Erectile dysfunction (ED) is a common complication of diabetes and has a multifactorial etiology that includes psychogenic factors, autonomic neuropathy, vascular disease, and drug intake. A number of drugs have been used for the medical treatment of ED in diabetic men. Several studies have investigated the effects of the intracavernosal treatment with alprostadil(1,2);60-87% of diabetic patients included in these studies reported satisfactory sexual activity. Transurethral alprostadil is a less invasive alternative with the advantages of a lower rate of priapism and penile fibrosis. In a recent study, 64.9% of patients treated with transurethral alprostadil had successful intercourse (3). A meta-analysis of seven controlled trials demonstrated that yohimbine is also a therapeutic option for ED when psychogenic causes are identified as the origin(4). More recently, oral sildenafil resulted to be an effective well-tolerated treatment for men with ED (5). A total of 56% of the diabetic patients taking sildenafil reported improved erections compared with 10% of patients taking placebo.

The aim of our study was to assess whether oral sildenafil citrate could be an effective alternative for the treatment of ED in diabetic men with a positive response to intracavernosal injection of alprostadil. We studied 52 men, aged 35-74 years (mean ± SEM 56.7 ± 4.5), with a diagnosis of ED (duration 2.2 ± 0.3 years, range 0.5-5.6) already effectively treated with alprostadil for no longer than 1 year (range 1-11 months). Only men in a stable sexual relationship for at least 6 months were included in the study. All of the patients were affected by diabetes (12 type 1 diabetic patients and 40 type 2 diabetic patients, duration 16.2 ± 1.9 years). No patients had a penile anatomical defect; a history of priapism or prostatectomy; the sickle-cell trait; major hematological, renal, or hepatic illnesses; or coronary artery disease. Other exclusion criteria included treatment with nitrate or anticoagulant therapy and evidence of drug abuse or alcoholism. The cause of ED had been determined from medical history, physical examination, laboratory evaluation, and other diagnostic procedures, including cardiovascular tests for autonomic neuropathy and penile duplex ultrasonography. The etiology of ED was 55.7% neurogenic, 19.2% psychogenic,9.6% vasculogenic, and 15.3% mixed. The 15-question International Index of Erectile Function (IIEF) had also been administered to all of the patients as part of our standard clinical practice for the diagnosis of ED in the outpatient clinic. At baseline, no patient had successful attempts at sexual intercourse.

The mean interval between the baseline and the beginning of our study was 7 months (range 2-16). On entry into the study, the patients were asked to treat their ED for 3 months with intracavernosal self-injection of alprostadil (no more than three times a week). They were instructed to document the number and the effectiveness of sexual attempts. The optimal dose of alprostadil had been established by titration. After a 15-day wash-out period, the patients were transferred to oral treatment with sildenafil. They were instructed to take sildenafil (50 mg) ∼1 h before sexual activity, no more than once a day,and to increase the dose to 100 mg based on two consecutive unsuccessful attempts at sexual intercourse. The IIEF questionnaire was self-administered again at the end of the alprostadil and sildenafil treatment periods.

The efficacy of the two treatments was assessed using responses to the following questions from the IIEF: question 3, “When you attempted sexual intercourse, how often were you able to penetrate your partner?”and question 4, “During sexual intercourse, how often were you able to maintain your erection to completion of intercourse?” Responses to the two questions were rated on a scale ranging from 1 to 5, with five response options: 1 = almost never/never, 2 = a few times (much less then half the time), 3 = sometimes (approximately half the time), 4 = most times (much more than half the time), and 5 = almost always/always. At the end of the two 3-month periods of treatment, patients used a mean dose of 16.8 ± 1.4μg (range 7.5-30) alprostadil and a mean dose of 86.5 ± 0.5 mg sildenafil.

Both treatments were associated with significantly higher scores for question 3 (frequency of penetration) and question 4 (maintenance of erection after sexual penetration) than baseline (P < 0.001). The mean scores for questions 3 and 4 were significantly higher after treatment with alprostadil than after treatment with sildenafil (P < 0.001)(Table 1). Of all the attempts at sexual intercourse, 79% (850 of 1,083) were successful during alprostadil treatment as compared with 48.7% (485 of 995) during sildenafil treatment(P < 0.001). All of the patients reported at least one successful attempt at sexual intercourse during alprostadil treatment as compared with 63.5% successful attempts during sildenafil treatment (P < 0.001). Glycated hemoglobin, blood pressure, etiology of ED, and prevalence of autonomic neuropathy of patients who responded to sildenafil were similar to those found in patients who did not respond to sildenafil. After alprostadil injection, at least one episode of penile pain was reported by 38.4% of men. However, only one patient discontinued treatment because of pain during the study period, and mild hematomas occurred in four patients (7.6%). One episode of prolonged erection was reported by two men (3.8%). During the sildenafil treatment period, 36.5% of the patients reported at least one episode of transient headache, 28.8% reported flushing, 5.7% reported dyspepsia, and 3.8%reported rhinitis. These adverse effects were sporadic, and no patient withdrew from the study because of these side effects. None of the seven patients using drugs that have the potential to interfere with the metabolism of sildenafil (one on diltiazem, one on verapamil, one on nifedipine, and four on statins) showed side effects related to a prolongation of the half-life of sildenafil (6). Because of insufficient response, six patients discontinued therapy with sildenafil before the end of the treatment period.

Unlike previous studies, our investigation considered the efficacy of sildenafil treatment in a group of diabetic patients already effectively treated with intracavernosal alprostadil. Sildenafil was associated with a significant increase, with respect to baseline, in the mean end-of-treatment scores for questions 3 and 4 of the IIEF. It is not surprising that alprostadil appeared to be more effective than sildenafil, because the patients enrolled in our study had already showed a positive response to intracavernosal treatment with alprostadil. We did not study diabetic patients who did not respond to alprostadil; therefore, it is possible that some of these patients could have been successfully treated with sildenafil.

It is known that some patients treated with intracavernosal alprostadil discontinue treatment because they recover erectile function. Therefore, in our study, the previous treatment with alprostadil could have increased the efficacy of sildenafil treatment.

Both treatments were well tolerated in our patients. Pain was common after alprostadil injection, but in most instances, it was mild. The optimal dose of alprostadil was accurately individualized by titration in the Diabetes Unit;this procedure reduced prolonged erections and avoided priapism.

Penile fibrosis did not occur in our study; this side effect of prolonged intracavernosal treatment is less frequent when using alprostadil rather than papaverine (7). Moreover, in our patients, the period of intracavernosal treatment was short.

In conclusion, sildenafil represents an effective treatment of ED in diabetic men already treated with intracavernosal alprostadil. Alprostadil showed a higher grade of effectiveness than sildenafil. Nevertheless, therapy with intracavernosal alprostadil is more invasive, has heavier side effects,and needs accurate instructions for self-injection. Sildenafil is a reliable therapy with minimal side effects and good patient acceptance; it is simple to use, and it permits discreet administration.

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