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Erectile dysfunction and chronic disease management

"A man presenting with erectile dysfunction is a cardiac case until proven otherwise."(1) Geoff Hackett reviews the chronic disease clinics and discusses the importance of healthcare professionals in asking the right questions about erectile dysfunction

Geoff Hackett
FRCPI MD MRCGP
Consultant Urologist
Good Hope Hospital
Sutton Coldfield

Erectile dysfunction (ED) diagnosis and treatment is central to the management of chronic diseases in general practice. There is now compelling evidence that ED is equivalent to current cigarette smoking as a cardiovascular risk factor.(2) As ED is usually caused by vascular disease involving small arteries, it produces symptoms roughly three years before the onset of symptoms in the larger coronary arteries.(3) Opportunities for early intervention to prevent the development or progression of CHD are missed by the failure to ask simple questions that would detect ED. Embarrassment should no longer be an acceptable excuse for not asking about ED.
The severity of ED as measured by the SHIM (sexual health inventory for men) accurately predicts the severity of the underlying cardiac lesion in terms of single and multiple vessel disease found at coronary angiography.(3) It could be argued that the single best question to assess the degree of cardiovascular risk is "are you consistently unable to attain and maintain an erection", as no other question directly assesses the vascular performance of smaller arteries, particularly in men with a sedentary lifestyle. In spite of the fact that men can no longer perform any other physical activity the way that they did when they were younger, they seem to believe that the penis should work by "divine right".
Unfortunately, while we diligently record data on smoking and calculate Framingham risk scores (usually inaccurately), we seldom ask the question of those patients attending chronic disease management clinics, even though these patients are at the greatest risk of suffering from ED. There is significantly more evidence for the inclusion of ED as a quality outcome assessment (QOF) than many of the currently included measurements.
Because the average UK male with ED waits two years from onset to consult a healthcare professional, there is currently potentially a narrow window of opportunity for effective intervention.

Hypertension and CKD
Recently published expert guidelines recommend that all patients with hypertension be questioned about ED and its severity at the time of diagnosis, and at least annually.(4) We are well aware that compliance (adherence to) with antihypertensive therapy is poor and that side-effects related to sexual activity are a frequent reason for discontinuation.(5) Most healthcare professionals are aware that thiazides and ß-blockers are associated with ED, and few physicians ask about ED before prescribing them.(5) Relying on self-reporting by the patient is seldom rewarding and changing drugs once established rarely reverses ED.
The definitive study on this issue was conducted by Dusing et al.(6,7) They studied 2,550 treated and 952 newly diagnosed hypertensive men and assessed sexual function using the International Index of Erectile Function (IIEF). In the first group, the ED rate was 75%. Patients were switched to the angiotensin-receptor blocker valsartan 80-160 mg, and in the newly diagnosed patients (baseline ED rate 65%), valsartan was the first treatment. In each group there was a reduction in patients with ED by 20% (see Figure 1). This effect was across all categories and domains of ED including desire, orgasm, intercourse and overall satisfaction. The magnitude of this effect was similar to that seen with drugs licensed to treat ED.
In another study comparing atenolol and valsartan, men on valsartan made significantly more sexual attempts than men on atenolol and a significant reduction in testosterone was seen with atenolol and a nonsignificant increase with valsartan.(8) Smaller studies with losartan suggests that this is probably a class effect.(9)

[[nip41_fig1_52]]

Other classes of antihypertensives have not been studied and data relate to volunteered ED, which is a gross underestimate of the real effect detected by validated questionnaires such as the SHIM and IIEF.5 The consensus is that angiotensin-converting enzyme inhibitors (ACEIs) and calcium channel blockers have little adverse affect on ED, but certainly do not have the positive benefit seen in the above studies.5 The reason for these class differences is believed to be through the effects on angiotensin II (AT2); ARBs lower AT2 more the ACEIs and thiazides raise AT2.(7)
Currently PCTs recommend ACEIs as firstline treatment for hypertension and prescribing incentive schemes are in place to restrict patients requiring either ACEIs or ARBs to less than 25% on ARB. These restrictions would not allow GPs to prescribe according to evidence-based guidelines in order to prevent ED. The savings made on antihypertensive medication is less than 20% of the cost of ED medication to reverse the ED with therapy (often self-funded). The requirement to take medication before each and every episode of sex cannot be compared with normal sexual function. It would be regarded as unacceptable to exacerbate asthma or peripheral vascular disease with a ß-blocker or rout, or diabetes with a thiazide, and yet we do not put ourselves in a position to offer our patients best treatment unless we ask the correct questions.

Coronary heart disease
Many of the principles discussed in relation to hypertension also apply to ED. Sex requires a degree of cardiac fitness roughly equivalent to walking one mile in 20 minutes or climbing two flights of stairs.(1) Patients need to have sufficient cardiac reserve for sex irrespective of whether they require a treatment to facilitate an erection.
Raised cholesterol is a significant risk factor for ED initially through endothelial dysfunction affecting the small arteries of the penis roughly three years before the coronary arteries.(3,10) Statins have been shown to improve ED in a small study where hyperlipidaemia was the only risk factor.(11) Many opportunities to address these issues were missed in large-scale statin studies. This benefit may be seen in patients with lower Framingham risk than would normally result in a statin prescription for coronary risk alone. Jackson et al showed that the addition of a statin in patients with established CHD worsened erectile function.(12) The same author showed that nitrates could be stopped in around 90% of patients to facilitate the prescription of oral therapy for ED.(13) Nitrates are regarded as old drugs with no prognostic benefit in CHD and many patients carry a spray around in their pocket, but have never used it for months or even years.
The DH guidance on ED, requires patients with CHD and ED to pay for medication or be prescribed under "severe distress" from hospital consultants or according to locally negotiated arrangements.(14) Obtaining medication from either of these sources increases the risk that the medications will not be shown on the list of repeat medications, increasing the risk that contraindicated medicine might be prescribed. By not asking the question about ED, the GP may be putting themselves and the patients at risk.

Diabetes
Vascular risk factors are highly prevalent in type 2 diabetes and reported ED rates are between 50% and 75%.(15) An additional risk factor in diabetes is testosterone deficiency, which is closely related to insulin resistance.(16) At 42%, the rate of testosterone deficiency is double the rate in the nondiabetic population. In the clinical trials on ED therapy, patients with low testosterone were excluded and yet the response rate to unlimited supplies of oral PDE5Is was 55%.(15) When we prescribe restricted quantities of medications, such as sildenafil to diabetics with low testosterone, response rates are no better than 35%. Treating low testosterone levels can significantly improve response rates and exciting research suggests that diabetes parameters including HbA1C and visceral adiposity also improve when testosterone is normalised.(16,17)
Obesity and metabolic syndrome are also major risk factors for ED. Asking about ED and explaining the links with coronary heart disease may be a significant motivating risk factor for lifestyle intervention in a group of men who otherwise would not present until a significant event has occurred. There is little evidence that advice on diet and exercise is currently proving effective in these men.

Assessment of patients with ED
Well-validated questionnaires, such as the five-question sexual health inventory for men (SHIM), facilitate the rapid assessment and follow-up of ED in everyday practice (see Figure 2).

Evidence-based guidelines from the European Urology Association and the British Society for Sexual Medicine define the standard investigations of the ED patient:(4)

  • Fasting glucose. In 20% of people with type 2 diabetes ED is the presenting symptom.
  • Lipid profile. Each unit rise in total cholesterol is associated with a doubling of the risk of ED.
  • Total testosterone between 8am and noon. Testosterone is an important reversible cause of ED in 10-20% of cases, especially people with diabetes, and a major cause of poor response to ED medications. 

Therapeutic implications
ED is an early manifestation of endothelial dysfunction occurring in the small arteries of the penis approximately three years before potentially fatal disease in the coronary arteries. Chronic diseases usually require chronic therapy. In June 2007, the long-acting phosphodiesterase-5 inhibitor (PDE5I) tadalafil was licensed for daily dosing. PDE5Is have been shown to have clinical efficacy in pulmonary hypertension (licensed for sildenafil), peripheral vascular disease, Raynaud's disease and benign prostatic hypertrophy.(19-21) Case reports have shown improvement in diabetic neuropathy.(22) Patterson studied the effect of a single dose of tadalafil on 26-hour ambulatory BP monitoring in 114 patients, and showed clinically meaningful reduction in blood pressure (see Figure 3).(23) PDE5Is were developed as cardiovascular drugs and these findings should come as little surprise. The fact that they are not licensed for these conditions reflect commercial considerations and the expiry of the first European patents in September 2008. Once these drugs become more affordable, these additional therapeutic benefits will be more publicised.

[[nip41_fig3_55]]

These effects are potentially beneficial in aging men with multiple pathologies. Licensing for these indications has been influenced by commercial factors, especially the expiry of the patents for sildenafil in Europe from September 2008.

Conclusion
ED diagnosis and treatment is central to the management of chronic diseases in general practice. Embarrassment can no longer be used as an excuse for failing to ask a simple question. A questionnaire can be incorporated into any standard chronic disease consultation (see Figure 1). Comprehensive evidence-based guidelines clearly define the investigation and management of patients. For too long ED has been marginalised as a "recreational" disorder, driving patients to seek help from dubious sources. The current drugs used to treat ED are important cardiovascular medications that should be managed in conjunction with the other standard treatment for chronic disease. Ultimately the decision to include ED as a QOF indicator may be the major factor to change behaviour.

[[nip41_fig2_54]]

References

  1. Jackson G, RC Rosen, RA Kloner, JB Kostis. The second Princeton consensus on sexual dysfunction and cardiac risk: new guidelines for sexual medicine. J Sex Med 2006;3:28-36.
  2. Thompson IM, CM Tangen, PJ Goodman, et al. Erectile dysfunction and subsequent cardiovascular disease. JAMA 2005;294:2996-3002.
  3. Montorsi P, PM Ravagnani, S Galli, et al. Common grounds for erectile dysfunction and coronary artery disease. Curr Opin Urol 2004;14:361-5.
  4. Hackett G. Guideline highlights association of erectile dysfunction with CVD. Guidelines in Practice 2007;10:15-9.
  5. Khan MA, RJ Morgan, DP Mikhailidis. The choice of antihypertensive drugs in patients with erectile dysfunction. Curr Med Res Opin 2002;18:103-7.
  6. Dusing R. Sexual dysfunction in male patients with hypertension: influence of antihypertensive drugs. Drugs 2005;65:773-86.
  7. Dusing R. Sexual dysfunction in male patients with hypertension patients treated with valsartan. Hypertension 2003;12:29-34. 
  8. Fogari R, Preti P, Derosa G, et al. Effect of antihypertensive treatment with valsartan or atenolol on sexual activity and plasma testosterone in hypertensive men. Eur J Clin Pharmacol 2002;58:177-80.
  9. Llisterri JL, et al. Sexual dysfunction in hypertensive patients treated with losartan. Am J Med Sci 2001;321:336-41.
  10. Wei M, Macera CA, Davis DR, et al. Total cholesterol and high density lipoprotein cholesterol as important predictors of erectile dysfunction. Am J Epidemiol 1994;142:930-7.
  11. 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.
  12. Solomon H, Samarasinghe YP, Feher MD. Erectile dysfunction and statin therapy in high risk cardiovascular patients. Int J Clin Pract 2006;60:141-5.
  13. Jackson G, Martin E, McGing E, Cooper A. Successful withdrawal of oral long-acting nitrates to facilitate phosphodiesterase type 5 inhibitor use in stable coronary disease patients with erectile dysfunction. J Sex Med 2005;2:513-6.
  14. Hackett G. Schedule 11 - impact on treating erectile dysfunction. Br J Diabetes Vasc Dis 2002;2:315-8.
  15. Sun P, Cameron A, Seftel A, et al. Erectile dysfunction - an observable marker of diabetes mellitus? A large national epidemiological study. J Urol 2006;176:1081-5.
  16. Shabsigh R, Rajfer J, Aversa A. The evolving role of testosterone in the treatment of erectile dysfunction. Int J Clin Pract 2006;60:1087-92.
  17. Shabsigh R, Kaufman JM, Steidle C, Padma-Nathan H. Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone. J Urol 2004;172:658-63.
  18. Urology Center of Florida. Sexual health inventory for men (SHIM). Available from: http://www.ucof.com/files/SHIM.pdf
  19. Tsai BM, Turrentine MW, Sheridan BC, et al. Differential effects of phosphodiesterase-5 inhibitors on hypoxic pulmonary vasoconstriction and pulmonary artery cytokine expression. Ann Thorac Surg 2006;81:272-8.
  20. Friedman EA, Harris PA, Wood AJJ, et al. The effects of tadalafil on cold-induced vasoconstriction in patients with Raynaud's phenomenon. Clin Pharmacol Ther 2007;81:503-9.
  21. McVary KT, Swierzewski MJ, Monnig WB, et al. Sildenafil improves erectile function and concomitant lower urinary tract symptoms in men. J Urol 2006;175:S298.
  22. Hackett G. PDE5 inhibitors in diabetic peripheral neuropathy. Int J Clin Pract 2006;60:1123-6
  23. Patterson D, McInnes GT, Webster J, et al. Influence of a single dose of 20 mg tadalafil, a phosphodiesterase 5 inhibitor, on ambulatory blood pressure in subjects with hypertension. Br J Clin Pharmacol 2006;62:280-7.