Introduction

Erectile dysfunction (ED) and cardiovascular disease are highly prevalent among men with diabetes. An estimated 20–85% of diabetic men have some form of ED¹ and are three times more likely to suffer from ED than nondiabetic men.² In addition to sharing many of the same risk factors, ED is also considered a marker for cardiovascular disease.³ Risk factors such as elevated hemoglobin A1c (HbA1c), blood pressure (BP) and hyperlipidemia/dyslipidemia have been associated with both cardiovascular disease^{4, 5} and ED in patients with diabetes.^{1, 6, 7, 8, 9}

Previous studies have shown a beneficial effect on ED of reduction in certain cardiovascular risk factors such as body mass index (BMI), cholesterol, increased physical activity, reduced BMI and smoking cessation in nondiabetic men.^{10, 11, 12, 13} However, data are lacking on the effect of changing multiple cardiovascular risk factors on ED among men with diabetes. This is one of the first studies to assess the impact of multifactorial cardiovascular risk reduction on ED in men with diabetes. Thus, we studied the effects of an intensive behavioral and pharmacological intervention targeting hyperglycemia, hypertension and hyperlipidemia on ED in a cohort of diabetic men.

Methods

Design

This is a retrospective analysis of the study 'Combined Behavioral and Pharmacological Intervention for Cardiovascular Risk Reduction in Diabetic Patients (ClinicalTrials.gov Identifier: NCT00357955)', where 109 participants were randomly assigned to receive an intensive behavioral and pharmacological group intervention, 'Multi-disciplinary Education in Diabetes and Intervention for Cardiac risk reduction (MEDIC)' program (n=58), or continue their usual care (n=51) at the Providence Veterans Affairs Medical Center during 2004–2007. The protocol received approval from the Institutional Review Board at the Providence Veterans Affairs Medical Center.

Intervention

Participants in the treatment arm attended weekly group sessions of MEDIC for 1 month, where clinical pharmacists provided education and behavioral modification to encourage diet, exercise and disease self-management, tobacco cessation and other comorbid risk reduction. Medication titration followed an algorithm to achieve tobacco cessation, glycemic, BP and lipid control. All participants returned for follow-up 3 months post intervention (4-month follow-up).

Data collection

Erectile dysfunction was assessed using the self-reported 5-item version of the International Index of Erectile Function (IIEF-5)¹⁴ at the beginning of the study and at the 4-month follow-up. We collected demographic factors, medical history and medication usage. All participants were assessed for weight, BP, HbA1C and lipids levels at the baseline of the study and again at the 4-month follow-up.

Subjects

Participants in the study were veterans, 18 years and older, with type II diabetes and an elevated HbA1c of 7–9% at least 6 months prior to the start of the study. Recruitment occurred at the Providence Veterans Affairs Medical Center from 2004–2007. The focus of the current analysis is restricted to the participants assigned to the treatment arm who completed the IIEF-5 at baseline and at the 4-month follow-up (n=41).

Risk-factor goals

HbA1c, BP and total cholesterol (TC) were assigned cutoff levels based on the Framingham coronary disease prediction algorithm⁴ and the American Diabetes Association standards of medical care.¹⁵ Participants were determined to have met goals for each of the risk factors if they achieved or maintained a level below the cutoff level. Cutoff levels were determined for HbA1c, BP and TC as follows:

1. Hemoglobin A1c: 7.0%
2. Blood pressure: 130/80 mm Hg
3. Total cholesterol: 160 mg per 100 ml.

Analyses

The distribution of different outcome variables was examined using the Shapiro–Wilk W test. If a deviation from normality was found, log transformation of the data points was performed and analyses were then performed for the variables on its original and log transformed states. If there was no difference in outcome of analysis between original and log transformed states, the original values were reported. All measured risk factors and medication use were compared between baseline and follow-up using paired Student's t-tests or two-tail Fisher's exact tests. First, change in IIEF-5 was modeled using univariate linear regression with change in systolic and diastolic BP, HbA1c and TC. Then change in IIEF-5 scores was compared among participants who did and did not meet each of the risk-factor goals. We compared demographics, comorbidities and medication use among people who did and did not meet each of the goals to assess for potential confounding factors. Change in IIEF-5 was then modeled with change in risk factors and risk-factor goals after adjusting for these confounding factors. To compare the effect of meeting multiple goals vs one vs zero goals on erectile function, we used Student's t-test for each pair. Only goals that showed an increase in IIEF-5 score were included in the latter analysis. All statistical analyses were conducted using SAS JMP (SAS Institute Inc., Cary, NC, USA). Statistical significance was defined as P<0.05. Data are presented as means.d.

Results

A total of 41 men completed the IIEF-5 at both baseline and the 4-month follow-up. Characteristics of the participants are shown in Table 1. The mean age of the participants was 62.49.7 years and 85.4% were white. There was a high prevalence of coronary artery disease (53.7%) and one-third of the participants were active smokers. There was a significant decrease from baseline in the levels of HbA1c, TC and diastolic BP at the 4-month follow-up. However, there was no change in the mean IIEF-5 score over that period (Table 2). There was no significant change in the categories of medication use before and after the intervention (Table 3).

Table 1 - Demographic and clinical characteristics of participants (n=41).

Full table

Table 2 - Change in measured factors over 4 months.

Full table

Table 3 - Medication use.

Full table

In univariate linear regression, there was a significant association between change in systolic and diastolic BP and change in IIEF-5 (r=0.4, P=0.01; r=0.4, P=0.01, respectively) whereas change in HbA1c and TC did not have any significant association (r=0.02, P=0.9; r=0.2, P=0.6, respectively). The number of people who met assigned goals in HbA1c, BP and TC were 16, 22 and 28, respectively (39.0, 53.7, 68.3%, respectively; Table 4). Participants who met HbA1c goals experienced a statistically significant improvement in IIEF-5 compared to participants not meeting the goal (1.63.7 vs -1.04.0, P=0.04) over the 4-month period. Participants meeting the BP goal also experienced a small improvement in IIEF-5 compared to participants not meeting the goal, who experienced a decline (0.64.4 vs -0.63.5, P=0.3). Participants meeting the TC goal experienced no change in their mean IIEF-5 score whereas there was a slight increase seen among patients not meeting the goal (0.04.7 vs 0.12.3, P=1.0; Figure 1).

Figure 1.

Change in IIEF-5 at 4-month follow-up for meeting risk-factor goals.

Hemoglobin A1c,

Blood pressure, Total cholesterol. Error Bars represent s.d.

Full figure and legend (49K)

Table 4 - Medication use at 4-month follow-up.

Full table

There was no significant difference in race, age, smoking status or testosterone levels between participants who did and did not meet goals for HbA1c, BP and TC. The only significant difference in medication usage between participants who did and did not meet each of the three goals was in sulfonylurea and insulin use for the BP goal (P=0.004, P=0.01, respectively; Table 4). However, there was an increasing trend in PDE5 inhibitor use for participants who met HbA1c and BP goals (12.5–25.0%, P=0.7 and 4.6–13.6%, P=0.6, respectively) and for participants who failed to meet the TC goal (15.4–30.8% P=0.6) from baseline to the 4-month follow-up. The average change in IIEF-5 among people who started using a PDE5 inhibitor over the course of the intervention was -0.31.2, P=0.9. Change in IIEF-5 was modeled using multiple linear regression adjusted first for age and then for PDE5 inhibitor use. Changes in systolic and diastolic BP were still significant predictors of change in IIEF-5 after adjusting for age (P=0.01 and P=0.01, respectively) and change in PDE5 inhibitor use (P=0.01 and P=0.01, respectively; Table 5). HbA1c goal also remained a significant predictor of change in IIEF-5 after adjusting for age (P=0.05) and change in PDE5 inhibitor use (P=0.05).

Table 5 - Age- and PDE5 inhibitor use-adjusted linear regression.

Full table

Participants who had met goals for both BP and HbA1c experienced the greatest improvement in IIEF-5 (2.21.6) followed by participants who met only one of the goals (BP or HbA1c) (-0.050.8), and then by those meeting none of the goals (-1.51.2). There was a significant difference between participants who had met two and zero goals (P=0.04), but no difference between participants meeting two and one goals (P=0.2) or between one and zero goals (P=0.3). There was a nonsignificant moderate correlation between change in IIEF-5 and the number of goals met (r=0.3, P=0.1; Figure 2).

Figure 2.

Change in IIEF-5 at 4-month follow-up for meeting multiple risk-factor goals. Error Bars represent s.d. Levels not connected by the same letter are significantly different.

Full figure and legend (28K)

Discussion

This is one of the first studies relating the isolated and combined effects of reduction in BP, HbA1c and TC levels to ED. Change in systolic and diastolic BP and a reduction in or maintenance of HbA1c below 7.0% were significantly associated with change in IIEF-5 score from baseline to the 4-month follow-up. Additionally there also appeared to be an additive effect as participants who met both HbA1c and BP goals improved to a greater degree than those meeting either only one of the goals or none of the goals.

Elevated HbA1c levels have been shown to be associated with ED.¹ In animal models, hyperglycemia leads to decreased Nitrous oxide (NO) production.¹⁶ Thus, a decrease in glycemia may allow for increased NO production leading to improved vasodilatation and erectile function. Hypertension is also highly prevalent among diabetic men with ED.¹⁷ Hypertension is most likely related to ED being a primary vascular risk factor and the resulting long-term vascular damage.¹⁸ Although treatment of hypertension with common antihypertensive medications has been associated with ED,^{19, 20} another study also showed recovery of erectile function after brief aggressive antihypertensive therapy.²¹ Moreover, antihypertensives at levels currently used in clinical settings are not likely to negatively influence ED significantly.²² Our results suggest that although it may be important to lower HbA1c levels below a clinically important threshold to experience improvement in ED, any reduction in BP may also provide beneficial effects. Additionally, as hyperglycemia and hypertension may affect ED through different mechanisms, improvement in both appears to lead to the greatest improvement in ED.

The role of lipid lowering and the use of statins in ED is controversial. Although one previous study has shown a decrease in TC accompanied with an improvement in ED following statin therapy,¹¹ another study showed a reduction in IIEF-5 scores following statin therapy.²³ It is possible that the reduction in TC in our study may have been through a manner which does not affect diabetic ED. Our intervention did not result in a significant change in high-density lipoprotein (HDL) or triglyceride levels, both of which have been associated with poor sexual function.^{6, 24, 25} Our finding of lowering of TC without significant changes in HDL and triglycerides is typical of statins and especially of simvastatin, which was the preferred statin used at the study institution.²⁶ The short time frame of our intervention makes it likely that the gains in risk-factor control were largely reflective of the weekly medication up titrations, and less from the behavioral modifications which often take longer time for their effects to be observed.¹⁰ Lastly, it may also be possible that in men with diabetes, the effect of TC on ED is minimal compared to that exerted by other factors such as hyperglycemia and hypertension.

Our study was limited by the small sample size resulting in reduced statistical power. Despite this shortcoming, we were able to see a statistically significant association between change in IIEF-5 and meeting the HbA1c goal and change in systolic and diastolic BP. A greater number of participants may allow us to stratify our goals to determine the effects of meeting multiple ED comorbidity goals and at different levels rather than at a singular cutoff point. We were also limited by the nonexperimental design, which may result in selection bias. However, to date very few studies have addressed the role of multifactorial cardiac risk reduction in improving the ED of diabetic men, and our data may provide the much-needed pilot data for the design of larger randomized controlled studies. The changes seen in IIEF-5 were relatively small, and may not be biologically meaningful. Given the short duration of our study, we believe that any change observed is important as it may suggest that more intensive and longer lasting interventions may result in greater changes in IIEF-5. In addition, the magnitude of the IIEF-5 changes were additive. A longer follow-up may also help to determine the longevity of the improvements in both the cardiovascular risk factors and the change in ED. Lastly, as the study employed the IIEF-5 questionnaire, the limitations inherent in the IIEF-5, such as focus on heterosexual sex, lack of inquiry regarding desire and lack of information on the etiology of the disorder²⁷ were a part of this study.

Although studies have been done on the prevalence of ED risk factors among men with diabetes,^{18, 28} there have been no previous studies examining the impact of reducing multiple cardiovascular risk on ED among diabetic men. Our study provides the first evidence of the beneficial effect of BP control and reduction and maintenance of a low HbA1c on ED in men with diabetes.

Notes

Financial disclosure

The authors state no conflict of interest.

References

1. Romeo JH, Seftel AD, Madhun ZT, Aron DC. Sexual function in men with diabetes type 2: association with glycemic control. J Urol 2000; 163: 788–791. | Article | PubMed | ChemPort |
2. Feldman HA, Goldstein I, Gatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts male aging study. J Urol 1994; 151: 54–61. | PubMed | ISI | ChemPort |
3. Ponholzer A, Temml C, Obermayr R, Wehrberger C, Madersbacher S. Is erectile dysfunction an indicator for increased risk of coronary heart disease and stroke? Eur Urol 2005; 48: 512–518. | Article | PubMed | ISI |
4. Wilson PWF, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation 1998; 97: 1837–1847. | PubMed | ISI | ChemPort |
5. Selvin E, Marinopoulos S, Berkenblit G, Rami T, Brancati FL, Powe NR et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004; 141: 421–431. | PubMed | ISI | ChemPort |
6. Wei M, Macera CA, Davis DR, Hornung CA, Nankin HR, Blair SN. Total cholesterol and high density lipoprotein cholesterol as important predictors of erectile dysfunction. Am J Epidemiol 1994; 140: 930–937. | PubMed | ISI | ChemPort |
7. Burchardt M, Burchardt T, Baer L, Kiss AJ, Pawar RV, Shabsigh A et al. Hypertension is associated with severe erectile dysfunction. J Urol 2000; 164: 1188–1191. | Article | PubMed | ISI | ChemPort |
8. Miyata Y, Shindo K, Matsuya F, Noguchi M, Nishikido M, Koga S et al. Erectile dysfunction in hemodialysis patients with diabetes mellitus: association with age and hemoglobin A1c levels. Int J Urol 2004; 11: 530–534. | Article | PubMed |
9. Ahn TY, Park JK, Lee SW, Hong JH, Park NC, Kim JJ et al. Prevalence and risk factors for erectile dysfunction in Korean men: results of an epidemiological study. J Sex Med 2007; 4: 1269–1276. | Article | PubMed |
10. Esposito K, Giugliano F, Di Palo C, Giugliano G, Marfella R, D'Andrea F et al. Effect of lifestyle changes on erectile dysfunction in obese men: a randomized controlled trial. JAMA 2004; 291: 2978–2984. | Article | PubMed | ISI | ChemPort |
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: 255–258. | Article | PubMed | ISI |
12. Guay AT, Perez JB, Heatley GJ. Cessation of smoking rapidly decreases erectile dysfunction. Endocr Pract 1998; 4: 23–26. | PubMed | ChemPort |
13. Derby CA, Mohr BA, Goldstein I, Feldman HA, Johannes CB, McKinlay JB. Modifiable risk factors and erectile dysfunction: can lifestyle changes modify risk? Urology 2000; 56: 302–306. | Article | PubMed | ISI | ChemPort |
14. Rosen RC, Cappelleri JC, Smith MD, Lipsky J, Peña BM. 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: 319–326. | Article | PubMed | ISI | ChemPort |
15. American Diabetes Association. Standards of medical care in diabetes—2008. Diabetes Care 2008; 31: S12–S54. | Article |
16. Du XL, Edelstein D, Dimmeler S, Ju Q, Sui C, Brownlee M. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest 2001; 108: 1341–1348. | Article | PubMed | ISI | ChemPort |
17. Siu SC, Lo SK, Wong KW, Ip KM, Wong YS. Prevalence of and risk factors for erectile dysfunction in Hong Kong diabetic patients. Diabet Med 2001; 18: 732–738. | Article | PubMed | ISI | ChemPort |
18. Burchardt M, Burchardt T, Baer L, Kiss AJ, Pawar RV, Shabsigh A et al. Hypertension is associated with severe erectile dysfunction. J Urol 2000; 164: 1188–1191. | Article | PubMed | ISI | ChemPort |
19. Wein AJ, Van Arsdalen K. Drug induced male sexual dysfunction. Urol Clin North Am 1988; 15: 23. | PubMed | ISI | ChemPort |
20. Francis ME, Kusek JW, Nyberg LM, Eggers PW. The contribution of common medical conditions and drug exposures to erectile dysfunction in adult males. J Urol 2007; 178: 591–596. | Article | PubMed |
21. Hale TM, Okabe H, Bushfield TL, Heaton JP, Adams MA. Recovery of erectile function after brief aggressive antihypertensive therapy. J Urol 2002; 168: 348–354. | Article | PubMed | ISI | ChemPort |
22. Thomas DR. Medications and sexual function. Clin Geriatr Med 2003; 19: 553–562. | Article | PubMed |
23. Solomon H, Samarasinghe YP, Feher MD, Man J, Rivas-Toro H, Lumb PJ et al. Erectile dysfunction and statin treatment in high cardiovascular risk patients. Int J Clin Pract 2006; 60: 141–145. | Article | PubMed | ChemPort |
24. Pinnock CB, Stapleton AM, Marshall VR. Erectile dysfunction in the community: a prevalence study. Med J Aust 1999; 171: 353–357. | PubMed | ISI | ChemPort |
25. Roumeguère T, Wespes E, Carpentier Y, Hoffmann P, Schulman CC. Erectile dysfunction is associated with a high prevalence of hyperlipidemia and coronary heart disease risk. Eur Urol 2003; 44: 355–359. | Article | PubMed | ISI |
26. Pedersen TR, Olsson AG, Faergeman O, Kjekshus J, Wedel H, Berg K et al. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation 1998; 97: 1453–1460. | PubMed | ChemPort |
27. Rosen RC, Cappelleri JC, Gendrano III N. The International Index of Erectile Function (IIEF): a state-of-the-science review. Int J Impot Res 2002; 14: 226–244. | Article | PubMed | ISI | ChemPort |
28. Fedele D, Coscelli C, Cucinotta D, Forti G, Santeusanio F, Viaggi S et al. Incidence of erectile dysfunction in Italian men with diabetes. J Urol 2001; 166: 1368–1371. | Article | PubMed | ISI | ChemPort |