Efficacy of Sildenafil Citrate intreatment of Erectile Dysfunction:EffectofType2Diabetes

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1 European Urology European Urology 46 (2004) Efficacy of Sildenafil Citrate intreatment of Erectile Dysfunction:EffectofType2Diabetes Ahmed I. El-Sakka a,b,* a Department of Urology, Suez Canal University, Ismailia, Egypt b Al-Noor Specialist Hospital, Makkah, Saudi Arabia Accepted 3 June 2004 Available online 22 June 2004 Abstract Purpose: To assess efficacy of sildenafil citrate in treatment of erectile dysfunction: effect of type 2 diabetes. Materials and Methods: A total of 466 male patients with erectile dysfunction (ED) were enrolled in this study. Of them 382 were diabetic and 84 were non-diabetic. Patients were screened for ED using the erectile function domain of the International Index for Erectile Function (IIEF). Patients underwent routine laboratory investigations, in addition to total testosterone and prolactin assessment. To assess the effect of diabetes on efficacy of sildenafil, we compared the pre and post sildenafil responses to erectile function domain, Q3, Q4. Overall satisfaction and global efficacy question (GEQ) were also assessed. Results: Mean age S.D. was and years for patients with and without diabetes respectively. There were significant associations between increased severity of ED and longer duration, poor metabolic control and presence of more than one diabetes-related complication ( p < 0.05 for each). Differences were significant between pre and post sildenafil administration regarding erectile function domain, Q3, Q4 ( p < 0.05 for each). In the non-diabetic patients the GEQ and the overall satisfaction were significantly higher than in diabetics ( p < 0.05 for each). Global efficacy question was significantly low in patients with fair and poor metabolic control, longer duration of diabetes, and patients with diabetic complications ( p < 0.05 for each). Conclusions: Sildenafil is an effective treatment for diabetic patients with ED. Although the efficacy of sildenafil was negatively affected by factors as poor control and longer duration of diabetes and presence of more than one diabetes-related complication, however, the global efficacy and the overall patients satisfaction were high. # 2004 Elsevier B.V. All rights reserved. Keywords: Erectile dysfunction; Sildenafil; Type 2 diabetes 1. Introduction Erectile dysfunction is a highly prevalent health problem [1]. The prevalence of diabetes mellitus is also increasing, with non-insulin-dependent (type 2) accounting for 90 95% of the diagnosed diabetic patients [2]. This high prevalence of both ED and diabetes is partly due to the increase in life expectancy and the high incidence of these conditions in the geriatric population. Due to a the large overlap between * Present address: Andrology Clinic, Diabetic Centre, Al-Noor Specialist Hospital, PO Box 6251, Makkah, Saudi Arabia. Tel. þ ; Fax: þ address: aielsakka@yahoo.com (A.I. El-Sakka). conditions typically associated with diabetes and ED, namely, vascular disease, hypertension, neuropathy, dyslipidemia, and obesity, the need for further connecting the ED and diabetes research fields becomes urgent. Other similarity between these two conditions is that; the currently available treatments for both diabetes and ED are not curative; however, a promising treatment is emerging. Sildenafil citrate, the first oral therapeutic agent for the treatment of ED [3], is a potent and selective inhibitor of cyclic guanosine monophosphate (cgmp)-specific phosphodiesterase type 5 (PDE5), the predominant isozyme metabolising cgmp in the corpus cavernosum [4]. By more release of nitric oxide during sexual stimulation and selective /$ see front matter # 2004 Elsevier B.V. All rights reserved. doi: /j.eururo

2 504 A.I. El-Sakka / European Urology 46 (2004) inhibition of cgmp catabolism in the cavernosal smooth muscle cells, Sildenafil citrate ultimately restores the erectile function [3]. Efficacy of sildenafil in treatment of ED was demonstrated regardless of its etiology, with similar responses reported for men with ED of organic, psychogenic, or mixed etiologies [5]. Recently, we have shown that ED is very common among type 2 diabetic patients in our community [6]. Further, since sildenafil had stood the test of time, and more convincing evidences of its efficacy and safety had been established, the users of the drug had significantly increased [2,3,7]. These findings prompted us to investigate the effect of type 2 diabetes on the efficacy of Sildenafil as a treatment option for erectile dysfunction. 2. Material and methods 2.1. Research design This is a prospective office-based, open-label, flexible-dose (taken as needed) study evaluating the effect of type 2 diabetes on the efficacy of sildenafil as a treatment for ED. Male patients above the age of 20 years with a clinical diagnosis of erectile dysfunction for at least 6 months and who were in stable relationship with a female partner for more than 6 months visiting our andrology clinic at Al-Noor Specialist Hospital (the main hospital, serving the city of Makkah and the surrounding area) were candidates of study. Patients were excluded from enrollment if they had penile anatomic defects that significantly impaired erections, major hematologic, renal or hepatic abnormalities, poorly controlled major psychiatric disorder, significant cardiovascular diseases, including myocardial infarction, or life threatening arrhythmia within the previous 6 months; blood pressure while seated <90/ 50 mmhg or >170/110 mmhg and/or taking nitrates or nitric oxide donors. The study period was 12 weeks. Patients were instructed to use initial dose of 50 mg sildenafil. Follow-up visits were scheduled at 4, 8, 12 weeks. The investigator could adjust the dose of Sildenafil to 100 mg or to 25 mg based on the efficacy and tolerability. Patients were instructed to take sildenafil as required approximately 1 hour before anticipated sexual activity, with a maximum frequency of once daily. From July 2001 to July 2003, 466 male patients who agreed to participate were enrolled in this study. Patients were divided into two groups, the first group were 382 patients who had type 2 diabetes diagnosed on clinical and biochemical bases; the second group were 84 non-diabetic patients. All patients were screened for ED using IIEF. The erectile function domain consists of questions 1 to 5 and question 15 for assessing the global erectile function. Scoring of the IIEF domain of erectile function allowed classification of each patient as having no (26 30), mild (17 25), moderate (11 16), or severe (0 10) erectile dysfunction. Specifically we compared responses to erectile function domain, Q3 (achieving erection), Q4 (maintaining an erection) pre and post sildenafil administration. Global efficacy question (GEQ Did treatment improve your erection? ) and overall patient satisfaction question (are you satisfied with the efficacy of your treatment?) were also addressed to assess sildenafil efficacy in both groups. Sexual desire was determined by the sexual desire domain of the IIEF that consists of questions 11, 12 and allowed classification of each patient as having normal desire (8 10) or low desire (<8). Premature ejaculation was defined as, the persistent or recurrent inability to voluntarily delay ejaculation upon or shortly after penetration or with minimal sexual stimulation [8,9]. The time to ejaculation was estimated by the patient. A thorough sexual, medical and psychosocial history was taken and a focused physical examination was performed on every patients. During the same visits, all patients were also interviewed for socio-demographic and medical history that included age, obesity, smoking habit, diabetes, hypertension, ischemic heart disease, dyslipidemia, cerebrovascular stroke and psychological disorders. Whenever useful, information provided by the patients was checked with the medical records. Patients underwent routine laboratory investigations, in addition to total testosterone and prolactin assessment Definitions The current age was defined as age at the time of the examination (July 2001 July 2003). Glycemic control was measured by glycosylated hemoglobin (HbA1c) using a high-performance liquid chromatography technique on a rinsed venous blood sample. Metabolic control was rated as follows: good ( %), fair (6.3 7%), poor >7%. Metabolic control was evaluated according to the glycosylated hemoglobin values dating not more than three months before interview. Body mass index (kg/m 2 ) was rated as follows: normal (<25), overweigh ( ) and obese (>27) Analysis of data The data were analyzed using the Statistical Package of Social Science (SPSS.11) software program. Non-Parametric patients characteristics according to presence of diabetes were compared using w 2 -test. Unpaired t-test and one-way ANOVA were used to compare means of each of the measured variables pre and post Sildenafil treatment. Multivariate analysis of factors affecting the efficacy of treatment was performed. 3. Results 3.1. Demographics A total of 466 male Saudi patients were the subject of this study. Mean age S.D. was and years for patients with and without diabetes respectively. Obesity was significantly higher in diabetic patients, while no significant differences were found regarding age, level of education, occupation, marital status, or smoking between diabetic and nondiabetic patients (Table 1) Evaluation of erectile function There was a significant association between diabetes and increased severity of ED. No significant differences were found regarding the duration, onset, and course of ED, low desire or premature ejaculation between diabetic and non-diabetic patients (Table 2). There were significant associations between the increased severity of ED and the longer duration of diabetes, poor metabolic control and presence of more than one diabetes-related complication (Table 3).

3 A.I. El-Sakka / European Urology 46 (2004) Table 1 Demographic characteristics of the study population according to Diabetes Variables Diabetes (N ¼ 382) No diabetes (N ¼ 84) p-value a Age groups >0.05 <60 years 120 (73.8%) 42 (83.3%) 60 years 262 (26.2%) 42 (16.7%) School education (years) >0.05 b Less than secondary 88 (23%) 22 (26.2%) Completed secondary 220 (57.6%) 44 (52.4%) High education 74 (19.4%) 18 (21.4%) Marital status >0.05 One 340 (89%) 78 (92.9%) More than one 42 (11%) 6 (7.1%) Occupation >0.05 c Governmental 188 (49.2%) 32 (38.1%) Private 82 (21.5%) 20 (23.8%) Retired 90 (23.6%) 20 (23.8%) No work 22 (5.8%) 12 (14.3%) BMI <25 52 (13.6%) 22 (26.2%) (25.1%) 24 (28.6%) > (61.3%) 38 (45.2%) Smoking >0.05 None 186 (48.7%) 42 (50%) Ex smoker 72 (18.8%) 10 (11.9%) Current 124 (32.5%) 32 (38.1%) BMI: Body Mass Index. a w 2. b High education vs. less than or completed secondary. c Governmental and private vs. retired and no work; significance level at p < 0.05; percentages are calculated for a total of 382 for patients with ED and diabetes and a total of 84 for patients with ED and no diabetes Evaluation of sildenafil efficacy There was a trend in diabetic patients to use a higher dose of sildenafil, however, no statistically significant Table 2 Distribution of the study population according to sexual dysfunction characteristics and Diabetes Characteristics of ED Diabetes (N ¼ 382) No diabetes (N ¼ 84) p-value a Duration >0.05 <5 278 (72.8%) 58 (69%) (27.2%) 26 (31%) Severity Mild 30 (7.9%) 6 (7.1%) Moderate 192 (50.3%) 60 (71.4%) Severe 160 (41.9%) 18 (21.4%) Onset >0.05 Sudden 72 (18.8%) 16 (19%) Gradual 225 (81.2%) 68 (81%) Course >0.05 Progressive 282 (73.8%) 52 (61.9%) Stationary 84 (22%) 26 (31%) Regressive 16 (4.2%) 6 (7.1%) Desire >0.05 Normal 313 (81.9%) 70 (83.3%) Low 69 (18.1%) 14 (16.7%) Ejaculation >0.05 Normal 230 (60.2%) 55 (65.5%) Premature 152 (39.8%) 29 (34.5%) ED: Erectile Dysfunction. a w 2 ; significance level at p < 0.05; percentages are calculated for a total of 382 for patients with ED and diabetes and a total of 84 for patients with ED and no diabetes. difference was detected in the used dose of sildenafil between the two study groups. The average frequency of sildenafil intake in diabetic and non-diabetic patients was 2.6 and 2.4 times/week respectively. Considering the severity of ED, there were significant differences in erectile function domain between pre and post Table 3 Distribution of the study population according to diabetes characteristics and ED severity Diabetes characteristics Erectile dysfunction severity (N ¼ 382) Mild (N ¼ 30) Moderate (N ¼ 192) Severe (N ¼ 160) p-value a Duration of diabetes < <5 years 12 (40%) 42 (21.9%) 20 (12.5%) 5 10 years 12 (40%) 54 (28.1%) 42 (26.3%) >10 years 6 (20%) 96 (50%) 98 (61.2%) Control of diabetes < Good 8 (26.7%) 10 (5.2%) 6 (3.8%) Fair 8 (26.7%) 36 (18.8%) 10 (6.3%) Poor 14 (46.7%) 146 (76%) 144 (90%) Number of complications <0.05 None 16 (53.3%) 128 (66.7%) 92 (57.5%) One 12 (40%) 49 (25.5%) 24 (15%) More than one 2 (6.7%) 15 (7.8%) 44 (27.5%) a w 2 ; significance level at p < 0.05; percentages are calculated for a total of 30 for patients with mild, 192 for patients with moderate and 160 for patients with severe ED.

4 506 A.I. El-Sakka / European Urology 46 (2004) Table 4 Distribution of erectile function domain according to Diabetes and ED severity pre and post Sildenafil administration Diabetes Erectile dysfunction severity (N ¼ 382) Mild Moderate Severe p-value a Erectile function domain with diabetes (N ¼ 382) < Pre-treatment 30 (7.9%) 192 (50.3%) 160 (41.9%) Post-treatment 232 (60.7%) 51 (13.3%) 99 (25.9%) Erectile function domain without diabetes (N ¼ 84) < Pre-treatment 6 (7.1%) 60 (71.4%) 18 (21.4%) Post-treatment 68 (81%) 14 (16.7%) 2 (2.4%) Erectile function domain pre-treatment < With diabetes (N ¼ 382) 30 (7.9%) 192 (50.3%) 160 (41.9%) Without diabetes (N ¼ 84) 6 (7.1%) 60 (71.4%) 18 (21.4%) Erectile function domain post-treatment < With diabetes (N ¼ 382) 232 (60.7%) 51 (13.3%) 99 (25.9%) Without diabetes (N ¼ 84) 68 (81%) 14 (16.7%) 2 (2.4%) a w 2 ; significance level at p < 0.05; percentages are calculated for a total of 382 for patients with ED and diabetes and a total of 84 for patients with ED and no diabetes. sildenafil administration in diabetic and non-diabetic patients (Table 4). Considering the presence of diabetes, there were significant differences in erectile function domain, Q3 and Q4 between pre and post Table 5 Comparison of erectile function domain, Q3, Q4 before and after sildenafil administration in patients with and without diabetes Risk factors Diabetes (N ¼ 466) Yes (N ¼ 382) No (N ¼ 84) Erectile function domain p < 0.05 p < 0.05 Pre-treatment Post-treatment Q3 p < 0.05 p < 0.05 Pre-treatment Post-treatment Q4 p < 0.05 p < 0.05 Pre-treatment Post-treatment sildenafil administration (Table 5). Also, there were significant differences in the mean of erectile function domain, Q3 and Q4 in pre sildenafil administration regarding metabolic control, diabetes duration, and diabetes-related complications. The same significant differences were observed in the post sildenafil administration in erectile function domain but not in Q3 and Q4 of patients with diabetes-related complications (Table 6). Global efficacy question was significantly low in patients with fair or poor metabolic control, longer duration of diabetes, and patients with more than one diabetes-related complications (p < 0.05 for each) (Table 6). The GEQ and the overall satisfaction rate were significantly higher in non-diabetic patients compared to diabetics (p < 0.05 for each) (Fig. 1). No significant difference between diabetic Q3 pre-treatment Q3 post-treatment p < 0.05 p < 0.05 With diabetes (N ¼ 382) Without diabetes (N ¼ 84) Q4 pre-treatment Q4 post-treatment p < 0.05 p < 0.05 With diabetes (N ¼ 382) Without diabetes (N ¼ 84) Unpaired t-test and one-way ANOVA; significance level at p < 0.05; percentages are calculated for a total of 382 for patients with ED and diabetes and a total of 84 for patients with ED and no diabetes. Fig. 1. GEQ and overall satisfaction of Sildenafil treatment in patients with and without diabetes. (1) global efficacy Question (*p < 0.05). (2) Overall satisfaction (*p < 0.05). (3) Causes of dissatisfaction (*p > 0.05). *w 2 ; Significance level at p < 0.05; percentages are calculated for a total of 382 for patients with ED and diabetes, a total of 84 for patients with ED and no diabetes, a total of 112 diabetic unsatisfied patients and a total of 14 non-diabetic unsatisfied patients.

5 A.I. El-Sakka / European Urology 46 (2004) Table 6 Comparison of efficacy parameters with metabolic control, duration, and complication of diabetes Metabolic control (N ¼ 382) Diabetes duration (N ¼ 382) Diabetes complications (N ¼ 382) Efficacy parameters p-value a p-value a <5 years 5 10 years >10 years p-value a No or one More than one (N ¼ 74) (N ¼ 108) (N ¼ 200) (N ¼ 320) (N ¼ 62) Mean S.D. Mean S.D. Mean S.D. Mean S.D. Mean S.D. Poor (N ¼ 304) Mean S.D. Fair (N ¼ 54) Mean S.D. Good (N ¼ 24) Mean S.D. EF domain Pre-treatment < < <0.05 Post-treatment < < <0.05 Q3 Pre-treatment <0.05 Post-treatment >0.05 Q4 Pre-treatment < <0.05 Post-treatment < >0.05 GEQ (N ¼ 24) (N ¼ 54) (N ¼ 304) <0.05 (N ¼ 74) (N ¼ 108) (N ¼ 200) (N ¼ 318) (N ¼ 64) <0.05 Yes 22 (91.7%) 39 (72.2%) 220 (72.4%) 64 (86.5%) 85 (78.7%) 132 (66%) 240 (75.5%) 41 (64.1%) No 2 (8.3%) 15 (27.8%) 84 (27.6%) 10 (13.5%) 23 (21.3%) 68 (34%) 78 (24.5%) 23 (35.9%) a Unpaired t-test and one-way ANOVA; significance level at p < 0.05; percentages are calculated for a total of 24, 54 and 304 for patients with good, fair and poor metabolic control; and a total of 74, 108 and 200 for patients with <5 years, 5 10 years and >10 years of diabetes; and a total of 320, and 62 for patients with no or one and patient with more than on diabetes-related complications. and non-diabetic patients regarding the causes of dissatisfaction was detected (Fig. 1). There were no significant differences in testosterone or prolactin levels between patients in the two study groups, p > 0.05 for both. Further studies are needed to delineate the impact of hormonal supplementation therapy on the efficacy of sildenafil citrate in treatment of diabetic patients with erectile dysfunction. 4. Discussion The overall prevalence of erectile dysfunction in the general population between the ages of years is 52% [1]; the prevalence is significantly higher in men with diabetes, which ranges from 20 85% [2,10]. Further, ED usually starts at an earlier age and is often related to duration and severity of diabetes [11]. The underlying mechanism of erectile dysfunction in diabetic patients is not well known. Although psychogenic factors, such as performance anxiety, depression, can contribute to its etiology. ED in diabetic patients is principally related to organic causes, such as vasculogenic and neurogenic abnormalities [12]. Others and we have investigated the cellular and molecular mechanisms of impotence with diabetes [13,14]. In an experimental study we showed that diabetes could induce down-regulation of gene and protein expression of growth factors and neurotransmitters, such as, nnos (large form), inos and estrogen receptor beta, which might explain the association of ED with diabetes [13]. There is a large overlap between conditions typically associated with diabetes and ED, namely, vascular disease, hypertension, neuropathy, hyperlipidemia, and obesity, which are all markedly more common in diabetic patients than in non-diabetic subjects. In this study the demographic data of study population were homogenous and there were no significant differences between diabetic and non-diabetic patients regarding age, level of education, occupation, marital status, or smoking. This will eliminate the statistical effect of these factors on the efficacy of sildenafil and enable to draw the difference in response to treatment in both groups. The current study agreed with previous studies that showed a significant association between diabetes and increase severity of ED [1,6], however the differences between diabetics and non-diabetics regarding the duration, onset or course of ED, low desire or premature ejaculation were insignificant. There were significant association between increase severity of ED and longer duration, poor metabolic

6 508 A.I. El-Sakka / European Urology 46 (2004) control and presence of more than one diabetes-related complication. Obesity was significantly higher in diabetic patients. Others and we have shown that erectile function decreases with poor glycemic control (increased blood glucose and HbA1c concentration) [6,15]. Advanced glycation end-products accumulating in tissue proteins are a result of increased blood glucose and play a part in many of the complications of diabetes. They have also been shown to decrease nitric oxide activity and modulate endothelium-dependent relaxation and thus could adversely affect nitric oxide-signalling mechanisms within the corpora cavernosa [16,17]. A multivariate analysis of a previous study of men with type2 diabetes showed that HbA1c was an independent predictor of erectile function and that patients with good metabolic control had no signs of neuropathy and scored 20.1 points on the erectile function domain score. In comparison, patients with poor metabolic control had signs of neuropathy and scored 14.7 points on erectile function domain score [18]. Concomitant medications that frequently used in diabetic patients, such as anti-hypertensive agents and lipid-lowering agents can contribute to a reduced efficacy of Sildenafil [19]. Our results agreed with previous studies showed that GEQ, Q3 and Q4 had improved significantly in diabetic men receiving sildenafil. More interestingly the current and other studies had shown that sildenafil was effective in improving ED even in cases of poor glycemic control or multiple diabetes-related complication [20]. In our study we showed that sildenafil markedly improves the ability to achieve and maintain erection and overall satisfaction of patients with type 2 diabetes. There were significant differences in erectile function domain between pre and post sildenafil administration regarding the severity of ED. Further the differences between each of pre and post sildenafil administration erectile function domain in diabetic and non-diabetic patients were significant. In the current study, although sildenafil was an effective oral therapy for men with type 2 diabetes and ED as determined by the IIEF (Q3 and Q4, erectile function domain) and the GEQ, however the differences in these parameters between diabetics and nondiabetics were significant. Duration, metabolic control and complications of diabetes were significant risk factors affecting the severity of ED and the efficacy of sildenafil. There were significant differences in the mean of erectile function domain, Q3 and Q4 in pre sildenafil administration regarding metabolic control, diabetes duration, and diabetes-related complications. The same significant differences were observed in the post sildenafil administration in erectile function domain but not in Q3 and Q4 of patients with diabetes-related complication. Our results were consistent with previous study showed that the highest scores on EF domain, Q3, Q4 and GEQ were obtained from patients who had none or only one complication of diabetes compared with those who had two or more complications [21], the number of these complications may reflect the severity of the disease process. Clinical trials data indicated that sildenafil has no adverse effects on blood glucose concentration in patients with diabetes. Furthermore, no clinically important changes in laboratory tests results were observed, suggesting that sildenafil did not impair metabolic control [22]. The GEQ (85.7% vs. 73.6%) and the overall satisfaction (83.3% vs. 70.7%) were significantly higher in non-diabetic patients in comparison to diabetic patients respectively. A significantly higher percentage of patients with poor metabolic control, long duration of diabetes and more than one diabetes-related complication had negative response to GEQ. In a previous study on diabetic patients, sildenafil was shown to be an effective treatment in a mixed (type 1 and type 2) group of 268 diabetic men with ED [2]. Further, efficacy of sildenafil was independent of age, duration of ED and duration of diabetes, and erections were improved by 56% with sildenafil [2]. Other studies showed improvement of up to 65% of diabetic patients on sildenafil treatment [23]. We hypothesize that the efficacy rate of sildenafil in our study is somewhat higher than previous studies, this could be due to (1) a more homogenous sample population, consisting exclusively of type 2 diabetic men, (2) ED risk factors are extremely common among our diabetic patients with a more severe ED complaint [6,7], thus those patients might appreciate even a moderate improvement of their erectile function, (3) collaboration with cardiologists allowed for modifications of patients treatment (e.g., beta blockers, thiazide diuretics) and control of risk factors as smoking, obesity and sedentary lifestyle could also be important factors. However further studies are warranted to investigate the control of risk factors and the impact of common comorbidities in ED patients using sildenafil treatment. Our study agreed with other studies that showed no significant difference between diabetics and non-diabetics patients regarding the causes of dissatisfaction [24]. Others and we have shown that poorly controlled diabetes is often associated with diabetic neuropathy and peripheral vascular disease [25 27], both of which can increase the risk of ED, it is of interest that;

7 A.I. El-Sakka / European Urology 46 (2004) although in our study the efficacy was higher in non diabetic men however, Sildenafil was able to improve erections in men with type 2 diabetes even with long duration, poor metabolic control, or presence of diabetic related complications. Therefore, unless there is a contraindication it would be reasonable to consider oral PDE5 inhibitors as an initial therapeutic choice for diabetic patients with ED. 5. Conclusions Sildenafil citrate is an effective treatment for erectile dysfunction in patients with type 2 diabetes. Although poor control, longer duration of diabetes and presence of more than one diabetes-related complication negatively affect the efficacy of sildenafil, however, the global efficacy and the overall patient s satisfaction were high. References [1] 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: [2] Rendell MS, Rajfer J, Wicker PA, Smith MD., Sildenafil Diabetes Study Group. Sildenafil for treatment of erectile dysfunction in men with diabetes. JAMA 1999; [3] Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med 1998;338(20): [4] Boolell M, Gepi-Attee S, Gingell JC, Allen MJ. Sildenafil, a novel effective oral therapy for male erectile dysfunction. Br J Urol 1996; 78(2): [5] Steers WD. Viagra after one year. Urology 1999;54(1):12 7. [6] El-Sakka AI, Tayeb KA. Erectile dysfunction risk factors in noninsulin dependent diabetic Saudi patients. J Urol 2003;169: [7] El-Sakka AI. Characteristics of erectile dysfunction in Saudi patients. Int J Impot Res 2004;16: [8] Vandereycken W. Towards a better delineation of ejaculatory disorders. Acta Psychiatrica Belgica 1986;86: [9] American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington (DC): APA; [10] Chew KK, Earle CM, Stuckey BG, Jamrozic K, Keogh EJ. Erectile dysfunction in general medicine practice: prevalence and clinical correlates. Int J Impot Res 2000;12:41 5. [11] Fedele D, Bortolotti A, Coscelli C, Santeusanio F, Chatenoud L, Colli E, et al. Erectile dysfunction in type 1 and type 2 diabetics in Italy. Int J Epidemiol 2000;29: [12] Saenz de Tejada I, Goldstein I. Diabetic penile neuropathy. Urol Clin North Am 1988;15: [13] El-Sakka AI, Lin CS, Chui RM, Dahiya R, Lue TF. Effects of diabetes on nitric oxide synthase and growth factor genes and protein expression in an animal model. Int J Impot Res 1999;11: [14] Rehman J, Chenven E, Brink P, Peterson B, Walcott B, Wen YP, et al. Diminished neurogenic but not pharmacological erections in the 2- to 3-month experimentally diabetic F-344 rat. Am J Physiol 1997; 272:H [15] Klein R, Klein BE, Lee KE, Moss SE, Cruickshanks KJ. Prevalence of self-reported erectile dysfunction in people with long-term IDDM. Diabetes Care 1996;19(2): [16] Seftel AD, Vaziri ND, Ni Z, Razmjouei K, Fogarty J, Hampel N, et al. Advanced glycation end products in human penis: elevation in diabetic tissue, site of deposition, and possible effect through inos or enos. Urology 1997;50(6): [17] Saenz de Tejada I, Goldstein I, Azadzoi K, Krane RJ, Cohen RA. Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med 1989;320(16): [18] Romeo JH, Seftel AD, Madhun ZT, Aron DC. Sexual function in men with diabetes type 2: association with glycemic control. J Urol 2000;163(3): [19] Keene LC, Davies PH. Drug-related erectile dysfunction. Adverse Drug React Toxicol Rev 1999;18(1):5 24. [20] Boulton AJM, Ziegler D, Sweeney M. The first study of sildenafil for erectile dysfunction in men with type 2 diabetes mellitus. Presented at the American Diabetes Association Meeting. June 9 13, 2000, San Antonio, TX. [21] Hirsch IB, Korenman SG, Stecher V, Diuguid C. Viagra (sildenafil citrate ) efficacy and safety in the treatment of erectile dysfunction (ED) in men with diabetes. Presented at the American Diabetes Association Meeting. June 19 22, 1999, San Diego, CA. [22] Price DE, Gingell JC, Gepi-Attee S, Wareham K, Yates P, Boolell M. Sildenafil: study of a novel oral treatment for erectile dysfunction in diabetic men. Diabet Med 1998;15(10): [23] Boulton AJ, Selam JL, Sweeney M, Ziegler D. Sildenafil citrate for the treatment of erectile dysfunction in men with type II diabetes mellitus. Diabetologia 2001;44(10): [24] Guay AT, Blonde L, Siegel R, et al. Safty and tolerability of sildenafil citrate for treatment of erectile dysfunction in men.with type 1 and type 2 diabetes mellitus. Diabetes 2000;49(Suppl 1):363. [25] Bemelmans BL, Meuleman EJ, Doesburg WH, Notermans SL, Debruyne FM. Erectile dysfunction in diabetic men: the neurological factor revisited. J Urol 1994;151(4): [26] Kadioglu A, Erdogru T, Karsidag K, Dinccag N, Satman I, Yilmaz MT, et al. Evaluation of penile arterial system with color Doppler ultrasonography in nondiabetic and diabetic males. Eur Urol 1995; 27(4): [27] El-Sakka AI. Penile axial rigidity and Doppler ultrasonography parameters in patients with erectile dysfunction: association with type 2 diabetes. Urology 2003;62(3):