Erectile Dysfunction and Statin Treatment in High Cardiovascular Risk Patients

H. Solomon; Y. P. Samarasinghe; M. D. Feher; J. Man; H. Rivas-Toro; P. J. Lumb; A. S. Wierzbicki; G. Jackson

Int J Clin Pract. 2006;60(2):141-145. 

Summary and Introduction

Summary

Erectile dysfunction (ED) has been associated with risk factors for atherosclerosis. Medications used for atherosclerosis have also been implicated in ED. The aim of this study is to investigate the relationship of erectile function to cardiovascular risk factors and specific drug therapies before and after 6 months of statin therapy.

In this prospective observational study, International Index of Erectile Function (IIEF) scores were measured in 93 men attending cardiovascular risk clinics. Cardiovascular risk factors and drug therapies were assessed prior to initiation and after 6 months of statin therapy.

Prior to statin therapy, the median IIEF score was 21 (range 0–25), and 57% had impairment of erectile function. After statin therapy, IIEF scores were reduced to 6.5 (range 0–25) (p < 0.001), and 22% experienced new onset ED. Before statin therapy no correlation was observed between IIEF score and any individual cardiovascular risk factor. After 6 months of statin therapy, correlations were observed between lower IIEF scores (r = 0.62; p < 0.001) and age and diabetes and weakly with smoking. Differences in dose, relative efficacy or relative lipophilicity of statin prescribed showed no correlation with change in IIEF score.

This study suggests ED following statin therapy is more likely in patients with severe endothelial dysfunction due to established cardiovascular risk factors including age, smoking and diabetes.

Introduction

Erectile dysfunction (ED) is commonly associated with atherosclerosis of the penile vasculature.[1,2] Many drugs used in the treatment of the underlying risk factors of atherosclerosis (e.g. β blockers, thiazide diuretics and statins) have been implicated in worsening erectile function.[3-5] Many of these cardio-protective therapies are associated with beneficial effects on endothelial function as measured in the brachial or coronary arteries. The precise mechanism of vascular ED and reasons why medication aimed at controlling the risk factors of atherosclerosis and thus affecting penile endothelial function[2,6] should initiate or exacerbate ED are unclear. Information in the literature is limited and generally based on case reports that often do not take into account the number of confounding variables amongst this patient group.

The aim of this study was to evaluate the association between individual atherosclerotic risk factors, their therapeutic interventions and erectile function in a population at high risk of cardiovascular disease following initiation of statin therapy.

Methods

Ninety-three male patients starting on lipid-lowering therapy were recruited from the cardiology and lipid clinics of two London teaching hospitals. All patients presented with ED or were diagnosed with the condition as part of cardiovascular risk assessment. Patients who were currently or had recently (<3 months) received drug treatment for ED were excluded. Full ethical approval for the study and questionnaire was obtained locally at both centres.

Their demographics, cardiovascular risk factors and drug treatments were ascertained on two occasions; firstly, immediately prior to the commencement of HMG-CoA reductase inhibitor (statin) therapy (period 1) then following 6 months of treatment with a statin (period 2). Drug compliance was assessed by direct questioning. Erectile function was assessed at these times using the validated International Index of Erectile Function-5 (IIEF).[7] A score of <21/25 indicated some degree of ED. Total serum cholesterol measurements were obtained at each visit. Relative lipophilicity for statins was extracted from the Physicians Drug Reference data internet site (http://www.pdr.net). The data for cardiovascular risk factors and drug therapies were analysed for both periods 1 and 2. The relationship between the prevalence of ED and the prevalence of individual risk factors was evaluated by Fisher's exact test. The relationship between statin therapy and ED scores was evaluated by Wilcoxon sign rank test for correlated groups. As specific drug therapies correlated strongly with underlying diseases, separate analyses were conducted for cardiovascular risk factors and drug therapies. The relationship between cardiovascular risk factors and drug therapy to IIEF scores was determined by forward stepwise multiple regression analysis for both periods 1 and 2 including all cardiovascular risk factors or drug classes as dependent variables.

Results

The study recruited 93 individuals, but the erectile function questionnaire was completed by only 82 men, as five declined on the basis of age-related celibacy and six questionnaires were incomplete. In two cases, cardiovascular risk data were incomplete leaving 80 evaluable patients. The baseline characteristics of the 80 subjects in the study are shown in . Coronary artery disease was present in 61%, hypertension (BP > 140/85 mmHg) in 37% and hyperlipidaemia (total cholesterol >5 mmol/l) in 37%. Drug therapy comprised antiplatelet therapy (aspirin or clopidogrel) in 70% and warfarin in 2%. Hypertension therapies included β blockers 37%; angiotensin-I-converting enzyme inhibitors (ACE-Is) 32%; diuretics 16% and angiotensin-II receptor blockers (ARBs) 11%. Other antiangina drugs included calcium antagonists 49% and nitrates 26%. Digoxin for atrial fibrillation was documented in 2%, oral hypoglycaemic agents in 19% and fibrates in 10% of respondents. The compliance rate for statin therapy following prescription was 77%.

Table 1.  Clinical Characteristics of Patients With Erectile Dysfunction

Parameter Units  
Age Year 61 ± 10
Smoking % 61
Type 2 diabetes mellitus % 25
Ischaemic heart disease % 61
Family history of ischaemic heart disease % 43
Blood pressure mmHg 132 ± 19/78 ± 11
Total cholesterol mmol/l 4.78 ± 0.96
mg/dl 185 ± 38

Prior to statin therapy, the mean IIEF score was 18.7 (SD ± 7.3 and median 21). Thirty-five of eighty-two (43%) men had an IIEF score >21/25, indicating that 47 (57%) already had some impairment of erectile function. After statin therapy, IIEF scores were reduced to 10.4 (SD ± 8.9; median 6.5) (p < 0.001) (Fig. 1). Only 17/82 men (21%) had an IIEF score of >21/25 (p = 0.002) indicating that 18/82 men (22%) experienced new onset ED after the initiation of statin therapy. After starting statin therapy, 43/82 (52%) experienced a significant reduction in IIEF score (five or more points) indicating a significant worsening of erectile function (Fig. 1).

Figure 1.

 

Effect of 6 months statin therapy on International Index of Erectile Function (IIEF) scores of erectile function in patients with cardiovascular disease and subgroups of the cohort with prior erectile dysfunction [erectile dysfunction (ED)(+)] and without [ED(-)]

Period 1 scores indicated that over half of men had some degree of ED prior to statin therapy. The high intercorrelation between individual drug classes and risk factors precluded a combined analysis. The relationship of drug interactions to the change in ED score over the study period was investigated by multiple regression analysis including only drug classes as dependent variables ( ). As specific drug therapies correlated strongly with underlying diseases, separate analyses were conducted for cardiovascular risk factors and drug therapies. Multiple regression analysis was performed between period 1 IIEF scores and correlated with cardiovascular risk factors (r = 0.45; p < 0.001), but this showed no relationship between ED and any individual risk factor and/or drug therapy. In contrast, trends to beneficial relationships, given limitations of numbers, were observed between IIEF scores and ACE-I or ARB therapy. Nonsignificant deleterious associations were seen with digoxin and fibrate therapy but again are limited by small numbers ( ). In contrast, analysis of period 2 scores with the same risk factors and added statin therapy showed a significant association of IIEF score with cardiovascular risk factors and drug therapies (r = 0.62; p < 0.001). Amongst drug therapies, β blockers were associated with worsening erectile function (p = 0.04), and an adverse trend was noted with concomitant ACE-I or ARB therapy (p = 0.07). No correlation was seen with concomitant fibrate therapy, statin dose or lipophilicity index with baseline, period 2 or change in ED score (r = 0.10; p = 0.37).

Table 2.  Relationships of Cardiovascular Risk Factors and Drug Therapies to International Index of Erectile Function (IIEF) Score in Men With Erectile Dysfunction

Parameter IIEF score
Prestatin therapy Poststatin therapy Change in score
β p β p β p
Cardiovascular risk factors (analysis 1)
Age −0.11 0.21 −0.23 0.01 −0.16 0.08
Smoking −1.71 0.34 −1.41 0.15 −0.59 0.57
Hypertension −1.23 0.56 1.89 0.44 −0.33 0.86
Diabetes −1.17 0.59 4.99 0.05 −2.82 0.20
Drug classes (analysis 2)
β blocker −1.36 0.52 −3.78 0.04 +1.54 0.39
Angiotensin-I-converting enzyme inhibitor 3.29 0.10 −1.89 0.53 −3.08 0.12
Angiotensin II type1 receptor blocker 12.4 <0.001 −5.86 0.07 −12.33 <0.001
Digoxin −9.51 0.10 3.29 0.68 +8.66 0.13
Fibrate −3.50 0.27 −3.84 0.69 +3.17 0.31
Anti-platelet −1.19 0.12 −2.90 0.15 +0.68 0.36

 

As specific drug therapies correlated strongly with underlying diseases separate analyses were conducted for cardiovascular risk factors and drug therapies.

Table 2.  Relationships of Cardiovascular Risk Factors and Drug Therapies to International Index of Erectile Function (IIEF) Score in Men With Erectile Dysfunction

Parameter IIEF score
Prestatin therapy Poststatin therapy Change in score
β p β p β p
Cardiovascular risk factors (analysis 1)
Age −0.11 0.21 −0.23 0.01 −0.16 0.08
Smoking −1.71 0.34 −1.41 0.15 −0.59 0.57
Hypertension −1.23 0.56 1.89 0.44 −0.33 0.86
Diabetes −1.17 0.59 4.99 0.05 −2.82 0.20
Drug classes (analysis 2)
β blocker −1.36 0.52 −3.78 0.04 +1.54 0.39
Angiotensin-I-converting enzyme inhibitor 3.29 0.10 −1.89 0.53 −3.08 0.12
Angiotensin II type1 receptor blocker 12.4 <0.001 −5.86 0.07 −12.33 <0.001
Digoxin −9.51 0.10 3.29 0.68 +8.66 0.13
Fibrate −3.50 0.27 −3.84 0.69 +3.17 0.31
Anti-platelet −1.19 0.12 −2.90 0.15 +0.68 0.36

 

As specific drug therapies correlated strongly with underlying diseases separate analyses were conducted for cardiovascular risk factors and drug therapies.

Discussion

ED is commonly associated with atherosclerosis.[8,9] Vascular ED can therefore be exacerbated by many of the risk factors which cause atherosclerosis, but it is also well documented that control of these risk factors with specific drug therapies can worsen or even precipitate ED. This study investigated the association of individual cardiovascular risk factors and their therapies with erectile function in a cohort of men attending cardiovascular disease clinics. In particular, it investigated the effect of statin therapy on erectile function in this group.

Over 50% of men attending routine cardiovascular disease clinics suffer from some degree of ED prior to the addition of statin therapy.[10] Similar results were obtained from the Massachusetts Male Aging Study (MMAS), which showed a prevalence of ED of 56% in men with ischaemic heart disease.[11] Statin therapy routinely recommended for cardiovascular disease has been associated with worsening erectile function. Case reports of this phenomenon with statin therapy have been previously documented.[12] Simvastatin was found to cause impotency in five men with coronary artery disease, and within 1 week of discontinuing simvastatin, sexual function was restored. The Australian Adverse Drug Reactions Committee reported 42 cases of ED associated with simvastatin.[13] In contrast, in one study in men aged 49.7 years and isolated hypercholesterolaemia [low-density lipoprotein (LDL)-C 4.3 mmol/l] as a risk factor which used penile Doppler ultrasound in a per protocol analysis of 50% of the cohort of 18 patients (n = 9), atorvastatin therapy was associated with improvement in erectile function (Sexual Health and Impotence Measurement 16→21) if LDL-C was reduced to 3 mmol/l.[14] One possible mechanism postulated was that statin lipophilicity may have an effect. Simvastatin is highly lipophilic and hence could act either centrally or induce a drug-induced peripheral neuropathy in the penile nerves. The current study confirmed the association between introduction of statin therapy but did not find any relationship with dose, cholesterol-lowering efficacy statin dose or relative lipophilicity of the statin and the extent of ED. In addition, the population in our study was 10 years older and more typical of patients with cardiovascular disease, as they had multiple cardiovascular risk factors indicating a more complex aetiology to their endothelial and ED.

A second hypothesis by which statin therapy may worsen erectile function is that it may interact with other agents that are also implicated in the causation of impotence.[12] In our study, prior to statin therapy, atherosclerotic risk factors accounted for only 20% of the variance (r = 0.45) in ED scores and were not clearly associated with ED. However, after initiation of statin therapy, this relationship strengthened to 38% (r = 0.62), and three key variables associated with ED could be defined. These were age, diabetes and (more weakly) smoking. The correlation of ED with age, smoking and diabetes is not surprising and probably reflects deterioration in endothelial function, and the associations with hypertension and diabetes are ameliorated with statin therapy ( ) as would be expected from their actions on endothelial function. ED is more common with advancing age or diabetes.[11] The MMAS showed that the probability of ED in men with CHD increased from 39% in nonsmokers to 56% in smokers,[11] and ED is a well-known side effect of β blockers.[15-17]

Table 2.  Relationships of Cardiovascular Risk Factors and Drug Therapies to International Index of Erectile Function (IIEF) Score in Men With Erectile Dysfunction

Parameter IIEF score
Prestatin therapy Poststatin therapy Change in score
β p β p β p
Cardiovascular risk factors (analysis 1)
Age −0.11 0.21 −0.23 0.01 −0.16 0.08
Smoking −1.71 0.34 −1.41 0.15 −0.59 0.57
Hypertension −1.23 0.56 1.89 0.44 −0.33 0.86
Diabetes −1.17 0.59 4.99 0.05 −2.82 0.20
Drug classes (analysis 2)
β blocker −1.36 0.52 −3.78 0.04 +1.54 0.39
Angiotensin-I-converting enzyme inhibitor 3.29 0.10 −1.89 0.53 −3.08 0.12
Angiotensin II type1 receptor blocker 12.4 <0.001 −5.86 0.07 −12.33 <0.001
Digoxin −9.51 0.10 3.29 0.68 +8.66 0.13
Fibrate −3.50 0.27 −3.84 0.69 +3.17 0.31
Anti-platelet −1.19 0.12 −2.90 0.15 +0.68 0.36

 

As specific drug therapies correlated strongly with underlying diseases separate analyses were conducted for cardiovascular risk factors and drug therapies.

Prior to statin therapy both ACE-Is and ARB improved ED. The relationship of antihypertensive drugs and ED is unclear,[18,19] as both ACE-Is and ARBs have been shown to improve ED in monotherapy.[17,20,21] However, another study of 101 men with hypertension found a prevalence of impotence of 26% of which 70% were associated with ACE-Is.[22] A prescribing survey study in 634 patients with diabetes and ED and 2525 without showed a similar paradoxical action with ACE-Is (RR 1.47) and a blockers (RR 1.54) when the data were analysed after correction for other drug therapies including statins, nitrates and digoxin.[18] These data suggest that cardiovascular drug interactions in the field of ED are complex and may depend on the extent of underlying atherosclerotic disease as well as the drug treatment. This may also be true for statins given the data in patients with isolated hypercholesterolaemia.[14] In addition, if either the LDL-lowering or antihypertensive dose was suboptimal then ED might result because of both disease burden and superficially drug treatment. As optimal levels for both blood pressure and LDL-C keep being redefined to lower targets in high-risk patients, this situation is far likelier to occur in patients at high rather than low cardiovascular risk. Reductions in targets imply increased doses of statins, and the extension of aggressive statin therapy from secondary to primary prevention may lead to an increase in the prevalence of statin-induced ED. This under-reported side effect may contribute to the high rates of discontinuation of statin therapy seen in practice and in clinical trials.[23]

This small study in patients at high cardiovascular risk shows that statin-induced ED is common in patients with high cardiovascular risk. Given the limitations of small study size and a clinical rather than a quantitative physiological (penile Doppler) assessment of ED, it seems that statin therapy may be associated in high-risk patients with worsening ED. It is impossible to delineate whether severity of atherosclerotic disease, drug doses or drug interactions are responsible for the effects seen in this study. Large-scale studies in high-risk patients of phosphodiesterase-5 inhibitors on quantitative measures of ED before and after achievement of optimal control of individual cardiovascular risk factors are required to clarify the pathogenesis of this effect.


CLICK HERE for subscription information about this journal.

References

  1. Bortolotti A, Parazzini F, Colli E et al. The epidemiology of erectile dysfunction and its risk factors. Int J Androl 1997; 20: 323–34.

  2. Solomon H, Man JW, Jackson G. Erectile dysfunction and the cardiovascular patient: endothelial dysfunction is the common denominator. Heart 2003; 89: 251–3.

  3. Bruckert E, Giral P, Heshmati HM et al. Men treated with hypolipidaemic drugs complain more frequently of erectile dysfunction. J Clin Pharm Ther 1996; 21: 89–94.

  4. Lewis RW. Epidemiology of erectile dysfunction. Urol Clin North Am 2001; 28: 209–16, vii.

  5. Modebe O. Erectile failure among medical clinic patients. Afr J Med Med Sci 1990; 19: 259–64.

  6. Maas R, Schwedhelm E, Albsmeier J et al. The pathophysiology of erectile dysfunction related to endothelial dysfunction and mediators of vascular function. Vasc Med 2002; 7: 213–25.

  7. Rosen RC, Cappelleri JC, Smith MD et al. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res 1999; 11: 319–26.

  8. Solomon H, Man JW, Wierzbicki AS et al. Relation of erectile dysfunction to angiographic coronary artery disease. Am J Cardiol 2003; 91: 230–1.

  9. Solomon H, Man J, Wierzbicki AS et al. Erectile dysfunction: cardiovascular risk and the role of the cardiologist. Int J Clin Pract 2003; 57: 96–9.

  10. Jackson G. Erectile dysfunction and cardiovascular disease. Int J Clin Pract 1999; 53: 363–8.

  11. Feldman HA, Johannes CB, Derby CA et al. Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts male aging study. Prev Med 2000; 30: 328–38.

  12. Jackson G, Simvastatin and Impotence. Br Med J 1997; 351: 31.

  13. Boyd IW. Comment: HMG-CoA reductase inhibitor-induced impotence. Ann Pharmacother 1996; 30: 1199.

  14. Saltzman EA, Guay AT, Jacobson J. Improvement in erectile function in men with organic erectile dysfunction by correction of elevated cholesterol levels: a clinical observation. J Urol 2004; 172: 255–8.

  15. Keene LC, Davies PH. Drug-related erectile dysfunction. Adverse Drug React Toxicol Rev 1999; 18: 5–24.

  16. Toda N. Vasodilating beta-adrenoceptor blockers as cardiovascular therapeutics. Pharmacol Ther 2003; 100: 215–34.

  17. Cruickshank JM. What does the future hold for ACE inhibitors? J Hum Hypertens 1991; 5 (Suppl. 2): 41–7.

  18. Blumentals WA, Brown RR, Gomez-Caminero A. Antihypertensive treatment and erectile dysfunction in a cohort of type II diabetes patients. Int J Impot Res 2003; 15: 314–7.

  19. Fogari R, Zoppi A. Effect of antihypertensive agents on quality of life in the elderly. Drugs Aging 2004; 21: 377–93.

  20. Dusing R. Effect of the angiotensin ii antagonist valsartan on sexual function in hypertensive men. Blood Press Suppl 2003; (Suppl. 2) 29–34.

  21. Llisterri JL, Lozano Vidal JV, Aznar VJ et al. Sexual dysfunction in hypertensive patients treated with losartan. Am J Med Sci 2001; 321: 336–41.

  22. Jensen J, Lendorf A, Stimpel H et al. The prevalence and etiology of impotence in 101 male hypertensive outpatients. Am J Hypertens 1999; 12: 271–5.

  23. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. Eur Heart J 1999; 20: 725–41.