Introduction. Original Article: Clinical Investigation. Lu Sun, 1,3 Fang-Li Peng, 2 Zhi-Ling Yu, 1 Cai-Ling Liu 1 and Jun Chen 3.

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1 bs_bs_banner International Journal of Urology (2014) 21, doi: /iju Original Article: Clinical Investigation Combined sildenafil with vacuum erection device therapy in the management of diabetic men with erectile dysfunction after failure of first-line sildenafil monotherapy Lu Sun, 1,3 Fang-Li Peng, 2 Zhi-Ling Yu, 1 Cai-Ling Liu 1 and Jun Chen 3 1 Department of Urology, People s Hospital of Yichun, 2 Aesthetic Medical School, Yichun University, Yichun, Jiangxi, and 3 Department of Infertility and Sexual Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China Abbreviations & Acronyms cgmp = cyclic guanosine monophosphate DM = diabetes mellitus ED = erectile dysfunction EDDM = erectile dysfunction associated with diabetes mellitus HbA 1c = glycosylated hemoglobin IIEF-5 = International Index of Erectile Function PDE5i = phosphodiesterase type 5 inhibitor SEP = Sexual Encounter Profile VED = vacuum erection devices Correspondence: Jun Chen M.D., Ph.D., Department of Infertility and Sexual Medicine, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou , China. jchen121121@hotmail.com Received 19 March 2014; accepted 15 June Online publication 14 July 2014 Objective: To evaluate the efficacy and safety of combination therapy of sildenafil plus vacuum erection devices in men with type 2 diabetes mellitus with moderate to severe erectile dysfunction who are dissatisfied with the results of using sildenafil alone. Methods: The study included 66 diabetes mellitus patients presenting erectile dysfunction for at least 6 months and dissatisfied with the use of 100 mg sildenafil monotherapy. The patients were randomized in two groups. Those in group A (n = 33) were instructed to use a vacuum erection device only, whereas those in group B (n = 33) were treated with combination therapy, including sildenafil 100 mg and a vacuum erection device. Erectile function was evaluated subjectively using the International Index of Erectile Function, Sexual Encounter Profile questionnaire questions 2 and 3 at visit 1 (baseline; study entry), visit 2 (4 weeks after baseline), and visit 3 (12 weeks after baseline; study end). Results: There were no significant differences in average patient age, duration of diabetes, duration of erectile dysfunction, baseline International Index of Erectile Function scores, hypertension, blood testosterone, smoking and alcohol consumption between two groups. Mean International Index of Erectile Function scores were significantly higher for group B at the 1-month (14.86 ± 2.17 vs ± 2.63; P < ) and 3-months (17.53 ± 2.95 vs ± 2.81; P < ) visits. Men in group B had better successful penetration (73.3% vs 46.6%) and successful intercourse (70% vs 46.6%) at 3 months compared with group A. Conclusion: Combined use of sildenafil and vacuum erection device therapy significantly enhances erectile function, and it is well tolerated by diabetes mellitus patients not responding to first-line sildenafil alone. Key words: Introduction diabetes mellitus, erectile dysfunction, sildenafil, vacuum erectile device. DM is a chronic disease, which affects 3 6% of the general population, and causes short- and long-term complications. ED, defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance, 1 is one of the medical affectations with the greatest impact on the quality of life of diabetic patients. 2 Results from the Massachusetts Male Aging Study show that men with DM have a threefold increase in the incidence of ED compared with those with no DM. 3 Prevalence estimates of ED in diabetic populations range from 20% to 71%, 4 with the condition occurring in 32% of men with type 1 and 46% of those with type 2 DM. 5 Selvin reported that the prevalence of ED was over 50% in men with DM in the USA. 6 A study from China stated that the prevalence of ED in patients with DM was approximately 75.2%. 7 Studies from Saudi Arabia reported moderate to severe ED among 80 90% of diabetic patients. 8 Hyperglycemia in DM causes multifactorial metabolic changes. Neuropathy, atherosclerosis of big vessels, endothelial dysfunction of small vessels, comorbid diseases, hormonal imbalance, physiological stress and various medications can be involved in the pathogenesis of EDDM. 9 Recently, the role of vascular endothelium deterioration and neural dysfunction, which adversely affect nitric oxide signaling mechanisms within the corpora cavernosa, has been well recognized and was considered to be the major pathogenic factor in these patients. 10 There are several methods currently available for the treatment of EDDM, including oral PDE5i, intracavernosal injections of vasoactive agents, intraurethral alprostadil, VED, implantation of penile prostheses and vascular reconstruction The Japanese Urological Association 1263

2 L SUN ET AL. Since introduced in 1998, PDE5i has been considered as a first-line strategy for most ED patients. However, not all patients respond to PDE5i, even with the use of the maximum recommended dose; in most published clinical trials, the efficacy of PDE5i as judged by successful sexual intercourse ranges from 52% to 94%. 11 A study by Rendell showed that just over 50% of diabetic men with ED respond favorably to PDE5i. 12 For these PDE5i non-responders, second-line treatments can be offered. Currently, the efficacy of the VED has also been reported. As a non-invasive, safe, drug-free and cost-effective ED treatment, the VED utilizes negative pressure to distend the corporal sinusoids and to increase the blood inflow to the penis, with the aid of an external constricting ring, which is placed at the base of penis to prevent blood outflow, maintaining the erection for sexual intercourse. It has been an important therapeutic option for those patients who do not benefit from oral agents, and was recommended as an alternative ED treatment by the American Urological Association in The European guidelines have listed the use of a VED as a first-line option when oral treatment fails. 14 Recently, the efficacy of combination therapy has gained widespread acceptance. The management of difficult-to-treat ED with a combination of available treatment modalities might be more efficacious when single treatment modalities fail, and appears to be synergistic in view of their different mechanisms of action. Thus, the objective of the present study was to assess the efficacy of combining VED and PDE5i for ED in DM patients after PDE5i monotherapy failure. Methods From January 2010 to March 2013, a total of 66 men were recruited into the trial at the Third Affiliated Hospital of Sun Yat-sen University in Guangzhou, China. The study was approved by the institution ethics committee. As a baseline criterion for inclusion, all patients were aged over 18 years and clinically diagnosed with type 2 DM together with ED during the minimum period of 6 months. All patients had acceptable metabolic control, glycosylated hemoglobin levels ranged between 6 8%, and were defined as non-responders after four to six unsuccessful attempts using a maximum dose of 100 mg for sildenafil citrate over at least a 3-month period. All patients provided detailed medical and sexual history, psychological profile, complete blood count, electrolytes, urea and creatinine, blood testosterone, liver enzymes, prolactin, and glucose examination before entry into the trial. The diagnosis of ED was established using a standardized questionnaire (IIEF- 5). 15 All patients having moderate (score 11 16) to severe ED (score 10 points or less) were recruited to the present study. The demographic characteristics of the patients, as well as the data regarding the duration of DM and their comorbidities, are presented in Table 1. All participants had a steady female sexual partner throughout the study for consistency in recording responses to efficacy questionnaires. Patients with Peyronie s disease, penile curvature or a history of penile surgery, radical prostatectomy, severe renal or hepatic abnormalities, congestive heart failure, low testosterone levels, alcohol/drugs abuse, receiving nitrates, anti-androgens, α-blockers or major psychiatric disorders were Table 1 Patient baseline characteristics Variable Group A Group B P-value No. patients P > 0.05 Mean age (years) 45.0 ± ± 9.5 Body mass index (kg/m 2 ) 27.3 ± ± 3.4 Mean IIEF-5 score ± ± 2.96 Mean duration of diabetes 5.37 ± ± 4.3 (years) Mean duration of ED (years) 2.85 ± ± 1.89 HbA 1c, n (%) 6.4 ± ± 2.5 Mean blood testosterone ± ± 2.9 (nmol/l) Patients with hypertension, n (%) 10 (30.3%) 11 (33.3%) Patients who smoke cigarettes, 7 (21.2%) 9 (27.2%) n (%) Patients who drink alcohol, n (%) 9 (27.2%) 8 (24.2%) Patients with benign prostatic hyperplasia, n (%) 6 (18.2%) 5 (15.1%) There was no significant difference between the two groups with regard these characteristics. P > excluded from the study. Men with a history of sickle-cell disease, multiple myeloma, leukemia or any other hematological disorders were also excluded. A block randomization procedure was applied. Patients were randomly assigned to each treatment group according to computer software-generated numbers (Excel 2007; Microsoft, Redmond, WA, USA), with each group containing 33 patients. Patients in group A were instructed on the proper use of a VED by personal tutoring and watching an instructional video (Timm Medical Technologies; Eden Prairie, MN, USA), and given a device for use without the constrictor ring; a battery-operated pump is then applied to create an artificial erection. Once the desired state of erection is achieved, the erect state is maintained for 1 2 min, released and then pumped again; this is practiced for at least 30 min every day, and the patients use a constriction ring during coitus, but this should not be left on for longer than 30 min to prevent ischemic injury to the penis. 15 Patients who underwent VED combined with sildenafil therapy were assigned to group B. They received sildenafil 100 mg daily 1 h before sexual activity or 2 h after a meal, and were given the same course of VED as group A. Use of another PDE5i was not allowed during the study. Patients were being asked to fill out the IIEF-5 questionnaire, which is a sensitive indicator of changes in erectile function. It is scored from 1 to 5 (1, never/occasionally; 2, less than one half the time; 3, sometimes/one half the time; 4, more than one half the time; and 5, almost always) and SEP questionnaire, which patients answered with yes/no. Questions asked were, SEP-2, Were you able to insert your penis into your partner s vagina? and for SEP-3, Did your erection last long enough to successfully complete coitus? Responses to the IIEF-5 were presented as mean values. The baseline, run-in period and end-point score for each SEP question was presented as counts and percentages, respectively. Data were collected at visit 1 (baseline; study entry), visit 2 (4 weeks after baseline) and visit 3 (12 weeks after baseline; study end), during each follow-up visit at the urological office The Japanese Urological Association

3 Therapy to treat diabetic men with ED Table 2 Comparison of various variables between two groups at baseline, 1-month and 3-month visits Efficacy variables VED group (n = 30) Sildenafil plus VED group (n = 30) P-value Baseline 1 month 3 months Baseline 1 month 3 months Mean IIEF-5 score ± ± ± ± ± 2.17* ± 2.95* <0.001 SEP-2 Successful penetration (%) 3 (10%) 9 (30%) 14 (46.6%) 3 (10%) 14 (43.7%)* 22 (73.3%)* <0.001 SEP-3 Successful intercourse (%) 2 (6.6%) 8 (26.6%) 14 (46.6%) 3 (10%) 13 (43.3%)* 21 (70%)* <0.001 P-value for mean change from baseline to endpoint, VED group versus sildenafil plus VED group. Treatment with sildenafil plus VED therapy significantly improved all domains of sexual functioning in EDDM patients (*P < 0.001). Statistical differences were determined with Student s t-test. Values of P < 0.05 were considered significant. We used the SPSS 13.0 software (SPSS, Chicago, IL, USA) for the computations. Results Three patients withdrew from group A two complained that the VED preparations were too bothersome and decided to pursue other more invasive treatment. Another withdrew because of a lack of efficacy. Three patients were lost to follow-up from group B. A total of 60 patients data were included in the final analysis. Two groups did not show statistical differences in measurements regarding to age, body mass index, IIEF-5, hypertension, smoking, duration of diabetes and duration of ED, and the values are summarized in Table 1. The baseline mean IIEF-5 scores were similar for patients randomized to group A or group B (11.36 ± 3.17 vs ± 2.96, respectively). During the 1-month and 3-month visits, the scores were significantly higher for the sildenafil plus VED group than for the VED group (14.86 ± 2.17 vs ± 2.63; P < ) and (17.53 ± 2.95 vs ± 2.81; P < ). Likewise, men in the combined group had better successful penetration (43.7% vs 30% and 73.3% vs 46.6%) successful intercourse (43.3% vs 26.6% and 70% vs 46.6%) at the 1-month and 3-months visits compared with the VED group. Combination therapy significantly improved erectile function compared with the VED group, as assessed by each of the three primary efficacy variables (Table 2). The overall adverse side-effects that occurred with sildenafil included flushing in six, nausea in five and headache in five, and with the VED included penile bruising in six and numbness in five. There were no adverse events associated with the use of tension rings during the trial. These adverse events were mostly mild, and did not affect the patients daily life; none of the patients withdrew from the study as a result of side-effects. Discussion PDE5 inhibitors, as a first-line treatment of EDDM, 13 work by inhibiting the degradation of cgmp in the penis. The cgmp signaling pathway within the cavernosal smooth muscle cell is a key mechanism responsible for erection. With sexual stimulation, the cavernous nerve endings and vascular endothelial cells produce nitric oxide, which stimulates guanylyl cyclase and cgmp production in cavernosal smooth muscle cells. PDE5 normally degrades cgmp, whereas PDE5i block the hydrolysis of cgmp to guanosine 5 -monophosphate, thus increasing suberectile levels of cgmp, which acts as a secondmessenger to activate a cgmp-specific protein kinase and lower intracellular calcium, potentiating smooth muscle relaxation, increasing blood flow to the corpus cavernosum and facilitating erection. Although large multicenter clinical trials have shown the efficacy and tolerability of sildenafil in erectile dysfunction with various etiologies and a broad range of severity, to DM patients, the efficacy is significantly lower. A review of the findings in the literature yielded a 62.9% positive response rate in 465 patients with DM evaluated by Carson et al., 16 and a 64.6% rate in the study of Boulton et al. 17 The analysis of a group of 276 EDDM patients who received sildenafil shows that just 147 (53.3%) responded positively. 18 The utility of PDE5i might be limited by the severity of cavernosal nerve injury and endothelial dysfunction of small vessels after DM, which reduce the cavernous nerves endings, and vascular endothelial cells produce nitric oxide, which in turn inhibits initiation of the required erectile cascade for PDE5i to be effective. These structural changes could explain the lower efficacy rates of PDE5i in EDDM than in the general population. Recently, with the introduction of the VED to the medical arsenal, men not entirely satisfied with erectile function FTER the use of sildenafil and not yet interested in invasive therapy are offered VED therapy before being switched to the more invasive alternatives. 19 Unlike the normal erection procedure, VED create a vacuum around the penis, utilizing negative pressure to engorge the corpora cavernosa sinusoids and increase blood flow, and are therefore not dependent on the neurogenic and vasculogenic mechanisms of erectogenesis. Application of the constriction ring reduces venous outflow of blood, thereby preventing early detumescence. Thus, VED represent an acceptable alternative primary treatment option after failed oral therapies. What s more, VED could be used without the application of a constriction ring, just to increase blood oxygenation to the corpora cavernosa. 20 However, no therapies are efficacious or tolerated by every patient. Vacuum therapy alone has a reported efficacy rate of 65 90%, and like oral medication, a significant number of patients have inadequate responses to VED as well. 21 Arauz-Pacheco et al. 22 and Bodansky et al. 23 reported successful rates of 75% and 58% for diabetic ED, respectively. The use of combination therapy regimens has recently been studied. The advantages not only include additive or synergistic effects that might be achieved by targeting two or more different erectile mechanisms of action within the erectile bodies optimizing erectile rigidity, but also reducing the incidence of 2014 The Japanese Urological Association 1265

4 L SUN ET AL. side-effects and cost per dose of drug. Canguven et al. studied 69 men who failed PDE5i therapy that were treated with both PDE5i and a VED. 24 At the end of the 4-week study, the IIEF scores, SEP-2, SEP-3 and the Global Patient Assessment Scale had significant increased. The conclusion of the study was that combination therapy with a PDE5i and a VED could restore erectile function in those men who did not fully respond to oral therapy. A similar study was reported by Chen et al., where 41 patients not satisfied with erectile function while using 100 mg sildenafil or a VED alone were treated with concomitant use of sildenafil and a VED. 19 All these patients responded positively to the Global Assessment Question, and IIEF-5 erectile function domain scores obtained for this group increased from 10.2 at baseline to 27, and had a greater level of satisfaction with the results of combined treatment than with each treatment alone. They concluded that combined use of sildenafil and a VED can be offered to patients not satisfied when either treatment is used alone. As shown in the present study, the improvement in the erectile function domain score on the IIEF-5 and the percentage of sexual intercourse attempts marked by successful vaginal penetration and completion according to SEP-2 and SEP-3 was statistically significantly improved at the 1-month and 3-month visits of the combined therapy group. The theoretical explanation for this successful combination relies on the following findings below: Kim et al. found that high oxygen tension is essential for the nitric oxide synthase activation whether neuronal or endothelial, and that the low oxygen tension (as in the flaccid state) is associated with inhibited nitric oxide synthase. 25 Cellek et al. concluded that restoring diminished blood flow to the vasa nervorum as early as possible before irreversible changes, such as fibrosis and neuronal degeneration, occur should be a key aim of the medical management of diabetic neuropathy. 26 Donatucci and Lue further determined that chronic VED usage increases cavernous arterial flow in men with mild vasculogenic ED as measured using a duplex ultrasonograph. 27 Bosshardt et al. confirmed that there is a passive congestion of mixed arterial and venous blood, with extra-tunica tissue making up a large component of the increased diameter. 28 Their data showed that mean SO 2 of corporeal blood immediately after VED-induced erection was 79.2% in patients. A total of 58% of blood with VED-induced erection was arterial and 42% of blood was venous in origin. Recently, Lin et al. applied VED therapy to a bilateral cavernous nerve crash rat model, which simulates human VED, their data showed that the calculated blood constructs in the corpus cavernosum right after VED application were 62% arterial and 38% venous blood. 29 The calculated blood constructs in the corpus cavernosum under traction were 27% arterial and 73% venous blood. The calculated blood constructs from the flaccid corpus cavernosum were 12% arterial and 88% venous blood; these results provide direct basic scientific evidence that VED therapy significantly increased penile oxygen levels. To EDDM patients, the mechanism of PDE5i plus VED therapy can circumvent the limitation of monotherapy. Since the hypoxia caused by microvascular deficit is the trigger leading to a series of events that eventually cause irreversible damage, 26 we then used VED to simulate natural erection half an hour every day, which allows reoxygenation of the penis. 30 The increased arterial inflow in the penis increased the cavernosal tissue oxygen levels, which effectively alleviated the tissue hypoxia damage caused by cavernous nerve injury, inhibiting tissue cell apoptosis, preventing cavernosal tissue fibrosis and allowing adequate stimulation of nitric oxide synthase to produce nitric oxide. At the same time, taking sildenafil citrate 100 mg daily can greatly exert its synergistic action in improving the ability to have a better erection. Despite successful results from the majority of patients in the study, in the combination therapy group, eight still patients showed a negative response to SEP-2 and nine patients showed a negative response to SEP-3 at the 3-month visit. Maybe severe, inconvertible neuropathy, endothelial dysfunction and progression of penile atherosclerosis could explanation as to why these patients responded poorly to combination therapy, but additional follow up would be required to confirm this conjecture. In contrast, the small sample size of the present study and the short observation time limited the inferences that can be drawn from statistical analyses in relation to sildenafil plus VED therapy. Also, we could not measure the actual frequency of VED use as well as the precise dose of sildenafil given, and 3 months might not be the optimum duration; it is possible that an extended period of up to 6 months might have further benefit. Large, multicenter, long-term trials are still required in order to identify the best strategy for EDDM. The present pilot study showed that statistically superior results were seen in IIEF-5, SEP-2, and SEP-3 measures after 1 month and 3 months of combination therapy consisting of sildenafil and VED as compared with sildenafil alone. These results suggest that this combination therapy could be effectively used for sildenafil non-responder EDDM patients, and could be considered before initiating more invasive alternatives. Conflict of interest None declared. References 1 Lue TF. Erectile dysfunction. N. Engl. J. Med. 2000; 342: Hidalgo-Tamola J, Chitaley K. Review. J. Sex. Med. 2009; 6: Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J. Urol. 1994; 151: Penson DF, Wessells H. Erectile dysfunction in diabetic patients. Diabetes Spectrum 2004; 17: Vickers MA, Satyanarayana R. 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