Treatment of Erectile Dysfunction in Men With Diabetes

Sildenafil citrate represents the most recent advance for the treatment of organic erectile dysfunction. The first effective pill for erectile dysfunction, this type 5-phosphodiesterase inhibitor has enjoyed tremendous popularity in its first year of availability. In an earlier double-blinded, placebo-controlled study, an overall 70% to 80% improvement in erections was reported in a mixed population of patients with both organic and psychogenic causes of erectile dysfunction.¹ However, because of sildenafil's relatively recent introduction, detailed analyses of its effects in subgroups of patients with specific causes of erectile dysfunction have been few in number.

The association between diabetes mellitus and erectile dysfunction is well established.² Approximately 35% to 75% of men with diabetes have erectile dysfunction, and these numbers could be even larger if milder degrees of erectile impairment were considered. Fortunately, treatment options have advanced significantly during the last 10 to 15 years. As recently as the early 1980s, placement of a penile prosthesis often was recommended as the first-line treatment for men with diabetes. However, despite high patient and partner satisfaction,³ the permanence of the device combined with long-term risks of mechanical malfunction and infection,⁴ particularly in persons with diabetes, led to an increased use of nonsurgical forms of therapy as first-line treatment options.

Intracavernous injection therapy was introduced in 1982⁵ and became a popular and effective choice with success rates of up to 80% to 85% in men with diabetes and others with erectile dysfunction.^{6 - 7} However, factors such as the requirement of a needle for injection, penile pain, and lack of spontaneity led to its fall in popularity. Vacuum constriction devices represent another nonsurgical treatment option for men with diabetes and are effective in producing penile venous engorgement. While the vacuum constriction device is successful in producing an erection,⁸ its cumbersome nature has limited its widespread appeal. The intraurethral alprostadil suppository, introduced in 1996,⁹ represented a novel delivery system for prostaglandin E₁, but unfortunately its inability to produce consistently rigid erections has been disappointing.¹⁰

In this issue of THE JOURNAL, Rendell et al² report the first detailed analysis of oral sildenafil for the treatment of diabetes-related erectile dysfunction with outcomes measured using a questionnaire-based approach. Although questionnaires have limitations in measuring erectile and sexual functioning, they are considered standard in US Food Drug Administration testing protocols for drugs to treat erectile dysfunction. The authors reported improved erections in 57% of patients receiving sildenafil vs 10% in the placebo group. Furthermore, 61% of those in the sildenafil group were able to have sexual intercourse compared with 22% of those in the placebo group. Although the success rates were lower than in a previously reported heterogeneous group of patients,¹ it is important to understand and to counsel patients that for certain subgroups of men because of the specific cause of their erectile dysfunction, the response may be less favorable. For example, men who have undergone nerve resections associated with prostatectomy are much less likely to have a favorable outcome than men who have psychogenic or other milder forms of organic erectile dysfunction.¹¹

The results reported by Rendell et al² are encouraging in view of the pathophysiologic alterations that diabetes mellitus can impose on erectile physiology, which is essentially a hemodynamic event with neural modulation. Diabetes can interfere with numerous critical erectile mechanisms, such as impairing arterial perfusion,^{12 - 13} producing a peripheral and autonomic sensory neuropathy,¹⁴ and altering normal corporeal smooth muscle activity in the penis.¹⁵ Despite these potential pathophysiologic changes, sildenafil was able to potentiate in a clinically significant fashion the nitric oxide–induced cyclic guanosine monophosphate–dependent relaxation of the corporeal smooth muscle for the majority of men with diabetes in this investigation. Of note, by its mechanism, sildenafil does not initiate or produce an erection, but enhances the quality of a stimulated erection. Interestingly, Rendell et al² found that patient age and duration of erectile dysfunction or diabetes did not affect the efficacy of sildenafil.

The men participating in this clinical investigation appeared on the basis of history and screening with fasting plasma glucose and hemoglobin A_1c levels to have relatively well-controlled diabetes. Specific exclusion criteria included active retinopathy, neuropathy, or ketoacidosis. Many men with diabetes seeking treatment for erectile dysfunction will not meet the selection criteria of this study and thus may have less clinical success than that reported. It will be interesting and revealing to compare results from a less strictly selected group of patients with diabetes and erectile disorders. Another question worthy of further investigation is whether the type of diabetes (type 1 vs type 2) will affect patient response to sildenafil. The majority of patients in this study had type 2 diabetes mellitus, and the numbers of men with type 1 diabetes were too small for adequate comparisons of efficacy.

Concerns recently raised about cardiovascular safety and sildenafil have led the Food Drug Administration¹⁶ to mandate labeling changes in the "warnings section," advising caution for men who have suffered a heart attack, stroke, or life-threatening arrhythmia within the previous six months, have resting hypotension (less than 90/50 mm Hg) or hypertension (greater than 170/110 mm Hg), have a history of cardiac failure or coronary artery disease causing unstable angina, and have retinitis pigmentosa.¹⁶ The study by Rendell et al² confirms that sildenafil is safe when properly prescribed, in selected men with diabetes. No increase in cardiovascular adverse events was observed, but contraindications to study participation included myocardial infarction within the previous 6 months, hypotension, uncontrolled hypertension, or nitrate administration. At our institution, men with cardiovascular risk factors are evaluated with an exercise stress test to assess potential cardiac ischemia before sildenafil is prescribed. This type of testing may be quite appropriate for men with diabetes because of their increased risk of cardiovascular disease and silent cardiac ischemia. In addition, use of sildenafil in men with diabetic retinopathy has theoretical and potential, but unproved, clinical consequences because of the mild cross-reactivity of sildenafil with the type 6-phosphodiesterase in the retina.

Sildenafil represents an important and effective treatment for the common problem of erectile dysfunction in carefully selected men with diabetes. When sildenafil is ineffective or contraindicated, patients should be offered other nonsurgical treatment choices such as intracavernous injection therapy, intraurethral alprostadil, and vacuum constriction devices. Penile prosthesis, although potentially quite successful, should be implanted only after nonsurgical options have been found ineffective or unacceptable. With other oral agents such as apomorphine and phentolamine in late stages of clinical testing, the future is increasingly promising for treatment of men with diabetes-induced erectile dysfunction.