Context Erectile dysfunction is common in men with diabetes.
Objective To assess the efficacy and safety of oral sildenafil
citrate in the treatment of erectile dysfunction in men with diabetes.
Design A multicenter, randomized, double-blind,
placebo-controlled, flexible dose-escalation study conducted May
through November 1996.
Setting Patients' homes and 19 clinical practice centers in the
United States.
Patients A total of 268 men (mean age, 57 years) with erectile
dysfunction (mean duration, 5.6 years) and diabetes (mean duration, 12
years).
Interventions Patients were randomized to receive sildenafil
(n=136) or placebo (n=132) as needed,
but not more than once daily, for 12 weeks. Patients took the study
drug or placebo 1 hour before anticipated sexual activity. The starting
dose of sildenafil citrate was 50 mg, with the option to adjust the
dose to 100 mg or 25 mg based on efficacy and tolerability, to be taken
as needed.
Main Outcome Measures Self-reported ability to achieve and
maintain an erection for sexual intercourse according to the
International Index of Erectile Function and adverse events.
Results Two hundred fifty-two patients (94%) completed the study
(131/136 in the sildenafil group, 121/132 in the placebo group). By
intention-to-treat analysis, at 12 weeks, 74 (56%) of 131 patients in
the sildenafil group reported improved erections compared with 13
(10%) of 127 patients in the placebo group (P<.001). The
proportion of men with at least 1 successful attempt at sexual
intercourse was 61% (71/117) for the sildenafil group vs 22% (25/114)
for the placebo group (P<.001). Adverse events related to
treatment were reported for 22 (16%) of 136 patients taking sildenafil
and 1 (1%) of 132 patients receiving placebo. The most common adverse
events were headache (11% sildenafil, 2% placebo), dyspepsia (9%
sildenafil, 0% placebo), and respiratory tract disorder (6%
sildenafil, 2% placebo), predominantly sinus congestion or drainage.
The incidence of cardiovascular adverse events was comparable for both
groups (3% sildenafil, 5% placebo).
Conclusion Oral sildenafil is an effective and well-tolerated
treatment for erectile dysfunction in men with diabetes.
Diabetes
mellitus affects an estimated 15.7 million people in the United States,
including 7.5 million men, with type 2, non–insulin-dependent,
diabetes accounting for 90% to 95% of the diagnosed cases and type 1,
insulin-dependent, diabetes accounting for 5% to 10%.1 A
common complication of diabetes in men is erectile dysfunction (ED),
defined by the National Institutes of Health Consensus Panel on
Impotence as the persistent inability to attain and maintain an
erection sufficient to permit satisfactory sexual
activity.2
The prevalence of ED of any degree in men aged 40 to 70 years was
estimated to be 52% in the Massachusetts Male Aging Study (MMAS), with
a prevalence of 25% for moderate ED and 10% for complete ED (ie, no
erections).3 The prevalence of ED is age dependent, with
the rate of complete ED increasing from 5% among men aged 40 years to
15% among those aged 70 years.3
Erectile dysfunction in men with diabetes is often
associated with diabetic neuropathy and peripheral vascular
disease.4,5 It occurs at an earlier age in men with
diabetes than in men
in the general population,6,7 and
several studies have demonstrated a high prevalence (35% to 75%) of
ED with diabetes.6,8-10 In men with treated diabetes in the
MMAS, the age-adjusted prevalence of complete ED (no erections) was
28%, which was approximately 3 times higher than the prevalence of
complete ED observed in the entire sample of men (10%).3
Penile erection is a hemodynamic event dependent on the relaxation of
smooth muscle cells and arteries of the corpus
cavernosum.11 Relaxation of corpus cavernosal smooth muscle
is mediated by nitric oxide–induced cyclic 3‘, 5‘-guanosine
monophosphate (cGMP) formation.12-14 In response to sexual
stimuli, nonadrenergic, noncholinergic nerves and endothelial cells
of the arterioles in the penis release nitric oxide, which induces
smooth muscle relaxation via stimulation of guanylate cyclase and the
production of cGMP. Subsequently, cGMP is hydrolyzed by cGMP-specific
phosphodiesterase type 5 (PDE5), the predominant PDE isozyme of the
corpus cavernosum.15
Sildenafil citrate is an orally active and selective inhibitor of PDE5.
When sexual stimulation causes local release of nitric oxide,
sildenafil enhances the effect of nitric oxide on the corpus cavernosum
by increasing the levels of cGMP in this tissue. Sildenafil is rapidly
absorbed following oral administration, has an onset of action within
25 to 60 minutes after dosing,15 and has a plasma half-life of approximately 4 hours.
Sildenafil has been shown to be an effective and well-tolerated
treatment in patients with ED of various etiologies.16 The
purpose of the present study was to assess the efficacy and safety of
sildenafil in the treatment of ED in men with diabetes. In a pilot
study of 21 men with ED and diabetes, treatment with sildenafil
improved erectile function, as assessed by penile plethysmography in a
clinic setting.17 This study evaluated sildenafil in a
larger population of men with ED and diabetes in a home setting, which
reflects the situation encountered in clinical practice.
Study Design
and Patient Population
The protocol for this multicenter, randomized, double-blind,
placebo-controlled, flexible-dose study was approved by the
institutional review boards at the 19 clinical practice centers, and
all participants provided written informed consent. The study consisted
of a 4-week, no-treatment, run-in phase, followed by a 12-week,
double-blind treatment period. Sildenafil citrate (Viagra) and placebo
of matching appearance were supplied by Pfizer Inc. Patients were
instructed to take a single dose of study medication as needed, 1 hour
prior to sexual activity but not more than once daily, during the
12-week treatment period. The initial dose was 50 mg of sildenafil
citrate or a medium dose of placebo. Based on the investigator's
judgment of efficacy and tolerability, the dose could be increased to
100 mg or decreased to 25 mg of sildenafil citrate or placebo.
Patients were eligible for inclusion in the study if they were
aged 18 years or older, had medically documented ED (as defined by the
National Institutes of Health Consensus Panel2), which was
documented in the prior medical record to be of at least 6 months'
duration, and a clinical diagnosis (as defined by the National Diabetes
Data Group18) of at least 5 years duration for type 1 and
at least 2 years duration for type 2 diabetes. The diagnosis and
etiology classification (ie, organic, psychogenic, or mixed) of ED was
based on the patient's medical history, a physical examination,
standard laboratory testing, and other diagnostic procedures performed
prior to the study. The medical management of patients' diabetes had
to be stable for at least 3 months prior to screening, with a
hemoglobin A1c value of less than 0.12 and a fasting plasma
glucose level of no more than 16.6 mmol/L (300 mg/dL) at screening. The
patients also had to be in a stable relationship with a female partner
for at least the previous 6 months. Exclusion criteria included the
following: penile anatomical deformities that would significantly
impair erection; a primary diagnosis of a sexual disorder other than
ED; a major psychiatric disorder that was not well controlled with
treatment; spinal cord injury; a history of major hematological, renal,
or hepatic abnormalities; stroke or myocardial infarction within the
previous 6 months; active peptic ulcer; hypotension (a resting blood
pressure of <90/50 mm Hg) or hypertension (a resting systolic blood
pressure >170 mm Hg or a resting diastolic blood pressure >100 mm
Hg); active, proliferative diabetic retinopathy or severe autonomic
neuropathy; history of ketoacidosis in the previous 3 years; or regular
treatment with nitrates or androgens. Patients were required to
discontinue other therapies for ED at screening.
Patients meeting inclusion criteria had their medical histories and
demographic information recorded and underwent a full physical
examination, which included blood pressure and heart rate measurements,
a 12-lead electrocardiogram, and standard biochemistry and
hematological laboratory tests. At week 0 (baseline), each eligible
patient was given a randomization number using an interactive voice
response system, which followed a randomization table generated by the
method of random permuted blocks.19 The investigator
provided the patient with study drug in bottles labeled with the
corresponding randomization number. The system generating the
randomization assignment was geographically and operationally
independent from the study investigators who executed the randomization
assignment and conducted the study.
The efficacy of oral sildenafil was assessed using the
self-administered International Index of Erectile Function (IIEF), a
15-question, validated measure of erectile dysfunction,20 a
global efficacy question ("Did the treatment improve your
erections?"), and an event log in which patients recorded the number
of attempts at sexual intercourse and the number of attempts that were
successful. International Index of Erectile Function question 3, which
assesses the ability to achieve an erection for sexual intercourse, and
question 4, which assesses the ability to
maintain an erection after penetration,
specifically address the key aspects of ED as defined by the National
Institutes of Health.2 Responses to these IIEF questions
assessed treatment outcomes for the previous 4 weeks and were scored
using a 5-point, ordered, categorical scale, with a score of 1
representing the worst response (almost never/never) and a score of 5
representing the best response (almost always/always). Where
applicable, a score of 0 indicated no attempts at sexual intercourse.
Patients completed the IIEF at week 0 (baseline) and week 12.
All adverse events occurring during treatment or within 7 days of the
end of treatment were recorded, regardless of causal relationship to
study drug, and standard biochemistry and hematological laboratory
tests were conducted at baseline and at 2, 4, 8, and 12 weeks of
treatment.
The number of patients required for enrollment in the study was
determined by the responses to questions 3 and 4 of the
IIEF.20 The treatment difference between sildenafil and placebo was assumed to be 0.75 and the common variance was assumed to
be 2.3. Using these assumptions, a sample size of 86 patients per
treatment group would be required to achieve a power of 90%. With a
projected patient dropout rate of 25%, the total number of patients
required for randomization was determined to be 230 (115 patients for
each treatment group).
Least squares mean response scores to the IIEF questions were
analyzed using analysis of covariance, which included main-effect terms
for treatment, investigational center, and baseline score, with
covariates for age, etiology of disease, duration of disease, and
smoking status. Responses to the global efficacy question and the
proportion of attempts at sexual intercourse that were successful were
analyzed using a logistic regression model with the same terms and
covariates as mentioned above for the analysis of covariance model.
Each subgroup analysis used the same model and terms as the full
analysis, omitting the subgroup variable as a covariate when
appropriate. Intention-to-treat analyses were performed on all efficacy
variables and included all subjects who had a baseline measurement and
at least 1 measurement after the start of treatment. All analyses of
significance were 2-sided and tested at the 5% level. All patients who
received the study drug were included in the safety analysis.
A total of 268 patients were randomized to treatment, with 136 patients
receiving sildenafil and 132 patients receiving placebo (Figure 1). The baseline characteristics of the
patients in the 2 the treatment groups were similar (Table 1). The majority of patients had
type 2 diabetes, were between the ages of 45 and 64 years, and had had
ED for several years. The median length of treatment was 85 days for
both the sildenafil and the placebo treatment groups. The median number
of doses taken as needed was 31 (range, 3-81) for patients receiving
sildenafil and 25 (range, 2-83) for patients receiving placebo. At the
end of the study, 126 patients (93%) were receiving 100 mg of
sildenafil citrate, 10 patients (7%) were receiving 50 mg of
sildenafil citrate, and no patient was receiving 25 mg of
sildenafil citrate. For patients receiving placebo, 127 patients
(96%), 5 patients (4%), and no patients were taking the high, medium,
and low doses, respectively. Of the 268 patients randomized to
treatment, 252 (94%)
completed the study (131/136 receiving
sildenafil and 121/132 receiving placebo).
After 12 weeks of treatment, patients receiving sildenafil demonstrated
significantly improved erectile function compared with those receiving
placebo. The least squares mean scores to the IIEF questions assessing
the ability to achieve (question 3) and maintain (question 4) erections
demonstrated significant improvements among patients receiving
sildenafil compared with those receiving placebo (P<.001;
Figure 2). For question 3, the mean
score was 3.2 for patients in the sildenafil group compared with 2.0
for those in the placebo group, which represent increases from baseline
of 78% (mean score at baseline, 1.8) and 25% (mean score at baseline,
1.6), respectively. For question 4, the mean score was 2.9 (93%
increase from baseline mean score of 1.5) for the sildenafil group
compared with 1.6 (14% increase from baseline mean score of 1.4) for
the placebo group.
Of the remaining 13 questions of the IIEF, mean scores to 11 questions
assessing other aspects of male sexual function, including orgasmic
function, satisfaction with sexual intercourse, and overall
satisfaction, showed significant improvements for the sildenafil group
compared with the placebo group (P<.001;
Table 2). The mean scores for IIEF questions 11
and 12, which assessed frequency of sexual desire and the level of
sexual desire, respectively, indicated no statistically significant
differences between the 2 groups (P=.71 and
P=.17, respectively).
At the 12-week end point, 74 (56%) of 131 patients taking sildenafil
reported improved erections compared with 13 (10%) of 127 patients
taking placebo (P<.001). Data from patient event logs showed
that the proportion of attempts at sexual intercourse that were
successful during the last 4 weeks of treatment was significantly
greater for all patients (both responders and nonresponders). The
proportion of men reporting this was 48% (56/117) in the sildenafil
group compared with 12% (14/114) in the placebo group
(P<.001). The proportion of men with at least 1 successful
attempt at intercourse was 61% (71/117) for the sildenafil group vs
22% (25/114) for the placebo group (P<.001).
The efficacy of treatment, as assessed with IIEF questions 3 and
4 and the global efficacy question, was also analyzed for various
subgroups of patients (Table 3). Treatment with sildenafil significantly improved erectile function
across all 3 efficacy variables regardless of patient age
(P<.002 vs placebo), the duration of ED (P<.001
vs placebo), and the duration of diabetes (P<.001 vs
placebo). For patients with type 1 diabetes and those with type 2
diabetes, the baseline mean scores for question 3 of the IIEF were 1.8
and 1.5 for the placebo group and 2.0 and 1.8 for the sildenafil group,
respectively (P=.103). The baseline mean
scores for question 4 for patients with type 1 and type 2 diabetes were
1.2 and 1.3 for the placebo group and 1.7 and 1.5 for the sildenafil
group,
respectively (P=.03).
Each of the 3 efficacy variables demonstrated a significant improvement
with sildenafil treatment in patients with type 2 diabetes
(P<.001 vs placebo). Despite the small number of patients, 2
of the 3 variables were significantly improved with sildenafil
treatment in patients with type 1 diabetes (P<.03 vs
placebo).
Of the patients taking sildenafil, 11% reported headache as an adverse
event vs 2% of patients taking placebo; 9% taking sildenafil reported
dyspepsia vs 0% taking placebo; and 6% taking sildenafil reported
respiratory tract disorder (predominantly sinus congestion or drainage)
vs 2% taking placebo (Table 4). A 0few patients taking sildenafil experienced flushing, rhinitis, or
abnormal vision (predominantly reported as a mild and transient change
in brightness perception). The overall incidence of cardiovascular
adverse events other than flushing occurred in 3% (4/136) of patients
taking sildenafil vs 5% (6/132) of patients taking placebo. In the
sildenafil group, 1 patient manifested a Q wave on
electrocardiogram with no myocardial infarction documented, 1 patient
had congestive heart failure, 1 patient had hypertension, and 1 patient
had a varicose vein. In the placebo group, 4 patients had new or
worsening chest pain, 1 patient had hypertension, and 1 patient had
thrombophlebitis.
Adverse events related to treatment were reported for 16% (22/136) of
patients taking sildenafil and 1% (1/132) of patients taking placebo.
The majority of adverse events were transient and mild to moderate in
nature. No case of priapism was reported. No patient in the sildenafil
group discontinued treatment because of a treatment-related adverse
event. The rate of discontinuation from treatment was 4% (5/136) of
the patients taking sildenafil and 8% (11/132) of patients taking
placebo. The reasons for discontinuation of treatment are listed in
Figure 1. There were no laboratory test abnormalities attributable to
sildenafil use.
Erectile dysfunction, which is a common complication of diabetes,
impairs a patient's quality of life, self-esteem, and relationship
with his partner.2 Although psychogenic factors, such as
performance anxiety, can contribute to its etiology,21,22
ED in men with diabetes is predominantly caused by organic factors (ie,
vasculogenic and/or neurological abnormalities).4,5
Sildenafil is a novel, orally active agent that is an effective and
well-tolerated treatment for patients with ED of organic, psychogenic,
or mixed etiology.16 In this study, treatment with
sildenafil significantly improved erectile function in men with ED and
diabetes. Mean scores for the 2 IIEF questions assessing the ability
to achieve and maintain erections indicated significant improvements
after treatment with sildenafil compared with mean scores after
treatment with placebo. In addition, 56% of patients taking sildenafil
reported that treatment had improved their erections compared with only
10% of those taking placebo. The proportion of attempts at sexual
intercourse that were successful was 4-fold higher for patients
receiving sildenafil than for those receiving placebo. Thus, treatment
with sildenafil was shown to be consistently superior to placebo for
the efficacy end points evaluated in the study.
The results of the present study support the findings of a
placebo-controlled pilot study of 21 diabetic men with ED, which
evaluated the efficacy of sildenafil citrate (25 or 50 mg) using penile
plethysmography during sexual stimulation, a global efficacy question,
and a patient event log.17 In the pilot study, treatment
with sildenafil citrate (50 mg) significantly increased the duration of
erections with more than 60% rigidity at the base of the penis
compared with placebo. Improved erections were reported by 52% of
patients receiving
sildenafil citrate (50 mg) compared with 10% of
those receiving placebo (P<.05), and the number of erections
sufficiently rigid for penetration increased significantly with
sildenafil treatment (P=.0002 compared with
placebo). In a previously reported study of patients with
broad-spectrum ED,16 the mean final scores for IIEF
questions 3 and 4 for patients taking sildenafil citrate (25 -100 mg)
were higher than those reported herein for patients with ED and
diabetes. However, mean baseline scores for these questions also were
somewhat higher in the patients with broad-spectrum ED, suggesting a
greater severity of ED in patients with diabetes.
In analyses of various subgroups of patients with ED and diabetes, the
efficacy of sildenafil was not affected by patient age, the duration of
ED, or the duration of diabetes. Although the present study was not
specifically designed to evaluate the subgroup of patients with type 1
diabetes, the results for this subgroup were broadly similar to those
for patients with type 2 diabetes. Additional studies with appropriate
sample sizes are needed to evaluate the efficacy of sildenafil in
patients with type 1 diabetes, diabetes and arterial insufficiency, and
diabetes and neuropathy.
Although patients with diabetes frequently are included in
placebo-controlled studies evaluating the efficacy of treatments for
ED, published articles have not reported treatment outcomes specific to
this patient population. However, in a retrospective study of 33 men
with ED and diabetes who received intracavernosal injection therapy,
Bell and associates23 reported a response rate of 36% (11
men). Patient age was a predictive factor for a response in this
previously reported study; only 1 (7%) of 14 patients with diabetes
older than 60 years reported a response to treatment. In the present
study, 57% of patients with diabetes and ED reported improved
erections with sildenafil treatment. Since different studies use
different criteria for defining a response, comparative studies are
needed to appropriately assess treatment outcomes with different types
of therapies in patients with diabetes and ED.
In this study, treatment with sildenafil was well tolerated. The
safety profile of sildenafil in patients with diabetes was reassuring
given the chronic complications associated with diabetes. The most
common adverse events associated with sildenafil treatment were
headache, dyspepsia, and respiratory tract disorder (sinus congestion
or drainage), which were predominantly transient and mild or moderate
in nature. These adverse events reflect the known pharmacological
properties of sildenafil as a PDE5 inhibitor. The incidences of
cardiovascular adverse events were comparable in the sildenafil and
placebo treatment groups. However, since a degree of risk is associated
with sexual activity, physicians should consider the cardiovascular
status of their patients prior to initiating any treatment for ED. No
patient discontinued treatment with sildenafil due to a
treatment-related adverse event, and laboratory test results showed no
evidence of abnormalities related to sildenafil treatment.
The exact pathogenesis of ED in men with diabetes remains to be
determined. However, advanced glycosylated end products, which
accumulate in tissue proteins and play a role in many of the
complications of diabetes, have been shown to decrease nitric oxide
activity and to modulate endothelium-dependent relaxation, possibly via
regulation of penile nitric oxide synthase isozymes.24 The
efficacy of sildenafil, a potent inhibitor of PDE5, in improving
erectile function in patients with diabetes suggests that PDE5 activity
remains at least partially intact in diabetes. However, studies in
animal models of diabetes are needed to confirm or refute this
hypothesis.
In summary, the results of this study indicate that oral sildenafil is
an effective and well-tolerated treatment for organic ED in men with
diabetes.
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