World Journal of Urology (2019) 37:1061–1074 https://doi.org/10.1007/s00345-018-2583-1 REVIEW Comparative efcacy and safety of phosphodiesterase type 5 inhibitors for erectile dysfunction in diabetic men: a Bayesian network meta‑analysis of randomized controlled trials Xinyang Liao1 · Shi Qiu1 · Yige Bao1 · Wanyu Wang2 · Lu Yang1 · Qiang Wei1 Received: 9 September 2018 / Accepted: 26 November 2018 / Published online: 6 December 2018 © Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Purpose To compare the efcacy and safety profles of diferent phosphodiesterase-5 inhibitors (PDE5Is) administrations for erectile dysfunction (ED) in diabetic men, including on-demand (PRN) and regular regimens (OAD). Materials and methods Searches were carried out in four electronic databases: PubMed (until April 17th, 2017); Scopus (until April 17th, 2017); Embase (until April 17th, 2017); and Cochrane (until April 18th, 2017). The outcomes for this study are as follows: (1) Global Assessment Question (GAQ) positive response rate; (2) changes from baseline to the end of the study in Erectile Function Domain of International Index of Erectile Function (IIEF-EF); and (3) treatment-related adverse events (TRAEs). The comparative efects of PDE5I regimens were analyzed with random-efect models in a Bayes- ian Framework using the GeMTC R package. Results We identifed 1056 records, of which 15 randomized trials with 5274 patients were included. The included stud- ies covered eight kinds of PDE5I administration: avanafl PRN; mirodenafl PRN; sildenafl PRN; tadalafl PRN; tadalafl OAD; udenafl PRN; udenafl OAD; vardenafl PRN; and placebo. In surface under the cumulative ranking curve analysis, vardenafl PRN ranked frst, third and frst, and mirodenafl PRN ranked second, frst and second in GAQ, IIEF-EF, and TRAEs, respectively. Conclusions PDE5I administrations were generally efcient and well-tolerated in diabetic men. Among these administrations, vardenafl PRN and mirodenafl PRN seem to have a possible advantage of efcacy and avoiding adverse efects compared to others. There is no signifcant diference between regular and on-demand regimens of PDE5Is. Keywords Erectile dysfunction · Diabetes · Phosphodiesterase type 5 inhibitors · Network meta-analysis Introduction Xinyang Liao, Shi Qiu and Yige Bao contributed equally as frst authors of this manuscript. Erectile dysfunction (ED) is defned as the persistent inabil- ity to attain and maintain an erection sufcient to permit Electronic supplementary material The online version of this satisfactory sexual performance [1]. A greater risk of ED article (https​://doi.org/10.1007/s0034​5-018-2583-1) contains is strongly associated with diabetes [2]. The prevalence of supplementary material, which is available to authorized users. ED in diabetic men has been reported to be 35–75% [3–7]. * Lu Yang The pathophysiology of ED in diabetic men is multifacto- [email protected] rial, and its main underlying causes fall into three classes: * Qiang Wei psychogenic, neurological, and vasogenic. Psychogenically, [email protected] diabetes-associated depression may decrease libido and 1 reduce the ability to have intercourse [8]. Neurologically, Department of Urology, Institute of Urology, West China diabetes may cause sensory neuropathy, which reduces sex- Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan 610041, People’s Republic of China ual stimulation that triggers the cognitive processes lead- ing to an erection [9]. In the NO/cGMP (nitric oxide/cyclic 2 Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, guanosine monophosphate) signaling pathway of penile People’s Republic of China erection, the cavernosal nerve releases NO in response to Vol.:(0123456789)1 3 1062 World Journal of Urology (2019) 37:1061–1074 sexual stimulation [10]. NO then stimulates the production intracavernous structural alterations due to aging, diabetes, of cGMP via interaction with guanylyl cyclase [11]. cGMP or surgical damage [18, 19]. However, no data are available acts downstream as a second messenger, leading to penile for humans. Tadalafl 2.5 and 5 mg once-daily for ED were erection. Given the reduced NO synthesis and impaired approved by the European Medicines Agency in 2007. As an activity of guanylyl cyclase [12] in diabetic men, it is easier alternative to on-demand regimens, the regular dosing regi- for such patients to experience erectile dysfunction, and mens aforded by PDE5Is allow couples to have spontaneous erectile dysfunction is harder to cure. and more frequent sexual activity because dosing time and Phosphodiesterase-5 inhibitors (PDE5Is), including time of sexual activity do not have to coincide [20]. avanafl, mirodenafl, sildenafl, tadalafl, vardenafl and ude- We aim to compare diferent administrations of PDE5Is nafl are currently the frst-line oral therapy for ED of any and diferent regimens for diabetic ED. Ideally, all PDE5I etiology [13]. The inhibition of PDE5I reduces the hydroly- administrations for diabetic ED should be evaluated via sis of cGMP in the cavernosal tissue, resulting in smooth direct comparisons in high-quality studies, but to date, muscle relaxation with increased arterial blood fow, which no data exist comparing diferent PDE5Is for diabetic ED compresses the subtunical venous plexus, leading to penile directly. A systematic review and network meta-analysis erection [14]. However, in diabetic patients, the decrease (NMA) is one feasible way of combining evidence of direct in NO and impaired activity of guanylyl cyclase restricts and indirect comparisons simultaneously. the production of cGMP. Therefore, PDE5Is might not be as efective for treating diabetic ED as they are for treating non-diabetic ED, as shown by several studies [15]. Evidence acquisition Traditionally, PDE5Is are prescribed as on-demand regimens (PRN) and taken 15–30 min before intercourse. Data source and search strategy Recently, however, some studies showed that the regular regimens (OAD) of PDE5Is yielded higher treatment sat- The study protocol was registered in PROSPERO, isfaction for patients [16, 17]. Further, animal studies have CRD42017062264 (http://www.crd.york.ac.uk/PROSPERO/ shown that PDE5I OAD signifcantly improves or prevents display_recor d.asp?ID=CRD42 01706 2264 ). Searches were Fig. 1 Flowchart of study selec- tion. ED Erectile dysfunction, PDE5Is phosphodiesterase type 5 inhibitors, RCT randomized controlled trial 1 3 World Journal of Urology (2019) 37:1061–1074 1063 Table 1 Estimates of efects (with 95% credible intervals) and confdence ratings for comparisons of PDE5Is for the treatment of erectile dys- function in diabetic men on the outcome Global Assessment Question (GAQ) positive response rate Outcome: GAQ Patients: diabetic men with erectile dysfunction Interventions: mirodenafil PRN, sildenafil PRN, tadalafil PRN, tadalafil OAD, udenafil PRN, udenafil OAD, vardenafil PRN Comparisons: placebo Outcomes: GAQ Comparator #13 RCTs, 2149 patients Mirodenafil Sildenafil Tadalafil Tadalafil Udenafil Udenafil Vardenafil Placebo PRN PRN OAD PRN OAD PRN PRN NA OR 0.61 OR 0.32 OR 0.31 OR 0.62 OR0.45 OR0.91 OR 0.07 Mirodenafil (0.16, 2.2) (0.08, 1.28) (0.07, 1.31) (0.08, 4.86) (0.11, 1.96) (0.21, 3.66) (0.02, 0.23) PRN NA ⨁◯◯◯ ⨁⨁◯◯ ⨁⨁◯◯ ⨁⨁◯◯ ⨁⨁◯◯ ⨁⨁◯◯ ⨁⨁⨁◯ Very low1,2,3 Low2,3 Low2,3 Low2,3 Low2,3 Low2,3 Moderate1 OR 1.64 NA OR 0.52 OR 0.52 OR 1.02 OR 0.75 OR 1.48 OR 0.12 Sildenafil (0.45, 6.15) (0.22, 1.23) (0.21, 1.26) (0.2, 5.82) (0.29, 1.94) (0.62, 3.56) (0.07, 0.19) PRN ⨁◯◯◯ NA ⨁⨁◯◯ ⨁⨁◯◯ ⨁◯◯◯ ⨁⨁◯◯ ⨁⨁◯◯ ⨁⨁⨁◯ Very low1,2,3 Low1,2 Low1,2 Very low1,2,3 Low1,2 Low1,2 Moderate1 Tadalafil OR 3.12 OR 1.92 NA OR 0.99 OR 1.96 OR 1.43 OR 2.83 OR 0.22 OAD (0.78, 13.2) (0.81, 4.51) (0.36, 2.8) (0.35, 12.07) (0.49, 4.23) (1.04, 7.81) (0.11, 0.45) ⨁⨁⨁◯ ⨁⨁◯◯ NA ⨁⨁⨁◯ ⨁⨁◯◯ ⨁⨁⨁◯ ⨁⨁⨁◯ ⨁⨁⨁◯ Moderate1 Low1,2 Moderate2 Low2,3 Moderate2 Moderate2 Moderate2 OR 3.19 OR 1.93 OR 1.01 NA OR 1.96 OR 1.45 OR 2.86 OR 0.22 Tadalafil (0.76, 13.5) (0.79, 4.71) (0.36, 2.82) (0.34, 12.24) (0.48, 4.4) (1, 8.14) (0.1, 0.47) PRN ⨁⨁◯◯ ⨁⨁◯◯ ⨁⨁⨁◯ NA ⨁⨁◯◯ ⨁⨁⨁◯ ⨁⨁⨁◯ ⨁⨁⨁⨁ Low2,3 Low1,2 Moderate2 Low2,3 Moderate2 Moderate2 High OR 1.62 OR 0.98 OR 0.51 OR 0.51 NA OR 0.73 OR 1.45 OR 0.11 Udenafil (0.21, 11.93) (0.17, 5.11) (0.08, 2.86) (0.08, 2.91) (0.18, 2.84) (0.23, 8.12) (0.02, 0.54) OAD ⨁⨁◯◯ ⨁◯◯◯ ⨁⨁◯◯ ⨁⨁◯◯ NA ⨁⨁⨁◯ ⨁⨁◯◯ ⨁⨁⨁◯ Low2,3 Very low1,2,3 Low2,3 Low2,3 Moderate3 Low2,3 Moderate3 OR 2.2 OR 1.34 OR 0.7 OR 0.69 OR 1.36 NA OR 1.98 OR 0.15 Udenafil (0.51, 9.51) (0.51, 3.43) (0.24, 2.02) (0.23, 2.08) (0.35, 5.71) (0.67, 5.79) (0.07, 0.34) PRN ⨁⨁◯◯ ⨁⨁◯◯ ⨁⨁⨁◯ ⨁⨁⨁◯ ⨁⨁⨁◯ NA ⨁⨁⨁◯ ⨁⨁⨁⨁ Low2,3 Low1,2 Moderate2 Moderate2 Moderate3 Moderate2 High OR 1.1 OR 0.67 OR 0.35 OR 0.35 OR 0.69 OR 0.5 NA OR 0.08 Vardenafil (0.27, 4.67) (0.28, 1.62) (0.13, 0.96) (0.12, 1) (0.12, 4.27) (0.17, 1.49) (0.04, 0.16) PRN ⨁⨁⨁◯ ⨁⨁◯◯ ⨁⨁⨁◯ ⨁⨁⨁◯ ⨁⨁⨁◯ ⨁⨁⨁◯ NA ⨁⨁⨁⨁ Moderate3 Low1,2 Moderate2 Moderate2 Moderate3 Moderate2 High OR 14.22 OR 8.66 OR 4.53 OR 4.48 OR 8.86 OR 6.47 OR 12.86 NA (4.32, 49.26) (5.37, 14.12) (2.24, 9.25) (2.12, 9.63) (1.85, 46.86) (2.93, 14.74) (6.27, 26.49) Placebo ⨁⨁⨁◯ ⨁⨁⨁◯ ⨁⨁⨁⨁ ⨁⨁⨁⨁ ⨁⨁⨁◯ ⨁⨁⨁⨁ ⨁⨁⨁⨁ NA Moderate3 Moderate1 High High Moderate3 High High GRADE Working Group grades of evidence—high quality: further research is very unlikely to change our confdence in the estimate of efect; moderate quality: further research is likely to have an important impact on our confdence in the estimate of efect and may change the estimate; low quality: further research is very likely to have