International Journal of Impotence Research (2002) 14, 466–471 ß 2002 Nature Publishing Group All rights reserved 0955-9930/02 $25.00 www.nature.com/ijir

Phosphodiesterase type 5 inhibitors for the treatment of in patients with mellitus

MA Vickers1,2* and R Satyanarayana1

1Department of Surgery, Togus VA Medical Center, Togus, Maine, USA; and 2Department of Surgery, Division of , University of Massachusetts Medical School, Worcester, Massachusetts, USA

Sildenafil, a 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 ) 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

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

Introduction (NO), vasointestinal peptide and , de- creases. Additionally, the endothelial cells that line the cavernosal arteries and sinusoids have a Pathophysiology of ED in diabetes decreased response to due to increased production of advanced glycation end-products and changes associated with resistance.5,6 The Diabetes mellitus is a risk factor for erectile diabetic also experiences a decreased level of dysfunction (ED). ED is present in 32% of insulin- glutathione, a reducing agent that protects against dependent diabetics and 46% of non-insulin de- oxidative stress.7 This results in the premature pendent diabetics. ED is the result of both structural death of the non-adenergic, non-cholinergic nerve and molecular abnormalities. Atrophy or apoptosis, endings in the , thus lowering levels of second owing to loss of Bcl-2 expression in , messenger nitric oxide. The end result of decreased and increased connective tissue synthesis, due to production or decreased response to nitric oxide is a TGF beta, result in decreased compliance of caver- decrease in the stimulation of . nosal tissue.1,2 Both these changes reduce or inter- This cleaves GTP with resultant production fere with the gap junctions and K channels in of cyclic guanosine monophosphate (cGMP), the cavernosal smooth muscle that are necessary for power source for the relaxation of cavernosal coordinated relaxation of cavernosal tissue.3 The smooth muscle. In situations in which sexual chemical changes involve a shift in the balance stimulation does not induce critical amounts of between molecules that induce cavernosal smooth cGMP, calcium remains in its intracellular location, muscle contraction and those that induce smooth cavernosal muscle remains contracted and caverno- muscle relaxation.4 The concentration of constric- sal blood vessels do not dilate. Blood flow into the tors, including endothelin, prostanoids, and possi- penis is inadequate to engorge the sinusoids and bly angiotensin, increases with aging as the compress the venules. Functional penile rigidity is production of the relaxants, including nitric oxide 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 *Correspondence: MA Vickers, Department of Surgery, VA Medical Center, Togus, ME 04330, USA. erectile levels by delaying the degradation of this E-mail: [email protected] molecule. This is achieved through the inhibition of Received 19 March 2002; accepted 1 May 2002 the enzyme phosphodiesterase 5. Phosphodiesterase type 5 inhibitors MA Vickers et al 467 PDE5 inhibitors in ED taken. Sixteen men with ED received sildenafilona 25 mg, three times daily, outpatient basis. The study The final chapter of discovery of an oral drug that patients kept diaries in which they recorded when would dependably increase cGMP to levels that they had , whether the erections resulted could promote cavernosal smooth muscle relaxation from sexual stimulation, and how firm the erections began in the vascular laboratory. Phosphodiesterase were. The patients were also studied with the type 5 (PDE5) had been identified as the enzyme that Rigiscan. The results were encouraging and showed degraded cGMP.8 It resides in vascular smooth a clear difference between the treatment and place- muscle cells and platelets. Researchers theorized bo. Subsequent studies confirmed the efficacy and that inhibition of this enzyme offered potential safety of sildenafil in the treatment of ED with a benefits for patients with or . variety of etiologies, including vascular, psycho- In 1986, Pfizer researchers began their search for a genic, and neurological. In 1998, the US FDA PDE5 inhibitor. In 1989, they synthesized sildenafil, approved sildenafil for the treatment of ED. It soon a chemical that selectively targeted and powerfully became the first-line therapy. Soon, a search for inhibited PDE5. Clinical studies on sildenafilasa novel, superior PDE5 inhibitors was initiated. Var- drug for angina began in 1991. The initial study, denafil (Bayer) and tadalafil (Lilly ICOS) are the designed to assess the drug’s safety, revealed no products of these efforts and are presently candi- unusual findings. In 1992, a multiple-dose phase 1 dates for US FDA approval. All three PDE5 inhibitors trial was initiated. A few of the study patients are similar in structure to cyclic guanosine mono- reported an ‘adverse event’—an increased tendency phosphate (Figure 1). to get erections. Later that year the drug was tested The phase three trials (efficacy and safety) for in men with angina. The hemodynamic effects were sildenafil, tadalafil and vardenafil in the general ‘fairly mild’. population (organic, psychogenic and mixed ED) In 1992, Rajfer and Ignarro published their work and the phase three trial of sildenafil in the diabetic showing that nitric oxide (NO) caused smooth population have been published in peer reviewed muscle relaxation in human cavernosal tissue. The journals.9 – 12 Additionally, the phase three trials of basic mechanism involved sexual stimulation that tadalafil and vardenafil in the diabetic population triggered the release of NO from nerve endings in the have been published in abstract=poster form.13,14 penis. This NO in turn stimulated the production of These publications have prompted speculation cGMP, which dilated penile blood vessels and concerning the role of the various PDE5 inhibitors relaxed the smooth muscle in the walls of the in the treatment of ED. The temptation to draw cavernosal sinusoids. These two effects promote conclusions based on simple comparison of these engorgement of the penis and penile rigidity. studies must be rejected for several reasons. On Several basic and clinical researchers at Pfizer review of these studies, it is apparent that inclusion lobbied for further study of the PDE5 inhibitor in and exclusion criteria vary. The criteria for the treatment of ED based on its ability to relax vascular classification of ED, the percentage of patients with smooth muscle, its ‘adverse event — tendency to get psychogenic ED, the dosing methodology (fixed vs an in the angina trials’, and the UCLA NO dose escalation), and the duration of the studies also research. Even before Pfizer scientists isolated PDE5 vary. These differences likely impacted treatment from human corpus cavernosal tissue (1994), the first outcomes. No head-to-head comparative trials with study (1993) of sildenafil for treating ED was under- the PDE5 inhibitors have been published.

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

International Journal of Impotence Research Phosphodiesterase type 5 inhibitors MA Vickers et al 468 Although no definite conclusion concerning drug diabetes mellitus, cancer agents, superiority can be made from these studies, a systemic corticosteroids, or antiandrogen comparative summary helps demonstrate the effi- therapy. Potential candidates in the vardenafil study cacy and safety of the class of PDE5 inhibitors and were excluded if they had not responded to the potential advantages of individual PDE5 inhibi- sildenafil. In addition, patients were excluded from tors. The general population trials are included to the study based on half (five of 10) of the provide an overall perspective for the use of exclusionary criteria of the sildenafil study. Patients individual PDE5 inhibitors in ED and to provide a with hypogonadal levels, TSH levels of background for the evaluation of the role of PDE5 < 0.28 mU=l, or with a previous radical prostatect- inhibitors in diabetic patients. The summary analy- omy were excluded. The percentage of patients with sis includes methodology, efficacy, and safety. 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 Methodology no significant difference from placebo in the various efficacy parameters. The limitations of a strict comparative analysis of The essential elements of each study are listed in the three PDE5 inhibitors based on the efficacy and Table 1. Patients were excluded from the sildenafil safety studies in diabetics are similar to those noted trial in the general population if they had penile in the general population studies. The duration of anatomical defects, a primary diagnosis of another ED varied among the studies. The tadalafil and sexual disorder (eg ), spinal vardenafil studies did not provide data on the cord injury, any major psychiatric disorder not well duration of type 1 and type 2 diabetes mellitus. controlled with treatment, poorly controlled dia- The exclusions for these studies were essentially the betes mellitus, active peptic ulcer disease, history of same as for the studies in the general population. alcohol or substance abuse, major hematologic, renal Additional criteria in one or more of the three or hepatic abnormalities, or a recent or studies excluded subgroups of diabetics with a , or if they were receiving hemoglobin Alc of greater than 0.12, with progres- therapy. In the tadalafil study, patients who sive, proliferative retinopathy or severe autonomic had prior unsuccessful use of a PDE5 inhibitor were neuropathy, with a history of ketoacidosis or excluded. In addition, patients were excluded based episodes of hypoglycemia requiring assistance, and on many (seven of 10) of the exclusionary criteria of with a penile implant. The initial dose in the the sildenafil study. Additional exclusions included sildenafil study was 50 mg. Based on the investiga- untreated endocrine disease, s=p radical prostatect- tor’s judgment of efficacy and tolerability, the dose omy, immune disease and the simple presence of could be increased to 100 mg or decreased to 25 mg.

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

Sildenafil Tadalafil Vardenafil

Type 1 and 2 Type 1 and 2 Type 1 and 2 General diabetes General diabetes General diabetes population9 mellitus12 population10 mellitus13 population11 mellitus14,15

Multi-center, randomized, double-blind, placebo-controlled X X X X X X On demand X X X X X X Fixed dose X X X X X Flexible dose-escalation X Duration (weeks) 24 12 24 12 24 12 Number of randomized patients 532 268 179 216 590 452 Number (%) of patients completing study 465 (87%) 252 (94%) 172 (96%) NR 506 (86%) NR Inclusion (11%)=O=M Indeterminate P(25%)=O=M Duration of ED  6 mo of ED 3 months 6 months Duration of diabetes mellitus, type 1  5 y of type 1 NR for type 1 NR for type 1 Duration of diabetes mellitus, type 2  2 y of type 2 NR for type 2 NR for type 2 Exclusion See Progressive Sildenafilþ Ketoacidosis Sildenafilþ Progressive discussion proliferative proliferative diabetic diabetic retinopathy, retinopathy, severe autonomic retinitis neuropathy, pigmentosa ketoacidosis

NR, not reported.

International Journal of Impotence Research Phosphodiesterase type 5 inhibitors MA Vickers et al 469 The tadalafil and vardenafil trials used fixed doses here are that PDE5 inhibitors significantly of 10 or 20 mg of the respective drugs. (P < 0.001) enhanced erectile function when com- pared to placebo. The 5 mg dose of tadalafil failed the significance test in two of the three parameters. Results In the diabetic population, response rates were evaluated with the International Index of Erectile The response rates of each study are listed in Table Function, the global efficacy question, and the 2. In the general population, response rates to the patient’s diary of sexual encounters. Two of the various drugs and dosages were evaluated by three studies, tadalafil (IC351) and vardenafil, did not vehicles. First, the International Index of Erectile isolate the scoring on IIEF-Question 3 and IIEF- Function, a 15-question validated, multidimen- Question 4. In their place was substituted the IIEF sional, self-administered questionnaire was used Erectile Function Domain Score which includes the for clinical assessment of erectile dysfunction and sum of questions 1 – 5 and 15 of the International the treatment outcome. The response to two ques- Index of Erectile Function. It is again impossible to tions (3 and 4) pertaining to the ability to achieve compare the results with one drug vs the results and maintain an erection sufficient for sexual with another, because of the high probability of the intercourse was analyzed in detail. Second, the presence of demographic variation in the various response (yes or no) to a global efficacy question (did study groups. In spite of this limitation, the analysis the treatment improve your erections?) was re- clearly demonstrates efficacy of the three PDE5 corded. Finally, an event log of sexual encounters inhibitors when compared to placebo. The P-value was compiled by each study patient. The date and for all three parameters of comparison was signifi- dose of taken, the presence of sexual cant, < 0.001. stimulation, the hardness of erections (graded on a four-point scale), and whether was successful were entered in this diary. Adverse events It is impossible to compare the results with one drug vs the results with another because of the high This data is based on the percentage of patients who probability of the presence of demographic variation experienced an adverse event (AE) at any time over in the various study groups. The critical findings the treatment period (Table 3). For the sildenafil and

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

Placebo=sildenafil Placebo=tadalafil (IC351) Placebo=vardenafil Placebo=25 – 50 – 100 Placebo=5 – 10 – 20 Placebo=5 – 10 – 20

Type 1 Type 1 and 2 Type 1 and 2 and 2 General diabetes General diabetes General diabetes population mellitus population mellitus population mellitus

IIEF-Question 3 (frequency of penetration) 5=60 – 84 – 100 25=78 0=39 – 32 – 46 NR 8=48 – 50 – 60 NR percentage in mean score from baseline for placebo, 25, 50, and 100 mg of sildenafil; for placebo, 5, 10, and 20 mg of tadalafil (IC351); for placebo, 5, 10, and 20 mg of vardenafil IEEF- Question 4 (maintenance of erections 24=121 – 133 – 130 14=93 10=60 – 71 – 74 NR 25=67 – 71 – 81 NR after penetration) increase in mean score from baseline in various groups for placebo, 25, 50, and 100 mg for placebo, 25, 50, and 100 mg of sildenafil for placebo, 5, 10, and 20 mg of tadalafil (IC351) for placebo, 5, 10, and 20 mg of vardenafil IIEF Erectile Function domain (the sum of NR 13=73 NR 5=50 – 62 NR 15=55 – 58 IIEF-Questions 1 – 5, and 15) Global efficacy 25=56 – 77 – 84 10=56 17=60 – 81 – 81 23=56 – 64 30=66 – 76 – 80 13=57 – 72 percentage of men in the various groups who responded ‘yes the treatment improved my erections’ Sexual Encounter Profile recorded in diary 50=72 – 80 – 85 12=48 26=62 – 70 – 70 2=28 – 29 39=71 – 71 – 74 23=49 – 54 Percentage of men, in the various groups, achieving erections hard enough for sexual intercourse with placebo vs various doses on trial

NR, not reported.

International Journal of Impotence Research Phosphodiesterase type 5 inhibitors MA Vickers et al 470 Table 3 Comparison of adverse events experienced by general patient population and type 1 and type 2 diabetes mellitus study population

Placebo=sildenafil Placebo=tadalafil Placebo=vardenafil Placebo=25 – 50 – 100 mg Placebo=5 – 10 – 25 mg Placebo=5 – 10 – 20 mg

Type 1 and 2 Type 1 and 2 Type 1 and 2 General diabetes General diabetes General diabetes population mellitus population mellitus population mellitus

Headache 6=14 – 21 – 30 2=11 6=3 – 17 – 14 1=8 – 64=7 – 9 – 15 2=9 – 10 1=13 – 27 – 20 0=4NRNR1=10 – 11 – 11 1=9 – 10 Dyspepsia 1=3 – 11 – 16 0=90=8 – 3 – 80=11 – 80=1 – 3 – 7NR Rhinitis 2=1 – 3 – 11 0=4NRNR3=5 – 3 – 70=3 – 6 Visual disturbance 1=2 – 6 – 91=4NRNRNRNR NR NR 0=0 – 8 – 3NRNRNR Repiratory tract disorder NR 2=6NRNRNRNR (sinus congestion or drainage)

NR, none reported.

vardenafil studies, percentages for the general associated with these drugs. The , rhini- patient population study were reported if they were tis, sinusitis, flushing and are secondary to equal to or exceeded 5%. For the tadalafil study, AEs the vasodilatory effect of inhibitors on PDE5 within were reported if the percentages were equal to or the capillary smooth muscle of the brain, nasal greater than 3% in the general patient population cavity, turbinates, sinuses, dermis, and retroperito- study. Again, it is impossible to compare the neum, respectively. The dyspepsia is related to the incidence of adverse effects. It does appear, how- inhibition of PDE5 in the muscle of the gastro- ever, that both tadalafil and vardenafil are less likely esophageal junction. The relative differences in to be associated with abnormalities of color vision frequency of these adverse effects can be explained than sildenafil. The higher incidence of muscle pain by variations in patient populations or by variation and the lower incidence of flushing and rhinitis in in molecular configuration among sildenafil, tadala- the tadalafil study warrants follow-up in future fil and vardenafil. Head-to-head studies are neces- studies. sary to clarify this issue and to determine the The reportable data in the diabetic population is eventual position of each of these PDE5 inhibitors based on the same criteria as utilized in the general in the treatment of ED. population studies. In the tadalafil and vardenafil Recent studies suggest potential advantages of studies, adverse events of all causes were reported if tadalafil and vardenafil in subsets of patients with they occurred in at least 5% of patients. As in the ED. The period of responsiveness of tadalafil general population studies, visual disturbances, (IC351), from as early as 16 min post-dosing to at flushing and rhinitis are not reported with the least 24 h post-dosing, offers the potential of multi- tadalafil. As in the general population studies, ple successful intercourse encounters.16 Perhaps, visual disturbances and myalgias are not reported this drug will be preferred for patients with with vardenafil. In contrast to the general popula- neurogenic or psychogenic ED and intact cardiovas- tion studies, tadalafil is not associated with myalgia cular systems. Conversely, the t1=2 of tadalafil in the diabetic population. (17.5 h) may preclude its use in patients with hypertension, peripheral vascular disease or angina. The maximum plasma concentration of sildenafilis Conclusion 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 In each of the six studies reviewed, PDE5 inhibitors characteristic potentially increases the spontaneity improved erectile function for all efficacy variables of intercourse. Vardenafil was shown to interact to a degree that was significantly (P < 0.001) greater minimally with nitroglycerin in healthy middle- than the placebo control. In addition, the inhibitors aged men. This finding, combined with the fact that were well tolerated. The adverse events were minor vardenafil has a plasma half life of less than one and varied among the inhibitors. The well-recog- hour offers the promise that it may have a role in nized visual disturbance associated with sildenafil patients with angina who require nitrate therapy.17 is the result of the relative selectivity of this Designing safety and efficacy studies in this patient inhibitor for PDE6, an isoenzyme found in the rod population will be very difficult and perhaps and cone cells of the . Conversely, the fact that impossible. Tadalafil or vardenafil therapy may be tadalafil and vardenafil are less selective for the an option in patients with retinopathy, due to the PDE6 explains the absence of visual disturbance lack of selectivity of these inhibitors for PDE6.

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International Journal of Impotence Research