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Sex/Erectile Dysfunction Caused by Elevated LDL, Atorvastatin Helped
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"Atorvastatin improves Viagra response in men with erectile dysfunction"
......The results of this pilot study support the hypothesis that vascular endothelial dysfunction can contribute to erectile dysfunction in men who do not initially respond to treatment with sildenafil. Treatment with the HMG-CoA reductase inhibitor, atorvastatin, improved sexual function and the response to oral sildenafil presumably by improving endothelial function...... Treatment with atorvastatin improved sexual function and the response to oral sildenafil in men who did not initially respond to treatment with sildenafil. The results of this pilot study support the hypothesis that vascular endothelial dysfunction contributes to ED in sildenafil nonresponders and deserves further testing in a large clinical trial..... Improvement in confidence to get and keep an erection (IIEF question 6) was reported by all eight patients treated with atorvastatin and only one patient receiving placebo (P = 0.02). Similarly, more patients receiving atorvastatin reported improved erections and sexual activity at 12 weeks than placebo patients.... overall sexual satisfaction and function improved more in patients treated with atorvastatin and sildenafil as compared with placebo and sildenafil..... Endothelium-dependent dilation is impaired in patients with atherosclerosis and is associated with many atherogenic risk factors ......Other reasons for a poor response to a phosphodiesterase type 5 inhibitor may include diabetic or surgical nerve injury, and severe endothelial dysfunction.... (see Author discussion below).
...The frequent coexistence of ED with coronary artery disease and cardiovascular risk factors may prompt further investigation of the lipid status in some patients with ED....
NEW YORK (Reuters Health, 3/6/06) - In men with erectile dysfunction who are not helped initially by taking sildenafil (Viagra), treatment with atorvastatin seems to improve the response, according to the results of a small study.
Erectile dysfunction may involve a generalized disturbance of endothelial function. "We theorized that if you could make the endothelium healthier through the use of statins - so that there is more nitric oxide available - you would improve the endothelial dysfunction and Viagra would work better for the patient," lead author Dr. Howard C. Herrmann said in a statement.
To investigate, Dr. Herrmann, from the University of Pennsylvania in Philadelphia, and colleagues assessed the effect of adding atorvastatin to sildenafil therapy in 12 men "with moderate-to-severe ED despite an adequate sildenafil trial." The subjects were randomized to receive atorvastatin 80 mg or placebo daily for 12 weeks.
The researchers' findings appear in the Journal of Sexual Medicine for March.
Treatment with atorvastatin, but not placebo, was associated with a significant improvement in the erectile response to sildenafil. An effect was seen by 6 weeks after beginning the trial.
As anticipated, atorvastatin therapy also reduced LDL-cholesterol levels, in this case, by 43%.
While encouraging, "the results are preliminary and warrant further testing in a larger clinical trial," Dr. Herrmann noted.
J Sex Med 2006;3:303-308.
Can Atorvastatin Improve the Response to Sildenafil in Men with Erectile Dysfunction Not Initially Responsive to Sildenafil? Hypothesis and Pilot Trial Results
.... Treatment with atorvastatin improved sexual function and the response to oral sildenafil in men who did not initially respond to treatment with sildenafil. The results of this pilot study support the hypothesis that vascular endothelial dysfunction contributes to ED in sildenafil nonresponders and deserves further testing in a large clinical trial.....
The Journal of Sexual Medicine
Volume 3 Page 303 - March 2006
This study was supported by an unrestricted medical center grant from Pfizer.
ORIGINAL RESEARCH-ED PHARMACOTHERAPY
Howard C. Herrmann, MD*, Laurence A. Levine, MD, Joseph Macaluso Jr, MD, Michelle Walsh, RN*, Danielle Bradbury, RN*, Stanley Schwartz, MD*, Emile R. Mohler III, MD , and Stephen E. Kimmel, MD
*Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Section of Urology, Rush University Medical Center, Chicago, IL, USA; Urological Institute of New Orleans, New Orleans, LA, USA; Division of Cardiovascular Medicine, Philadelphia Heart Institute, Philadelphia, PA, USA; Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
ABSTRACT
Background. Erectile dysfunction (ED) may be one manifestation of a generalized vascular disorder characterized by endothelial dysfunction. Statin drugs may improve endothelial function, even before altering the lipid profile.
Objective. We sought to determine whether the addition of a statin with sildenafil would improve ED in men who initially responded poorly to sildenafil.
Methods. Men with moderate-to-severe ED despite an adequate sildenafil trial were enrolled in this randomized, double-blind, placebo-controlled pilot study. ED was defined using a validated self-administered questionnaire as a score of ≦16 on the International Index of Erectile Function (erectile function domain score range of 6-30). Improvement in ED score with sildenafil was reassessed at 6 and 12 weeks of treatment with atorvastatin (80 mg daily) or matching placebo.
Results. Twelve men (mean age 58 ± 13 years) with a mean domain score of 8.2 ± 6.9 and a mean duration of ED of 3.7 years were enrolled in the study. Treatment with atorvastatin decreased mean low-density lipoprotein cholesterol by 43% and resulted in an improvement with sildenafil in domain score of 7.8 (P = 0.036); an effect was apparent by 6 weeks. The increase in domain score in placebo patients was not statistically significant.
Conclusions. Treatment with atorvastatin improved sexual function and the response to oral sildenafil in men who did not initially respond to treatment with sildenafil. The results of this pilot study support the hypothesis that vascular endothelial dysfunction contributes to ED in sildenafil nonresponders and deserves further testing in a large clinical trial.
INTRODUCTION
Erectile dysfunction (ED) is a complex disorder, and may be one manifestation of a generalized vascular disorder characterized by endothelial dysfunction [1-3]. In such patients, the loss of normal nitric oxide formation by the vascular endothelium results in reduced production of cyclic guanosine monophosphate (cGMP), the second messenger that causes arterial and corporal vasodilation in the corpus cavernosum [4]. Sildenafil improves ED by inhibiting phosphodiesterase type 5 which degrades cGMP [5]. However, some patients do not respond to sildenafil. It is conceivable that sildenafil "nonresponders" have more severe endothelial dysfunction and might benefit from therapies targeted at their underlying vascular disease process. In this regard, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors rapidly improve endothelial function, even before altering the lipid profile [6-9]. We hypothesized that the combination of a statin with sildenafil would improve ED in men who initially responded poorly to sildenafil alone, and initiated a pilot study to test this hypothesis.
RESULTS
Baseline Characteristics
The study population included 12 men with a mean age of 58 ± 13 years (range 29-74 years). Six patients had a history of smoking, 10 had a history of elevated cholesterol, four had hypertension, and diabetes was present in two patients. The mean baseline serum LDL cholesterol was 139 ± 16 mg/dL. The mean IIEF domain score for ED was 8.2 ± 6.9. The etiology of ED was unknown in seven patients, due to prior surgery for pathological prostate conditions in three patients, and due to low testosterone level in one patient. The mean duration of ED was 3.7 ± 4.2 years (range 1-15 years). Of the 12 subjects enrolled, eight were randomized to treatment with atorvastatin and four were randomized to placebo. There were no differences between the groups in baseline characteristics (Table 1).
Effect of Treatment
Treatment with atorvastatin lowered the mean LDL cholesterol from 135 ± 19 to 78 ± 20 mg/dL (43%) after 12 weeks (P = 0.012). In the placebo group, there was no change in LDL from a baseline value of 146 ± 10 to 139 ± 24 mg/dL at 12 weeks (P = 0.46).
The mean IIEF domain score increased 7.8 from 10.3 ± 7.4 to 18.0 ± 10.6 (P = 0.036) with sildenafil in atorvastatin-treated patients (Figure 1). The improvement was apparent by 6 weeks (18.6 ± 7.8, P = 0.012 compared with baseline). The increase in domain score in placebo patients was not statistically significant (4.0 ± 3.6 to 12.3 ± 12.4, P = 0.11), and influenced by a single outlier patient who had the largest increase in score from 9 to 29. If this patient is excluded from analysis, the increase in mean domain score is 4.3 for placebo patients.
Secondary Analyses
Improvement in confidence to get and keep an erection (IIEF question 6) was reported by all eight patients treated with atorvastatin and only one patient receiving placebo (P = 0.02). Similarly, more patients receiving atorvastatin reported improved erections and sexual activity at 12 weeks than placebo patients (Table 2). There was no correlation between the degree of LDL lowering and improvement in domain score (r = -0.04). Two patients (both in the atorvastatin group) had measurement of brachial artery blood flow. Flow-mediated dilation was reduced at baseline (5.6 ± 4.6%) and improved in both patients with atorvastatin (mean increase = 3.5 ± 1.7%).
DISCUSSION
The results of this pilot study support the hypothesis that vascular endothelial dysfunction can contribute to ED in men who do not initially respond to treatment with sildenafil. Treatment with the HMG-CoA reductase inhibitor, atorvastatin, improved sexual function and the response to oral sildenafil presumably by improving endothelial function. Although this study was terminated prematurely due to lack of enrollment, there were several consistent signals which support the primary hypothesis. Not only was the improvement in the IIEF erectile function domain score statistically significant, but overall sexual satisfaction and function improved more in patients treated with atorvastatin and sildenafil as compared with placebo and sildenafil. The differences between the atorvastatin and placebo groups are even more marked if a single outlier patient whose score improved more than any other patient in the study is excluded. In this regard, it is possible that this patient was not a true sildenafil nonresponder.
Patients may not respond well to sildenafil for a number of reasons. This agent should be taken 30-60 minutes before sexual activity, not in conjunction with a high fat meal, and requires sexual stimulation to produce an erection. All of our patients were instructed on proper usage and received the highest approved dose of sildenafil in an attempt to maximize compliance and efficacy [14]. Other reasons for a poor response to a phosphodiesterase type 5 inhibitor may include diabetic or surgical nerve injury [15], and severe endothelial dysfunction. Although higher doses of sildenafil may improve efficacy, doses greater than 100 mg are not approved and may be limited by side-effects [16]. For these reasons, we chose to investigate the potential of atorvastatin as a way to improve endothelial dysfunction for patients not initially responsive to sildenafil.
Endothelial-dependent dilation requires release of nitric oxide to stimulate cGMP production necessary for arteriolar vasodilatation in the corpus cavernosum leading to erection [4]. Endothelium-dependent dilation is impaired in patients with atherosclerosis and is associated with many atherogenic risk factors [1,17], and several previous studies have demonstrated that ED may be a manifestation of generalized endothelial dysfunction [2,3]. Our patients with ED had risk factors for atherosclerosis and we were able to demonstrate impaired peripheral artery vasodilatation in response to cuff occlusion in the small subset that were tested.
Several strategies, including the use of lipid-lowering therapies, angiotensin-converting enzyme inhibitors, therapeutic lifestyles changes, and others, are effective in restoring endothelial-dependent dilation [18]. Sildenafil may also im-prove endothelial dysfunction [19]. HMG-CoA reductase inhibitors can improve nitric oxide bioavailability, vascular endothelial function, and even myocardial ischemia over a 6-month time period in conjunction with lipid lowering [7,20]. Our patients had only mildly elevated LDL cholesterol values, but a marked decrease (>50%) with statin therapy. However, some beneficial effects of intensive statin therapy on endothelial function occur as soon as 3 days after treatment and are independent of lipid levels [6-9], suggesting a role for the nonlipid-lowering, pleiotropic effects of these agents [21]. In the study of Wassmann and colleagues, 18 patients with a mean LDL cholesterol of 112 mg/dL were treated with 80 mg of atorvastatin for 6 weeks with improvement in hyperemic forearm blood flow and with reduction in serum markers of oxidative stress and inflammation [9].
Many patients will have both coronary artery disease and ED due to shared risk factors, the common pathophysiology related to generalized endothelial dysfunction, and the high incidence of both diseases in adult males [1,3,22]. The three currently approved oral phosphodiesterase type 5 inhibitor agents for ED (sildenafil, vardenafil, and tadalafil) are both safe and effective in this population [5,23]. There are no randomized, controlled trials comparing the relative efficacy of these three agents. However, the perception that one of the newer agents might be efficacious in patients who did not initially respond to sildenafil, and the strict inclusion criteria which required patients to be sildenafil nonresponders with an untreated, elevated LDL cholesterol, contributed to the lack of full enrollment in this trial. Despite the low number of patients in this trial, the randomized, double-blind, placebo-controlled design utilizing a validated questionnaire resulted in a clear signal for benefit of atorvastatin in our subjects.
The frequent coexistence of ED with coronary artery disease and cardiovascular risk factors may prompt further investigation of the lipid status in some patients with ED. Our study does not provide sufficient rationale for prescribing atorvastatin to patients with ED who do not have dyslipidemia, but it suggests that atherosclerotic risk factor modification could favorably improve ED in patients with or without hyperlipidemia. Our study strengthens this hypothesis and deserves further testing in a large clinical trial.
METHODS
Study Population
The study population was comprised of 12 men with moderate-to-severe ED despite an adequate sildenafil trial. ED was defined as having an In-ternational Index of Erectile Function (IIEF) score ≦16 on the erectile function domain (questions 1-5 and 15) on a self-administered questionnaire [10]. The IIEF erectile function domain score is a validated instrument, which includes six questions scored from 1 to 5 to yield a total score of 6-30 [11]. Patients with scores ≥
26 are considered to have no ED, while scores ≦16 have moderate-to-severe ED. Additional questions from the Global Assessment Questionnaire (questions 1 and 2) were also asked [12].
All subjects reported an inadequate response to a maximal dose (100 mg) of sildenafil after instruction on proper usage (nonresponders). Other inclusion criteria included a serum low-density lipoprotein (LDL) cholesterol ≥
100 mg/dL. Patients were excluded from study participation if they had a history of psychogenic ED, had severe endocrinopathy including diabetics with neuropathy, had recent (<6 months) surgery including prostatectomy, were experiencing an acute coronary syndrome, required nitrate medications, had an elevated creatine kinase valve (>25% above ULN [upper limit normal]), or had a contraindication to either statin therapy or were currently taking a statin.
Study Design
Each study subject signed informed consent and then completed a baseline questionnaire. Patients with ED who met the inclusion and exclusion criteria had baseline blood tests. Qualifying subjects were then randomized using a permuted block technique to receive either atorvastatin 80 mg daily or an identical placebo pill. Each patient was also provided sildenafil (100 mg) to use at their discretion to a maximum dose of 1 daily.
All patients reported to an investigator at 6 and 12 weeks to complete an additional IIEF survey and to be interviewed and examined for possible side-effects. At 12 weeks, blood samples were obtained for a lipid profile, liver function, and creatine kinase testing.
Patients were enrolled at three sites. At one site (University of Pennsylvania), subjects also underwent vascular testing at baseline and at 12 weeks. Endothelial-dependent dilation of the brachial artery was assessed by ultrasound with pulsed Doppler [13]. Scans were obtained after 5 minutes of cuff occlusion, and the percent flow-mediated dilation was calculated as: (postcuff diameter - precuff diameter)/precuff diameter X 100.
Statistical Analysis
The primary analysis was a comparison with baseline of the IIEF domain score for the efficacy of sildenafil at 12 weeks of treatment. With an estimated initial IIEF erectile function domain score (mean ± SD) of approximately 12 ± 8.5 for the placebo group, an a of 0.05, and a power of 80%, 32 patients would be needed in each group to detect a difference in means of 6 (mean score in atorvastatin plus sildenafil group of 18). We therefore planned to enroll 64 patients. However, during enrollment, the concurrent release of two additional medications to treat ED (vardenafil and tadalafil) made patient recruitment difficult. Thus, the trial was prematurely halted after enrollment of 16 subjects, four of whom did not complete the protocol (one due to side-effects presumed related to atorvastatin). The remaining 12 patients are reported in this article. The results of the study were not known when the decision to terminate the trial was made.
Planned secondary analyses included comparisons of individual questions assessing overall sexual function and satisfaction, quantitative analysis of the degree of lipid lowering vs. improvement in IIEF domain scores, comparison of flow mediated brachial artery dilation with vs. without atorvastatin, correlation of the changes in flow-mediated vasodilation with the change in domain score, and comparison of changes in domain scores at 6 weeks of treatment. All results are shown as mean ± SD. Comparisons were made with Wilcoxon signed-rank test (paired within a group) or Wilcoxon rank sum test (unpaired between groups) for continuous data and Fisher's exact test for contingency tables of individual questions. Results were considered significant if P ≦ 0.05.
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