ED occurs at an earlier age in men with diabetes, and there is also a higher prevalence. In an Australian study, 40% of diabetic men aged ≥60-years had constant ED. In men with ED, diabetes is often associated with diabetic neuropathy and peripheral vascular disease.
In corpus cavernosum tissue obtained at the time of penile prosthesis in diabetic men with impotence, there was an impaired neurogenic and endothelium-mediated relaxation compared to the tissue from non-diabetic men.
ED is also commonly associated with a range of other conditions. In patients with localised prostate cancer treated with radiotherapy, ED estimates range from 15% to 60%. In end-stage renal disease patients on dialysis, the incidence of ED is ~75%.
ED is a side-effect commonly associated with use of the selective serotonin uptake inhibitors to treat depression. When the effect of a range of lifestyle factors on ED was determined, it was shown that level of education, marital status, and amount of alcohol and coffee consumption had no effect, whereas obesity and current smoking increased the incidence.
Pharmacodynamics and pharmacokinetics
Sildenafil, vardenafil, and tadalafil are selective inhibitors of phosphodiesterase type 5 inhibitor (PDE5) with inhibitory concentration of 50% values of 3.9nM and 5nM, respectively. For tadalafil, there is 1000-fold selectivity for PDE5 over other PDEs, including PDE6.
The maximum plasma concentration with sildenafil, vardenafil and tadalafil is obtained 60 min after administration of sildenafil and vardenafil, but later with tadalafil (two hours). The half-life of tadalafil is 17.5 hours, compared to 3.8 hours for sildenafil and 3.9 hours for vardenafil.
Consequently, sildenafil and vardenafil have short duration of action (four hours compared with the longer period of responsiveness with tadalafil (≤36 hours).
Vardenafil undergoes substantial first pass liver metabolism. All three PDE5 inhibitors are metabolised by cytochrome P450 3A4, and non-selective (cimetidine) or selective inhibitors of this enzyme (eg erythromycin) increase their plasma levels.
In patients with moderate hepatic failure, the plasma levels of vardenafil may be elevated, and a lower starting dose is recommended. Sildenafil, vardenafil and tadalafil are excreted as metabolites, mainly in the faeces. A high fat meal delays the onset of action of sildenafil and vardenafil, but not tadalafil.
Efficacy of tadalafil
The first major trial of the effects of tadalafil in ED was published in 2001, and compared tadalafil 2mg, 5mg, 10mg or 20mg with placebo in 179 men over three weeks, excluding patients taking nitrates.
Patients were instructed to take a maximum of one dose per day as needed over 21 days, but not to exceed 14 doses. A maximum effect seemed to be apparent with tadalafil 10mg, which was ~70% of successful attempts, compared to 27% with placebo. Headache and dyspepsia were the most common adverse effects reported with tadalafil. No alterations of colour vision were reported.
A clinical trial with 1112 men with ED (~60% organic, ~30% mixed) was able to show greater benefit with tadalafil 25mg than 10mg on erectile function over 12 weeks.
With self-administration prior to sexual intercourse, there were no timing restrictions or restrictions on food and alcohol intake. The successful intercourse attempts were 61% and 75% with tadalafil 10mg and 25mg, respectively, compared with 32% in the control group. Patients most severely affected with ED tended to have greater improvements in erectile function.
The efficacy of tadalafil was similar for patients >65-years and their younger counterparts. About 20% of patients in this trial had diabetes, and in this population ≤76% reported improved erections. The most common adverse effects reported were headache (14% vs 6%) and dyspepsia (10% vs 2%), and there were no effects on vision.
In a trial of 207 US and Puerto Rican men, it was shown that the most successful intercourse attempts occurred between four and 36 hours after taking tadalafil, with 83% of men taking tadalafil reporting improved erections versus 20% of those taking placebo.
In another trial, it was shown that the chances of successful sexual intercourse were increased 24 and 36 hours after the administration of tadalafil. In this group of 327 patients, 53% had successful intercourse at 24 hours (placebo, 29%) and 59% at 36 hours (placebo, 28%). Excesses of headache, flushing, dyspepsia and myalgia were reported with tadalafil.
The long-term safety and tolerability of tadalafil was confirmed in a 24-month, open-label extension of previous studies. Headache, dyspepsia, nasopharyngitis and back pain (15.8%, 11.8%, 11.4% and 8.2%, respectively) were the most common adverse effects. The rate of discontinuation due to adverse events for the 18- to 24-month study was 6.3%.
In a separate trial, the ability of tadalafil to enhance erectile function in men with diabetes (predominantly type 2) and ED was confirmed. Tadalafil, taken on demand, is also effective in the ED following bilateral nerve-sparing radical retropubic prostatectomy.
In healthy subjects, tadalafil causes small changes in blood pressure that are not considered to be clinically relevant. Tadalafil has a similar interaction with nitrates in patients with coronary artery disease (eg it increases the blood pressure lowering normally observed with nitro-glycerine and isosorbide mononitrate).
Tadalafil is safe in patients receiving antihypertensives. Across the studies where tadalafil has been used for ED, there is no evidence for increased myocardial infarction or cardiac death with tadalafil.
In comparison with sildenafil, the major differences, which are evident from comparing trials with either sildenafil or tadalafil, are that there is no requirement to take tadalafil one hour prior to sexual intercourse, and tadalafil does not affect vision.
A most interesting development, which has not occurred with vardenafil, is comparison trials between tadalafil and sildenafil. These trials show that men with ED often prefer tadalafil over sildenafil.
A fixed dose, two-period, crossover trial of 213 men with ED, compared tadalafil 20mg with sildenafil 50mg, either in tadalafil-sildenafil or sildenafil-tadalafil sequence.
Subjects had never received tadalafil, most (85%) had never received sildenafil, and some (15%) had undergone a previously inadequate trial of sildenafil. Most cases of ED were mixed or organic (42% and 39%, respectively).
Of the 190 evaluable patients, 66 and 34% preferred tadalafil and sildenafil, respectively. The most common adverse effects for tadalafil and sildenafil, respectively, were headache (11.2% versus 8.8%), dyspepsia (6% versus 4.2%), nasopharyngitis (4.7% versus 2.8%) and flushing (2.8% versus 4.7%).
The findings of this trial only apply to the doses tested. As most trials of sildenafil alone show that most men with ED prefer sildenafil 100mg over 50mg, it may have been more appropriate to have compared tadalafil 20mg to sildenafil 100mg.
In a second trial of sildenafil and tadalafil, ED patients who were taking sildenafil were switched to tadalafil and then asked which they preferred, with most preferring tadalafil. The 147 evaluable men in this study had been taking stable fixed doses of sildenafil 25mg, 50mg or 100mg as needed, for at least six weeks and up to 24 weeks.
After a three-week pre-study sildenafil dose, there was a nine-week tadalafil initiation/assessment phase, at the end of which, the ED subjects could select either sildenafil or tadalafil for a six-month extension. Most (90%) of the men selected tadalafil, and the proportions preferring tadalafil were similar irrespective of age, severity of ED, aetiology of ED, and sildenafil dose at study entry.
The obvious limitation to this study was that it was not blinded, and another limitation was that it did not determine the effect on erectile function. When a blinded trial was undertaken to evaluate patient preference between tadalafil 20mg and sildenafil 50mg-100mg, most ED patients preferred tadalafil.
Thus, 73% of 181 ED patients chose to receive tadalafil during the extension period. These studies have the same limitation as the crossover study, namely, that the comparison should have been between tadalafil 20mg and sildenafil 100mg. For instance, in the blinded trial, only 35% of the men had the ability to titrate to sildenafil 100mg. This may have biased the preference towards tadalafil.
Sildenafil versus tadalafil
There is a major point of difference between sildenafil and tadalafil in that tadalafil is considered to have a much longer duration of action. Tadalafil therefore allows more choice regarding the onset of sexual intercourse. The dosing instructions for sildenafil are that patients take sildenafil one hour before sexual activity, whereas those for tadalafil suggest that sexual activity can be initiated between 30 min and 24 hour after dosing.
This seems to be very important, as in comparison trials of sildenafil and tadalafil, most men prefer to take tadalafil. As these trials did not investigate why tadalafil was preferred, it is possible that there may be another, at present unclear, reason why men prefer tadalafil over sildenafil in ED.
Given that these agents have similar safety and tolerability profiles, these preference results of tadalafil over sildenafil become important, and tadalafil may displace sildenafil as the drug of choice in the treatment of ED.
Doggrell SA. Comparison of clinical trials with sildenafil, vardenafil and tadalafil in erectile dysfunction. Expert Opin Pharmacother, 2005.