ED, diabetes, and CV risk: Update on treatment, risk reduction

Of the commonly recognized causes of erectile dysfunction, diabetes is the second most common behind vascular causes (figure 1). The prevalence of erectile dysfunction in the general population is estimated to be 52% in men between age 40 and 70 years with a staggering 322 million men affected worldwide. According to 2012 U.S. census data, 15.5 million American men have diabetes, 50% of whom have sexual troubles caused by their disease. The prevalence of ED in diabetics is independently associated with duration of diabetes mellitus, occurs 10 to 15 years earlier than in men without diabetes, and is more severe and less responsive to oral treatment than in patients without the disease. 

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The etiology of ED in diabetics is multifactorial and the determinants of pathogenesis include age, duration of diabetes, degree of glycemic control, presence of microvascular complications, and coexistence of cardiovascular disease. Normal penile erection requires an increase in neurologically mediated cavernosal arterial inflow, cavernosal smooth muscle relaxation, and restriction of venous outflow. Diabetes can cause irreversible damage to vascular endothelium, decreasing blood flow to the penis. Up to 60% to 70% of diabetic men have neuropathy, which impedes neurogenic activation of erections. Cavernosal smooth muscle fibrosis due to chronic inflammation is also common in diabetics and prevents normal smooth muscle relaxation. Inadequate inflow ultimately results in ineffective restriction to outflow.

ED and diabetes: Pathophysiology

Erectile dysfunction in diabetics is mediated by insulin resistance, which leads to endothelial dysfunction and atherosclerosis (figure 2). In epidemiologic studies, worse glycemic control correlates with higher rates of ED, and in animal studies insulin administration relieves diabetes-associated ED and improves surrogates for erectile function (J Urol 2003; 170:291-7). In men without diabetes, the addition of metformin to sildenafil citrate (Viagra) results in improved erectile function, suggesting that insulin regulation is involved in the pathogenesis of vasculogenic ED, even when overt diabetes mellitus is not present (J Androl 2012; 33:608-14).

Diabetes, obesity, and the metabolic syndrome (MetS) are chronic inflammatory states that result in structural damage to the vascular endothelium of the penis and other vascular beds and impaired nitric oxide (NO) release in men with ED. NO causes cavernosal smooth muscle relaxation and inhibits platelet aggregation and adhesion. Reduced bioavailability of NO therefore results in vasoconstriction, platelet adhesion, and smooth muscle cell proliferation, which potentiates the atherosclerotic burden of the penile vasculature, further compromising cavernosal arterial inflow.

Insulin resistance may also cause endothelial dysfunction through an NO-independent pathway mediated by endothelin-1. Insulin stimulates production of endothelin-1, a potent vasoconstrictor, and NO in vascular endothelium. In non-diabetic individuals, the vasodilatory effects of NO predominate; in insulin-resistant states, this does not occur, suggesting that in diabetes there is preservation of endothelin in the face of impaired NO production.

Next: ED, DM, and metabolic syndrome

ED, DM, and metabolic syndrome

There is a close link between erectile dysfunction and MetS. MetS is a cluster of conditions that include increased blood pressure, a high blood sugar level, excess body fat around the waist, and abnormal cholesterol levels. These occur together, increasing risk of heart disease, stroke, and diabetes. In the Massachusetts Male Aging Study, ED at baseline predicted subsequent MetS and in a cross-sectional analysis of a cohort of 2,371 men, men over 50 with MetS had a 48% increased risk of severe ED (J Urol 2006; 176:222-6; J Urol 2007; 177: 651-4). Also, prevalence of ED increases as the number of components of MetS increase (Diabetes Care 2005; 28:1201-3).

Testosterone deficiency is independently associated with diabetes and other components of the metabolic syndrome (figure 3). Testosterone deficiency and MetS share multiple comorbidities, including insulin resistance, hyperglycemia, dyslipidemia, and obesity, and both are characterized by common pathophysiologic pathways of inflammation and endothelial dysfunction. What’s unclear is whether low testosterone causes diabetes and components of the MetS, or vice versa. However, the evidence suggests that the relationship is bidirectional. What is clear is that low testosterone should be recognized as an additional independent risk factor for cardiometabolic disease in men with DM and ED.

Treatment of ED in diabetics

The phosphodiesterase type-5 (PDE-5) inhibitors (sildenafil, vardenafil [Levitra], tadalafil [Cialis], avanafil [Stendra]), which work by augmenting nitric oxide, are still the mainstay of treatment for ED. PDE-5 inhibitors require an intact neurologic response and endothelial function, which explains why they are less effective in men with longstanding diabetes. Still, a meta-analysis of 14 randomized controlled trials found a 63% improvement in erectile function in diabetic men taking sildenafil compared to 19% of those taking placebo (Arch Intern Med 2002; 162:1349-60).

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Men who have demonstrated suboptimal response to PDE-5 inhibitor therapy should be informed of the benefits and risks of other therapies, including alprostadil intraurethral suppositories (MUSE), vacuum erection devices (VED), intracavernosal drug injection (ICI), and penile prostheses. While response rates to vacuum devices and ICI are good to excellent in diabetic men, compliance rates are poor and dropout rates high. A recent study suggests that diabetic men are more likely to require aggressive therapy for ED, such as insertion of a penile implant (Int J Impot Res 2013; 26:112–5).

Next: Management of CV risk in diabetics with ED

Management of CV risk in diabetics with ED

ED is now a well-established precursor of coronary artery disease (CAD) and may predict occult CAD, particularly in men under age 60 years. This is particularly true for men with ED and diabetes, where ED is a strong predictor of silent CAD. A recent study of over 4,500 men with ED found that men with ED and at baseline were more than twice as likely to develop subsequent diabetes than those without ED, suggesting that ED may not only predict CAD but may also predict diabetes in some men (Ann Fam Med 2015; 13:331-5).

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Endothelial dysfunction is the link between ED, DM, and CAD; thus the identification and modification of shared risk factors for endothelial function through pharmacologic and/or lifestyle interventions can reduce CV risk while mitigating complications due to diabetes such as ED.

Diabetics, like all men with vasculogenic ED, warrant assessment of cardiovascular risk factors, screening for occult cardiovascular disease, and aggressive modification of atherosclerotic risk factors, especially those with a suboptimal response to PDE-5 inhibition who are likely to be at greatest risk for CAD.

The Yale Cardiovascular and Sexual Health program, a virtual and real-time multidisciplinary collaboration between urology, cardiology, and health psychology, was established to address CV reduction in men with ED, and is comprised largely of men with DM and other causes of vasculogenic ED. Our approach comprises recommendations originally outlined by the Princeton III Consensus Conference (Mayo Clin Proc 2012; 87:766-8), including: a thorough history emphasizing identification of comorbid conditions, family history, and lifestyle factors; physical examination with attention to waist circumference or BMI, peripheral pulses, and cardiac auscultation; assessment of ED severity and duration; fasting plasma glucose and or hemoglobin A1c; serum creatinine; total testosterone; and plasma lipid levels.

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We endorse use of noninvasive risk assessment for all men with (and without) ED and indeterminate or high risk for CVD, which may include one or more of the following at the discretion of our collaborating cardiologist: EKG, cardiac stress test (or in some cases use of emerging biomarkers), and C-reactive protein.

Next: Lifestyle modification

Lifestyle modification

Lifestyle modification must be the cornerstone of any effective CV risk-reduction plan in men with ED and diabetes. The benefits of dietary modification in reducing cardiometabolic risk are well established. Numerous studies have demonstrated the association between Mediterranean diet and reduction in overall and cardiovascular mortality. A Mediterranean diet or a diet rich in fruits, nuts, vegetables, and fish and low in red meat has been shown to be associated with lower rates of ED; and conversion to a Mediterranean-style diet improves erectile and endothelial function, and reduces systemic markers of inflammation in men with ED and MetS (Int J Impot Res 2006; 18:405-10).

The benefits of exercise in reducing CV risk and complications of disease among diabetics are well established. Exercise enhances arterial blood flow, which in turn increases endothelial production of NO through shear stress, promotes fat reduction, increases lean muscle mass, reduces insulin resistance, and improves glycemic control and lipid profiles. When combined with dietary or weight loss intervention, moderate physical activity also leads to improvement and preservation of erectile function in diabetics (J Sex Med 2010; 7:156-65).

Pharmacologic risk reduction

Data on the dual benefit of pharmacotherapy for CV risk reduction and improvement of ED in men with diabetes, while limited, appear to be promising. In diabetic patients with erectile dysfunction, use of a PDE-5 inhibitor and statin has been shown to decrease the risk of major adverse cardiac events (Int J Androl 2009; 32:587-98). Testosterone replacement therapy (TRT) in hypogonadal diabetic patients may improve cardiometabolic risk and has been shown to decrease CV mortality while improving insulin resistance and central obesity. Reduction in total/LDL cholesterol and triglycerides, improvements in HDL and fasting glucose, and decreased waist circumference have all been observed in men with MetS and DM on TRT. TRT also appears to improve response to PDE-5 inhibitors in diabetic men.

Next: Summary

Summary

ED is prevalent in men with diabetes and is associated with duration of DM, occurs earlier, and is more severe than in patients without diabetes. ED is an independent risk factor for CAD, and CAD is more severe in diabetics with ED.

Diabetic men are less responsive to oral ED therapies and are likely to require more aggressive therapy for ED. All diabetic men should be assessed for CV risk factors and co-managed with interventions to modify risk and improve erectile function when possible.

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