Determinants of erectile dysfunction in type 2 diabetes - Nature

International Journal of Impotence Research (2010) 22, 204–209 & 2010 Nature Publishing Group All rights reserved 0955-9930/10 $32.00

www.nature.com/ijir

ORIGINAL ARTICLE

Determinants of erectile dysfunction in type 2 diabetes F Giugliano1, M Maiorino2, G Bellastella2, M Gicchino2, D Giugliano2 and K Esposito2 1

Division of Urology, Department of Geriatrics and Metabolic Diseases, Second University of Naples, Naples, Italy and Division of Diabetology and Metabolic Diseases, Department of Geriatrics and Metabolic Diseases, Second University of Naples, Naples, Italy 2

This study was designed to evaluate the prevalence and correlates of ED in a population of diabetic men. Consecutive patients with type 2 diabetes were recruited among outpatients regularly attending Diabetes Clinics. Inclusion criteria for the initial selection of patients were a diagnosis of type 2 diabetes for at least 6 months but less than 10 years, age 35–70 years, body mass index (BMI) of 24 or higher, HbA1c of 6.5% or higher: a total of 555 (90.8%) of the 611 men were analyzed in this study. ED was assessed by the IIEF-5 instrument. Approximately, 6 in 10 men in our sample of diabetic men had varying degrees of erectile dysfunction: mild 9%, mild to moderate 11.2%, moderate 16.9% and severe 22.9%. The prevalence of severe ED increased with age. Higher hemoglobin A1c (HbA1c) levels were associated with ED; similarly, the presence of metabolic syndrome, hypertension, atherogenic dyslipidemia (low levels of HDL-cholesterol and high levels of triglycerides) and depression was associated with ED. Physical activity was protective of ED; men with higher levels of physical activity were 10% less likely to have ED as compared with those with the lowest level. In conclusion, among subjects with type 2 diabetes glycemic control and other metabolic covariates were associated with ED risk, whereas higher level of physical activity was protective. These results encourage the implementation of current medical guidelines that place intensive lifestyle changes as the first step of the management of type 2 diabetes. International Journal of Impotence Research (2010) 22, 204–209; doi:10.1038/ijir.2010.1; published online 11 February 2010 Keywords: epidemiology; erectile dysfunction; type 2 diabetes; glycemic control; metabolic comorbidities

Introduction ED is the persistent inability to achieve or maintain penile erection for satisfactory sexual intercourse.1 Diabetes is one of the most common comorbidities of ED. The prevalence of ED among diabetic men varies from 35 to 90%.2 In the Massachusetts male aging study,3 men with treated diabetes had more than three times the probability of having ED than men without diabetes; moreover, the annual, age-adjusted incidence of ED in diabetic men was twice than in nondiabetic men.4 ED in men with diabetes occurs 10–15 years earlier,3 is more severe and associated with a poorer quality of life,5 and is less responsive to oral treatment6 than nondiabetic

Correspondence: Dr K Esposito, Department of Geriatrics and Metabolic Diseases, Second University of Naples, Piazza L. Miraglia, Naples, Italy. E-mail: [email protected] Received 20 November 2009; revised 9 December 2009; accepted 9 December 2009; published online 11 February 2010

men with ED. In the recent multinational survey study Men’s Attitudes to Life Events and Sexuality, diabetic men rated their ED as more severe and debilitating than nondiabetic men and were more likely to seek professional help for their disorder.7 Chronic hyperglycemia represents the major biochemical abnormality in the diabetic patient and is supposed to have a role in both microvascular and macrovascular diabetic complications.8 However, there is still disagreement about the role of glycemic control as a risk factor for ED in diabetic men. Some observational studies have shown that a poor glycemic control, as reflected by higher values of glycated hemoglobin A1c (HbA1c), was associated with higher risk of ED,9–11 whereas other studies did not find an association.12–14 The reasons for these divergent results are not evident; however, diabetic men may be afflicted by a multitude of comorbidities, including hypertension, overweight or obesity, the metabolic syndrome, atherogenic dyslipidemia, cigarette smoking, autonomic neuropathy, and so on, all of which are by themselves risk factors for ED.11,15,16 Moreover, the different approaches used in the different studies, such as, although not limited to inappropriate sample

Erectile dysfunction in type 2 diabetes F Giugliano et al

size, and statistical analyses, may have contributed to these divergent results. This study was designed to evaluate the prevalence and correlates of ED in a population of diabetic men. The Campanian Post-prandial Hyperglycemia Study17,18 provided the opportunity to evaluate ED in the context of a large observational study of type 2 diabetic patients.

Methods Participants The rationale and preliminary data of the CAPRI (CAmpanian post-PRandIal hyperglycemia group) study have been published.17,18 In brief, consecutive patients of both sexes with type 2 diabetes were recruited among outpatients regularly attending Diabetes Clinics located in the area of the Campania County, South Italy. Inclusion criteria for the initial selection of patients were; a diagnosis of type 2 diabetes for at least 6 months but less than 10 years, age 35–70 years, body mass index of 24 or higher, HbA1c of 6.5% or higher, treatment with diet or oral drugs. Criteria for exclusion were need for insulin use, concomitant chronic diseases, including kidney, liver and cardiovascular diseases, recent acute illness, or change in diet, treatment or lifestyle within the 3 months before the initial assessment. The study was approved by the Institutional Committee of Ethical Practice of our institution, and all participants gave informed written consent. After the initial screening visit, with verification of inclusion and exclusion criteria, patients were invited to follow their usual treatment and eat their usual diet during the month. All patients were invited to the reference center (Department of Geriatrics and Metabolic Diseases at the Second University of Naples) for blood sampling and any other centralized assessment. A total of 1290 patients (611 men and 659 women) were invited to complete a food-frequency questionnaire, as well as self-report measures of sexual dysfunction and urological complications (that is, bladder dysfunction and urinary tract infections). A total of 555 (90.8%) of the 611 men completed both questionnaires and were analyzed in this study. Assessment of sexual function Erectile function was assessed by completing the IIEF-5 which consists of Items 5, 15, 4, 2 and 7 from the full-scale IIEF-15.19,20 The abbreviated score was used for its simplicity and immediacy. ED was classified according to the sum score: a score of 21 or less indicates the presence of ED: mild ED (score 21– 17), mild to moderate ED (score 16–12), moderate ED (score 11–8), and severe ED (score 7–1). In addition, participants were asked whether or not they had sought medical help for their ED problem and about previous use of medical treatments for ED.

Anthropometric measures and laboratory analyses Height and weight were measured to the nearest 0.5 cm and 100 g, respectively, with participants wearing lightweight clothing and no shoes. Body mass index was calculated as weight (in kilograms) divided by standing height (in meters squared). Waist-to-hip ratio was calculated as the waist circumference in centimeters divided by the hip circumference in centimeters. Arterial blood pressure was measured three times, at the end of the physical examination with the subject in sitting position. Before blood pressure evaluation all participants were at least 15 min at rest. Patients whose average blood pressure levels were greater or equal to 140/90 mm Hg or who were under antihypertensive medication were classified as hypertensive. The diagnosis of the metabolic syndrome was done as recommended by the Adult Treatment Panel III for men:21 (1) abdominal adiposity as defined by a waist circumference of (1) 4102 cm; (2) low serum HDL-cholesterol (o40 mg dl–1); (3) high triglyceride levels (X150 mg dl–1); (4) elevated blood pressure as defined by a blood pressure of at least 130/85 mm Hg; and (5) abnormal glucose homeostasis as defined by a fasting plasma glucose concentration of X110 mg dl–1. The presence of at least three of the above criteria qualified for the diagnosis of metabolic syndrome. Atherogenic dyslipidemia was defined as the combination of triglyceride levels 4200 mg dl–1 and HDL-cholesterol levels o40 mg dl–1.22 For the ascertainment of physical activity status we used the International Physical Activity Questionnaire,23 as an index of weekly energy expenditure using frequency (times per week), duration (in minutes per time) and intensity of sports or other habits related to physical activity. Participants who did not report any physical activities were defined as sedentary. Physical activity was computed in metabolic equivalent tasks per week. Laboratory assessment was centralized. Blood glucose and serum lipids were measured by enzymatic assays in the hospital’s chemistry laboratory, HbA1c by nephelometry, and serum insulin by radioimmunoassay (Pharmacia, Milan, Italy). The interassay coefficient of variation was below 6% for all measurements. Fasting glucose is the mean of the two home blood glucose assessments.

205

Statistical analyses Descriptive statistics were used to characterize the study sample. Chi-square was used for trend test, and Kruskall–Wallis test for comparison of numeric variables without normal distribution. Multivariate analyses were used to characterize the association between the usual risk factors for ED while adjusting for covariates. Forward logistic regression models were tested, including ED status and medication as International Journal of Impotence Research

Erectile dysfunction in type 2 diabetes F Giugliano et al 206

dependent variables in the model. Correlation analyses were used to assess and control for the effect of collinearity. The final model was tested by means of the Holmer and Lemeshow goodness-of-fit test. All statistical analyses were performed using SPSS software (version 10.05, SPSS Inc, Chicago, IL, USA).

Results

the presence of metabolic syndrome, hypertension and atherogenic dyslipidemia was found to be associated with ED. The mean Hb1c level was significantly higher in diabetic patients with ED than those without ED (8.7±1.0% vs 7.9±0.9, P ¼ 0.01). Physical activity was protective of ED: men with higher levels of declared physical activity

Table 1 Demographic, lifestyle, and clinical characteristics of type 2 diabetic men at baseline

A total of 555 men (response rate 90.8%) completed the questionnaires. The sample that completed the survey did not differ on the variables at baseline compared with the 56 men who did not participate in the study. Table 1 shows the demographic and clinical characteristics of the study population. Most diabetic patients had HbA1c level higher than 7% which is now considered the cutoff point, below which good glycemic control may apply (24). The prevalence of metabolic syndrome, hypertension and atherogenic dyslipidemia was 69.5, 56.9 and 21.8%, respectively. ED characteristics of the sample are shown in Table 2. Approximately, 6 in 10 men in our sample of diabetic men had varying degrees of erectile dysfunction. Specifically, the severity of ED was mild in 9%, mild to moderate in 11.2%, moderate in 16.9% and severe in 22.9%. The prevalence of severe ED increased sharply in the older age group (about 23%). In addition, 42.7% of participants had consulted with a physician about their sexual problems, and 32.5% had used medications (PDE-5 inhibitors) in the recent past. The contribution of age, HbA1c, duration of diabetes, anthropometric characteristics, including body mass index and waist-to-hip ratio, metabolic syndrome, hypertension, atherogenic dyslipidemia, smoking status, physical activity, and depression score to risk of ED, based on multivariate logistic regression, is shown in Table 3. Age and higher HbA1c levels were associated with ED. Similarly,

Variable

555 Diabetic men 57.9±6.9 53 (9.5) 128 (23.1) 374 (67.4) 29.5±4.8 103.3±11.7 0.94±0.09 4.9±1.5 8.4±1.3 396 (71.3)

Age (years) 35–45 46–55 56–70 BMI (kg m–2) Waist (cm) WHR Duration of diabetes in years (mean) HbA1c (%) Patients with HbA1c 47% Glucose (mg dl–1) Fasting Post-meal (120 min)

150±34 189±45

Fasting insulin (mU ml–1) Metabolic syndrome, n (%) Hypertension, n (%)

13±5 386 (69.5) 316 (56.9)

Smoking status, n (%) Never Past Present

199 (35.8) 242 (44.0) 111 (20.0) 11.7±7.8

Physical activity (METs/week) –1

Lipids (mg dl ) Total cholesterol HDL-cholesterol Triglycerides

204±36 44±9 165±58

Atherogenenic dyslipidemia, n (%)

121 (21.8)

Abbreviations: BMI, body mass index; MET, metabolic equivalent task; WHR, waist-to-hip ratio. Data are presented as mean±s.d. or numbers and percent.

Table 2 ED severity by age groups in type 2 diabetic men

ED severity No ED (score 421) Mild ED (score 21–17) Mild to moderate ED (score 16–12) Moderate ED (score 11–7) Severe ED (score 7–1) Treatment seeking Consulted doctor Used ED medications Data are by numbers and (%).

International Journal of Impotence Research

(35–45)

(46–55)

(56–70)

Total

N ¼ 53

N ¼ 128

N ¼ 374

N ¼ 555

50 (94.3) 35 (66)

70 (54.6) 12 (9)

102 (27.2) 3 (0.8)

222 (40) 50 (9)

0.01 0.01

7 (13.2) 1 (1.8) 2 (3.7)

25 (19.5) 33 (25.7) 17 (13.2)

30 (8.0) 60 (16.0) 108 (28.8)

62 (11.2) 94 (16.9) 127 (22.9)

0.45 0.16 0.001

237 (42.7) 180 (32.4)

P-value

Erectile dysfunction in type 2 diabetes F Giugliano et al Table 3 Contribution of HbA1c and other risk factors to risk of ED in the diabetic population (based on multivariate logistic regression) OR for ED

95% CI

P-value

1.10 1.05 1.18 2.08

1.05–1.15 1.01–1.10 1.02–1.37 1.17–3.26

0.001 0.01 0.03 0.01

1.03 1.04 1.34 1.23

1.00–1.07 1.01–1.08 1.08–2.03 1.04–1.49

0.04 0.03 0.02 0.01

Cigarette smoking status Never Past Current

1.00 1.15 1.36

0.86–1.98 0.81–2-09

0.56 0.35

Physical activity (per MET) Depression (yes vs no)

0.90 1.09

0.77–0.98 1.02–1.19

0.04 0.03

Age (years) Duration of diabetes (years) HbA1c (per 1%) Metabolic syndrome (present vs absent) BMI (per kg m–2) WHR Hypertension (yes vs no) Atherogenic dyslipidemia (yes vs no)

were 10% less likely to have ED as compared with those with the lowest level. Finally, self-reported ED was positively associated with depression score (OR ¼ 1.09; 95% CI 1.02–1.19, P ¼ 0.03).

Discussion In this study, about 60% of our sample of more than 500 overweight diabetic men had some degree of ED of which 23% had severe or complete ED. Interestingly, nearly 40% of diabetic men had sought medical advice for sexual difficulties, and 32% had used PDE-5 inhibitors in the recent past. This study also showed that glycemic control, as assessed by HbA1c level, was a risk factor for ED in diabetic men. In previous studies, glycemic control was reported to be positively and significantly associated with ED,9–11,24 whereas in other studies it was of marginal25–27 or null12–14 significance. The reasons for these discrepancies among different observational studies are not readily apparent; apart from evident differences in sample size, the role of glycemic control as a risk factor for ED in diabetic men has been studied by adopting multivariate analysis strategy for most; the number and the diversity of covariates included in the model, as well as the way to select covariates for model building might have produced biased results. In a Chinese population of 792 diabetic men, for example, Lu et al.28 found that HbA1c level was a significant and independent risk factor for severe ED, compared with non- or mild-to-moderate ED, in the younger group (age p60 years), whereas only age was so in the older group (460 years). Advancing age and longer duration of diabetes have been consistently shown to increase the risk of ED,9,24,25 a finding that is confirmed by our data.

Hyperlipidemia characterized by high cholesterol and/or low HDL-cholesterol levels,9,29 hypertension15 and obesity16 are conditions that often coexist with diabetes; all may be independent risk factors for ED among diabetic men. It is noteworthy that in two population-based observational studies carried out in China and the United States24,28 on type 2 diabetic men, there was no significant association between circulating lipid levels (total cholesterol, LDLD-cholesterol, HDL-cholesterol and triglyceride) and the risk of ED, pointing to the apparent conclusion that dyslipidemia does not have a significant role in the risk of diabetic ED. In our study, we found that the presence of mixed dyslipidemia, the so called diabetic or atherogenic dyslipidemia, is a significant and independent risk factor for ED. This form of dyslipidemia is particularly present in the diabetic patient and is characterized by high triglyceride levels and low HDLcholesterol levels. In our sample, atherogenic dyslipidemia was present in 21% of diabetic men. Interestingly enough, features of atherogenic dyslipidemia represent two inclusion criteria for the diagnosis of metabolic syndrome,21 and metabolic syndrome is a risk factor for ED,30 an association also present in our diabetic population. A sedentary lifestyle, defined as spending less than 200 kcl day–1 on moderate to intense physical activity, has been shown to be associated with higher prevalence of ED in the general population,31 as well as in diabetic men.12 A recent assessment of the association between physical activity and ED comes from a meta-analysis of population-based studies showing the existence of a simple dose— response relationship, with higher physical activity conferring lower risks. The adjusted reduction of the risk of having ED was 58% for high activity and 37% for moderate activity, as compared with men with low physical activity.32 In the Look AHEAD (Action for Health in Diabetes),24 cardiorespiratory fitness was found to be protective of ED among the 373 diabetic men aged 45–75 years. In particular, fitness was measured by a symptom-limited graded exercise treadmill test to voluntary exhaustion; after adjustment for age and other covariates, men with greater fitness had a 39% lower risk of ED. In our study, men with higher levels of declared physical activity were 10% less likely to have ED as compared with those with the lowest level. It is interesting to note that previous interventional studies have already shown that physical activity is beneficial in reducing rates of ED in nondiabetic men.16,33–35 The results of our study should be interpreted in the context of several possible limitations. Its crosssectional nature does not allow us to make inference about cause and effect. In addition, there is a possibility that the therapeutic recommendations for the diabetic patients may somehow influence certain components of lifestyle, in a positive or

207


Erectile dysfunction in type 2 diabetes F Giugliano et al 208

negative way. Moreover, diabetic patients who care for their health may be those choosing a healthier lifestyle. Finally, as in most epidemiological studies, the potential for residual confounding by uncontrolled covariates is possible. Major strengths of this study include the use of validated measures of sexual dysfunction, and the relatively large number of subjects investigated. In conclusion, among subjects with type 2 diabetes glycemic control was associated with ED risk. Moreover, hypertension, overweight and the presence of metabolic syndrome or atherogenic dyslipidemia (a mix of high triglyceride and low HDL-cholesterol levels) were also independent risk factors for ED. Higher level of physical activity was protective. These results agree with, and encourage for implementation of current medical guidelines that put intensive lifestyle changes as the first step of the management of type 2 diabetes.36

Conflict of interest The authors declare no conflict of interest.

References 1 NIH Consensus Conference. Impotence NIH consensus development panel on impotence. JAMA 1993; 270: 83–90. 2 Malavige LS, Levy JC. Erectile dysfunction in diabetes mellitus. J Sex Med 2009; 6: 1232–1247. 3 Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinley JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts male aging study. J Urol 1994; 151: 54–61. 4 Johannes CB, Araujo AB, Feldman HA, Derby CA, Kleinman KP, McKinlay JB. Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massacusetts male aging study. J Urol 2000; 163: 460–463. 5 Penson DF, Latini DM, Lubek DP, Wallace KL, Henning JM, Lue TF. Do impotent men with diabetes have more severe erectile dysfunction and worse quality of life than the general population of impotent patients? Results from the Exploratory Comprehensive Evaluation of Erectile Dysfunction (ExCEED) Database. Diabetes Care 2003; 26: 1093–1099. 6 Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction: Sildenafil study group. N Engl J Med 1998; 338: 1397–1404. 7 Eardley I, Fisher W, Rosen RC, Niederberger C, Nadel A, Sand M. The multinational men’s attitudes to life events and sexuality study: the influence of diabetes on self-reported erectile function, attitudes and treatment seeking patterns in men with erectile dysfunction. Int J Clin Pract 2007; 61: 1446–1453. 8 Hidalgo-Tamola J, Chitaley K. Type 2 diabetes mellitus and erectile dysfunction. J Sex Med 2009; 6: 916–926. 9 Fedele D, Coscelli C, Santeusanio F, Bortolotti A, Chatenoud L, Colli E et al. Erectile dysfunction in diabetic subjects in Italy. Diabetes Care 1998; 21: 1973–1977. 10 Romeo JH, Seftel AD, Madhum ZT, Aron DC. Sexual function in men with diabetes type 2: association with glycemic control. J Urol 2000; 163: 788–791. 11 De Angelis L, Marfella R, Siniscalchi M, Marino L, Nappo F, Giugliano F et al. Erectile and endothelial dysfunction in type II diabetes: a possible link. Diabetologia 2001; 44: 1155–1160.


12 Zheng H, Fan W, Li G, Tam T. Predictors for erectile dysfunction among diabetics. Diabetes Res Clin Pract 2006; 71: 313–319. 13 Shiri R, Ansari M, Falah Hassani K. Association between comorbidity and erectile dysfunction in patients with diabetes. Int J Impot Res 2006; 18: 348–353. 14 Al-Hunayan A, Al. Mutar M, Kehinde EO, Thalib L, Al-ghorory M. The prevalence and predictors of erectile dysfunction in men with newly diagnosed type 2 diabetes mellitus. BIU Int 2007; 99: 130–134. 15 Seftel AD, Sun P, Swindle R. The prevalence of hypertension, hyperlipidemia, diabetes mellitus and depression in men with erectile dysfunction. J Urol 2004; 171: 2341–2345. 16 Esposito K, Giugliano F, Ciotola M, De Sio M, D’Armiento M, Giugliano D. Obesity and sexual dysfunction, male and female. Int J Impot Res 2008; 20: 358–365. 17 Esposito K, Giugliano D, Nappo F, Marfella R. Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus. Circulation 2004; 110: 214–219. 18 Esposito K, Ciotola M, Carleo D, Schisano B, Sardelli L, Di Tommaso D et al. Post-meal glucose peaks at home associate with carotid intima-media thickness in type 2 diabetes. J Clin Endocrinol Metab 2008; 93: 1345–1350. 19 Rosen RC, Cappelleri JC, Smith MD, Lipsky J, Pena 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. 20 Cappelleri JC, Rosen RC. The sexual health inventory for men (SHIM): a 5-year review of research and clinical experience. Int J Impot Res 2005; 17: 307–319. 21 Expert Panel on Detection Evaluation Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA 2001; 285: 2486–2497. 22 Grundy SM. Atherogenic dyslipidemia associated with metabolic syndrome and insulin resistance. Clin Cornerstone 2006; 8(1): S21–S27. 23 IPAQ Research Committee. Guidelines for data processing and analysis of the international physical activity questionnaire (IPAQ). International Physical Activity Questionnaire. Available at http://www.ipaq.ki.se. Last accessed 20 October 2009. 24 Wing RR, Rosen RC, Fava JL, Bahnson J, Brancati F, Gendrano III IN et al. Effects of weight loss intervention on erectile function in older men with type 2 diabetes in the look AHEAD trial. J Sex Med 2009; 6: 1414–1422. 25 Cho NH, Ahn CW, Park JY, Ahn TY, Lee HW, Park TS et al. Prevalence of erectile dysfunction in Korean men with type 2 diabetes mellitus. Diabet Med 2006; 23: 198–203. 26 Thomas GN, Tomlinson B, Abdullah AS, Yeung VT, Chan JC, Wong KS. Association of erectile dysfunction with cardiovascular risk factors and increasing existing vascular disease in male chinese type 2 diabetic patients. Diabetes Care 2005; 28: 2051–2053. 27 Sasaki H, Yamasaki H, Ogawa K, Nanjo K, Kawamori R, Iwamoto Y et al. Prevalence and risk factors for erectile dysfunction in Japanese diabetics. Diabetes Res Clin Pract 2005; 70: 81–89. 28 Lu CC, Jiann BP, Sun CC, Lam HC, Chu CH, Lee JK. Association of glycemic control with risk of erectile dysfunction in men with type 2 diabetes. J Sex Med 2009; 6: 1719–1728. 29 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. 30 Esposito K, Giugliano F, Marted E, Feola G, Marfella R, D’Armiento M et al. High proportions of erectile dysfunction in men with the metabolic syndrome. Diabetes Care 2005; 28: 1201–1203. 31 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.

Erectile dysfunction in type 2 diabetes F Giugliano et al 32 Cheng JYW, Ng EML, Chen RYL. Physical activity and erectile dysfunction: meta-analysis of population-based studies. Int J Impot Res 2007; 19: 245–252. 33 Rosen RC, Wing R, Schneider S, Gendrano IIIN. Epidemiology of erectile dysfunction. The Role of Medical Comorbidities and Lifestyle Factors. Urol Clin North Am 2005; 32: 403–417. 34 Esposito K, Ciotola M, Giugliano F, Maiorino MI, Autorino R, De Sio M et al. Effects of intensive lifestyle changes on erectile dysfunction in men. J Sex Med 2009; 6: 243–250.

35 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. 36 Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American diabetes association and the European association for the study of diabetes. Diabetes Care 2009; 32: 193–203.

209
