Treatment is Selected Taking Into Account the Medical and Psychosocial Contraindications and Patient Preference and Availability Conjoint Psychosocial and Medical Treatment is Preferred
Local Therapies Pharmacological ■ Mechanical
Local Therapies Pharmacological ■ Mechanical
Reevaluate and adjust therapy •Treat Hypogonadism if Present
• Dose Titration
• Instruct Patient on Optimal Use of Treatment
Consider Alternative Oral or Local Therapy as Above _Additional Education and Counseling_
Consider Alternative Oral or Local Therapy as Above _Additional Education and Counseling_
Refer to a specialist
Depending on the Predominant Etiology and Circumstances the Specialist coud be a:
• Urologist: Penile Prosthesis, Penile Revascularization or Correction of Penile Deformity
• Psychosocial Therapist or Psychiatrist: Treatment of Complicated Psychosexual Problems
• Other Medical Specialist
9PDE5 inhibitors are the preferred treatment option in the large majority of patients
FIGURE 2 Algorithm for treatment of erectile dysfunction. Source: From Ref. 100.
protein were independently associated with changes in IIEF score. Thus, lifestyle changes are associated with improvement in sexual function in obese men with ED (120).
A second study from the same group evaluated the effect of a Mediterranean-style diet on ED in men with the metabolic syndrome. After 2 years, men on the Mediterranean diet (n = 35) consumed more fruits, vegetables, nuts, whole grain, and olive oil as compared with men on the control diet (n = 30). Endothelial function score and inflammatory markers (C-reactive protein) improved in the intervention group, but remained stable in the control group. There were 13 men in the intervention group and two in the control group (P = 0.015) that reported an IIEF score of >22 (121). Thus, Mediterranean-style diet might be effective per se in improving ED in men with the metabolic syndrome.
Oral Agents central initiators. Yohimbine was the first drug officially listed for this indication. Yohimbine acts via central alpha-2-receptor blockade and thus increases the centrally initiated efferences of the erectogenic axis. Although its effectivity is often debated due to insufficient historic data, it showed a significant effect in a recent double-blind prospective study compared to placebo. Its side effect profile is benign including palpitations, tremor, hypertension, and anxiety. The pro-erectile effect usually starts after about 2 weeks (122). In a meta-analysis yohimbine has been found to be more effective than placebo for all types of ED combined, but the effect was most prominent in non-organic ED (123). Because of its marginal effect on organic ED, yohimbine cannot be generally recommended for treatment of ED in diabetic men.
Apomorphine is a potent emetic agent that acts via central dopaminergic (D1 or D2) receptors as well as central m-, 8-, and K-receptors. In the hypothalamus, it increases the centrally initiated efferences of the erectogenic axis thus improving the erectile response in a patient with erectile failure (124). The FDA concluded from the available evidence data that even though the 4mg dose and the combined analysis showed statistical significance, the clinical significance is questionable due to the relatively modest benefits noted over placebo (125). Indeed, the NNT for the 4mg dose based on the aforementioned results is relatively high, i.e., 10 patients need to be treated in order to achieve an erection firm enough for intercourse in one of these patients. The rates of nausea, the most prominent adverse effect of apomorphine, were 21.2%, 12.9%, and 1.0% for 4mg, 5mg, and placebo, respectively. The corresponding rates of vomiting were 6.7%, 1.0%, and 0%, respectively. Moreover, three syncopal events and three episodes of significant hypotension were reported in patients taking apomorphine (125).
Peripheral Conditioners phosphodiesterase 5 inhibitors
Sildenafil (Viagra®). To understand the mode of action of Sildenafil, a drug believed to act predominantly via PDE-5 inhibition, the basic physiology is briefly explained: cAMP and cGMP are synthesized from the corresponding nucleoside triphosphates by their respective membrane bound or soluble adenylate or guanylate cyclases. cAMP and cGMP are inactivated by PDE by hydrolytic cleavage of the 3'-ribose-phosphate bond (Fig. 1). Because the distribution and functional role of PDE isoenzymes varies in different tissues, selective inhibitors have the potential to exert at least partially specific tissue effects. Currently, over 40 PDE isoenzymes and isoforms are known (126). The functional assays revealed a predominant functional role for PDE 3 and 5 (127). There was no difference in PDE expression in diabetic compared to non-diabetic patients with ED.
Sildenafil acts as conditioner on the cavernous smooth muscle side by blocking PDE5. It is taken 60 minutes before anticipated sexual activity and its effects last approximately 4 hours. The drug is available in three doses (25, 50, or 100 mg). lt does not stimulate the sexual desire and provoke an erection as such, but enhances the continued relaxation of the cavernous smooth muscle initiated by the release of endogenous NO with an improved quality of erection (Fig. 1).
In a controlled, flexible-dose US multicenter trial including a mixed group of 268 type 1 and type 2 diabetic men the rates of those with improved erections after 12 weeks of treatment with 25 to 100 mg sildenafil were 56% as compared with 10% in the placebo group (128). In a 12-week European multicenter trial including 219 type 2 diabetic men the response rate was even higher achieving 64.6% on sildenafil versus 10.5% on placebo (129). The estimated percentages of intercourse attempts that were successful significantly improved from baseline to end of treatment in patients receiving sildenafil (14.4-58.8%) compared with those receiving placebo (13.2-14.4%). Three quarters of the patients required the 100 mg sildenafil dose. The response rates were independent of the baseline HbA1c levels and number of chronic complications, suggesting that sildenafil is effective in improving ED even in cases with poor glycemic control and in presence of angiopathy and neuropathy. In a combined analysis of 11 controlled trials of sildenafil (25-100 mg) the percentages of the maximum score for the six questions in the erectile function domain of the IIEF were 61.3% among 69 type 1 and 60.8%
among 399 type 1 diabetic men on sildenafil as compared to 39.3% among 452 diabetic men on placebo (130).
Side effects consist mainly of headache (18%), facial flushing (15%), and dyspepsia (2%). A mild and transient disturbance of color vision and also increased sensitivity to light or blurred vision has been found in 4.5% of diabetic men (129). Concerns have been expressed regarding an increased number of deaths associated with sildenafil as compared with other treatments for ED (131). However, after an average follow-up of 6 months the Prescription Event Monitoring Study including 5601 sildenafil users from England showed an expected mortality rate of 28.9 per 1000/year for ischemic heart disease/myocardial infarctions. The comparison rate in the general population of England in 1998 was 73.9 per 1000/year (132). The prevalence of diabetes in the cohort was 15%, which is similar to the rate of 16% included in the clinical trials of sildenafil, but much higher than the rate of 3.3% of men with diabetes in England in 1998. Although these results are reassuring, further follow-up of this study and other pharmacoepidemiological research is needed for confirmation. In men with severe stenosis of at least one coronary artery acute administration of sildenafil (100 mg) did not result in adverse hemodynamic effects on coronary blood flow or vascular resistance, but coronary flow reserve was improved (133).
Apart from its effect on ED, favorable effects of sildenafil have recently been reported in studies of various disorders including primary pulmonary hypertension, achalasia, and endothelial dysfunction (134).
According to the recommendations of the American Heart Association sildenafil is contraindicated in men taking nitrates due to the risk of hypotension and those with severe cardiovascular disease. Before sildenafil is prescribed, treadmill testing may be indicated in men with heart disease to assess the risk of cardiac ischemia during sexual intercourse. Initial monitoring of blood pressure after the administration of sildenafil may be indicated in men with congestive heart disease who have borderline low blood pressure and low volume status and men being treated with complicated, multidrug antihypertensive regimens (134).
Because some men do not respond to sildenafil treatment, attempts have been undertaken to characterize these non-responders. A recent penile biopsy study identified severe vascular lesions and atrophy of cavernous smooth muscle to represent the main factors that determined the lacking response to 100 mg sildenafil in men with ED aged from 28 to 74 years. The age, diabetes and low testosterone level were not related to the response failures (135).
Tadalafil (Cialis®). In a 12-week multicenter trial including 216 diabetic men (type 2:91%), but excluding sildenafil non-responders, the rates of men with improved erections were 64% with 20 mg tadalafil, 56% with 10 mg tadalafil, and 25% on placebo (136). Both tadalafil 10 and 20 mg were superior to placebo in improving penetration ability (IIEF question 3) and ability to maintain an erection during intercourse. Thus, although non-responders to sildenafil were excluded, the effect of tadalafil was not superior to that of sildenafil. Treatment-related adverse events (>5%) on 20 mg, 10 mg, and placebo were dyspepsia (8.3%, 11.0%, and 0%) and headache (6.9%, 8.2%, and 1.4%). Despite more severe baseline ED in men with diabetes as compared to the non-diabetic population of men with ED, tadalafil was efficacious and well tolerated. As reported for other phosphodiesterase 5 inhibitors, the response to tadalafil was slightly lower in men with diabetes than in men without diabetes (137). The pharmacokinetic profile of tadalafil differs from that of sildenafil and vardenafil in that it has a much longer half-life (Fig. 3). This means that the effect of tadalafil may last over 24 hours or even longer, while the duration of action for the other two drugs is around 4 to 5 hours. Such a longer "window of opportunity" may be preferable by some men, but in the same way possible side effects may also be prolonged.
So far trials of PDE-5 inhibitors in men with ED assessed exclusively on-demand treatment. In contrast, two recent studies evaluated once-a-day dosing of tadalafil (2.5-10 mg/ day) over 12 and 24 weeks, respectively. Both trials have demonstrated that once-daily tadalafil improves erectile function in men with ED and is well tolerated (138,139). Against the background of potential favorable effects on endothelial function a daily administration of PDE-5 inhibitors appears an attractive option. However, the pros and cons of such a long-term treatment are unknown. One advantage could be the lower dose required for daily dosing, but the cost of this approach would obviously be high.
Parameter Vardenafil 20 mg Sildenafil 100 mg Tadalafil 20 mg
Vardenafil (Levitra®). In a large 12-week multicenter trial including 439 diabetic men (type 2: 88%) that excluded sildenafil non-responders, the rates of men with improved erections were 72% with 20 mg vardenafil, 57% with 10 mg vardenafil, and 13% on placebo (140). Both vardenafil 10 and 20 mg were superior to placebo in improving the IIEF erectile function domain score (questions 1-5, 15). Similar to tadalafil, despite the exclusion of non-responders to sildenafil the effect of vardenafil was comparable to that reported previously for sildenafil. Treatment-related adverse events (>5%) on 20 mg, 10 mg, and placebo were headache (10%, 9%, and 2%), flushing (10%, 9%, and <1%), and headache (6%, 3%, and 0%).
In a multicenter, double-blind, placebo-controlled clinical trial, PDE-5 inhibitor-naive type 1 diabetic patients were randomized to receive placebo (n = 149) or flexible-dose (5-20 mg) (n = 153) vardenafil. Vardenafil significantly improved mean success rates for Sexual Encounter Profile 2 and 3 compared with baseline and placebo at 4, 8, and 12 weeks. These rates were unaffected by stratification into distinct subsets according to the level of HbA(1c) (HbA(1c) < 7%, good glycemic control; HbA(1c) >7 to >8%, moderate glycemic control; and HbA(1c) >8%, poor glycemic control). The most commonly reported treatment-emergent adverse events were headache (3.1%) and flushing (2.5%), which were mild to moderate and transient in nature. These data suggest that vardenafil significantly improves erectile function in men with type 1 diabetes and is well tolerated, regardless of the level of glycemic control (141).
Data from head-to-head clinical trials of PDE-5 inhibitors are scarce. One recent randomized, double-blind, crossover head-to-head clinical trial compared patient preference, efficacy, and safety of vardenafil and sildenafil in men with ED and diabetes, hypertension, and/or hyperlipidemia. Prospective analysis was performed on two studies in which 1057 men were randomized to vardenafil 20 mg (n = 530) or sildenafil 100 mg (2 x 50 mg encapsulated tablets) (n = 527) for 4 weeks. Following a 1-week washout, patients switched treatment for 4 weeks. Non-inferiority of vardenafil over sildenafil was achieved for overall preference (vardenafil 38.9%; sildenafil 34.5%; and no preference 26.6%). Additionally, the change from baseline in the EF domain score of the IIEF achieved nominal significance for vardenafil over sildenafil (10.00 vs. 9.40; P = 0.0052). Patients also had a higher percentage of positive responses for vardenafil for SEP2, SEP3, GAQ, and 12 of 19 questions on the TSS. However, several sources of potential bias such as the sildenafil formulation, pooled analysis of two studies, and sponsorship of the study by the manufacturer of vardenafil have to be considered when interpreting these data (142).
A recent systematic review assessed the overall effect of PDE-5 inhibitors on the management of ED in diabetic men. The weighted mean difference (WMD) for the IIEF questions 3 and 4 (frequency of penetration during and maintaining erection to completion of intercourse) was 0.9 (95% CI 0.8-1.1) and 1.1 (95% CI 1.0-1.2) at the end of the study period, in favor of the intervention group. The WMD for the IIEF ED domain at the end of the study period was 6.6 (95% CI 5.2-7.9) in favor of the PDE-5 inhibitors arm. The relative risk for answering "yes" to a global efficacy question ("did the treatment improve your erections?") was 3.8 (95% CI 3.1-4.5) in the PDE-5 inhibitors compared with the control arm. The WMD between the percentage of successful attempts in the PDE-5 inhibitors and in the control arm was 26.7 (95% CI 23.1-30.3). The overall risk ratio for developing any adverse reaction was 4.8 (95% CI 3.74-6.16) in the PDE-5 inhibitors arm as compared to the control. Thus, sufficient evidence exists that PDE-5 inhibitors form a care that improves ED in diabetic men (143).
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