP levels is to selectively inhibit cGMP degradation, and it is generally believed that all effects of PDE5Is are mediated by selective inhibition of the degradation of cyclic GMP.
Mechanism of action of PDE5-Is: In several animal species, including humans, the entire LUT expresses PDE5, with a relatively higher abundance within the bladder [16]
Although it is well established that PDE5 is expressed and biologically active in LUT, its functional role is still a matter of debate. Clinical studies demonstrated that its inhibition, through all the aforementioned PDE5-Is, resulted in amelioration of LUTS. Several mechanisms of action of PDE5-Is in LUTS have been hypothesized.
Immunohistochemical studies indicate that PDE5 is localized in the endothelial and smooth muscle cells of the LUT blood vessels [17]
Several in vitro studies have demonstrated that PDE5-Is can relax isolated prostate and bladder neck strips [27]
In the human prostate [17]
The NO/cGMP signaling pathway is likely to have a significant role in the innervation of the LUT. In human, neuronal NO synthase and guanylate cyclase are expressed in the uroepithelium, in neural fibers of the bladder neck and prostatic urethra, and in afferent nerves and interstitial cells, respectively [35]
Emerging evidences indicate that metabolic derangements, clustered in the metabolic syndrome (MetS) construct, may have a role in BPH pathophysiology. Within MetS, visceral obesity and dyslipidemia are the major predictors of an enlarged prostate size [3]
A systematic literature search in PubMed and Scopus was performed until May 2015, to identify systematic reviews of randomized controlled trial (RCTs), including the following MeSH terms: phosphodiesterase type 5 inhibitor and tadalafil PLUS urinary symptoms OR lower urinary tract symptoms OR benign prostatic hyperplasia OR prostate. We included only systematic reviews of RCTs comparing PDE5-Is treatment with different oral therapies or placebos for LUTS/BPH, while we excluded reviews of RTCs without PDE5-Is, nonclinical trials with PDE5-Is, or nonsystematic review. A total of eight papers were analyzed (Fig. 1; Table 1).
Table 1 Characteristics of the studies included in the review
a Significant improvement versus placebo.
b PDE5-Is + ABs versus ABs alone.
c Significant improvement versus ABs alone.
d PDE5-Is nonspecified.
* p = 0.04 for Tadalafil 5 mg.
ABs = alpha-blockers; BPH = benign prostatic hyperplasia; diff. = difference; ED = erectile dysfunction; IIEF = International Index Of Erectile Function; IPSS = International Prostatic Symptom Score; MRAs = muscarinic receptor antagonists; O = other PDE5-Is; PDE5-Is = phosphodiesterase 5 inhibitors; PLA = placebo; P.ts = patients; Qmax = maximum flow rate at uroflowmetry; S = sildenafil; T = tadalafil;. V = vardenafil; 5ARIs = 5a-reductase inhibitors.
Moreover, we selected more clinically relevant data from current literature on the clinical use of all PDE5-Is, including all post-hoc pooled data analyses (Table 2), with a nonsystematic approach (studies published only as abstract or presented without abstract and reports from meetings and studies not published in English were not considered for this review).
Table 2 Summary of posthoc pooled-data analyses of patients treated with tadalafil 5 mg once daily versus placebo for lower urinary tract symptoms/benign prostatic enlargement
Publication | No. of patients (n) |
Follow up (wk) |
Main findings | |
---|---|---|---|---|
Tadalafil | Placebo | |||
Oelke et al., 2015 [47] J.C. Nickel, G.B. Brock, S. Herschorn, R. Dickson, C. Henneges, L. Viktrup. Proportion of tadalafil-treated patients with clinically meaningful improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia. BJU Int. 2015;115:815-821 Crossref |
742 | 735 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from baseline to endpoint in significantly more patients with tadalafil (69.1%) vs placebo (54.8%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from baseline to endpoint in significantly more patients with tadalafil (59.8%) vs placebo (43.7%; p < 0.001) • 59.8% (50.2%) and 79.3% (72.5%) of the responders had ≥3 (≥25%) IPSS point improvement already after wk 1 and wk 4, respectively |
Nickel et al., 2015 [48] M. Oelke, B. Wiese, R. Berges. Nocturia and its impact on health related quality of life and health care seeking behavior in German community-dwelling men aged 50 years or older. World J Urol. 2014;32:1155-1162 Crossref |
752 | 747 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from randomization to endpoint in significantly more patients with tadalafil (71.1%) vs placebo (56.0%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from randomization to endpoint in significantly more patients with tadalafil (61.7%) vs placebo (45.5%; p < 0.001) • 38.5% (22.4%) of patients with tadalafil and 41.0% (23.3%) of patients with placebo had ≥3 (≥25%) IPSS point improvement during the placebo run-in phase |
Oelke et al., 2014 [50] H. Porst, C.G. Roehrborn, R.J. Secrest, A. Esler, L. Viktrup. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia and on erectile dysfunction in sexually active men with both conditions: analyses of pooled data from four randomized, placebo-controlled tadalafil clinical studies. J Sex Med. 2013;10:2044-2052 Crossref |
752 | 748 | 12 | Effects of tadalafil on nocturia (nocturnal voiding frequency): • for men with ≥1 nocturia episode at baseline, reduction with tadalafil (–0.5) was significantly greater than with placebo at study end (–0.4; LS mean change –0.2, p = 0.002) • for men with ≥2 nocturia episodes at baseline, reduction with tadalafil (–0.8) was significantly greater than with placebo at study end (–0.6; LS mean change –0.2, p = 0.003) • tadalafil (placebo) treatment resulted in reduction of ≥1 nocturia episodes in 47.5% (41.3%) of patients |
Porst et al., 2013 [51] G.B. Brock, K.T. McVary, C.G. Roehrborn, et al. Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: integrated data analyses from 4 placebo controlled clinical studies. J Urol. 2014;191:405-411 Crossref |
505 | 521 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • analysis only of men who were sexually active at baseline • significant improvement of total IPSS with tadalafil (–6.0) vs placebo (–3.6; p < 0.001) from baseline to study end • significant improvement of IIEF-EF with tadalafil (+6.4) vs placebo (+1.4, p < 0.001) from baseline to study end • similar IPSS improvements in men with ED vs without ED: no significant impact of ED severity on LUTS (IPSS) outcome |
Brock et al., 2014 [52] H. Porst, M. Oelke, E.R. Goldfischer, et al. Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational, randomized, placebo-controlled clinical studies. Urology. 2013;82:667-673 Crossref |
752 | 744 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • similar LUTS (IPSS) improvement with tadalafil vs placebo in men without ED (–5.4 vs –2.2, p = 0.0007) compared with men with ED (–5.9 vs –2.3, p < 0.0001); ED subgroup interaction not significant • bidirectional path analysis for sexually-active men (n = 1250) only: 92.5% of the total effects of tadalafil on LUTS/BPH via direct effect on LUTS and 7.5% via indirect effects by IIEF-EF domain improvement |
Porst et al., 2013 [53] O. Nishizawa, M. Yoshida, M. Takeda, et al. Tadalafil 5 mg once daily for the treatment of Asian men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: analyses of data pooled from three randomized, double-blind, placebo-controlled studies. Int J Urol. 2015;22:378-384 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in different patient subgroups: • improvements in IPSS and BPH-Impact Index in all patient subgroups identical (investigated patient parameters: age, symptom severity, serum testosterone concentration, prostate volume, previous α–blocker or PDE5-inhibitor use, arterial hypertension, diabetes mellitus, cardio-vascular diseases) • no baseline item was identified to predict a favorable or unfavorable treatment outcome |
Nishizawa et al., 2015 [54] C. Vlachopoulos, M. Oelke, M. Maggi, et al. Impact of cardiovascular risk factors and related comorbid conditions on the treatment response to tadalafil once-daily in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: an integrated analysis of four randomized, double-blind, placebo-controlled clinical trials. Int J Clin Pract. 2015;69:1496-1507 |
601 | 598 | 12 | Effects of tadalafil on LUTS/BPH in different subgroups of Asian patients: • analysis of Japanese, Korean, or Taiwanese men • significant improvements in total IPSS (tadalafil vs placebo) at wk 4 (–3.69 vs –2.47), wk 8 (–4.72 vs –3.43), and wk 12 (–5.32 vs –3.79), each p < 0.001 • additionally, significant improvements at wk 4, wk 8, and wk 12 for IPSS storage and IPSS voiding subscores as well as for IPSS-QoL • older patients (≥65 yr) showed significantly lower IPSS improvement than younger patients (<65 yr); otherwise, no significant impact of any other baseline item on LUTS improvement |
Vlachopoulos et al., 2015 [55] C.G. Roehrborn, C. Chapple, M. Oelke, D. Cox, A. Esler, L. Viktrup. Effects of tadalafil once-daily on maximum urinary flow rate in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. J Urol. 2014;191:1045-1050 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in patients with cardio-vascular risk factors and therapy: • subanalysis of comorbid, cardio-vascular diseases on LUTS/BPH outcome • no significant differences in efficacy of tadalafil vs placebo for various cardio-vascular diseases/comorbidities • but patients with >1 antihypertensive drugs have significantly lower IPSS improvement compared with men taking ≤1 drug • use of diuretics resulted in significantly lower IPSS improvement compared to men taking other antihypertensives or no drugs |
Roehrborn et al., 2014 [56] D.V. Singh, U.K. Mete, A.K. Mandal, S.K. Singh. 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;11:187-196 Crossref |
752 (612a) |
748 (585a) |
12 | Effects of tadalafil on uroflow (maximum urinary flow rate): • in total study population, patients with tadalafil had significantly greater Qmax improvement (mean +1.1 ml/s) compared with patients with placebo (mean +0.4 ml/s; p = 0.003) • significant Qmax improvement in the total study population was mainly driven by effects in patients who voided 250–450 ml (p = 0.011) and had a baseline Qmax 10–15 ml/s (p = 0.044) |
a With valid measurement.
BPH = benign prostatic enlargement; ED = erectile dysfunction; IPSS = International Prostate Symptom Score; LUTS = lower urinary tract symptoms; PDE5 = phosphodiesterase type 5; QoL = quality of life.
Efficacy: In the first systematic review on PDE5-Is for LUTS secondary to BPH published in literature, Laydner et al [38]
In the first meta-regression analysis on PDE5-Is alone or in combination with α-blockers, Gacci et al [2]
In a subset analysis on tadalafil based on data extrapolated from a systematic review on all PDE5-Is, Gacci et al [42]
Safety: In the review from Liu et al [39]
The first meta-analysis of AEs due to PDE5-Is reported that flushing, gastro-esophageal reflux, headache, and dyspepsia had the higher risk of occurrence (odds ratio: 4.88; 2.21; 1.88; 1.85; respectively). Moreover, regarding the overall tolerability of the association between PDE5-Is and α-blockers, Gacci et al [42]
In a recent review on tadalafil once daily, the Authors underlined the good safety profile with a relative risk of AEs from tadalafil similar to those reported with vardenafil or sildenafil (2.27 vs 1.86 vs 1.22, respectively); overall, the occurrence of AEs reported was very similar to that reported with all PDE5-Is versus placebo: 16.0% versus 6.0% [42]
Clinically-meaningful symptom improvement: Clinically-meaningful LUTS improvement is defined as a decrease of ≥3 points or ≥25% reduction of total IPSS [45]
Similar post-hoc analyses were done in 1499 patients treated with tadalafil 5 mg once daily or placebo [47]
Nocturia: Nocturia, defined as one or more voids per night, is one of the most prevalent and bothersome single urinary symptoms in community-dwelling men or patients with LUTS/BPH and the main reason for physician consultations [48]
Tadalafil for men with or without ED: The majority of the randomized, placebo-controlled tadalafil trials included patients with ED (approximately 60–70% of trial participants). Pooled data analyses evaluated whether symptom improvement was related to baseline ED status or ED improvement during tadalafil treatment [50]
Other baseline characteristics: The impact of several patient characteristics was evaluated in 1500 pooled patients with LUTS/BPH with regard to symptom improvement and adverse events, including age (≤65 vs >65 yr), symptom severity (IPSS < 20 vs ≥ 20), testosterone concentration (<300 ng/dl vs ≥300 ng/dl), prostate-specific antigen-predicted prostate volume (<40 ml vs ≥40 ml), previous α-blockers use (yes vs no), previous PDE5 inhibitor use (yes vs no), arterial hypertension (yes vs no), diabetes mellitus (yes vs no), and cardiovascular disease (yes vs no) [52]
Finally, an integrated analysis on 1371 patients, demonstrated that tadalafil 5 mg once daily for 12 wk allowed to achieve a very small, but statistically significant increase in Qmax versus the placebo (median: 1.1 ml/s vs 0.4 ml/s) [55]
Tadalafil has been also proposed in combination with alpha blockers or 5-alpha reductase inhibitors. In a prospective randomized study on 133 men with LUTS/BPH treated with tamsulsoin plus tadalafil versus tamsulosin or tadalafil alone, combination therapy was more effective than monotherapy for ED (%IIEF change from baseline: 60.2 vs 39.3 and 46.0 respectively) with similar improvement for urinary symptoms (% IPSS change from baseline: 53.9 vs 50.9 and 33.5), with a good safety profile [56]
Regarding the impact of tadalafil on sexual activity of men with ED and LUTS due to BPH tadalafil, Giuliano et al [58]
There is a large body of scientific evidence supporting the role of the NO-cGMP pathway including PDE5I in: (1) regulation of the tone of the smooth muscle fibers of the prostate, urethra, and bladder neck and in a lesser extent of the bladder (relaxant effect), (2) control of the arterial supply of the LUT (vasodilatory effect), and (3) modulation of the micturition reflex via the afferent bladder innervation (decrease in the afferent signaling). PDE5-Is may also downregulate inflammatory processes in LUT and exert antiproliferative effects.
Several meta-analyses demonstrated that PDE5-Is are effective in improving LUTS and erectile function compared with placebo. The combination of PDE5-Is with α-blockers induce a small, but statistically significant improvement of maximum flow rate as compared with α-blockers alone, in addition to the positive effect on micturition and sexual activity. PDE5-Is alone or in combination with α-blockers are well tolerated: flushing, gastroesophageal reflux, headache, and dyspepsia are the most common treatment-associated AEs.
Tadalafil 5 mg once daily achieves an improvement of clinically-meaningful urinary symptoms and nocturnal voiding frequency compared with placebo. Furthermore, the effects on LUTS are independent of ED severity at baseline and ED improvement.
Data on the long-term effects prostate size, reduction of disease progression, or prostate cancer prevalence related to the use of PDE5-Is are not available; long-term outcomes and cost-effectiveness analyses are needed.
Author contributions: Mauro Gacci had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Gacci, Giuliano.
Acquisition of data: Gacci, Giuliano, Andersson, Maggi, Oelke.
Analysis and interpretation of data: Gacci, Andersson, Chapple, Maggi, Mirone, Oelke, Porst, Roehrborn, Stief, Giuliano.
Drafting of the manuscript: Gacci, Giuliano, Andersson, Maggi, Oelke.
Critical revision of the manuscript for important intellectual content: Chapple, Mirone, Porst, Roehrborn, Stief.
Statistical analysis: Gacci.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Giuliano.
Other: None.
Financial disclosures: Mauro Gacci certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Gacci: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Pierre Fabre; Andersson: Consultancy and Advisory Boards for Allergan, Astellas, Ferring; Chapple: Consultant, Researcher and Speaker for Allergan, Astellas, Medtronic and Recordati. Consultant and speaker for Lilly. Researcher and speaker for ONO and Pfizer. Speaker for Ranbaxy; Maggi: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Intercept, Menarini; Mirone: consultant, speaker, and/or trial participant for Eli Lilly Italia, Menarini, Zambon, Recordati, GSK, Bracco; Oelke: consultant, speaker, and/or trial participant for Bayer Healthcare, Eli Lilly and Company, and Pfizer; Porst: consultant, speaker for Eli Lilly and Compani, Menarini Group and Sanofi; CRoehrborn: has financial interests and/or other relationships with Eli Lilly and Company, and with Allergan, Afferent Pharmaceuticals, Auxiliary Medical Services, Cancer and Leukemia Group B Clinical Trial Group, GlaxoSmithKline, New England Research Institutes, NeoTract, National Institute of Diabetes and Digestive and Kidney Diseases, Protox, Southwest Oncology Group, Urologix, VA Corporate Studies, and Watson Pharmaceuticals. Giuliano: consultant for Lilly, Sanofi, Pfizer.
Funding/Support and role of the sponsor: None.
Lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE) and erectile dysfunction (ED) are both highly prevalent in elderly men [1]
The aim of this review is to provide an update on the current knowledge on the potential mechanisms of action of PDE5-Is on LUTS/BPE, critically analyze systematic reviews and relevant data from the current literature on the clinical use of all PDE5-Is, and report the latest evidence on pooled-data analyses of tadalafil once daily to provide a definite rationale for the clinical use of tadalafil for the treatment of LUTS/BPE.
The pathways mediating the activity of PDE5-Is: LUTS have a multifactorial pathophysiology and have been discussed extensively [7]
The role of the bladder in male LUTS has been emphasized [9]
In the pathophysiology of LUTS, the NO/cyclic guanosine monophosphate (cGMP) (NO/cGMP) signaling pathway is believed to play a central role. Since NO signaling occurs via stimulation of soluble guanylate cyclase producing cGMP, it is reasonable to assume that the level of cGMP in different LUT tissues can influence their ability to generate LUTS. One way of modulating cGMP levels is to selectively inhibit cGMP degradation, and it is generally believed that all effects of PDE5Is are mediated by selective inhibition of the degradation of cyclic GMP.
Mechanism of action of PDE5-Is: In several animal species, including humans, the entire LUT expresses PDE5, with a relatively higher abundance within the bladder [16]
Although it is well established that PDE5 is expressed and biologically active in LUT, its functional role is still a matter of debate. Clinical studies demonstrated that its inhibition, through all the aforementioned PDE5-Is, resulted in amelioration of LUTS. Several mechanisms of action of PDE5-Is in LUTS have been hypothesized.
Immunohistochemical studies indicate that PDE5 is localized in the endothelial and smooth muscle cells of the LUT blood vessels [17]
Several in vitro studies have demonstrated that PDE5-Is can relax isolated prostate and bladder neck strips [27]
In the human prostate [17]
The NO/cGMP signaling pathway is likely to have a significant role in the innervation of the LUT. In human, neuronal NO synthase and guanylate cyclase are expressed in the uroepithelium, in neural fibers of the bladder neck and prostatic urethra, and in afferent nerves and interstitial cells, respectively [35]
Emerging evidences indicate that metabolic derangements, clustered in the metabolic syndrome (MetS) construct, may have a role in BPH pathophysiology. Within MetS, visceral obesity and dyslipidemia are the major predictors of an enlarged prostate size [3]
A systematic literature search in PubMed and Scopus was performed until May 2015, to identify systematic reviews of randomized controlled trial (RCTs), including the following MeSH terms: phosphodiesterase type 5 inhibitor and tadalafil PLUS urinary symptoms OR lower urinary tract symptoms OR benign prostatic hyperplasia OR prostate. We included only systematic reviews of RCTs comparing PDE5-Is treatment with different oral therapies or placebos for LUTS/BPH, while we excluded reviews of RTCs without PDE5-Is, nonclinical trials with PDE5-Is, or nonsystematic review. A total of eight papers were analyzed (Fig. 1; Table 1).
Table 1 Characteristics of the studies included in the review
a Significant improvement versus placebo.
b PDE5-Is + ABs versus ABs alone.
c Significant improvement versus ABs alone.
d PDE5-Is nonspecified.
* p = 0.04 for Tadalafil 5 mg.
ABs = alpha-blockers; BPH = benign prostatic hyperplasia; diff. = difference; ED = erectile dysfunction; IIEF = International Index Of Erectile Function; IPSS = International Prostatic Symptom Score; MRAs = muscarinic receptor antagonists; O = other PDE5-Is; PDE5-Is = phosphodiesterase 5 inhibitors; PLA = placebo; P.ts = patients; Qmax = maximum flow rate at uroflowmetry; S = sildenafil; T = tadalafil;. V = vardenafil; 5ARIs = 5a-reductase inhibitors.
Moreover, we selected more clinically relevant data from current literature on the clinical use of all PDE5-Is, including all post-hoc pooled data analyses (Table 2), with a nonsystematic approach (studies published only as abstract or presented without abstract and reports from meetings and studies not published in English were not considered for this review).
Table 2 Summary of posthoc pooled-data analyses of patients treated with tadalafil 5 mg once daily versus placebo for lower urinary tract symptoms/benign prostatic enlargement
Publication | No. of patients (n) |
Follow up (wk) |
Main findings | |
---|---|---|---|---|
Tadalafil | Placebo | |||
Oelke et al., 2015 [47] J.C. Nickel, G.B. Brock, S. Herschorn, R. Dickson, C. Henneges, L. Viktrup. Proportion of tadalafil-treated patients with clinically meaningful improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia. BJU Int. 2015;115:815-821 Crossref |
742 | 735 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from baseline to endpoint in significantly more patients with tadalafil (69.1%) vs placebo (54.8%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from baseline to endpoint in significantly more patients with tadalafil (59.8%) vs placebo (43.7%; p < 0.001) • 59.8% (50.2%) and 79.3% (72.5%) of the responders had ≥3 (≥25%) IPSS point improvement already after wk 1 and wk 4, respectively |
Nickel et al., 2015 [48] M. Oelke, B. Wiese, R. Berges. Nocturia and its impact on health related quality of life and health care seeking behavior in German community-dwelling men aged 50 years or older. World J Urol. 2014;32:1155-1162 Crossref |
752 | 747 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from randomization to endpoint in significantly more patients with tadalafil (71.1%) vs placebo (56.0%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from randomization to endpoint in significantly more patients with tadalafil (61.7%) vs placebo (45.5%; p < 0.001) • 38.5% (22.4%) of patients with tadalafil and 41.0% (23.3%) of patients with placebo had ≥3 (≥25%) IPSS point improvement during the placebo run-in phase |
Oelke et al., 2014 [50] H. Porst, C.G. Roehrborn, R.J. Secrest, A. Esler, L. Viktrup. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia and on erectile dysfunction in sexually active men with both conditions: analyses of pooled data from four randomized, placebo-controlled tadalafil clinical studies. J Sex Med. 2013;10:2044-2052 Crossref |
752 | 748 | 12 | Effects of tadalafil on nocturia (nocturnal voiding frequency): • for men with ≥1 nocturia episode at baseline, reduction with tadalafil (–0.5) was significantly greater than with placebo at study end (–0.4; LS mean change –0.2, p = 0.002) • for men with ≥2 nocturia episodes at baseline, reduction with tadalafil (–0.8) was significantly greater than with placebo at study end (–0.6; LS mean change –0.2, p = 0.003) • tadalafil (placebo) treatment resulted in reduction of ≥1 nocturia episodes in 47.5% (41.3%) of patients |
Porst et al., 2013 [51] G.B. Brock, K.T. McVary, C.G. Roehrborn, et al. Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: integrated data analyses from 4 placebo controlled clinical studies. J Urol. 2014;191:405-411 Crossref |
505 | 521 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • analysis only of men who were sexually active at baseline • significant improvement of total IPSS with tadalafil (–6.0) vs placebo (–3.6; p < 0.001) from baseline to study end • significant improvement of IIEF-EF with tadalafil (+6.4) vs placebo (+1.4, p < 0.001) from baseline to study end • similar IPSS improvements in men with ED vs without ED: no significant impact of ED severity on LUTS (IPSS) outcome |
Brock et al., 2014 [52] H. Porst, M. Oelke, E.R. Goldfischer, et al. Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational, randomized, placebo-controlled clinical studies. Urology. 2013;82:667-673 Crossref |
752 | 744 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • similar LUTS (IPSS) improvement with tadalafil vs placebo in men without ED (–5.4 vs –2.2, p = 0.0007) compared with men with ED (–5.9 vs –2.3, p < 0.0001); ED subgroup interaction not significant • bidirectional path analysis for sexually-active men (n = 1250) only: 92.5% of the total effects of tadalafil on LUTS/BPH via direct effect on LUTS and 7.5% via indirect effects by IIEF-EF domain improvement |
Porst et al., 2013 [53] O. Nishizawa, M. Yoshida, M. Takeda, et al. Tadalafil 5 mg once daily for the treatment of Asian men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: analyses of data pooled from three randomized, double-blind, placebo-controlled studies. Int J Urol. 2015;22:378-384 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in different patient subgroups: • improvements in IPSS and BPH-Impact Index in all patient subgroups identical (investigated patient parameters: age, symptom severity, serum testosterone concentration, prostate volume, previous α–blocker or PDE5-inhibitor use, arterial hypertension, diabetes mellitus, cardio-vascular diseases) • no baseline item was identified to predict a favorable or unfavorable treatment outcome |
Nishizawa et al., 2015 [54] C. Vlachopoulos, M. Oelke, M. Maggi, et al. Impact of cardiovascular risk factors and related comorbid conditions on the treatment response to tadalafil once-daily in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: an integrated analysis of four randomized, double-blind, placebo-controlled clinical trials. Int J Clin Pract. 2015;69:1496-1507 |
601 | 598 | 12 | Effects of tadalafil on LUTS/BPH in different subgroups of Asian patients: • analysis of Japanese, Korean, or Taiwanese men • significant improvements in total IPSS (tadalafil vs placebo) at wk 4 (–3.69 vs –2.47), wk 8 (–4.72 vs –3.43), and wk 12 (–5.32 vs –3.79), each p < 0.001 • additionally, significant improvements at wk 4, wk 8, and wk 12 for IPSS storage and IPSS voiding subscores as well as for IPSS-QoL • older patients (≥65 yr) showed significantly lower IPSS improvement than younger patients (<65 yr); otherwise, no significant impact of any other baseline item on LUTS improvement |
Vlachopoulos et al., 2015 [55] C.G. Roehrborn, C. Chapple, M. Oelke, D. Cox, A. Esler, L. Viktrup. Effects of tadalafil once-daily on maximum urinary flow rate in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. J Urol. 2014;191:1045-1050 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in patients with cardio-vascular risk factors and therapy: • subanalysis of comorbid, cardio-vascular diseases on LUTS/BPH outcome • no significant differences in efficacy of tadalafil vs placebo for various cardio-vascular diseases/comorbidities • but patients with >1 antihypertensive drugs have significantly lower IPSS improvement compared with men taking ≤1 drug • use of diuretics resulted in significantly lower IPSS improvement compared to men taking other antihypertensives or no drugs |
Roehrborn et al., 2014 [56] D.V. Singh, U.K. Mete, A.K. Mandal, S.K. Singh. 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;11:187-196 Crossref |
752 (612a) |
748 (585a) |
12 | Effects of tadalafil on uroflow (maximum urinary flow rate): • in total study population, patients with tadalafil had significantly greater Qmax improvement (mean +1.1 ml/s) compared with patients with placebo (mean +0.4 ml/s; p = 0.003) • significant Qmax improvement in the total study population was mainly driven by effects in patients who voided 250–450 ml (p = 0.011) and had a baseline Qmax 10–15 ml/s (p = 0.044) |
a With valid measurement.
BPH = benign prostatic enlargement; ED = erectile dysfunction; IPSS = International Prostate Symptom Score; LUTS = lower urinary tract symptoms; PDE5 = phosphodiesterase type 5; QoL = quality of life.
Efficacy: In the first systematic review on PDE5-Is for LUTS secondary to BPH published in literature, Laydner et al [38]
In the first meta-regression analysis on PDE5-Is alone or in combination with α-blockers, Gacci et al [2]
In a subset analysis on tadalafil based on data extrapolated from a systematic review on all PDE5-Is, Gacci et al [42]
Safety: In the review from Liu et al [39]
The first meta-analysis of AEs due to PDE5-Is reported that flushing, gastro-esophageal reflux, headache, and dyspepsia had the higher risk of occurrence (odds ratio: 4.88; 2.21; 1.88; 1.85; respectively). Moreover, regarding the overall tolerability of the association between PDE5-Is and α-blockers, Gacci et al [42]
In a recent review on tadalafil once daily, the Authors underlined the good safety profile with a relative risk of AEs from tadalafil similar to those reported with vardenafil or sildenafil (2.27 vs 1.86 vs 1.22, respectively); overall, the occurrence of AEs reported was very similar to that reported with all PDE5-Is versus placebo: 16.0% versus 6.0% [42]
Clinically-meaningful symptom improvement: Clinically-meaningful LUTS improvement is defined as a decrease of ≥3 points or ≥25% reduction of total IPSS [45]
Similar post-hoc analyses were done in 1499 patients treated with tadalafil 5 mg once daily or placebo [47]
Nocturia: Nocturia, defined as one or more voids per night, is one of the most prevalent and bothersome single urinary symptoms in community-dwelling men or patients with LUTS/BPH and the main reason for physician consultations [48]
Tadalafil for men with or without ED: The majority of the randomized, placebo-controlled tadalafil trials included patients with ED (approximately 60–70% of trial participants). Pooled data analyses evaluated whether symptom improvement was related to baseline ED status or ED improvement during tadalafil treatment [50]
Other baseline characteristics: The impact of several patient characteristics was evaluated in 1500 pooled patients with LUTS/BPH with regard to symptom improvement and adverse events, including age (≤65 vs >65 yr), symptom severity (IPSS < 20 vs ≥ 20), testosterone concentration (<300 ng/dl vs ≥300 ng/dl), prostate-specific antigen-predicted prostate volume (<40 ml vs ≥40 ml), previous α-blockers use (yes vs no), previous PDE5 inhibitor use (yes vs no), arterial hypertension (yes vs no), diabetes mellitus (yes vs no), and cardiovascular disease (yes vs no) [52]
Finally, an integrated analysis on 1371 patients, demonstrated that tadalafil 5 mg once daily for 12 wk allowed to achieve a very small, but statistically significant increase in Qmax versus the placebo (median: 1.1 ml/s vs 0.4 ml/s) [55]
Tadalafil has been also proposed in combination with alpha blockers or 5-alpha reductase inhibitors. In a prospective randomized study on 133 men with LUTS/BPH treated with tamsulsoin plus tadalafil versus tamsulosin or tadalafil alone, combination therapy was more effective than monotherapy for ED (%IIEF change from baseline: 60.2 vs 39.3 and 46.0 respectively) with similar improvement for urinary symptoms (% IPSS change from baseline: 53.9 vs 50.9 and 33.5), with a good safety profile [56]
Regarding the impact of tadalafil on sexual activity of men with ED and LUTS due to BPH tadalafil, Giuliano et al [58]
There is a large body of scientific evidence supporting the role of the NO-cGMP pathway including PDE5I in: (1) regulation of the tone of the smooth muscle fibers of the prostate, urethra, and bladder neck and in a lesser extent of the bladder (relaxant effect), (2) control of the arterial supply of the LUT (vasodilatory effect), and (3) modulation of the micturition reflex via the afferent bladder innervation (decrease in the afferent signaling). PDE5-Is may also downregulate inflammatory processes in LUT and exert antiproliferative effects.
Several meta-analyses demonstrated that PDE5-Is are effective in improving LUTS and erectile function compared with placebo. The combination of PDE5-Is with α-blockers induce a small, but statistically significant improvement of maximum flow rate as compared with α-blockers alone, in addition to the positive effect on micturition and sexual activity. PDE5-Is alone or in combination with α-blockers are well tolerated: flushing, gastroesophageal reflux, headache, and dyspepsia are the most common treatment-associated AEs.
Tadalafil 5 mg once daily achieves an improvement of clinically-meaningful urinary symptoms and nocturnal voiding frequency compared with placebo. Furthermore, the effects on LUTS are independent of ED severity at baseline and ED improvement.
Data on the long-term effects prostate size, reduction of disease progression, or prostate cancer prevalence related to the use of PDE5-Is are not available; long-term outcomes and cost-effectiveness analyses are needed.
Author contributions: Mauro Gacci had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Gacci, Giuliano.
Acquisition of data: Gacci, Giuliano, Andersson, Maggi, Oelke.
Analysis and interpretation of data: Gacci, Andersson, Chapple, Maggi, Mirone, Oelke, Porst, Roehrborn, Stief, Giuliano.
Drafting of the manuscript: Gacci, Giuliano, Andersson, Maggi, Oelke.
Critical revision of the manuscript for important intellectual content: Chapple, Mirone, Porst, Roehrborn, Stief.
Statistical analysis: Gacci.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Giuliano.
Other: None.
Financial disclosures: Mauro Gacci certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Gacci: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Pierre Fabre; Andersson: Consultancy and Advisory Boards for Allergan, Astellas, Ferring; Chapple: Consultant, Researcher and Speaker for Allergan, Astellas, Medtronic and Recordati. Consultant and speaker for Lilly. Researcher and speaker for ONO and Pfizer. Speaker for Ranbaxy; Maggi: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Intercept, Menarini; Mirone: consultant, speaker, and/or trial participant for Eli Lilly Italia, Menarini, Zambon, Recordati, GSK, Bracco; Oelke: consultant, speaker, and/or trial participant for Bayer Healthcare, Eli Lilly and Company, and Pfizer; Porst: consultant, speaker for Eli Lilly and Compani, Menarini Group and Sanofi; CRoehrborn: has financial interests and/or other relationships with Eli Lilly and Company, and with Allergan, Afferent Pharmaceuticals, Auxiliary Medical Services, Cancer and Leukemia Group B Clinical Trial Group, GlaxoSmithKline, New England Research Institutes, NeoTract, National Institute of Diabetes and Digestive and Kidney Diseases, Protox, Southwest Oncology Group, Urologix, VA Corporate Studies, and Watson Pharmaceuticals. Giuliano: consultant for Lilly, Sanofi, Pfizer.
Funding/Support and role of the sponsor: None.
Lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE) and erectile dysfunction (ED) are both highly prevalent in elderly men [1]
The aim of this review is to provide an update on the current knowledge on the potential mechanisms of action of PDE5-Is on LUTS/BPE, critically analyze systematic reviews and relevant data from the current literature on the clinical use of all PDE5-Is, and report the latest evidence on pooled-data analyses of tadalafil once daily to provide a definite rationale for the clinical use of tadalafil for the treatment of LUTS/BPE.
The pathways mediating the activity of PDE5-Is: LUTS have a multifactorial pathophysiology and have been discussed extensively [7]
The role of the bladder in male LUTS has been emphasized [9]
In the pathophysiology of LUTS, the NO/cyclic guanosine monophosphate (cGMP) (NO/cGMP) signaling pathway is believed to play a central role. Since NO signaling occurs via stimulation of soluble guanylate cyclase producing cGMP, it is reasonable to assume that the level of cGMP in different LUT tissues can influence their ability to generate LUTS. One way of modulating cGMP levels is to selectively inhibit cGMP degradation, and it is generally believed that all effects of PDE5Is are mediated by selective inhibition of the degradation of cyclic GMP.
Mechanism of action of PDE5-Is: In several animal species, including humans, the entire LUT expresses PDE5, with a relatively higher abundance within the bladder [16]
Although it is well established that PDE5 is expressed and biologically active in LUT, its functional role is still a matter of debate. Clinical studies demonstrated that its inhibition, through all the aforementioned PDE5-Is, resulted in amelioration of LUTS. Several mechanisms of action of PDE5-Is in LUTS have been hypothesized.
Immunohistochemical studies indicate that PDE5 is localized in the endothelial and smooth muscle cells of the LUT blood vessels [17]
Several in vitro studies have demonstrated that PDE5-Is can relax isolated prostate and bladder neck strips [27]
In the human prostate [17]
The NO/cGMP signaling pathway is likely to have a significant role in the innervation of the LUT. In human, neuronal NO synthase and guanylate cyclase are expressed in the uroepithelium, in neural fibers of the bladder neck and prostatic urethra, and in afferent nerves and interstitial cells, respectively [35]
Emerging evidences indicate that metabolic derangements, clustered in the metabolic syndrome (MetS) construct, may have a role in BPH pathophysiology. Within MetS, visceral obesity and dyslipidemia are the major predictors of an enlarged prostate size [3]
A systematic literature search in PubMed and Scopus was performed until May 2015, to identify systematic reviews of randomized controlled trial (RCTs), including the following MeSH terms: phosphodiesterase type 5 inhibitor and tadalafil PLUS urinary symptoms OR lower urinary tract symptoms OR benign prostatic hyperplasia OR prostate. We included only systematic reviews of RCTs comparing PDE5-Is treatment with different oral therapies or placebos for LUTS/BPH, while we excluded reviews of RTCs without PDE5-Is, nonclinical trials with PDE5-Is, or nonsystematic review. A total of eight papers were analyzed (Fig. 1; Table 1).
Table 1 Characteristics of the studies included in the review
a Significant improvement versus placebo.
b PDE5-Is + ABs versus ABs alone.
c Significant improvement versus ABs alone.
d PDE5-Is nonspecified.
* p = 0.04 for Tadalafil 5 mg.
ABs = alpha-blockers; BPH = benign prostatic hyperplasia; diff. = difference; ED = erectile dysfunction; IIEF = International Index Of Erectile Function; IPSS = International Prostatic Symptom Score; MRAs = muscarinic receptor antagonists; O = other PDE5-Is; PDE5-Is = phosphodiesterase 5 inhibitors; PLA = placebo; P.ts = patients; Qmax = maximum flow rate at uroflowmetry; S = sildenafil; T = tadalafil;. V = vardenafil; 5ARIs = 5a-reductase inhibitors.
Moreover, we selected more clinically relevant data from current literature on the clinical use of all PDE5-Is, including all post-hoc pooled data analyses (Table 2), with a nonsystematic approach (studies published only as abstract or presented without abstract and reports from meetings and studies not published in English were not considered for this review).
Table 2 Summary of posthoc pooled-data analyses of patients treated with tadalafil 5 mg once daily versus placebo for lower urinary tract symptoms/benign prostatic enlargement
Publication | No. of patients (n) |
Follow up (wk) |
Main findings | |
---|---|---|---|---|
Tadalafil | Placebo | |||
Oelke et al., 2015 [47] J.C. Nickel, G.B. Brock, S. Herschorn, R. Dickson, C. Henneges, L. Viktrup. Proportion of tadalafil-treated patients with clinically meaningful improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia. BJU Int. 2015;115:815-821 Crossref |
742 | 735 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from baseline to endpoint in significantly more patients with tadalafil (69.1%) vs placebo (54.8%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from baseline to endpoint in significantly more patients with tadalafil (59.8%) vs placebo (43.7%; p < 0.001) • 59.8% (50.2%) and 79.3% (72.5%) of the responders had ≥3 (≥25%) IPSS point improvement already after wk 1 and wk 4, respectively |
Nickel et al., 2015 [48] M. Oelke, B. Wiese, R. Berges. Nocturia and its impact on health related quality of life and health care seeking behavior in German community-dwelling men aged 50 years or older. World J Urol. 2014;32:1155-1162 Crossref |
752 | 747 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from randomization to endpoint in significantly more patients with tadalafil (71.1%) vs placebo (56.0%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from randomization to endpoint in significantly more patients with tadalafil (61.7%) vs placebo (45.5%; p < 0.001) • 38.5% (22.4%) of patients with tadalafil and 41.0% (23.3%) of patients with placebo had ≥3 (≥25%) IPSS point improvement during the placebo run-in phase |
Oelke et al., 2014 [50] H. Porst, C.G. Roehrborn, R.J. Secrest, A. Esler, L. Viktrup. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia and on erectile dysfunction in sexually active men with both conditions: analyses of pooled data from four randomized, placebo-controlled tadalafil clinical studies. J Sex Med. 2013;10:2044-2052 Crossref |
752 | 748 | 12 | Effects of tadalafil on nocturia (nocturnal voiding frequency): • for men with ≥1 nocturia episode at baseline, reduction with tadalafil (–0.5) was significantly greater than with placebo at study end (–0.4; LS mean change –0.2, p = 0.002) • for men with ≥2 nocturia episodes at baseline, reduction with tadalafil (–0.8) was significantly greater than with placebo at study end (–0.6; LS mean change –0.2, p = 0.003) • tadalafil (placebo) treatment resulted in reduction of ≥1 nocturia episodes in 47.5% (41.3%) of patients |
Porst et al., 2013 [51] G.B. Brock, K.T. McVary, C.G. Roehrborn, et al. Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: integrated data analyses from 4 placebo controlled clinical studies. J Urol. 2014;191:405-411 Crossref |
505 | 521 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • analysis only of men who were sexually active at baseline • significant improvement of total IPSS with tadalafil (–6.0) vs placebo (–3.6; p < 0.001) from baseline to study end • significant improvement of IIEF-EF with tadalafil (+6.4) vs placebo (+1.4, p < 0.001) from baseline to study end • similar IPSS improvements in men with ED vs without ED: no significant impact of ED severity on LUTS (IPSS) outcome |
Brock et al., 2014 [52] H. Porst, M. Oelke, E.R. Goldfischer, et al. Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational, randomized, placebo-controlled clinical studies. Urology. 2013;82:667-673 Crossref |
752 | 744 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • similar LUTS (IPSS) improvement with tadalafil vs placebo in men without ED (–5.4 vs –2.2, p = 0.0007) compared with men with ED (–5.9 vs –2.3, p < 0.0001); ED subgroup interaction not significant • bidirectional path analysis for sexually-active men (n = 1250) only: 92.5% of the total effects of tadalafil on LUTS/BPH via direct effect on LUTS and 7.5% via indirect effects by IIEF-EF domain improvement |
Porst et al., 2013 [53] O. Nishizawa, M. Yoshida, M. Takeda, et al. Tadalafil 5 mg once daily for the treatment of Asian men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: analyses of data pooled from three randomized, double-blind, placebo-controlled studies. Int J Urol. 2015;22:378-384 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in different patient subgroups: • improvements in IPSS and BPH-Impact Index in all patient subgroups identical (investigated patient parameters: age, symptom severity, serum testosterone concentration, prostate volume, previous α–blocker or PDE5-inhibitor use, arterial hypertension, diabetes mellitus, cardio-vascular diseases) • no baseline item was identified to predict a favorable or unfavorable treatment outcome |
Nishizawa et al., 2015 [54] C. Vlachopoulos, M. Oelke, M. Maggi, et al. Impact of cardiovascular risk factors and related comorbid conditions on the treatment response to tadalafil once-daily in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: an integrated analysis of four randomized, double-blind, placebo-controlled clinical trials. Int J Clin Pract. 2015;69:1496-1507 |
601 | 598 | 12 | Effects of tadalafil on LUTS/BPH in different subgroups of Asian patients: • analysis of Japanese, Korean, or Taiwanese men • significant improvements in total IPSS (tadalafil vs placebo) at wk 4 (–3.69 vs –2.47), wk 8 (–4.72 vs –3.43), and wk 12 (–5.32 vs –3.79), each p < 0.001 • additionally, significant improvements at wk 4, wk 8, and wk 12 for IPSS storage and IPSS voiding subscores as well as for IPSS-QoL • older patients (≥65 yr) showed significantly lower IPSS improvement than younger patients (<65 yr); otherwise, no significant impact of any other baseline item on LUTS improvement |
Vlachopoulos et al., 2015 [55] C.G. Roehrborn, C. Chapple, M. Oelke, D. Cox, A. Esler, L. Viktrup. Effects of tadalafil once-daily on maximum urinary flow rate in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. J Urol. 2014;191:1045-1050 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in patients with cardio-vascular risk factors and therapy: • subanalysis of comorbid, cardio-vascular diseases on LUTS/BPH outcome • no significant differences in efficacy of tadalafil vs placebo for various cardio-vascular diseases/comorbidities • but patients with >1 antihypertensive drugs have significantly lower IPSS improvement compared with men taking ≤1 drug • use of diuretics resulted in significantly lower IPSS improvement compared to men taking other antihypertensives or no drugs |
Roehrborn et al., 2014 [56] D.V. Singh, U.K. Mete, A.K. Mandal, S.K. Singh. 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;11:187-196 Crossref |
752 (612a) |
748 (585a) |
12 | Effects of tadalafil on uroflow (maximum urinary flow rate): • in total study population, patients with tadalafil had significantly greater Qmax improvement (mean +1.1 ml/s) compared with patients with placebo (mean +0.4 ml/s; p = 0.003) • significant Qmax improvement in the total study population was mainly driven by effects in patients who voided 250–450 ml (p = 0.011) and had a baseline Qmax 10–15 ml/s (p = 0.044) |
a With valid measurement.
BPH = benign prostatic enlargement; ED = erectile dysfunction; IPSS = International Prostate Symptom Score; LUTS = lower urinary tract symptoms; PDE5 = phosphodiesterase type 5; QoL = quality of life.
Efficacy: In the first systematic review on PDE5-Is for LUTS secondary to BPH published in literature, Laydner et al [38]
In the first meta-regression analysis on PDE5-Is alone or in combination with α-blockers, Gacci et al [2]
In a subset analysis on tadalafil based on data extrapolated from a systematic review on all PDE5-Is, Gacci et al [42]
Safety: In the review from Liu et al [39]
The first meta-analysis of AEs due to PDE5-Is reported that flushing, gastro-esophageal reflux, headache, and dyspepsia had the higher risk of occurrence (odds ratio: 4.88; 2.21; 1.88; 1.85; respectively). Moreover, regarding the overall tolerability of the association between PDE5-Is and α-blockers, Gacci et al [42]
In a recent review on tadalafil once daily, the Authors underlined the good safety profile with a relative risk of AEs from tadalafil similar to those reported with vardenafil or sildenafil (2.27 vs 1.86 vs 1.22, respectively); overall, the occurrence of AEs reported was very similar to that reported with all PDE5-Is versus placebo: 16.0% versus 6.0% [42]
Clinically-meaningful symptom improvement: Clinically-meaningful LUTS improvement is defined as a decrease of ≥3 points or ≥25% reduction of total IPSS [45]
Similar post-hoc analyses were done in 1499 patients treated with tadalafil 5 mg once daily or placebo [47]
Nocturia: Nocturia, defined as one or more voids per night, is one of the most prevalent and bothersome single urinary symptoms in community-dwelling men or patients with LUTS/BPH and the main reason for physician consultations [48]
Tadalafil for men with or without ED: The majority of the randomized, placebo-controlled tadalafil trials included patients with ED (approximately 60–70% of trial participants). Pooled data analyses evaluated whether symptom improvement was related to baseline ED status or ED improvement during tadalafil treatment [50]
Other baseline characteristics: The impact of several patient characteristics was evaluated in 1500 pooled patients with LUTS/BPH with regard to symptom improvement and adverse events, including age (≤65 vs >65 yr), symptom severity (IPSS < 20 vs ≥ 20), testosterone concentration (<300 ng/dl vs ≥300 ng/dl), prostate-specific antigen-predicted prostate volume (<40 ml vs ≥40 ml), previous α-blockers use (yes vs no), previous PDE5 inhibitor use (yes vs no), arterial hypertension (yes vs no), diabetes mellitus (yes vs no), and cardiovascular disease (yes vs no) [52]
Finally, an integrated analysis on 1371 patients, demonstrated that tadalafil 5 mg once daily for 12 wk allowed to achieve a very small, but statistically significant increase in Qmax versus the placebo (median: 1.1 ml/s vs 0.4 ml/s) [55]
Tadalafil has been also proposed in combination with alpha blockers or 5-alpha reductase inhibitors. In a prospective randomized study on 133 men with LUTS/BPH treated with tamsulsoin plus tadalafil versus tamsulosin or tadalafil alone, combination therapy was more effective than monotherapy for ED (%IIEF change from baseline: 60.2 vs 39.3 and 46.0 respectively) with similar improvement for urinary symptoms (% IPSS change from baseline: 53.9 vs 50.9 and 33.5), with a good safety profile [56]
Regarding the impact of tadalafil on sexual activity of men with ED and LUTS due to BPH tadalafil, Giuliano et al [58]
There is a large body of scientific evidence supporting the role of the NO-cGMP pathway including PDE5I in: (1) regulation of the tone of the smooth muscle fibers of the prostate, urethra, and bladder neck and in a lesser extent of the bladder (relaxant effect), (2) control of the arterial supply of the LUT (vasodilatory effect), and (3) modulation of the micturition reflex via the afferent bladder innervation (decrease in the afferent signaling). PDE5-Is may also downregulate inflammatory processes in LUT and exert antiproliferative effects.
Several meta-analyses demonstrated that PDE5-Is are effective in improving LUTS and erectile function compared with placebo. The combination of PDE5-Is with α-blockers induce a small, but statistically significant improvement of maximum flow rate as compared with α-blockers alone, in addition to the positive effect on micturition and sexual activity. PDE5-Is alone or in combination with α-blockers are well tolerated: flushing, gastroesophageal reflux, headache, and dyspepsia are the most common treatment-associated AEs.
Tadalafil 5 mg once daily achieves an improvement of clinically-meaningful urinary symptoms and nocturnal voiding frequency compared with placebo. Furthermore, the effects on LUTS are independent of ED severity at baseline and ED improvement.
Data on the long-term effects prostate size, reduction of disease progression, or prostate cancer prevalence related to the use of PDE5-Is are not available; long-term outcomes and cost-effectiveness analyses are needed.
Author contributions: Mauro Gacci had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Gacci, Giuliano.
Acquisition of data: Gacci, Giuliano, Andersson, Maggi, Oelke.
Analysis and interpretation of data: Gacci, Andersson, Chapple, Maggi, Mirone, Oelke, Porst, Roehrborn, Stief, Giuliano.
Drafting of the manuscript: Gacci, Giuliano, Andersson, Maggi, Oelke.
Critical revision of the manuscript for important intellectual content: Chapple, Mirone, Porst, Roehrborn, Stief.
Statistical analysis: Gacci.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Giuliano.
Other: None.
Financial disclosures: Mauro Gacci certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Gacci: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Pierre Fabre; Andersson: Consultancy and Advisory Boards for Allergan, Astellas, Ferring; Chapple: Consultant, Researcher and Speaker for Allergan, Astellas, Medtronic and Recordati. Consultant and speaker for Lilly. Researcher and speaker for ONO and Pfizer. Speaker for Ranbaxy; Maggi: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Intercept, Menarini; Mirone: consultant, speaker, and/or trial participant for Eli Lilly Italia, Menarini, Zambon, Recordati, GSK, Bracco; Oelke: consultant, speaker, and/or trial participant for Bayer Healthcare, Eli Lilly and Company, and Pfizer; Porst: consultant, speaker for Eli Lilly and Compani, Menarini Group and Sanofi; CRoehrborn: has financial interests and/or other relationships with Eli Lilly and Company, and with Allergan, Afferent Pharmaceuticals, Auxiliary Medical Services, Cancer and Leukemia Group B Clinical Trial Group, GlaxoSmithKline, New England Research Institutes, NeoTract, National Institute of Diabetes and Digestive and Kidney Diseases, Protox, Southwest Oncology Group, Urologix, VA Corporate Studies, and Watson Pharmaceuticals. Giuliano: consultant for Lilly, Sanofi, Pfizer.
Funding/Support and role of the sponsor: None.
Lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE) and erectile dysfunction (ED) are both highly prevalent in elderly men [1]
The aim of this review is to provide an update on the current knowledge on the potential mechanisms of action of PDE5-Is on LUTS/BPE, critically analyze systematic reviews and relevant data from the current literature on the clinical use of all PDE5-Is, and report the latest evidence on pooled-data analyses of tadalafil once daily to provide a definite rationale for the clinical use of tadalafil for the treatment of LUTS/BPE.
The pathways mediating the activity of PDE5-Is: LUTS have a multifactorial pathophysiology and have been discussed extensively [7]
The role of the bladder in male LUTS has been emphasized [9]
In the pathophysiology of LUTS, the NO/cyclic guanosine monophosphate (cGMP) (NO/cGMP) signaling pathway is believed to play a central role. Since NO signaling occurs via stimulation of soluble guanylate cyclase producing cGMP, it is reasonable to assume that the level of cGMP in different LUT tissues can influence their ability to generate LUTS. One way of modulating cGMP levels is to selectively inhibit cGMP degradation, and it is generally believed that all effects of PDE5Is are mediated by selective inhibition of the degradation of cyclic GMP.
Mechanism of action of PDE5-Is: In several animal species, including humans, the entire LUT expresses PDE5, with a relatively higher abundance within the bladder [16]
Although it is well established that PDE5 is expressed and biologically active in LUT, its functional role is still a matter of debate. Clinical studies demonstrated that its inhibition, through all the aforementioned PDE5-Is, resulted in amelioration of LUTS. Several mechanisms of action of PDE5-Is in LUTS have been hypothesized.
Immunohistochemical studies indicate that PDE5 is localized in the endothelial and smooth muscle cells of the LUT blood vessels [17]
Several in vitro studies have demonstrated that PDE5-Is can relax isolated prostate and bladder neck strips [27]
In the human prostate [17]
The NO/cGMP signaling pathway is likely to have a significant role in the innervation of the LUT. In human, neuronal NO synthase and guanylate cyclase are expressed in the uroepithelium, in neural fibers of the bladder neck and prostatic urethra, and in afferent nerves and interstitial cells, respectively [35]
Emerging evidences indicate that metabolic derangements, clustered in the metabolic syndrome (MetS) construct, may have a role in BPH pathophysiology. Within MetS, visceral obesity and dyslipidemia are the major predictors of an enlarged prostate size [3]
A systematic literature search in PubMed and Scopus was performed until May 2015, to identify systematic reviews of randomized controlled trial (RCTs), including the following MeSH terms: phosphodiesterase type 5 inhibitor and tadalafil PLUS urinary symptoms OR lower urinary tract symptoms OR benign prostatic hyperplasia OR prostate. We included only systematic reviews of RCTs comparing PDE5-Is treatment with different oral therapies or placebos for LUTS/BPH, while we excluded reviews of RTCs without PDE5-Is, nonclinical trials with PDE5-Is, or nonsystematic review. A total of eight papers were analyzed (Fig. 1; Table 1).
Table 1 Characteristics of the studies included in the review
a Significant improvement versus placebo.
b PDE5-Is + ABs versus ABs alone.
c Significant improvement versus ABs alone.
d PDE5-Is nonspecified.
* p = 0.04 for Tadalafil 5 mg.
ABs = alpha-blockers; BPH = benign prostatic hyperplasia; diff. = difference; ED = erectile dysfunction; IIEF = International Index Of Erectile Function; IPSS = International Prostatic Symptom Score; MRAs = muscarinic receptor antagonists; O = other PDE5-Is; PDE5-Is = phosphodiesterase 5 inhibitors; PLA = placebo; P.ts = patients; Qmax = maximum flow rate at uroflowmetry; S = sildenafil; T = tadalafil;. V = vardenafil; 5ARIs = 5a-reductase inhibitors.
Moreover, we selected more clinically relevant data from current literature on the clinical use of all PDE5-Is, including all post-hoc pooled data analyses (Table 2), with a nonsystematic approach (studies published only as abstract or presented without abstract and reports from meetings and studies not published in English were not considered for this review).
Table 2 Summary of posthoc pooled-data analyses of patients treated with tadalafil 5 mg once daily versus placebo for lower urinary tract symptoms/benign prostatic enlargement
Publication | No. of patients (n) |
Follow up (wk) |
Main findings | |
---|---|---|---|---|
Tadalafil | Placebo | |||
Oelke et al., 2015 [47] J.C. Nickel, G.B. Brock, S. Herschorn, R. Dickson, C. Henneges, L. Viktrup. Proportion of tadalafil-treated patients with clinically meaningful improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia. BJU Int. 2015;115:815-821 Crossref |
742 | 735 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from baseline to endpoint in significantly more patients with tadalafil (69.1%) vs placebo (54.8%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from baseline to endpoint in significantly more patients with tadalafil (59.8%) vs placebo (43.7%; p < 0.001) • 59.8% (50.2%) and 79.3% (72.5%) of the responders had ≥3 (≥25%) IPSS point improvement already after wk 1 and wk 4, respectively |
Nickel et al., 2015 [48] M. Oelke, B. Wiese, R. Berges. Nocturia and its impact on health related quality of life and health care seeking behavior in German community-dwelling men aged 50 years or older. World J Urol. 2014;32:1155-1162 Crossref |
752 | 747 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from randomization to endpoint in significantly more patients with tadalafil (71.1%) vs placebo (56.0%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from randomization to endpoint in significantly more patients with tadalafil (61.7%) vs placebo (45.5%; p < 0.001) • 38.5% (22.4%) of patients with tadalafil and 41.0% (23.3%) of patients with placebo had ≥3 (≥25%) IPSS point improvement during the placebo run-in phase |
Oelke et al., 2014 [50] H. Porst, C.G. Roehrborn, R.J. Secrest, A. Esler, L. Viktrup. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia and on erectile dysfunction in sexually active men with both conditions: analyses of pooled data from four randomized, placebo-controlled tadalafil clinical studies. J Sex Med. 2013;10:2044-2052 Crossref |
752 | 748 | 12 | Effects of tadalafil on nocturia (nocturnal voiding frequency): • for men with ≥1 nocturia episode at baseline, reduction with tadalafil (–0.5) was significantly greater than with placebo at study end (–0.4; LS mean change –0.2, p = 0.002) • for men with ≥2 nocturia episodes at baseline, reduction with tadalafil (–0.8) was significantly greater than with placebo at study end (–0.6; LS mean change –0.2, p = 0.003) • tadalafil (placebo) treatment resulted in reduction of ≥1 nocturia episodes in 47.5% (41.3%) of patients |
Porst et al., 2013 [51] G.B. Brock, K.T. McVary, C.G. Roehrborn, et al. Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: integrated data analyses from 4 placebo controlled clinical studies. J Urol. 2014;191:405-411 Crossref |
505 | 521 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • analysis only of men who were sexually active at baseline • significant improvement of total IPSS with tadalafil (–6.0) vs placebo (–3.6; p < 0.001) from baseline to study end • significant improvement of IIEF-EF with tadalafil (+6.4) vs placebo (+1.4, p < 0.001) from baseline to study end • similar IPSS improvements in men with ED vs without ED: no significant impact of ED severity on LUTS (IPSS) outcome |
Brock et al., 2014 [52] H. Porst, M. Oelke, E.R. Goldfischer, et al. Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational, randomized, placebo-controlled clinical studies. Urology. 2013;82:667-673 Crossref |
752 | 744 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • similar LUTS (IPSS) improvement with tadalafil vs placebo in men without ED (–5.4 vs –2.2, p = 0.0007) compared with men with ED (–5.9 vs –2.3, p < 0.0001); ED subgroup interaction not significant • bidirectional path analysis for sexually-active men (n = 1250) only: 92.5% of the total effects of tadalafil on LUTS/BPH via direct effect on LUTS and 7.5% via indirect effects by IIEF-EF domain improvement |
Porst et al., 2013 [53] O. Nishizawa, M. Yoshida, M. Takeda, et al. Tadalafil 5 mg once daily for the treatment of Asian men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: analyses of data pooled from three randomized, double-blind, placebo-controlled studies. Int J Urol. 2015;22:378-384 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in different patient subgroups: • improvements in IPSS and BPH-Impact Index in all patient subgroups identical (investigated patient parameters: age, symptom severity, serum testosterone concentration, prostate volume, previous α–blocker or PDE5-inhibitor use, arterial hypertension, diabetes mellitus, cardio-vascular diseases) • no baseline item was identified to predict a favorable or unfavorable treatment outcome |
Nishizawa et al., 2015 [54] C. Vlachopoulos, M. Oelke, M. Maggi, et al. Impact of cardiovascular risk factors and related comorbid conditions on the treatment response to tadalafil once-daily in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: an integrated analysis of four randomized, double-blind, placebo-controlled clinical trials. Int J Clin Pract. 2015;69:1496-1507 |
601 | 598 | 12 | Effects of tadalafil on LUTS/BPH in different subgroups of Asian patients: • analysis of Japanese, Korean, or Taiwanese men • significant improvements in total IPSS (tadalafil vs placebo) at wk 4 (–3.69 vs –2.47), wk 8 (–4.72 vs –3.43), and wk 12 (–5.32 vs –3.79), each p < 0.001 • additionally, significant improvements at wk 4, wk 8, and wk 12 for IPSS storage and IPSS voiding subscores as well as for IPSS-QoL • older patients (≥65 yr) showed significantly lower IPSS improvement than younger patients (<65 yr); otherwise, no significant impact of any other baseline item on LUTS improvement |
Vlachopoulos et al., 2015 [55] C.G. Roehrborn, C. Chapple, M. Oelke, D. Cox, A. Esler, L. Viktrup. Effects of tadalafil once-daily on maximum urinary flow rate in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. J Urol. 2014;191:1045-1050 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in patients with cardio-vascular risk factors and therapy: • subanalysis of comorbid, cardio-vascular diseases on LUTS/BPH outcome • no significant differences in efficacy of tadalafil vs placebo for various cardio-vascular diseases/comorbidities • but patients with >1 antihypertensive drugs have significantly lower IPSS improvement compared with men taking ≤1 drug • use of diuretics resulted in significantly lower IPSS improvement compared to men taking other antihypertensives or no drugs |
Roehrborn et al., 2014 [56] D.V. Singh, U.K. Mete, A.K. Mandal, S.K. Singh. 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;11:187-196 Crossref |
752 (612a) |
748 (585a) |
12 | Effects of tadalafil on uroflow (maximum urinary flow rate): • in total study population, patients with tadalafil had significantly greater Qmax improvement (mean +1.1 ml/s) compared with patients with placebo (mean +0.4 ml/s; p = 0.003) • significant Qmax improvement in the total study population was mainly driven by effects in patients who voided 250–450 ml (p = 0.011) and had a baseline Qmax 10–15 ml/s (p = 0.044) |
a With valid measurement.
BPH = benign prostatic enlargement; ED = erectile dysfunction; IPSS = International Prostate Symptom Score; LUTS = lower urinary tract symptoms; PDE5 = phosphodiesterase type 5; QoL = quality of life.
Efficacy: In the first systematic review on PDE5-Is for LUTS secondary to BPH published in literature, Laydner et al [38]
In the first meta-regression analysis on PDE5-Is alone or in combination with α-blockers, Gacci et al [2]
In a subset analysis on tadalafil based on data extrapolated from a systematic review on all PDE5-Is, Gacci et al [42]
Safety: In the review from Liu et al [39]
The first meta-analysis of AEs due to PDE5-Is reported that flushing, gastro-esophageal reflux, headache, and dyspepsia had the higher risk of occurrence (odds ratio: 4.88; 2.21; 1.88; 1.85; respectively). Moreover, regarding the overall tolerability of the association between PDE5-Is and α-blockers, Gacci et al [42]
In a recent review on tadalafil once daily, the Authors underlined the good safety profile with a relative risk of AEs from tadalafil similar to those reported with vardenafil or sildenafil (2.27 vs 1.86 vs 1.22, respectively); overall, the occurrence of AEs reported was very similar to that reported with all PDE5-Is versus placebo: 16.0% versus 6.0% [42]
Clinically-meaningful symptom improvement: Clinically-meaningful LUTS improvement is defined as a decrease of ≥3 points or ≥25% reduction of total IPSS [45]
Similar post-hoc analyses were done in 1499 patients treated with tadalafil 5 mg once daily or placebo [47]
Nocturia: Nocturia, defined as one or more voids per night, is one of the most prevalent and bothersome single urinary symptoms in community-dwelling men or patients with LUTS/BPH and the main reason for physician consultations [48]
Tadalafil for men with or without ED: The majority of the randomized, placebo-controlled tadalafil trials included patients with ED (approximately 60–70% of trial participants). Pooled data analyses evaluated whether symptom improvement was related to baseline ED status or ED improvement during tadalafil treatment [50]
Other baseline characteristics: The impact of several patient characteristics was evaluated in 1500 pooled patients with LUTS/BPH with regard to symptom improvement and adverse events, including age (≤65 vs >65 yr), symptom severity (IPSS < 20 vs ≥ 20), testosterone concentration (<300 ng/dl vs ≥300 ng/dl), prostate-specific antigen-predicted prostate volume (<40 ml vs ≥40 ml), previous α-blockers use (yes vs no), previous PDE5 inhibitor use (yes vs no), arterial hypertension (yes vs no), diabetes mellitus (yes vs no), and cardiovascular disease (yes vs no) [52]
Finally, an integrated analysis on 1371 patients, demonstrated that tadalafil 5 mg once daily for 12 wk allowed to achieve a very small, but statistically significant increase in Qmax versus the placebo (median: 1.1 ml/s vs 0.4 ml/s) [55]
Tadalafil has been also proposed in combination with alpha blockers or 5-alpha reductase inhibitors. In a prospective randomized study on 133 men with LUTS/BPH treated with tamsulsoin plus tadalafil versus tamsulosin or tadalafil alone, combination therapy was more effective than monotherapy for ED (%IIEF change from baseline: 60.2 vs 39.3 and 46.0 respectively) with similar improvement for urinary symptoms (% IPSS change from baseline: 53.9 vs 50.9 and 33.5), with a good safety profile [56]
Regarding the impact of tadalafil on sexual activity of men with ED and LUTS due to BPH tadalafil, Giuliano et al [58]
There is a large body of scientific evidence supporting the role of the NO-cGMP pathway including PDE5I in: (1) regulation of the tone of the smooth muscle fibers of the prostate, urethra, and bladder neck and in a lesser extent of the bladder (relaxant effect), (2) control of the arterial supply of the LUT (vasodilatory effect), and (3) modulation of the micturition reflex via the afferent bladder innervation (decrease in the afferent signaling). PDE5-Is may also downregulate inflammatory processes in LUT and exert antiproliferative effects.
Several meta-analyses demonstrated that PDE5-Is are effective in improving LUTS and erectile function compared with placebo. The combination of PDE5-Is with α-blockers induce a small, but statistically significant improvement of maximum flow rate as compared with α-blockers alone, in addition to the positive effect on micturition and sexual activity. PDE5-Is alone or in combination with α-blockers are well tolerated: flushing, gastroesophageal reflux, headache, and dyspepsia are the most common treatment-associated AEs.
Tadalafil 5 mg once daily achieves an improvement of clinically-meaningful urinary symptoms and nocturnal voiding frequency compared with placebo. Furthermore, the effects on LUTS are independent of ED severity at baseline and ED improvement.
Data on the long-term effects prostate size, reduction of disease progression, or prostate cancer prevalence related to the use of PDE5-Is are not available; long-term outcomes and cost-effectiveness analyses are needed.
Author contributions: Mauro Gacci had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Gacci, Giuliano.
Acquisition of data: Gacci, Giuliano, Andersson, Maggi, Oelke.
Analysis and interpretation of data: Gacci, Andersson, Chapple, Maggi, Mirone, Oelke, Porst, Roehrborn, Stief, Giuliano.
Drafting of the manuscript: Gacci, Giuliano, Andersson, Maggi, Oelke.
Critical revision of the manuscript for important intellectual content: Chapple, Mirone, Porst, Roehrborn, Stief.
Statistical analysis: Gacci.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Giuliano.
Other: None.
Financial disclosures: Mauro Gacci certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Gacci: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Pierre Fabre; Andersson: Consultancy and Advisory Boards for Allergan, Astellas, Ferring; Chapple: Consultant, Researcher and Speaker for Allergan, Astellas, Medtronic and Recordati. Consultant and speaker for Lilly. Researcher and speaker for ONO and Pfizer. Speaker for Ranbaxy; Maggi: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Intercept, Menarini; Mirone: consultant, speaker, and/or trial participant for Eli Lilly Italia, Menarini, Zambon, Recordati, GSK, Bracco; Oelke: consultant, speaker, and/or trial participant for Bayer Healthcare, Eli Lilly and Company, and Pfizer; Porst: consultant, speaker for Eli Lilly and Compani, Menarini Group and Sanofi; CRoehrborn: has financial interests and/or other relationships with Eli Lilly and Company, and with Allergan, Afferent Pharmaceuticals, Auxiliary Medical Services, Cancer and Leukemia Group B Clinical Trial Group, GlaxoSmithKline, New England Research Institutes, NeoTract, National Institute of Diabetes and Digestive and Kidney Diseases, Protox, Southwest Oncology Group, Urologix, VA Corporate Studies, and Watson Pharmaceuticals. Giuliano: consultant for Lilly, Sanofi, Pfizer.
Funding/Support and role of the sponsor: None.
Lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE) and erectile dysfunction (ED) are both highly prevalent in elderly men [1]
The aim of this review is to provide an update on the current knowledge on the potential mechanisms of action of PDE5-Is on LUTS/BPE, critically analyze systematic reviews and relevant data from the current literature on the clinical use of all PDE5-Is, and report the latest evidence on pooled-data analyses of tadalafil once daily to provide a definite rationale for the clinical use of tadalafil for the treatment of LUTS/BPE.
The pathways mediating the activity of PDE5-Is: LUTS have a multifactorial pathophysiology and have been discussed extensively [7]
The role of the bladder in male LUTS has been emphasized [9]
In the pathophysiology of LUTS, the NO/cyclic guanosine monophosphate (cGMP) (NO/cGMP) signaling pathway is believed to play a central role. Since NO signaling occurs via stimulation of soluble guanylate cyclase producing cGMP, it is reasonable to assume that the level of cGMP in different LUT tissues can influence their ability to generate LUTS. One way of modulating cGMP levels is to selectively inhibit cGMP degradation, and it is generally believed that all effects of PDE5Is are mediated by selective inhibition of the degradation of cyclic GMP.
Mechanism of action of PDE5-Is: In several animal species, including humans, the entire LUT expresses PDE5, with a relatively higher abundance within the bladder [16]
Although it is well established that PDE5 is expressed and biologically active in LUT, its functional role is still a matter of debate. Clinical studies demonstrated that its inhibition, through all the aforementioned PDE5-Is, resulted in amelioration of LUTS. Several mechanisms of action of PDE5-Is in LUTS have been hypothesized.
Immunohistochemical studies indicate that PDE5 is localized in the endothelial and smooth muscle cells of the LUT blood vessels [17]
Several in vitro studies have demonstrated that PDE5-Is can relax isolated prostate and bladder neck strips [27]
In the human prostate [17]
The NO/cGMP signaling pathway is likely to have a significant role in the innervation of the LUT. In human, neuronal NO synthase and guanylate cyclase are expressed in the uroepithelium, in neural fibers of the bladder neck and prostatic urethra, and in afferent nerves and interstitial cells, respectively [35]
Emerging evidences indicate that metabolic derangements, clustered in the metabolic syndrome (MetS) construct, may have a role in BPH pathophysiology. Within MetS, visceral obesity and dyslipidemia are the major predictors of an enlarged prostate size [3]
A systematic literature search in PubMed and Scopus was performed until May 2015, to identify systematic reviews of randomized controlled trial (RCTs), including the following MeSH terms: phosphodiesterase type 5 inhibitor and tadalafil PLUS urinary symptoms OR lower urinary tract symptoms OR benign prostatic hyperplasia OR prostate. We included only systematic reviews of RCTs comparing PDE5-Is treatment with different oral therapies or placebos for LUTS/BPH, while we excluded reviews of RTCs without PDE5-Is, nonclinical trials with PDE5-Is, or nonsystematic review. A total of eight papers were analyzed (Fig. 1; Table 1).
Table 1 Characteristics of the studies included in the review
a Significant improvement versus placebo.
b PDE5-Is + ABs versus ABs alone.
c Significant improvement versus ABs alone.
d PDE5-Is nonspecified.
* p = 0.04 for Tadalafil 5 mg.
ABs = alpha-blockers; BPH = benign prostatic hyperplasia; diff. = difference; ED = erectile dysfunction; IIEF = International Index Of Erectile Function; IPSS = International Prostatic Symptom Score; MRAs = muscarinic receptor antagonists; O = other PDE5-Is; PDE5-Is = phosphodiesterase 5 inhibitors; PLA = placebo; P.ts = patients; Qmax = maximum flow rate at uroflowmetry; S = sildenafil; T = tadalafil;. V = vardenafil; 5ARIs = 5a-reductase inhibitors.
Moreover, we selected more clinically relevant data from current literature on the clinical use of all PDE5-Is, including all post-hoc pooled data analyses (Table 2), with a nonsystematic approach (studies published only as abstract or presented without abstract and reports from meetings and studies not published in English were not considered for this review).
Table 2 Summary of posthoc pooled-data analyses of patients treated with tadalafil 5 mg once daily versus placebo for lower urinary tract symptoms/benign prostatic enlargement
Publication | No. of patients (n) |
Follow up (wk) |
Main findings | |
---|---|---|---|---|
Tadalafil | Placebo | |||
Oelke et al., 2015 [47] J.C. Nickel, G.B. Brock, S. Herschorn, R. Dickson, C. Henneges, L. Viktrup. Proportion of tadalafil-treated patients with clinically meaningful improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia. BJU Int. 2015;115:815-821 Crossref |
742 | 735 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from baseline to endpoint in significantly more patients with tadalafil (69.1%) vs placebo (54.8%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from baseline to endpoint in significantly more patients with tadalafil (59.8%) vs placebo (43.7%; p < 0.001) • 59.8% (50.2%) and 79.3% (72.5%) of the responders had ≥3 (≥25%) IPSS point improvement already after wk 1 and wk 4, respectively |
Nickel et al., 2015 [48] M. Oelke, B. Wiese, R. Berges. Nocturia and its impact on health related quality of life and health care seeking behavior in German community-dwelling men aged 50 years or older. World J Urol. 2014;32:1155-1162 Crossref |
752 | 747 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from randomization to endpoint in significantly more patients with tadalafil (71.1%) vs placebo (56.0%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from randomization to endpoint in significantly more patients with tadalafil (61.7%) vs placebo (45.5%; p < 0.001) • 38.5% (22.4%) of patients with tadalafil and 41.0% (23.3%) of patients with placebo had ≥3 (≥25%) IPSS point improvement during the placebo run-in phase |
Oelke et al., 2014 [50] H. Porst, C.G. Roehrborn, R.J. Secrest, A. Esler, L. Viktrup. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia and on erectile dysfunction in sexually active men with both conditions: analyses of pooled data from four randomized, placebo-controlled tadalafil clinical studies. J Sex Med. 2013;10:2044-2052 Crossref |
752 | 748 | 12 | Effects of tadalafil on nocturia (nocturnal voiding frequency): • for men with ≥1 nocturia episode at baseline, reduction with tadalafil (–0.5) was significantly greater than with placebo at study end (–0.4; LS mean change –0.2, p = 0.002) • for men with ≥2 nocturia episodes at baseline, reduction with tadalafil (–0.8) was significantly greater than with placebo at study end (–0.6; LS mean change –0.2, p = 0.003) • tadalafil (placebo) treatment resulted in reduction of ≥1 nocturia episodes in 47.5% (41.3%) of patients |
Porst et al., 2013 [51] G.B. Brock, K.T. McVary, C.G. Roehrborn, et al. Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: integrated data analyses from 4 placebo controlled clinical studies. J Urol. 2014;191:405-411 Crossref |
505 | 521 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • analysis only of men who were sexually active at baseline • significant improvement of total IPSS with tadalafil (–6.0) vs placebo (–3.6; p < 0.001) from baseline to study end • significant improvement of IIEF-EF with tadalafil (+6.4) vs placebo (+1.4, p < 0.001) from baseline to study end • similar IPSS improvements in men with ED vs without ED: no significant impact of ED severity on LUTS (IPSS) outcome |
Brock et al., 2014 [52] H. Porst, M. Oelke, E.R. Goldfischer, et al. Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational, randomized, placebo-controlled clinical studies. Urology. 2013;82:667-673 Crossref |
752 | 744 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • similar LUTS (IPSS) improvement with tadalafil vs placebo in men without ED (–5.4 vs –2.2, p = 0.0007) compared with men with ED (–5.9 vs –2.3, p < 0.0001); ED subgroup interaction not significant • bidirectional path analysis for sexually-active men (n = 1250) only: 92.5% of the total effects of tadalafil on LUTS/BPH via direct effect on LUTS and 7.5% via indirect effects by IIEF-EF domain improvement |
Porst et al., 2013 [53] O. Nishizawa, M. Yoshida, M. Takeda, et al. Tadalafil 5 mg once daily for the treatment of Asian men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: analyses of data pooled from three randomized, double-blind, placebo-controlled studies. Int J Urol. 2015;22:378-384 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in different patient subgroups: • improvements in IPSS and BPH-Impact Index in all patient subgroups identical (investigated patient parameters: age, symptom severity, serum testosterone concentration, prostate volume, previous α–blocker or PDE5-inhibitor use, arterial hypertension, diabetes mellitus, cardio-vascular diseases) • no baseline item was identified to predict a favorable or unfavorable treatment outcome |
Nishizawa et al., 2015 [54] C. Vlachopoulos, M. Oelke, M. Maggi, et al. Impact of cardiovascular risk factors and related comorbid conditions on the treatment response to tadalafil once-daily in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: an integrated analysis of four randomized, double-blind, placebo-controlled clinical trials. Int J Clin Pract. 2015;69:1496-1507 |
601 | 598 | 12 | Effects of tadalafil on LUTS/BPH in different subgroups of Asian patients: • analysis of Japanese, Korean, or Taiwanese men • significant improvements in total IPSS (tadalafil vs placebo) at wk 4 (–3.69 vs –2.47), wk 8 (–4.72 vs –3.43), and wk 12 (–5.32 vs –3.79), each p < 0.001 • additionally, significant improvements at wk 4, wk 8, and wk 12 for IPSS storage and IPSS voiding subscores as well as for IPSS-QoL • older patients (≥65 yr) showed significantly lower IPSS improvement than younger patients (<65 yr); otherwise, no significant impact of any other baseline item on LUTS improvement |
Vlachopoulos et al., 2015 [55] C.G. Roehrborn, C. Chapple, M. Oelke, D. Cox, A. Esler, L. Viktrup. Effects of tadalafil once-daily on maximum urinary flow rate in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. J Urol. 2014;191:1045-1050 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in patients with cardio-vascular risk factors and therapy: • subanalysis of comorbid, cardio-vascular diseases on LUTS/BPH outcome • no significant differences in efficacy of tadalafil vs placebo for various cardio-vascular diseases/comorbidities • but patients with >1 antihypertensive drugs have significantly lower IPSS improvement compared with men taking ≤1 drug • use of diuretics resulted in significantly lower IPSS improvement compared to men taking other antihypertensives or no drugs |
Roehrborn et al., 2014 [56] D.V. Singh, U.K. Mete, A.K. Mandal, S.K. Singh. 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;11:187-196 Crossref |
752 (612a) |
748 (585a) |
12 | Effects of tadalafil on uroflow (maximum urinary flow rate): • in total study population, patients with tadalafil had significantly greater Qmax improvement (mean +1.1 ml/s) compared with patients with placebo (mean +0.4 ml/s; p = 0.003) • significant Qmax improvement in the total study population was mainly driven by effects in patients who voided 250–450 ml (p = 0.011) and had a baseline Qmax 10–15 ml/s (p = 0.044) |
a With valid measurement.
BPH = benign prostatic enlargement; ED = erectile dysfunction; IPSS = International Prostate Symptom Score; LUTS = lower urinary tract symptoms; PDE5 = phosphodiesterase type 5; QoL = quality of life.
Efficacy: In the first systematic review on PDE5-Is for LUTS secondary to BPH published in literature, Laydner et al [38]
In the first meta-regression analysis on PDE5-Is alone or in combination with α-blockers, Gacci et al [2]
In a subset analysis on tadalafil based on data extrapolated from a systematic review on all PDE5-Is, Gacci et al [42]
Safety: In the review from Liu et al [39]
The first meta-analysis of AEs due to PDE5-Is reported that flushing, gastro-esophageal reflux, headache, and dyspepsia had the higher risk of occurrence (odds ratio: 4.88; 2.21; 1.88; 1.85; respectively). Moreover, regarding the overall tolerability of the association between PDE5-Is and α-blockers, Gacci et al [42]
In a recent review on tadalafil once daily, the Authors underlined the good safety profile with a relative risk of AEs from tadalafil similar to those reported with vardenafil or sildenafil (2.27 vs 1.86 vs 1.22, respectively); overall, the occurrence of AEs reported was very similar to that reported with all PDE5-Is versus placebo: 16.0% versus 6.0% [42]
Clinically-meaningful symptom improvement: Clinically-meaningful LUTS improvement is defined as a decrease of ≥3 points or ≥25% reduction of total IPSS [45]
Similar post-hoc analyses were done in 1499 patients treated with tadalafil 5 mg once daily or placebo [47]
Nocturia: Nocturia, defined as one or more voids per night, is one of the most prevalent and bothersome single urinary symptoms in community-dwelling men or patients with LUTS/BPH and the main reason for physician consultations [48]
Tadalafil for men with or without ED: The majority of the randomized, placebo-controlled tadalafil trials included patients with ED (approximately 60–70% of trial participants). Pooled data analyses evaluated whether symptom improvement was related to baseline ED status or ED improvement during tadalafil treatment [50]
Other baseline characteristics: The impact of several patient characteristics was evaluated in 1500 pooled patients with LUTS/BPH with regard to symptom improvement and adverse events, including age (≤65 vs >65 yr), symptom severity (IPSS < 20 vs ≥ 20), testosterone concentration (<300 ng/dl vs ≥300 ng/dl), prostate-specific antigen-predicted prostate volume (<40 ml vs ≥40 ml), previous α-blockers use (yes vs no), previous PDE5 inhibitor use (yes vs no), arterial hypertension (yes vs no), diabetes mellitus (yes vs no), and cardiovascular disease (yes vs no) [52]
Finally, an integrated analysis on 1371 patients, demonstrated that tadalafil 5 mg once daily for 12 wk allowed to achieve a very small, but statistically significant increase in Qmax versus the placebo (median: 1.1 ml/s vs 0.4 ml/s) [55]
Tadalafil has been also proposed in combination with alpha blockers or 5-alpha reductase inhibitors. In a prospective randomized study on 133 men with LUTS/BPH treated with tamsulsoin plus tadalafil versus tamsulosin or tadalafil alone, combination therapy was more effective than monotherapy for ED (%IIEF change from baseline: 60.2 vs 39.3 and 46.0 respectively) with similar improvement for urinary symptoms (% IPSS change from baseline: 53.9 vs 50.9 and 33.5), with a good safety profile [56]
Regarding the impact of tadalafil on sexual activity of men with ED and LUTS due to BPH tadalafil, Giuliano et al [58]
There is a large body of scientific evidence supporting the role of the NO-cGMP pathway including PDE5I in: (1) regulation of the tone of the smooth muscle fibers of the prostate, urethra, and bladder neck and in a lesser extent of the bladder (relaxant effect), (2) control of the arterial supply of the LUT (vasodilatory effect), and (3) modulation of the micturition reflex via the afferent bladder innervation (decrease in the afferent signaling). PDE5-Is may also downregulate inflammatory processes in LUT and exert antiproliferative effects.
Several meta-analyses demonstrated that PDE5-Is are effective in improving LUTS and erectile function compared with placebo. The combination of PDE5-Is with α-blockers induce a small, but statistically significant improvement of maximum flow rate as compared with α-blockers alone, in addition to the positive effect on micturition and sexual activity. PDE5-Is alone or in combination with α-blockers are well tolerated: flushing, gastroesophageal reflux, headache, and dyspepsia are the most common treatment-associated AEs.
Tadalafil 5 mg once daily achieves an improvement of clinically-meaningful urinary symptoms and nocturnal voiding frequency compared with placebo. Furthermore, the effects on LUTS are independent of ED severity at baseline and ED improvement.
Data on the long-term effects prostate size, reduction of disease progression, or prostate cancer prevalence related to the use of PDE5-Is are not available; long-term outcomes and cost-effectiveness analyses are needed.
Author contributions: Mauro Gacci had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Gacci, Giuliano.
Acquisition of data: Gacci, Giuliano, Andersson, Maggi, Oelke.
Analysis and interpretation of data: Gacci, Andersson, Chapple, Maggi, Mirone, Oelke, Porst, Roehrborn, Stief, Giuliano.
Drafting of the manuscript: Gacci, Giuliano, Andersson, Maggi, Oelke.
Critical revision of the manuscript for important intellectual content: Chapple, Mirone, Porst, Roehrborn, Stief.
Statistical analysis: Gacci.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Giuliano.
Other: None.
Financial disclosures: Mauro Gacci certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Gacci: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Pierre Fabre; Andersson: Consultancy and Advisory Boards for Allergan, Astellas, Ferring; Chapple: Consultant, Researcher and Speaker for Allergan, Astellas, Medtronic and Recordati. Consultant and speaker for Lilly. Researcher and speaker for ONO and Pfizer. Speaker for Ranbaxy; Maggi: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Intercept, Menarini; Mirone: consultant, speaker, and/or trial participant for Eli Lilly Italia, Menarini, Zambon, Recordati, GSK, Bracco; Oelke: consultant, speaker, and/or trial participant for Bayer Healthcare, Eli Lilly and Company, and Pfizer; Porst: consultant, speaker for Eli Lilly and Compani, Menarini Group and Sanofi; CRoehrborn: has financial interests and/or other relationships with Eli Lilly and Company, and with Allergan, Afferent Pharmaceuticals, Auxiliary Medical Services, Cancer and Leukemia Group B Clinical Trial Group, GlaxoSmithKline, New England Research Institutes, NeoTract, National Institute of Diabetes and Digestive and Kidney Diseases, Protox, Southwest Oncology Group, Urologix, VA Corporate Studies, and Watson Pharmaceuticals. Giuliano: consultant for Lilly, Sanofi, Pfizer.
Funding/Support and role of the sponsor: None.
Lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE) and erectile dysfunction (ED) are both highly prevalent in elderly men [1]
The aim of this review is to provide an update on the current knowledge on the potential mechanisms of action of PDE5-Is on LUTS/BPE, critically analyze systematic reviews and relevant data from the current literature on the clinical use of all PDE5-Is, and report the latest evidence on pooled-data analyses of tadalafil once daily to provide a definite rationale for the clinical use of tadalafil for the treatment of LUTS/BPE.
The pathways mediating the activity of PDE5-Is: LUTS have a multifactorial pathophysiology and have been discussed extensively [7]
The role of the bladder in male LUTS has been emphasized [9]
In the pathophysiology of LUTS, the NO/cyclic guanosine monophosphate (cGMP) (NO/cGMP) signaling pathway is believed to play a central role. Since NO signaling occurs via stimulation of soluble guanylate cyclase producing cGMP, it is reasonable to assume that the level of cGMP in different LUT tissues can influence their ability to generate LUTS. One way of modulating cGMP levels is to selectively inhibit cGMP degradation, and it is generally believed that all effects of PDE5Is are mediated by selective inhibition of the degradation of cyclic GMP.
Mechanism of action of PDE5-Is: In several animal species, including humans, the entire LUT expresses PDE5, with a relatively higher abundance within the bladder [16]
Although it is well established that PDE5 is expressed and biologically active in LUT, its functional role is still a matter of debate. Clinical studies demonstrated that its inhibition, through all the aforementioned PDE5-Is, resulted in amelioration of LUTS. Several mechanisms of action of PDE5-Is in LUTS have been hypothesized.
Immunohistochemical studies indicate that PDE5 is localized in the endothelial and smooth muscle cells of the LUT blood vessels [17]
Several in vitro studies have demonstrated that PDE5-Is can relax isolated prostate and bladder neck strips [27]
In the human prostate [17]
The NO/cGMP signaling pathway is likely to have a significant role in the innervation of the LUT. In human, neuronal NO synthase and guanylate cyclase are expressed in the uroepithelium, in neural fibers of the bladder neck and prostatic urethra, and in afferent nerves and interstitial cells, respectively [35]
Emerging evidences indicate that metabolic derangements, clustered in the metabolic syndrome (MetS) construct, may have a role in BPH pathophysiology. Within MetS, visceral obesity and dyslipidemia are the major predictors of an enlarged prostate size [3]
A systematic literature search in PubMed and Scopus was performed until May 2015, to identify systematic reviews of randomized controlled trial (RCTs), including the following MeSH terms: phosphodiesterase type 5 inhibitor and tadalafil PLUS urinary symptoms OR lower urinary tract symptoms OR benign prostatic hyperplasia OR prostate. We included only systematic reviews of RCTs comparing PDE5-Is treatment with different oral therapies or placebos for LUTS/BPH, while we excluded reviews of RTCs without PDE5-Is, nonclinical trials with PDE5-Is, or nonsystematic review. A total of eight papers were analyzed (Fig. 1; Table 1).
Table 1 Characteristics of the studies included in the review
a Significant improvement versus placebo.
b PDE5-Is + ABs versus ABs alone.
c Significant improvement versus ABs alone.
d PDE5-Is nonspecified.
* p = 0.04 for Tadalafil 5 mg.
ABs = alpha-blockers; BPH = benign prostatic hyperplasia; diff. = difference; ED = erectile dysfunction; IIEF = International Index Of Erectile Function; IPSS = International Prostatic Symptom Score; MRAs = muscarinic receptor antagonists; O = other PDE5-Is; PDE5-Is = phosphodiesterase 5 inhibitors; PLA = placebo; P.ts = patients; Qmax = maximum flow rate at uroflowmetry; S = sildenafil; T = tadalafil;. V = vardenafil; 5ARIs = 5a-reductase inhibitors.
Moreover, we selected more clinically relevant data from current literature on the clinical use of all PDE5-Is, including all post-hoc pooled data analyses (Table 2), with a nonsystematic approach (studies published only as abstract or presented without abstract and reports from meetings and studies not published in English were not considered for this review).
Table 2 Summary of posthoc pooled-data analyses of patients treated with tadalafil 5 mg once daily versus placebo for lower urinary tract symptoms/benign prostatic enlargement
Publication | No. of patients (n) |
Follow up (wk) |
Main findings | |
---|---|---|---|---|
Tadalafil | Placebo | |||
Oelke et al., 2015 [47] J.C. Nickel, G.B. Brock, S. Herschorn, R. Dickson, C. Henneges, L. Viktrup. Proportion of tadalafil-treated patients with clinically meaningful improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia. BJU Int. 2015;115:815-821 Crossref |
742 | 735 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from baseline to endpoint in significantly more patients with tadalafil (69.1%) vs placebo (54.8%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from baseline to endpoint in significantly more patients with tadalafil (59.8%) vs placebo (43.7%; p < 0.001) • 59.8% (50.2%) and 79.3% (72.5%) of the responders had ≥3 (≥25%) IPSS point improvement already after wk 1 and wk 4, respectively |
Nickel et al., 2015 [48] M. Oelke, B. Wiese, R. Berges. Nocturia and its impact on health related quality of life and health care seeking behavior in German community-dwelling men aged 50 years or older. World J Urol. 2014;32:1155-1162 Crossref |
752 | 747 | 12 | Clinically-meaningful improvements of tadalafil on LUTS/BPH: • clinically-meaningful improvement (≥3 IPSS points) from randomization to endpoint in significantly more patients with tadalafil (71.1%) vs placebo (56.0%; p < 0.001) • clinically-meaningful improvement (≥25% of IPSS) from randomization to endpoint in significantly more patients with tadalafil (61.7%) vs placebo (45.5%; p < 0.001) • 38.5% (22.4%) of patients with tadalafil and 41.0% (23.3%) of patients with placebo had ≥3 (≥25%) IPSS point improvement during the placebo run-in phase |
Oelke et al., 2014 [50] H. Porst, C.G. Roehrborn, R.J. Secrest, A. Esler, L. Viktrup. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia and on erectile dysfunction in sexually active men with both conditions: analyses of pooled data from four randomized, placebo-controlled tadalafil clinical studies. J Sex Med. 2013;10:2044-2052 Crossref |
752 | 748 | 12 | Effects of tadalafil on nocturia (nocturnal voiding frequency): • for men with ≥1 nocturia episode at baseline, reduction with tadalafil (–0.5) was significantly greater than with placebo at study end (–0.4; LS mean change –0.2, p = 0.002) • for men with ≥2 nocturia episodes at baseline, reduction with tadalafil (–0.8) was significantly greater than with placebo at study end (–0.6; LS mean change –0.2, p = 0.003) • tadalafil (placebo) treatment resulted in reduction of ≥1 nocturia episodes in 47.5% (41.3%) of patients |
Porst et al., 2013 [51] G.B. Brock, K.T. McVary, C.G. Roehrborn, et al. Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: integrated data analyses from 4 placebo controlled clinical studies. J Urol. 2014;191:405-411 Crossref |
505 | 521 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • analysis only of men who were sexually active at baseline • significant improvement of total IPSS with tadalafil (–6.0) vs placebo (–3.6; p < 0.001) from baseline to study end • significant improvement of IIEF-EF with tadalafil (+6.4) vs placebo (+1.4, p < 0.001) from baseline to study end • similar IPSS improvements in men with ED vs without ED: no significant impact of ED severity on LUTS (IPSS) outcome |
Brock et al., 2014 [52] H. Porst, M. Oelke, E.R. Goldfischer, et al. Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational, randomized, placebo-controlled clinical studies. Urology. 2013;82:667-673 Crossref |
752 | 744 | 12 | Effects of tadalafil on LUTS/BPH in men with vs without ED: • similar LUTS (IPSS) improvement with tadalafil vs placebo in men without ED (–5.4 vs –2.2, p = 0.0007) compared with men with ED (–5.9 vs –2.3, p < 0.0001); ED subgroup interaction not significant • bidirectional path analysis for sexually-active men (n = 1250) only: 92.5% of the total effects of tadalafil on LUTS/BPH via direct effect on LUTS and 7.5% via indirect effects by IIEF-EF domain improvement |
Porst et al., 2013 [53] O. Nishizawa, M. Yoshida, M. Takeda, et al. Tadalafil 5 mg once daily for the treatment of Asian men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: analyses of data pooled from three randomized, double-blind, placebo-controlled studies. Int J Urol. 2015;22:378-384 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in different patient subgroups: • improvements in IPSS and BPH-Impact Index in all patient subgroups identical (investigated patient parameters: age, symptom severity, serum testosterone concentration, prostate volume, previous α–blocker or PDE5-inhibitor use, arterial hypertension, diabetes mellitus, cardio-vascular diseases) • no baseline item was identified to predict a favorable or unfavorable treatment outcome |
Nishizawa et al., 2015 [54] C. Vlachopoulos, M. Oelke, M. Maggi, et al. Impact of cardiovascular risk factors and related comorbid conditions on the treatment response to tadalafil once-daily in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: an integrated analysis of four randomized, double-blind, placebo-controlled clinical trials. Int J Clin Pract. 2015;69:1496-1507 |
601 | 598 | 12 | Effects of tadalafil on LUTS/BPH in different subgroups of Asian patients: • analysis of Japanese, Korean, or Taiwanese men • significant improvements in total IPSS (tadalafil vs placebo) at wk 4 (–3.69 vs –2.47), wk 8 (–4.72 vs –3.43), and wk 12 (–5.32 vs –3.79), each p < 0.001 • additionally, significant improvements at wk 4, wk 8, and wk 12 for IPSS storage and IPSS voiding subscores as well as for IPSS-QoL • older patients (≥65 yr) showed significantly lower IPSS improvement than younger patients (<65 yr); otherwise, no significant impact of any other baseline item on LUTS improvement |
Vlachopoulos et al., 2015 [55] C.G. Roehrborn, C. Chapple, M. Oelke, D. Cox, A. Esler, L. Viktrup. Effects of tadalafil once-daily on maximum urinary flow rate in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. J Urol. 2014;191:1045-1050 Crossref |
752 | 746 | 12 | Effects of tadalafil on LUTS/BPH in patients with cardio-vascular risk factors and therapy: • subanalysis of comorbid, cardio-vascular diseases on LUTS/BPH outcome • no significant differences in efficacy of tadalafil vs placebo for various cardio-vascular diseases/comorbidities • but patients with >1 antihypertensive drugs have significantly lower IPSS improvement compared with men taking ≤1 drug • use of diuretics resulted in significantly lower IPSS improvement compared to men taking other antihypertensives or no drugs |
Roehrborn et al., 2014 [56] D.V. Singh, U.K. Mete, A.K. Mandal, S.K. Singh. 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;11:187-196 Crossref |
752 (612a) |
748 (585a) |
12 | Effects of tadalafil on uroflow (maximum urinary flow rate): • in total study population, patients with tadalafil had significantly greater Qmax improvement (mean +1.1 ml/s) compared with patients with placebo (mean +0.4 ml/s; p = 0.003) • significant Qmax improvement in the total study population was mainly driven by effects in patients who voided 250–450 ml (p = 0.011) and had a baseline Qmax 10–15 ml/s (p = 0.044) |
a With valid measurement.
BPH = benign prostatic enlargement; ED = erectile dysfunction; IPSS = International Prostate Symptom Score; LUTS = lower urinary tract symptoms; PDE5 = phosphodiesterase type 5; QoL = quality of life.
Efficacy: In the first systematic review on PDE5-Is for LUTS secondary to BPH published in literature, Laydner et al [38]
In the first meta-regression analysis on PDE5-Is alone or in combination with α-blockers, Gacci et al [2]
In a subset analysis on tadalafil based on data extrapolated from a systematic review on all PDE5-Is, Gacci et al [42]
Safety: In the review from Liu et al [39]
The first meta-analysis of AEs due to PDE5-Is reported that flushing, gastro-esophageal reflux, headache, and dyspepsia had the higher risk of occurrence (odds ratio: 4.88; 2.21; 1.88; 1.85; respectively). Moreover, regarding the overall tolerability of the association between PDE5-Is and α-blockers, Gacci et al [42]
In a recent review on tadalafil once daily, the Authors underlined the good safety profile with a relative risk of AEs from tadalafil similar to those reported with vardenafil or sildenafil (2.27 vs 1.86 vs 1.22, respectively); overall, the occurrence of AEs reported was very similar to that reported with all PDE5-Is versus placebo: 16.0% versus 6.0% [42]
Clinically-meaningful symptom improvement: Clinically-meaningful LUTS improvement is defined as a decrease of ≥3 points or ≥25% reduction of total IPSS [45]
Similar post-hoc analyses were done in 1499 patients treated with tadalafil 5 mg once daily or placebo [47]
Nocturia: Nocturia, defined as one or more voids per night, is one of the most prevalent and bothersome single urinary symptoms in community-dwelling men or patients with LUTS/BPH and the main reason for physician consultations [48]
Tadalafil for men with or without ED: The majority of the randomized, placebo-controlled tadalafil trials included patients with ED (approximately 60–70% of trial participants). Pooled data analyses evaluated whether symptom improvement was related to baseline ED status or ED improvement during tadalafil treatment [50]
Other baseline characteristics: The impact of several patient characteristics was evaluated in 1500 pooled patients with LUTS/BPH with regard to symptom improvement and adverse events, including age (≤65 vs >65 yr), symptom severity (IPSS < 20 vs ≥ 20), testosterone concentration (<300 ng/dl vs ≥300 ng/dl), prostate-specific antigen-predicted prostate volume (<40 ml vs ≥40 ml), previous α-blockers use (yes vs no), previous PDE5 inhibitor use (yes vs no), arterial hypertension (yes vs no), diabetes mellitus (yes vs no), and cardiovascular disease (yes vs no) [52]
Finally, an integrated analysis on 1371 patients, demonstrated that tadalafil 5 mg once daily for 12 wk allowed to achieve a very small, but statistically significant increase in Qmax versus the placebo (median: 1.1 ml/s vs 0.4 ml/s) [55]
Tadalafil has been also proposed in combination with alpha blockers or 5-alpha reductase inhibitors. In a prospective randomized study on 133 men with LUTS/BPH treated with tamsulsoin plus tadalafil versus tamsulosin or tadalafil alone, combination therapy was more effective than monotherapy for ED (%IIEF change from baseline: 60.2 vs 39.3 and 46.0 respectively) with similar improvement for urinary symptoms (% IPSS change from baseline: 53.9 vs 50.9 and 33.5), with a good safety profile [56]
Regarding the impact of tadalafil on sexual activity of men with ED and LUTS due to BPH tadalafil, Giuliano et al [58]
There is a large body of scientific evidence supporting the role of the NO-cGMP pathway including PDE5I in: (1) regulation of the tone of the smooth muscle fibers of the prostate, urethra, and bladder neck and in a lesser extent of the bladder (relaxant effect), (2) control of the arterial supply of the LUT (vasodilatory effect), and (3) modulation of the micturition reflex via the afferent bladder innervation (decrease in the afferent signaling). PDE5-Is may also downregulate inflammatory processes in LUT and exert antiproliferative effects.
Several meta-analyses demonstrated that PDE5-Is are effective in improving LUTS and erectile function compared with placebo. The combination of PDE5-Is with α-blockers induce a small, but statistically significant improvement of maximum flow rate as compared with α-blockers alone, in addition to the positive effect on micturition and sexual activity. PDE5-Is alone or in combination with α-blockers are well tolerated: flushing, gastroesophageal reflux, headache, and dyspepsia are the most common treatment-associated AEs.
Tadalafil 5 mg once daily achieves an improvement of clinically-meaningful urinary symptoms and nocturnal voiding frequency compared with placebo. Furthermore, the effects on LUTS are independent of ED severity at baseline and ED improvement.
Data on the long-term effects prostate size, reduction of disease progression, or prostate cancer prevalence related to the use of PDE5-Is are not available; long-term outcomes and cost-effectiveness analyses are needed.
Author contributions: Mauro Gacci had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Gacci, Giuliano.
Acquisition of data: Gacci, Giuliano, Andersson, Maggi, Oelke.
Analysis and interpretation of data: Gacci, Andersson, Chapple, Maggi, Mirone, Oelke, Porst, Roehrborn, Stief, Giuliano.
Drafting of the manuscript: Gacci, Giuliano, Andersson, Maggi, Oelke.
Critical revision of the manuscript for important intellectual content: Chapple, Mirone, Porst, Roehrborn, Stief.
Statistical analysis: Gacci.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Giuliano.
Other: None.
Financial disclosures: Mauro Gacci certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Gacci: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Pierre Fabre; Andersson: Consultancy and Advisory Boards for Allergan, Astellas, Ferring; Chapple: Consultant, Researcher and Speaker for Allergan, Astellas, Medtronic and Recordati. Consultant and speaker for Lilly. Researcher and speaker for ONO and Pfizer. Speaker for Ranbaxy; Maggi: consultant, speaker and/or trial participant for Bayer Healthcare, GSK, Eli Lilly, Intercept, Menarini; Mirone: consultant, speaker, and/or trial participant for Eli Lilly Italia, Menarini, Zambon, Recordati, GSK, Bracco; Oelke: consultant, speaker, and/or trial participant for Bayer Healthcare, Eli Lilly and Company, and Pfizer; Porst: consultant, speaker for Eli Lilly and Compani, Menarini Group and Sanofi; CRoehrborn: has financial interests and/or other relationships with Eli Lilly and Company, and with Allergan, Afferent Pharmaceuticals, Auxiliary Medical Services, Cancer and Leukemia Group B Clinical Trial Group, GlaxoSmithKline, New England Research Institutes, NeoTract, National Institute of Diabetes and Digestive and Kidney Diseases, Protox, Southwest Oncology Group, Urologix, VA Corporate Studies, and Watson Pharmaceuticals. Giuliano: consultant for Lilly, Sanofi, Pfizer.
Funding/Support and role of the sponsor: None.