ORIGINAL ARTICLE Determinants of erectile dysfunction in type 2 diabetes

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1 (2010) 22, & 2010 Nature Publishing Group All rights reserved /10 $ ORIGINAL ARTICLE Determinants of erectile dysfunction in type 2 diabetes F Giugliano 1, M Maiorino 2, G Bellastella 2, M Gicchino 2, D Giugliano 2 and K Esposito 2 1 Division of Urology, Department of Geriatrics and Metabolic Diseases, Second University of Naples, Naples, Italy and 2 Division of Diabetology and Metabolic Diseases, Department of Geriatrics and Metabolic Diseases, Second University of Naples, Naples, Italy 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 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. (2010) 22, ; doi: /ijir ; 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 years earlier, 3 is more severe and associated with a poorer quality of life, 5 and is less responsive to oral treatment 6 than nondiabetic Correspondence: Dr K Esposito, Department of Geriatrics and Metabolic Diseases, Second University of Naples, Piazza L. Miraglia, Naples, Italy. Katherine.esposito@unina2.it 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 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

2 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 Study 17,18 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 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 ,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 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. 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 205

3 206 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). 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 Results 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, Table 1 Demographic, lifestyle, and clinical characteristics of type 2 diabetic men at baseline Variable 555 Diabetic men Age (years) 57.9± (9.5) (23.1) (67.4) BMI (kg m 2 ) 29.5±4.8 Waist (cm) 103.3±11.7 WHR 0.94±0.09 Duration of diabetes in years (mean) 4.9±1.5 HbA1c (%) 8.4±1.3 Patients with HbA1c 47% 396 (71.3) Glucose (mg dl 1 ) Fasting 150±34 Post-meal (120 min) 189±45 Fasting insulin (muml 1 ) 13±5 Metabolic syndrome, n (%) 386 (69.5) Hypertension, n (%) 316 (56.9) Smoking status, n(%) Never 199 (35.8) Past 242 (44.0) Present 111 (20.0) Physical activity (METs/week) 11.7±7.8 Lipids (mg dl 1 ) Total cholesterol 204±36 HDL-cholesterol 44±9 Triglycerides 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 (35 45) (46 55) (56 70) Total P-value N ¼ 53 N ¼ 128 N ¼ 374 N ¼ 555 ED severity No ED (score 421) 50 (94.3) 70 (54.6) 102 (27.2) 222 (40) 0.01 Mild ED (score 21 17) 35 (66) 12 (9) 3 (0.8) 50 (9) 0.01 Mild to moderate ED (score 16 12) 7 (13.2) 25 (19.5) 30 (8.0) 62 (11.2) 0.45 Moderate ED (score 11 7) 1 (1.8) 33 (25.7) 60 (16.0) 94 (16.9) 0.16 Severe ED (score 7 1) 2 (3.7) 17 (13.2) 108 (28.8) 127 (22.9) Treatment seeking Consulted doctor 237 (42.7) Used ED medications 180 (32.4) Data are by numbers and (%).

4 Table 3 Contribution of HbA1c and other risk factors to risk of ED in the diabetic population (based on multivariate logistic regression) 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 , P ¼ 0.03). Discussion OR for ED 95% CI P-value 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) Cigarette smoking status Never 1.00 Past Current Physical activity (per MET) Depression (yes vs no) 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 marginal or null 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 hypertension 15 and obesity 16 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 States 24,28 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 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

5 208 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. 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