Cross-sectional and longitudinal epidemiological studies demonstrate that diabetes and several measures of adiposity significantly and independently increase the risk of ED. Multivariate analyses of several population based cohorts show that of all risk factors diabetes imparts the highest risk for ED with an age adjusted relative risk of 1.3 to 3 depending on diabetes type.5-7
In men with diabetes ED begins earlier than in the general population, and is associated with decreased health related quality of life and decreased success of all known ED treatments, including oral pharmacological therapy and penile implants. An association exists between glycemic control and ED in men with diabetes, in that patients with poor control are at 2 to 5-fold increased risk for ED compared to patients with good control.8,9
Other diabetic complications associated with ED in longitudinal and cross-sectional studies were summarized previously, including diabetes duration, limb loss, retinopathy, nephropathy and untreated hypertension.4
Body weight and adiposity are significantly associated with ED.3,6,7
Convergent data from the Health Professionals Follow-up Study, the National Health and Nutrition Examination Study and MMAS show that compared to men with a BMI of less than 25 kg/m2
the odds of ED are higher in men with a BMI of 25 to 30 kg/m2
and even higher in men with a BMI of greater than 30 kg/m2
. The risk is increased 1.5 to 3-fold. Other measures of adiposity, including the waist-to-hip ratio and abdominal circumference, are also independently associated with ED risk.
While low levels of physical activity are often associated with obesity, they impart an additional risk for ED. Independent of BMI, physically active men (greater than 16 MET hours per week of exercise) are at 30% lower risk for ED than sedentary men. Also, increases in physical activity are independently associated with a lower risk of incident ED. In men without ED at baseline who were followed for 8 years in MMAS the lowest risk of ED was in those who were sedentary at baseline and became physically active (200 kcal or greater per day of activity), whereas the highest risk was in men who were sedentary at each time.7
It has become axiomatic that ED shares important risk factors with cardiovascular disease. Results from a longitudinal prostate cancer prevention study showed that incident ED is associated with a higher risk of subsequent cardiovascular events.10
More recently a similar association was noted in men with T2D and ED.11
Data from MMAS show that ED predicts subsequent metabolic syndrome in men with BMI less than 25 kg/m2
, a group otherwise considered at low risk for cardiovascular disease (multivariate adjusted RR 2.09; 95% CI 1.09, 4.02).12
ED also predicts cardiovascular disease events and increased cardiovascular mortality, confirming earlier cited reports.13
Hypogonadism may be a link between T2D/metabolic syndrome and ED. Men with ED and T2D have a higher prevalence of hypogonadism,14
and low testosterone correlates with poor glycemic control and worsening ED.15
Visceral adiposity and general obesity prevalent in men with T2D and metabolic syndrome can directly impact testosterone. Increased aromatase in adipose tissue can lead to increased androgen conversion from testosterone to estrogens. An association between increased BMI, and waist circumference and hypogonadism has been established in men with T2D 15-17
Hypogonadism is also associated with other components of metabolic syndrome, such as altered lipid status. Hypogonadal patients with T2D ED have increased triglycerides and lower HDL cholesterol.14
Insights From Clinical Trials
Robust drug discovery programs for ED helped move the field forward in 2 important ways. Clinical trials data in specialized populations, including those with diabetes, provided material for potential future biomarker discovery. The second way is the development and use of well validated outcome measures, including IIEF, to determine ED prevalence, incidence and risk factors in epidemiological studies, and response to treatment in clinical trials.
In a significant number of clinical trials groups have investigated the efficacy of PDE5-I for diabetes associated ED. The proportion of men with diabetes who experience improvement in ED by PDE5-I administration was 57% to 74% in 2 pivotal trials.18,19
A recent Cochrane Review showed that PDE5-I improved ED in diabetic men.20
However, these trial results are not fully generalizable to clinical practice. Selection bias at enrollment, and the exclusion of men with poor glycemic control and more severe diabetic complications make it likely that in the general population PDE5-I would be less efficacious than in clinical trials.
Given the limitations of oral pharmacotherapy and the unrelenting increase in the prevalence of ED, expenditures for ED will become unsustainable. Thus, strategies have been sought to reverse or improve ED.
Glycemic Control and ED Risk
Although a number of studies show an association between poor glycemic control and an increased risk of ED, to our knowledge no study has been specifically designed to determine whether intensive improvements in glycemic control would have a beneficial effect on erectile function. The EDIC (Epidemiology of Diabetes Intervention and Complication Study) is a longitudinal cohort followup study for the Diabetes Control and Complication Trial, in which patients with T1D were randomized to conventional or intensive glycemic control. In an ancillary study of urological complications, the Uro-EDIC, the effect of intensive glycemic control on the subsequent risk of ED was assessed.21
ED was measured using IIEF in a subset of 291 men witha1to 5-year history of diabetes and no microvascular complications (primary prevention), and another group of 280 with a 1 to 15-year history of diabetes with minor complications (secondary intervention). In analyses comparing men initially randomized to intensive vs conventional therapy there was no difference in ED in the primary prevention cohort (OR 1.24; 95% CI 0.68, 2.28). In the secondary intervention cohort ED was significantly less likely in those assigned to intensive control than in those assigned to conventional therapy (OR 0.33; 95% CI 0.18, 0.60).
In men with T2D only limited data have been reported on risk reduction strategies for ED. The 41 men with T2D in a behavioral and pharmacological intervention for cardiac risk reduction experienced significant improvements in hemoglobin A1c, diastolic blood pressure and total cholesterol during 4 weeks of intervention.22
Changes in systolic and diastolic blood pressure, and a decrease in or maintenance of hemoglobin A1c below 7.0% were significantly associated with a change on IIEF-5.
A limitation of these 2 studies is that neither was designed specifically to test the hypothesis that ED would improve with the intervention. Future studies including validated ED measurements, adequate sample size and important potential confounders would have the potential to more definitively reveal a benefit to intensive glycemic control in men with poorly controlled diabetes and ED or those at high risk for its development.
A number of lines of investigation suggest that weight loss by bariatric surgery or intensive diet and exercise programs improves erectile function in obese men with ED.23-26
Lifestyle interventions improve endothelial function and NO bioavailability, and may have beneficial effects on ED via this mechanism. Weight loss may also improve ED through other mechanisms, including decreased inflammation, increased testosterone, and improved mood and self-esteem.
The strongest evidence supporting the benefit of lifestyle intervention for ED is from the randomized, controlled trial of 110 obese men by Esposito et al in Italy.24
Men with a mean BMI of 36 kg/m2
and moderate ED (mean IIEF-EF score 13.7) were randomly assigned to a lifestyle intervention including exercise and weight loss or to an educational control. Notably men with hypertension, diabetes or hyperlipidemia were excluded from study and participants were not seeking help for ED. During 2 years the intervention group lost more weight than controls (15 vs 2 kg) and had greater increases in physical activity (195 vs 84 minutes per week). Erectile function improved in the intervention group (IIEF-EF score 13.9 to 17.0, p <0.001) but did not change in the control group (mean score 13.5 to 13.6, p = 0.89). Moreover, 30% of participants in the intervention group recovered normal erectile function (IIEF-EF score 22 or greater) compared to 5% of controls. Improved erectile function correlated significantly with the amount of weight loss and increased activity with each independently explaining about 25% of the variance of change in the IIEF score. Men in the intervention group also had significantly greater improvement in endothelial function (blood pressure and platelet aggregation response to L-arginine), decreases in C-reactive protein and improvement in standard cardiovascular risk factors. Changes in C-reactive protein but not in the surrogate markers of endothelial function were related to changes in IIEF.
Future clinical trials are needed to determine whether lifestyle intervention should be recommended as first line therapy in obese men with ED and identify those most likely to respond to lifestyle changes. Important additional studies are also needed to determine whether diabetes changes the treatment response to weight loss. Any treatment approach that can address these health problems simultaneously would be important for public health.