¹Department of Surgery, Togus VA Medical Center, Togus, Maine, USA

²Department of Surgery, Division of Urology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

Correspondence to: M A Vickers, Department of Surgery, VA Medical Center, Togus, ME 04330, USA. E-mail: Martyn.Vickers@med.va.gov

Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, has become a first-line therapy for diabetic patients with erectile dysfunction (ED). The efficacy in this subgroup, based on the Global Efficacy Question, is 56% vs 84% in a selected group of non-diabetic men with ED. Two novel PDE5 inhibitors, tadalafil (Lilly ICOS) and vardenafil (Bayer), have recently completed efficacy and safety clinical trials in 'general' and diabetic study populations and are now candidates for US FDA approval. A summary analysis of the phase three clinical trials of sildenafil, tadalafil and vardenafil in both study populations is presented to provide a foundation on which the evaluation of the role of the individual PDE5 inhibitors for the treatment of patients with ED and DM can be built.

International Journal of Impotence Research (2002) 14, 466-471. doi:10.1038/sj.ijir.3900910

phosphodiesterase inhibitor; erectile dysfunction; diabetes mellitus; sildenafil; tadalafil; vardenafil

Introduction

Pathophysiology of ED in diabetes

Diabetes mellitus is a risk factor for erectile dysfunction (ED). ED is present in 32% of insulin-dependent diabetics and 46% of non-insulin dependent diabetics. ED is the result of both structural and molecular abnormalities. Atrophy or apoptosis, owing to loss of Bcl-2 expression in smooth muscle, and increased connective tissue synthesis, due to TGF beta, result in decreased compliance of cavernosal tissue.^1,2 Both these changes reduce or interfere with the gap junctions and K channels in cavernosal smooth muscle that are necessary for coordinated relaxation of cavernosal tissue.³ The chemical changes involve a shift in the balance between molecules that induce cavernosal smooth muscle contraction and those that induce smooth muscle relaxation.⁴ The concentration of constrictors, including endothelin, prostanoids, and possibly angiotensin, increases with aging as the production of the relaxants, including nitric oxide (NO), vasointestinal peptide and prostacyclin, decreases. Additionally, the endothelial cells that line the cavernosal arteries and sinusoids have a decreased response to nitric oxide due to increased production of advanced glycation end-products and changes associated with insulin resistance.^5,6 The diabetic also experiences a decreased level of glutathione, a reducing agent that protects against oxidative stress.⁷ This results in the premature death of the non-adenergic, non-cholinergic nerve endings in the penis, thus lowering levels of second messenger nitric oxide. The end result of decreased production or decreased response to nitric oxide is a decrease in the stimulation of guanylate cyclase. This enzyme cleaves GTP with resultant production of cyclic guanosine monophosphate (cGMP), the power source for the relaxation of cavernosal smooth muscle. In situations in which sexual stimulation does not induce critical amounts of cGMP, calcium remains in its intracellular location, cavernosal muscle remains contracted and cavernosal blood vessels do not dilate. Blood flow into the penis is inadequate to engorge the sinusoids and compress the venules. Functional penile rigidity is not achieved.

The oral treatment of ED in the diabetic is based on amplification of the response to NO stimulation. Sub-erectile levels of cGMP are increased to critical erectile levels by delaying the degradation of this molecule. This is achieved through the inhibition of the enzyme phosphodiesterase 5.

PDE5 inhibitors in ED

The final chapter of discovery of an oral drug that would dependably increase cGMP to levels that could promote cavernosal smooth muscle relaxation began in the vascular laboratory. Phosphodiesterase type 5 (PDE5) had been identified as the enzyme that degraded cGMP.⁸ It resides in vascular smooth muscle cells and platelets. Researchers theorized that inhibition of this enzyme offered potential benefits for patients with hypertension or angina. In 1986, Pfizer researchers began their search for a PDE5 inhibitor. In 1989, they synthesized sildenafil, a chemical that selectively targeted and powerfully inhibited PDE5. Clinical studies on sildenafil as a drug for angina began in 1991. The initial study, designed to assess the drug's safety, revealed no unusual findings. In 1992, a multiple-dose phase 1 trial was initiated. A few of the study patients reported an 'adverse event'¾an increased tendency to get erections. Later that year the drug was tested in men with angina. The hemodynamic effects were 'fairly mild'.

In 1992, Rajfer and Ignarro published their work showing that nitric oxide (NO) caused smooth muscle relaxation in human cavernosal tissue. The basic mechanism involved sexual stimulation that triggered the release of NO from nerve endings in the penis. This NO in turn stimulated the production of cGMP, which dilated penile blood vessels and relaxed the smooth muscle in the walls of the cavernosal sinusoids. These two effects promote engorgement of the penis and penile rigidity.

Several basic and clinical researchers at Pfizer lobbied for further study of the PDE5 inhibitor in treatment of ED based on its ability to relax vascular smooth muscle, its 'adverse event¾tendency to get an erection in the angina trials', and the UCLA NO research. Even before Pfizer scientists isolated PDE5 from human corpus cavernosal tissue (1994), the first study (1993) of sildenafil for treating ED was undertaken. Sixteen men with ED received sildenafil on a 25 mg, three times daily, outpatient basis. The study patients kept diaries in which they recorded when they had erections, whether the erections resulted from sexual stimulation, and how firm the erections were. The patients were also studied with the Rigiscan. The results were encouraging and showed a clear difference between the treatment and placebo. Subsequent studies confirmed the efficacy and safety of sildenafil in the treatment of ED with a variety of etiologies, including vascular, psychogenic, and neurological. In 1998, the US FDA approved sildenafil for the treatment of ED. It soon became the first-line therapy. Soon, a search for novel, superior PDE5 inhibitors was initiated. Vardenafil (Bayer) and tadalafil (Lilly ICOS) are the products of these efforts and are presently candidates for US FDA approval. All three PDE5 inhibitors are similar in structure to cyclic guanosine monophosphate (Figure 1).

The phase three trials (efficacy and safety) for sildenafil, tadalafil and vardenafil in the general population (organic, psychogenic and mixed ED) and the phase three trial of sildenafil in the diabetic population have been published in peer reviewed journals.^9,10,11,12 Additionally, the phase three trials of tadalafil and vardenafil in the diabetic population have been published in abstract/poster form.^13,14 These publications have prompted speculation concerning the role of the various PDE5 inhibitors in the treatment of ED. The temptation to draw conclusions based on simple comparison of these studies must be rejected for several reasons. On review of these studies, it is apparent that inclusion and exclusion criteria vary. The criteria for the classification of ED, the percentage of patients with psychogenic ED, the dosing methodology (fixed vs dose escalation), and the duration of the studies also vary. These differences likely impacted treatment outcomes. No head-to-head comparative trials with the PDE5 inhibitors have been published.

Although no definite conclusion concerning drug superiority can be made from these studies, a comparative summary helps demonstrate the efficacy and safety of the class of PDE5 inhibitors and the potential advantages of individual PDE5 inhibitors. The general population trials are included to provide an overall perspective for the use of individual PDE5 inhibitors in ED and to provide a background for the evaluation of the role of PDE5 inhibitors in diabetic patients. The summary analysis includes methodology, efficacy, and safety.

Methodology

The essential elements of each study are listed in Table 1. Patients were excluded from the sildenafil trial in the general population if they had penile anatomical defects, a primary diagnosis of another sexual disorder (eg premature ejaculation), spinal cord injury, any major psychiatric disorder not well controlled with treatment, poorly controlled diabetes mellitus, active peptic ulcer disease, history of alcohol or substance abuse, major hematologic, renal or hepatic abnormalities, or a recent stroke or myocardial infarction, or if they were receiving nitrate therapy. In the tadalafil study, patients who had prior unsuccessful use of a PDE5 inhibitor were excluded. In addition, patients were excluded based on many (seven of 10) of the exclusionary criteria of the sildenafil study. Additional exclusions included untreated endocrine disease, s/p radical prostatectomy, immune disease and the simple presence of diabetes mellitus, cancer chemotherapy agents, systemic corticosteroids, warfarin or antiandrogen therapy. Potential candidates in the vardenafil study were excluded if they had not responded to sildenafil. In addition, patients were excluded from the study based on half (five of 10) of the exclusionary criteria of the sildenafil study. Patients with hypogonadal testosterone levels, TSH levels of <0.28 mU/l, or with a previous radical prostatectomy were excluded. The percentage of patients with organic, psychogenic, or mixed ED was not provided in the tadalafil study. The tadalafil 2 mg dose results are not included in this analysis because there was no significant difference from placebo in the various efficacy parameters.

The limitations of a strict comparative analysis of the three PDE5 inhibitors based on the efficacy and safety studies in diabetics are similar to those noted in the general population studies. The duration of ED varied among the studies. The tadalafil and vardenafil studies did not provide data on the duration of type 1 and type 2 diabetes mellitus. The exclusions for these studies were essentially the same as for the studies in the general population. Additional criteria in one or more of the three studies excluded subgroups of diabetics with a hemoglobin Alc of greater than 0.12, with progressive, proliferative retinopathy or severe autonomic neuropathy, with a history of ketoacidosis or episodes of hypoglycemia requiring assistance, and with a penile implant. The initial dose in the sildenafil study was 50 mg. Based on the investigator's judgment of efficacy and tolerability, the dose could be increased to 100 mg or decreased to 25 mg. The tadalafil and vardenafil trials used fixed doses of 10 or 20 mg of the respective drugs.

Results

The response rates of each study are listed in Table 2. In the general population, response rates to the various drugs and dosages were evaluated by three vehicles. First, the International Index of Erectile Function, a 15-question validated, multidimensional, self-administered questionnaire was used for clinical assessment of erectile dysfunction and the treatment outcome. The response to two questions (3 and 4) pertaining to the ability to achieve and maintain an erection sufficient for sexual intercourse was analyzed in detail. Second, the response (yes or no) to a global efficacy question (did the treatment improve your erections?) was recorded. Finally, an event log of sexual encounters was compiled by each study patient. The date and dose of medications taken, the presence of sexual stimulation, the hardness of erections (graded on a four-point scale), and whether sexual intercourse was successful were entered in this diary.

It is impossible to compare the results with one drug vs the results with another because of the high probability of the presence of demographic variation in the various study groups. The critical findings here are that PDE5 inhibitors significantly (P<0.001) enhanced erectile function when compared to placebo. The 5 mg dose of tadalafil failed the significance test in two of the three parameters.

In the diabetic population, response rates were evaluated with the International Index of Erectile Function, the global efficacy question, and the patient's diary of sexual encounters. Two of the studies, tadalafil (IC351) and vardenafil, did not isolate the scoring on IIEF-Question 3 and IIEF-Question 4. In their place was substituted the IIEF Erectile Function Domain Score which includes the sum of questions 1-5 and 15 of the International Index of Erectile Function. It is again impossible to compare the results with one drug vs the results with another, because of the high probability of the presence of demographic variation in the various study groups. In spite of this limitation, the analysis clearly demonstrates efficacy of the three PDE5 inhibitors when compared to placebo. The P-value for all three parameters of comparison was significant, <0.001.

Adverse events

This data is based on the percentage of patients who experienced an adverse event (AE) at any time over the treatment period (Table 3). For the sildenafil and vardenafil studies, percentages for the general patient population study were reported if they were equal to or exceeded 5%. For the tadalafil study, AEs were reported if the percentages were equal to or greater than 3% in the general patient population study. Again, it is impossible to compare the incidence of adverse effects. It does appear, however, that both tadalafil and vardenafil are less likely to be associated with abnormalities of color vision than sildenafil. The higher incidence of muscle pain and the lower incidence of flushing and rhinitis in the tadalafil study warrants follow-up in future studies.

The reportable data in the diabetic population is based on the same criteria as utilized in the general population studies. In the tadalafil and vardenafil studies, adverse events of all causes were reported if they occurred in at least 5% of patients. As in the general population studies, visual disturbances, flushing and rhinitis are not reported with the tadalafil. As in the general population studies, visual disturbances and myalgias are not reported with vardenafil. In contrast to the general population studies, tadalafil is not associated with myalgia in the diabetic population.

Conclusion

In each of the six studies reviewed, PDE5 inhibitors improved erectile function for all efficacy variables to a degree that was significantly (P<0.001) greater than the placebo control. In addition, the inhibitors were well tolerated. The adverse events were minor and varied among the inhibitors. The well-recognized visual disturbance associated with sildenafil is the result of the relative selectivity of this inhibitor for PDE6, an isoenzyme found in the rod and cone cells of the retina. Conversely, the fact that tadalafil and vardenafil are less selective for the PDE6 explains the absence of visual disturbance associated with these drugs. The headaches, rhinitis, sinusitis, flushing and myalgias are secondary to the vasodilatory effect of inhibitors on PDE5 within the capillary smooth muscle of the brain, nasal cavity, turbinates, sinuses, dermis, and retroperitoneum, respectively. The dyspepsia is related to the inhibition of PDE5 in the muscle of the gastro-esophageal junction. The relative differences in frequency of these adverse effects can be explained by variations in patient populations or by variation in molecular configuration among sildenafil, tadalafil and vardenafil. Head-to-head studies are necessary to clarify this issue and to determine the eventual position of each of these PDE5 inhibitors in the treatment of ED.

Recent studies suggest potential advantages of tadalafil and vardenafil in subsets of patients with ED. The period of responsiveness of tadalafil (IC351), from as early as 16 min post-dosing to at least 24 h post-dosing, offers the potential of multiple successful intercourse encounters.¹⁶ Perhaps, this drug will be preferred for patients with neurogenic or psychogenic ED and intact cardiovascular systems. Conversely, the t_1/2 of tadalafil (17.5 h) may preclude its use in patients with hypertension, peripheral vascular disease or angina. The maximum plasma concentration of sildenafil is decreased by 29% when the drug is ingested with food. In contrast, food has no effect on the maximum plasma concentration of tadalafil. This tadalafil characteristic potentially increases the spontaneity of intercourse. Vardenafil was shown to interact minimally with nitroglycerin in healthy middle-aged men. This finding, combined with the fact that vardenafil has a plasma half life of less than one hour offers the promise that it may have a role in patients with angina who require nitrate therapy.¹⁷ Designing safety and efficacy studies in this patient population will be very difficult and perhaps impossible. Tadalafil or vardenafil therapy may be an option in patients with retinopathy, due to the lack of selectivity of these inhibitors for PDE6. Certainly, additional studies are needed to clarify these issues and many more before any conclusions can be made and algorithms suggested for the use of PDE5 inhibitors in subsets of patients with ED.

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10 Padma-Nathan H et al. On-demand IC351 (Cialis^TM) enhances erectile function in patients with erectile dysfunction. Int J Impot Res 2001; 13: 2-9. Article MEDLINE

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14 Goldstein I et al. Vardenafil improved erectile function in diabetic men with erectile dysfunction. Int J Impot Res 2001; 13: S65.

15 Goldstein I et al. Vardenafil, a new selective PDE5 inhibitor, significantly improved all IIEF domains and showed a favorable safety profile in patients with impaired erectile function and diabetes mellitus. Int J Impot Res 2001; 13: S64.

16 Padma-Nathan H et al. Cialis^TM (IC351) provides prompt response and extended period of responsiveness for the treatment of men with erectile dysfunction (ED). J Urol 2001; ((Suppl)) 165: 224.

17 Mazzu A, Nicholls A, Zinny M. Vardenafil, a new selective PDE-5 inhibitor, interacts minimally with nitroglycerin in healthy middle-aged male subjects. Int J Impot Res 2001; 13: S64.

Figure 1 The structures of three PDE5 inhibitors have components which are similar to cyclic GMP.

Table 1 Comparison of PDE5 inhibitors for the treatment of ED in the general patient population and patients with type 1 and 2 diabetes mellitus

Table 2 Evaluation of response rates of general patient population and patients with type 1 and 2 diabetes mellitus to various drugs and dosages

Table 3 Comparison of adverse events experienced by general patient population and type 1 and type 2 diabetes mellitus study population