The treatment of ED in general was revolutionized by the availability of sildenafil (Viagra), followed by tadalafil (Cialis) and vardenafil (Levitra). Each of these medications has been prospectively examined in a variety of populations, including diabetics. The three medications work by a similar pathway. Sexual stimulation provokes the release of nitric oxide (NO), leading to increased cellular concentrations of cyclic guanosine monophosphate (cGMP) and subsequent penile smooth muscle relaxation. This process is reversed by the conversion of cGMP to guanosine monophosphate, which is mediated by phosphodiesterase type 5 (PDE5)- the predominant functional PDE type found in the penis. PDE5i act at this step to maintain elevated levels of cGMP and continued smooth muscle relaxation. Since the release of NO is a neurologically-mediated event, neuropathology may impede this step and, theoretically, make diabetics less sensitive to the effects of PDE5i. This is indeed borne out clinically, as diabetics have a poorer response overall to PDE5i than men with ED of other causes.

A prospective, multi-center, randomized, double-blinded (RCDB) trial of vardenafil in diabetics was carried out by Goldstein, et al . The study consisted of 430 men with chronic ED, a hemoglobin A1c (HbA1c) of <12%, and without other serious confounding causes of ED (e.g. radical pelvic surgery, spinal cord injury, etc.). Additionally, patients were excluded if they had unstable coronary disease or other contraindications to PDE5i use. The patients were evaluated using the erectile function (EF) domain of the 15 question validated International Index of Erectile Function (IIEF), 2 diary questions regarding the patient’s ability to penetrate and have successful intercourse, and a global assessment question (GAQ) about whether or not the treatment had improved their erections. There were statistically and clinically significant improvements in all of the evaluated endpoints, with most of the improvements demonstrating a dose-relation. With 20 mg of vardenafil, the EF score was 19 (out of a total possible of 25) and 54% of men were able to complete intercourse, with an overall responder rate (as measured by the GAQ) of 72%. The effect was attenuated in patients with severe underlying ED but improvement remained significant. There was no correlation noted between different strata of HgA1c levels. The drug was well-tolerated with few patients discontinuing the study due to adverse side-effects.

A similar RCDB trial of tadalafil in diabetics was performed by Saenz de Tejada, et al . A total of 191 patients completed this study; evaluated parameters were very similar to the vardenafil study above. Exclusion criteria were also similar to the vardenafil study, except that patients with hypertension and hypercholesterolemia were also excluded in the tadalafil study. As in the vardenafil study, statistically and clinically significant improvements were noted in all of the evaluated parameters for men using tadalafil, regardless of severity of underlying DM or level of HgA1c, with an overall responder rate (as assessed by GAQ) of 64% by those using 20 mg. The drug was also well-tolerated with few discontinuations.

A unique study from Denmark attempted to assess the “real-life” use of sildenafil in diabetics in terms of how many patients wanted to try an agent, how many were eligible to do so, and how efficacious the medicine was . Examining a diabetes outpatient clinic population of 326 men, 192 (59%) self-reported ED and 187 of these were over 40 years old. Of these 187 patients, 79 (42%) were excluded because of medical or pharmacologic contraindications to sildenafil use. A further 63 patients either declined to participate in the study or did not respond. This left 45 patients for the study (23% of those patients with self-reported ED). Of these, 10 dropped out due to lack of sexual partner and 2 others without recorded reason. Sixty-one percent of the remaining patients self-titrated to a maximum dose of 100 mg. Of the 33 patients remaining, 36% noted consistent improvement, 27% noted variable improvement, and 36% felt they had no improvement; overall, 54% felt that the medicine had met their expectations. If we consider that 18 patients total felt that the medicine met their expectations and that the starting pool was 187 patients with self-reported ED, this leaves less than 10% of patients with a satisfactory outcome, thus pointing out that PDE5i, while efficacious under normal study conditions, do not represent a panacea.