Association of Glycemic Control with Risk of Erectile Dysfunction in Men with Type 2 Diabetes

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Association of Glycemic Control with Risk of Erectile Dysfunction in Men with Type 2 Diabetes jsm_1219

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Chih-Chen Lu, MD,*§¶ Bang-Ping Jiann, MD,†¶ Chun-Chin Sun, MD,§¶ Hing-Chung Lam, MD,§¶ Chih-Hsun Chu, MD,§¶** and Jenn-Kuen Lee, MD‡§¶ *Department of Internal Medicine, Division of General Medicine, †Department of Surgery, Division of Urology, ‡ Department of Pathology and Laboratory Medicine, Division of Biochemistry, §Department of Internal Medicine, Division of Endocrinology and Metabolism, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; ¶Internal Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; **Department of Rehabilitation Technology, TzuHui Institute of Technology, Pingtung, Taiwan DOI: 10.1111/j.1743-6109.2009.01219.x

ABSTRACT

Introduction. Improvement in glycemic control is likely to reduce the risk of diabetic complication, while its effect on erectile dysfunction (ED) remains unclear. Aim. The aim of this study was to evaluate the association of glycemic control with risk of ED in type 2 diabetics. Methods. A self-administered questionnaire containing Sexual Health Inventory for Men was obtained from 792 subjects with type 2 diabetes at our institution. Clinical data were obtained through chart review. Main Outcome Measures. The contribution of glycemic control assessed by glycated hemoglobin (HbA1c) level as well as age, duration of diabetes, hypertension (HT), dyslipidemia, and cigarette smoking to risk of ED was evaluated. Results. Of 792 subjects, 83.6% reported having ED and 43.2% had severe ED. HbA1c level (%) adjusted for age and duration of diabetes was significantly associated with ED (OR 1.12, 95% CI: 1.01–1.25). None of HT, dyslipidemia, and cigarette smoking was a significant risk factor for ED after adjusted for age and duration of diabetes. HbA1c level, age, and duration of diabetes were significant independent risk factors for ED among the younger group (age ⱕ 60 years), and only age and duration of diabetes were independent risk factors among the older group (age > 60 years). For the risk of severe ED, compared with no and mild to moderate ED, HbA1c level, duration of diabetes, and HT were independent risk factors among the younger group, and only age was an independent factor among the older group. Conclusions. Better glycemic control probably would reduce the prevalence of ED and its severity among the younger men with type 2 diabetes. For the older group, aging was the major determinant for ED risk among this population with type 2 diabetes. Lu C-C, Jiann B-P, Sun C-C, Lam H-C, Chu C-H, Lee J-K. Association of glycemic control with risk of erectile dysfunction in men with type 2 diabetes. J Sex Med 2009;6:1719–1728. Key Words. Glycemic Control; Type 2 Diabetes; Erectile Dysfunction; Glycated Hemoglobin; Vascular Risk Factors

Introduction

E

rectile dysfunction (ED) is defined as a persistent inability to achieve or maintain penile erection for satisfactory sexual intercourse [1]. ED has a negative impact on emotional well-being and is frequently associated with various comorbidities. Diabetes is one of the most common comorbidities. In our previous report, 20% of ED patients had diabetes [2]. Most of the diabetic ED

© 2009 International Society for Sexual Medicine

(DMED) is organic rather than psychogenic [3,4], and it develops insidiously over a period of months to years in diabetic patients [4]. Chronic hyperglycemia is a major initiator to cause microvascular complications of diabetes (retinopathy, neuropathy, and nephropathy) and macrovascular complications (coronary artery disease and stroke). Recently, several prospective clinical trials demonstrated that intensive glycemic control could substantially reduce microvascular J Sex Med 2009;6:1719–1728

1720 complications of diabetes, but the reduction in risk of macrovascular complications was of borderline significance or not clear [5–7]. Men with treated diabetes had more than three times the probability of having ED than men without diabetes [8]. Some observational studies demonstrated a poor glycemic control was associated with a higher risk of ED [9–11], but others did not [12–18]. Only a few investigations focused on the association of glycemic control and ED risk, and they were based on a small case number or used univariate analysis to evaluate the relation [11,19]. Glycated hemoglobin (HbA1c), an indicator of glycemia from the preceding 6 to 12 weeks [20], is a more accurate and stable measure than fasting blood glucose level in assessing long-term glycemic control [21]. In addition to diabetes by itself, the derangement of vasculopathy in diabetics is increased at the same time by exposure to other vascular risk factors including hypertension (HT), dyslipidemia, and cigarette smoking that are commonly present in men with diabetes [22]. All of these vascular risk factors lead to endothelial dysfunction and decrease bioavailability of nitric oxide (NO) [23], the principal mediator of penile erection [24]. Therefore, we conducted this study to assess the contribution of glycemic control assessed by HbA1c level, as well as HT, dyslipidemia, and cigarette smoking to the risk of ED in men with type 2 diabetes. Methods

Study Population The study subjects were based on the consecutive subjects who had visited the outpatient setting of our endocrinology unit for the treatment of diabetes from January 2004 to May 2006. A self-administered questionnaire composed of demographic data, and a Chinese version of Sexual Health Inventory for Men (SHIM) [25] was mailed to each of them. The nonrespondents to the mailed questionnaire would be further invited to answer the questionnaire if they had presented themselves in the outpatient setting during the period of June 2006 to May 2007. The total respondent rate was 23.7% (958/4,040). After excluding 94 subjects with SHIM scores inappropriate or inadequate for analysis, seven aged older than 85 years, three with type 1 diabetes, and 52 without data of HbA1c level available, a total of 792 subjects with type 2 diabetes were eligible for analysis in this study. The details of recruitment J Sex Med 2009;6:1719–1728

Lu et al. procedure and contents of the questionnaire have been described previously [26]. Their data of duration of diabetes and medications were obtained by chart review. Their latest data of blood pressure (BP) and laboratory data, including HbA1c levels and concentrations of serum low-density lipoprotein cholesterol (LDLC), high-density lipoprotein cholesterol (HDLC), and triglyceride (TG) were also obtained by chart review. The laboratory data were considered valid only those determined within 6 months before the investigation.

Definition of Vascular Risk Factors In addition to diabetes, vascular risk factors (HT, dyslipidemia, and cigarette smoking) were assessed for risk of ED. Cigarette smoking habit was categorized as never, former, or current smokers. HT was considered present if the subjects were taking anti-HT medication or had systolic BP ⱖ 140 or diastolic BP ⱖ 90 mm Hg. Dyslipidemia was defined as having one of the following: having anti-dyslipidemia medication, serum concentration of HDL-C < 40, LDL-C ⱖ 130, or TG ⱖ 150 mg/dL. This study was reviewed and approved by the Independent Review Board at our institution. Main Outcome Measures ED was classified according to the sum score of SHIM as 25–22 being no, 21–17 mild, 16–12 mild moderate, 11–8 moderate, and 7–1 severe ED. After adjusted for age of the subjects and duration of diabetes, odds ratio (OR) of ED was evaluated for HbA1c level, as well as vascular risk factors. The contribution of HbA1c level to ED was assessed with control of age, duration of diabetes, and vascular risk factors. For considering the aging effect on risk of ED, the analysis was further done among younger (age ⱕ 60 years) and older (age > 60 years) groups of the subjects. Statistical Analysis The data were analyzed by descriptive statistics. All the numeric data were expressed as mean ⫾ 1 standard deviation. Chi-square was used for trend test, and Kruskall–Wallis test for comparison of numeric variables without normal distribution. Multivariate logistic regression was used to adjust age and duration of diabetes for risk factor evaluation. Multivariate logistic regression was also applied to assess the contribution of the risk factors to ED. The level of significance was considered as P < 0.05.

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Association of Glycemic Control with ED 70

Prevalence of severe ED, %

60 50 40 30 20 10 0

27-40 (N = 22)

41-50 (N = 88)

51-60 (N = 61-70 (N = 162) 139) Age group, years

71-80 (N = 271)

81-85 (N = 110)

Figure 1 The distribution of prevalence of severe erectile dysfunction according to the age of the 792 subjects with type 2 diabetes.

Results

Of the 792 subjects, the mean age was 65.6 ⫾ 13.2 years (range 27–85; median 68), mean duration of diabetes was 9.0 ⫾ 7.5 years (range 1–39; median 7.0), and mean HbA1c level was 8.2 ⫾ 2.0% (range 4.3–17.5; median 7.7). Of them, 83.6% (662) reported having ED, with the severity of ED being mild in 15.5%, mild moderate 16.8%, moderate 8.1%, and severe 43.2%. The prevalence of severe ED in the age groups of below 61 years ranged below 20%, and it increased markedly in the age groups of over 60 years (Figure 1). The prevalence of severe ED was 14.4% (41/285) in the younger group and 59.4% (301/507) in the older group (P = 0.0000). According to the definition of HT, 67.2% (532/ 792) of the subjects had HT, with 48.9% having received anti-HT medication and 18.3% having no treatment. Those with HT had a significantly higher mean BP than those without; their mean systolic BP being 138 ⫾ 15 and 121 ⫾ 10 mm Hg, respectively (P = 0.000), and diastolic BP being 81 ⫾ 11 and 75 ⫾ 8 mm Hg, respectively (P = 0.000). Of the 792 subjects, 570 (78.0%) had dyslipidemia, while 113 (19.8%) received antidyslipidemia treatment and the rest 457 (80.2%) did not. Of the 457 subjects, 188 (41.1%) subjects’ lipid profiles met the treatment criteria as LDLC ⱖ 130 mg/dL or as TG ⱖ 200 mg/dL and HDL-C < 40 mg/dL. Of the 188 subjects, 26 (13.8%) had LDL-C ⱖ 160 mg/dL, 100 (53.2%) had LDL-C ⱖ 130 but <160 mg/dL, and 62 (33.0%) had TG ⱖ 200 and LDL-C < 130 mg/ dL. Mean LDL-C in those with dyslipidemia and those without was 110 ⫾ 31 and 103 ⫾ 19 mg/dL, respectively (P = 0.049); HDL-C was 37 ⫾ 8 and 48 ⫾ 7 mg/dL, respectively (P = 0.000); and TG was 173 ⫾ 116 and 88 ⫾ 29 mg/dL, respectively (P = 0.000).

The distributions of age, duration of diabetes, HbA1c level, HT, dyslipidemia, and cigarette smoking according to the presence of ED in the 792 subjects were listed in Table 1. The prevalence of ED was positively correlated with subjects’ age and duration of diabetes (chi-square trend test for both, P = 0.000). There was a trend that a higher HbA1c level was associated with a higher risk of ED with borderline significance (chi-square trend test, P = 0.059). The ORs of ED for risk factors, including HbA1c level, HT, dyslipidemia, and cigarette smoking after adjusted for age and duration of diabetes, are displayed in Table 2. Only HbA1c level was significantly associated with risk of ED. The prevalence of ED was 66.7% (190/285) in the younger group, and 93.1% (472/507) in the older group, P = 0.000. Those with ED had a significantly higher mean HbA1c level than those without ED in the younger group (8.8 ⫾ 2.2 vs. 7.9 ⫾ 2.0%, P = 0.0009), while there was no significant difference in mean HbA1c level between those with and without ED in the older group

Table 1 Distribution of selected risk factors in the 792 subjects with type 2 diabetes according to the presence of erectile dysfunction Variable Age (years) 27–45 (N = 67) 46–55 (N = 139) 56–65 (N = 161) 66–75 (N = 159) 76–85 (N = 266) Chi-square for linear trend Duration of diabetes (years) 0–5 (N = 337) 6–10 (N = 194) 11–15 (N = 110) >15 (N = 150) Chi-square for linear trend Serum HbA1c level (%) 4.3–6.0 (N = 67) 6.1–7.0 (N = 175) 7.1–9.0 (N = 313) >9.0 (N = 237) Chi-square for linear trend Hypertension No (N = 260) Yes (N = 532) Dyslipidemia No (N = 222) Yes (N = 570) Cigarette smoking status Never (N = 327) Former (N = 289) Current (N = 165)

Prevalence of ED (%) 52.2 67.6 82.6 91.8 95.5 Age group, yrs

OR of ED (95% CI) 1.00 1.91 4.34 10.27 19.35 102.12

(1.05–3.47) (2.31–8.15) (4.89–21.58) (9.13–41.04) (P = 0.000)

73.6 88.7 89.1 95.3

1.00 2.81 2.93 7.33 39.32

(1.69–4.65) (1.54–5.59) (3.31–16.26) (P = 0.000)

77.6 81.1 84.3 86.1

1.00 1.24 1.55 1.78 3.57

(0.62–2.47) (0.81–2.98) (0.90–3.53) (P = 0.059)

77.7 86.5

1.00 1.83 (1.25–2.69)

84.7 83.2

1.00 0.89 (0.58–1.37)

83.2 85.8 80.6

1.00 1.22 (0.79–1.90) 0.84 (0.52–1.36)

ED = erectile dysfunction; OR (95% CI) = odds ratio (95% confidence interval).

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Table 2 Odds ratio of erectile dysfunction for risk factors including HbA1c level, cigarette smoking, dyslipidemia, and hypertension adjusted for age and duration of diabetes in the 792 subjects with type 2 diabetes Variables

OR of ED* (95% CI)

P value

HbA1c level (%) Hypertension No Yes Dyslipidemia No Yes Cigarette smoking status Never Former Current

1.12 (1.009–1.25)

0.034

1.00 1.04 (0.67–1.60)

0.86

1.00 1.08 (0.67–1.73)

0.74

1.00 1.26 (0.77–2.05) 1.55 (0.90–2.65)

0.35 0.11

*Adjusted for age and duration of diabetes. ED = erectile dysfunction; OR (95% CI) = odds ratio (95% confidence interval).

(8.0 ⫾ 1.8 vs. 8.1 ⫾ 2.0%, P = 0.63). The contribution of HbA1c, HT, dyslipidemia, cigarette smoking, age, and duration of diabetes to risk of ED, based on multivariate logistic regression, is described in Table 3. It shows that in the younger group, HbA1c, age, and duration of diabetes were significant independent risk factors for ED, and in the older group, only age and duration of diabetes were so (Table 3). The mean HbA1c level was significantly higher in those with severe ED than those without severe ED among the younger group (9.6 ⫾ 2.3 vs. 8.3 ⫾ 2.1%, P = 0.0002). The mean HbA1c level did not show significant difference between those with severe ED and those without among the older group (8.0 ⫾ 1.9 vs. 8.0 ⫾ 1.7%, P = 0.99). HbA1c level, duration of diabetes, and HT were signifi-

cant independent risk factors for severe ED, compared with non- or mild to moderate ED, in the younger group, while only age was so in the older group (Table 4). Discussion

This study showed that glycemic control was a risk factor, while other vascular risk factors (HT, dyslipidemia, and cigarette smoking) had less significance, for ED in type 2 diabetics. Previous studies showed inconsistent results about these factors in DMED. Glycemic control was reported to be a significant [9–11], a borderline [13,14], or an insignificant [12,15–18] risk factor for DMED. HT was reported as a risk factor for DMED in some [10,16], but not in other studies [13,14,17,18]; hyperlipidemia in some [10], but not in other studies [14,17]; and cigarette smoking similarly in some [10,16], but not in others [13,15,18]. Most of these studies adopted multivariate analysis for risk factor assessment, and included a great diversity of covariates such as demographic data, treatment of diabetes, biochemical data, and complications of diabetes, etc. They used automatic or semiautomatic strategies to select covariates for model building rather than pathological reasoning, and this might lead to biased results [27]. The present study evaluated glycemic control and covariates of other vascular risk factors, as well as age and duration of diabetes for ED risk. It demonstrated that in men with type 2 diabetes, glycemic control was associated with risk of ED

Table 3 Contribution of HbA1c and other risk factors to risk of erectile dysfunction among the younger and the older groups of the 792 subjects with type 2 diabetes (based on multivariate logistic regression) The younger group (age ⱕ 60 years)

Total subjects OR of ED (95% CI) Age (yrs) Duration of diabetes (years) HbA1c (%) Hypertension, yes/no Dyslipidemia, yes/no Former/Never smoker Current/Never smoker

1.08 (1.06–1.10) 1.06 (1.02–1.11) 1.13 (1.02–1.27) 1.05 (0.68–1.65) 1.05 (0.64–1.70) 1.24 (0.76–2.03) 1.51 (0.88–2.61)

P value 0.000 0.003 0.026 0.82 0.86 0.39 0.13

ED = erectile dysfunction; OR (95% CI) = odds ratio (95% confidence interval).

J Sex Med 2009;6:1719–1728

OR of ED (95% CI) 1.06 (1.02–1.10) 1.06 (1.001–1.12) 1.21 (1.06–1.39) 0.96 (0.56–1.64) 1.07 (0.56–2.02) 1.34 (0.71–2.55) 1.47 (0.78–2.78)

The older group (age > 60 years) P value 0.002 0.045 0.004 0.88 0.85 0.37 0.24

OR of ED (95% CI) 1.07 (1.02–1.13) 1.07 (1.01–1.14) 0.93 (0.77–1.13) 1.33 (0.60–2.95) 1.21 (0.55–2.64) 1.17 (0.54–2.54) 1.93 (0.60–6.18)

P value 0.009 0.019 0.48 0.49 0.63 0.69 0.27

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Association of Glycemic Control with ED Table 4 Contribution of HbA1c and other risk factors to risk of severe erectile dysfunction in the younger and older groups of the 792 subjects with type 2 diabetes (based on multivariate logistic regression)

Age (years) Duration of DM (years) HbA1c (%) Hypertension, yes/no Dyslipidemia, yes/no Former/Never smoker Current/Never smoker

The younger group (age ⱕ 60 years)

The older group (age > 60 years)

OR of severe ED* (95% CI)

OR of severe ED* (95% CI)

1.03 (0.97–1.09) 1.09 (1.03–1.16) 1.27 (1.09–1.49) 2.68 (0.64–1.53) 0.65 (0.28–1.55) 0.75 (0.30–1.88) 1.50 (0.64–3.52)

P value 0.37 0.003 0.003 0.015 0.34 0.53 0.36

1.08 (1.05–1.11) 1.02 (0.99–1.04) 1.02 (0.92–1.13) 0.99 (1.21–5.93) 1.23 (0.82–1.84) 1.02 (0.69–1.53) 1.55 (0.87–2.76)

P value 0.000 0.14 0.73 0.96 0.32 0.91 0.13

*OR of severe ED compared with other severities of ED and non-ED. ED = erectile dysfunction; OR (95% CI) = odds ratio (95% confidence interval).

and its severity among the younger group, but not so in the older group, where aging was the crucial determinant for ED and its severity in this population. Except HT that was associated with risk of severe ED among the younger group, the other vascular risk factors were not major risk factors for ED in type 2 diabetics.

Chronic Hyperglycemia Either by generating toxic and reactive metabolites or altering intracellular signaling pathways, chronic hyperglycemia induces derangement on vascular and neuronal cells including hemodynamic alteration, endothelial dysfunction, activation of inflammatory cells, and a change in the expression of vascular and neurotrophic factors. These changes are tissue specific according to the needs of local physiology [28]. For example, the injury to periocytes by hyperglycemia is a disaster for the integrity of capillaries in retina or peripheral nerve. In contrast, the loss of periocytes in other peripheral capillaries is probably not pathologically important, because they are outnumbered by endothelial cells and have less crucial role in maintaining vascular integrity [29]. Many clinical observational studies and laboratory investigations provided direct and indirect evidence that neuropathy, and micro- and macro-vasculopathy were the principal pathways of DMED [22]. Endothelial Dysfunction and Advanced Glycation End Products (AGEs) Among the hyperglycemia-induced biological and biochemical changes, endothelial dysfunction and

AGEs play key roles to affect DMED. Persons with type 2 diabetes have an early-altered endothelial function [30]. The endothelium controls the tone of underlining vascular smooth muscle through the production of some mediators including NO [31], which plays a key role in penile erection. Endothelial dysfunction the “functional atherosclerosis” will become “morphological atherosclerosis” in decades [32]. And atherosclerosis is the most common organic cause for ED [33]. AGEs are a heterogenous group of moieties formed by nonenzymatic and irreversible bindings between reducing sugar (such as glucose) and amino group in proteins, lipids, or nucleic acids [34]. AGEs formation occurs during normal aging process, and is markedly accelerated in hyperglycemic condition [35,36]. AGEs are suggested to induce many pathological effects at the tissue and cellular levels [20]. They play an important role in the development of endothelial dysfunction [37], and can quench NO in vitro [38]. Accumulation of AGEs in connective tissue would result in increased vascular rigidity [31]. Seftel et al. found a significant elevation of pentosidine (one of AGEs) in penile tissue of diabetic patients [39], and pentosidine level in penile tissue was positively correlated with increasing age [40].

Glycemic Control and Aging The effects of intensive glucose control on microvascular and macrovascular complications in type 2 diabetes from the three large prospective randomized clinical trials (UK Prospective Diabetes Study [UKPDS] 33, ADVANCE, and J Sex Med 2009;6:1719–1728

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Table 5 Summary of the three prospective randomized clinical trials on effects of intensive glucose lowering in type 2 diabetes

Age at baseline* (years) Duration of diabetes at baseline (years) HbA1c at baseline* (%) Target of glucose control Intensive Standard or conventional Follow-up interval† (years) HbA1c during follow-ups† (%) Intensive Standard or conventional Effects of intensive blood glucose control, RR (95% CI) Death from all causes Microvascular complications Macrovascular complications

UKPDS 33 [5] (N = 3,867)

ADVANCE [6] (N = 11,140)

ACCORD [7] (N = 10,251)

53 ⫾ 9 Newly diagnosed 7.1 ⫾ 1.5

66 ⫾ 6 8 ⫾ 6* 7.5 ⫾ 1.6

62 ⫾ 7 10† 8.3 ⫾ 1.1

FPG < 108 mg/dL FPG < 270 mg/dL 10.0

HbA1c < 6.5% HbA1c < 7.0% 5.0

HbA1c < 6.0% HbA1c 7.0–7.9% 3.4

6.3 7.0

6.4 7.5

0.93 (0.83–1.06) 0.86 (0.77–0.97) 0.94 (0.84–1.06)§

1.22 (1.01–1.46) Not available 0.90 (0.78–1.04)§

7.0 7.9 0.94 (0.80–1.10) 0.75 (0.60–0.93) 0.84 (0.71–1.00)‡ 1.11 (0.81–1.51)¶

*Mean ⫾ SD. † Median. ‡ Myocardial infarction (fatal and nonfatal). §Nonfatal myocardial infarction or nonfatal stroke or death from cardiovascular causes. ¶ Stroke (fatal and nonfatal). FPG = fasting plasma glucose; RR (95% CI) = relative risk (95% confidence interval).

ACCORD) are summarized in Table 5. Although the effects on ED were not investigated in those trials, it seemed possible that improved glycemic control would reduce risk of ED in diabetic men. However, there was paucity of prospective trial to support this assumption. A pilot study performed by Yaman et al. showed no improvement of International Index of Erectile Function score in men with DMED after HbA1c level was reduced from 8.9 to 6.6% in 6 months [41]. Because some changes induced by hyperglycemia such as the accumulation of AGEs were irreversible, this might be the reason why erectile function could not be reversed by a better glycemic control. But it did not mean that a tighter glycemic control could not prevent or reduce the risk of ED. A 10-year posttrial follow-up [42] of the UKPDS trial [5] showed that intensive glucose control group had a significant reduction for any diabetic-related end point including myocardial infarction and death from all causes than conventional group did. The posttrial follow-up of UKPDS supported early aggressive lowering of glucose in type 2 diabetes had protective effects in not only microvascular, but also macrovascular complications. This result contradicted those from the ADVANCE [6] and ACCORD [7] trials, and one of the differences among them was that the subjects in UKPDS were newly diagnosed diabetic patients, while in the other two were those having had diabetes for several years already. ED is an age-dependent disorder that is accelerated an average 10–15 years earlier in diaJ Sex Med 2009;6:1719–1728

betic men than in general population [22]. The “Cologne Male Survey” found that among the general population, the prevalence of ED increased linearly in the age groups from 30 to 59 years, while the age groups from 60 upward showed an exponential increase in prevalence [43]. Grimm et al. noted that for men with HT, the rate of having erectile problem was relatively constant from 45 to 60 years of age, while it substantially rose up in men older than 60 years [44]. It was compatible with our result that the prevalence of severe ED also surged in the diabetic subjects older than 60 years (Figure 1). This prompted us to perform age-stratified analysis. The results demonstrated that glycemic control was more important to risk of ED among younger diabetic subjects than the older ones. It might indicate that when the aging process (induced by normal aging process and accelerated by diabetes itself) achieved some level, glycemic control became less crucial than aging was to risk of ED. However, mean HbA1c level of our subjects was around 8.2%, and was higher than that of standard (7.0%) [45] and of intensive glycemic control (<6.5%). UKPDS 35 reported that any improvement in glycemic control across the diabetic range was likely to reduce the risk of diabetic complications [46]. If our subjects had a better control of hyperglycemia from the beginning, the prevalence of ED might be lower than that of our observation in this study. This finding and assumption warrant confirmation through a prospective study.

Association of Glycemic Control with ED

BP Virag et al. found that diabetes was a stronger factor to induce arterial impairment than other isolated arterial risk factors, including HT, hyperlipidemia, and cigarette smoking [47]. Our results also showed that the weight of other vascular risk factors (e.g., HT, dyslipidemia, or cigarette smoking) could not compare with diabetes itself for the risk of DMED. HT is associated with a higher risk of ED in general population [8]. In the present study, HT was shown to increase risk of ED at first (Table 1). But after adjusted for age and duration of diabetes, HT became an insignificant factor for risk of ED in the younger and older groups (Tables 2 and 3), except that for severe ED in the younger group (Table 4). These results, plus that severe ED in the younger group was less common (prevalence rate 14.4%), might suggest that the influence of aging and diabetes was not so strong for risk of severe ED in the younger group and, therefore, HT shared a significant contribution for its occurrence in them. Another point was that our study subjects did not have adequate control of BP, as mean BP value (138/81 mm Hg) of those with HT was higher than the recommended value for diabetic patients (<130/80 mm Hg) [45] and than that of the subjects without HT (121/75 mm Hg). Evidences indicated that a tighter control of BP could reduce diabetic complications [48,49]. However, of those receiving anti-HT medication, only few could achieve the recommended value [50,51]. It was assumed that suboptimal control of BP might also contribute to the formation of severe ED in the younger group. Dyslipidemia Increase of LDL-C level would affect NO and decrease blood flow [52]. A higher level of total cholesterol, as well as a lower level of HDL-C, is a risk factor for ED [53]. In the subjects with type 2 diabetes, dyslipidemia did not play a significant role in the risk of ED. Based on our finding that there was no significant difference in the levels of LDL-C between those with and without dyslipidemia, it seemed easier to control high LDL-C than to control BP or glycemia. However, 62.6% (188/301) of the subjects did not receive antidyslipidemia treatment, although their lipid profiles met the criteria for treatment. This low treatment rate was possibly attributed to: (i) the physicians’ attitude such as putting priority on glucose control and preferring lifestyle modulation at first to medical treatment; (ii) poor moti-

1725 vation of patients to take more medication for comorbidities of diabetes; (iii) some patients being unsuitable for medication, such as having impaired liver function; and (iv) restriction of medical expense from Health Insurance Bureau of Taiwan.

Cigarette Smoking Cigarette smoking increases AGEs formation [54] and decreases bioavailability of NO [55], and was reported to increase ED risk in diabetic men [56]. But Mirone et al. reported that the association between cigarette smoking and ED risk disappeared when the subjects had a history of any cardiovascular disease, HT, diabetes, or neuropathy [57]. Our results also demonstrated that cigarette smoking was not a major risk factor for ED in men with type 2 diabetes. However, the ORs for ED or severe ED for current smokers were more deviated to the right side than never or former smokers, although there was no statistical significance (Tables 3 and 4). Limitations The low respondent rate in our study was a limitation that might make the prevalence of ED overestimated especially in the young subjects. We have reported this previously [26]. The study population from a medical center possibly possessed a more serious medical condition and might not be able to represent a diverse population of type 2 diabetes. This study was a cross-sectional observation that provided less convincing results. Another problem was that the analysis on the association of the numeric variables (e.g., HbA1c level, age, and duration of diabetes) with the risk of ED was based on the assumption of the presence of a linear relationship between them, while this was not necessarily true. We used cut points to define HT and dyslipidemia as categorical variables to assess the effect of BP and lipid profile on ED risk, and this might also result in biased estimates and P values. And we used single measurement of risk factors to evaluate their association with ED. A single measurement cannot reflect a long-term condition. Nevertheless, “regression dilution bias” was likely to be introduced and led to underestimation of the strength of the risk factors in results [58]. Therefore, the association of risk factors with ED we estimated might be underestimated than real conditions. Besides, our number of study subjects was not small. Furthermore, we used validated SHIM score to evaluate ED, and took more consideration of the impact of aging and duration of diabetes on ED risk. J Sex Med 2009;6:1719–1728

1726 Conclusions

Among subjects with type 2 diabetes, glycemic control was associated with ED risk and its severity among the younger group, while for the older group, aging was the most important risk factor. Except that HT was associated with risk of severe ED in younger type 2 diabetics, HT and dyslipidemia under supervision of physicians were not major risk factors for ED, and neither was cigarette smoking. But current smokers possessed a higher OR for ED in spite of no statistical significance. A tight control of glycemia and comorbidities in early stage of diabetes might delay the occurrence of ED and its severity. Acknowledgments

This study was supported by a grant from our institution VGHKS96-039, and an independent grant from Pfizer, Inc., IRG No.: 200607. Corresponding Author: Bang-Ping Jiann, MD, Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, 386 Ta-Chung 1st Road, Kaohsiug 813, Taiwan. Tel: 886-7-3422121 ext 3010; E-mail: [email protected] Conflict of Interest: None declared.

Statement of Authorship

Category 1 (a) Conception and Design Bang-Ping Jiann; Chih-Chen Lu (b) Acquisition of Data Chih-Chen Lu; Chun-Chin Sun; Hing-Chung Lam; Chih-Hsun Chu; Jenn-Kuen Lee (c) Analysis and Interpretation of Data Bang-Ping Jiann

Category 2 (a) Drafting the Article Bang-Ping Jiann; Chih-Chen Lu (b) Revising It for Intellectual Content Bang-Ping Jiann; Chih-Chen Lu

Category 3 (a) Final Approval of the Completed Article Bang-Ping Jiann; Chih-Chen Lu; Jenn-Kuen Lee

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