Brandy N. Rutledge

Effect of Glycemic Exposure on the Risk of Microvascular Complications in the Diabetes Control and Complications Trial—Revisited

OBJECTIVE— The Diabetes Control and Complications Trial (Diabetes 44:968–983, 1995) presented statistical models suggesting that subjects with similar A1C levels had a higher risk of retinopathy progression in the conventional treatment group than in the intensive treatment group. That analysis has been cited to support the hypothesis that specific patterns of glucose variation, in particular postprandial hyperglycemia, contribute uniquely to an increased risk of microvascular complications above and beyond that explained by the A1C level. RESEARCH DESIGN AND METHODS— We performed statistical evaluations of these models and additional analyses to assess whether the original analyses were flawed. RESULTS— Statistically, we show that the original results are an artifact of the assumptions of the statistical model used. Additional analyses show that virtually all (96%) of the beneficial effect of intensive versus conventional therapy on progression of retinopathy is explained by the reductions in the mean A1C levels, similarly for other outcomes. Furthermore, subjects within the intensive and conventional treatment groups with similar A1C levels over time have similar risks of retinopathy progression, especially after adjusting for factors in which they differ. CONCLUSIONS— A1C explains virtually all of the difference in risk of complications between the intensive and conventional groups, and a given A1C level has similar effects within the two treatment groups. While other components of hyperglycemia, such as glucose variation, may contribute to the risk of complications, such factors can only explain a small part of the differences in risk between intensive and conventional therapy over time.

Sexual Dysfunction in Women With Type 1 Diabetes: Long-term findings from the DCCT/ EDIC study cohort

OBJECTIVE This study aimed to investigate the prevalence and risk factors associated with sexual dysfunction in a well-characterized cohort of women with type 1 diabetes. RESEARCH DESIGN AND METHODS The study was conducted in women enrolled in the long-term Epidemiology of Diabetes Interventions and Complications (EDIC) study, a North American study of men and women with type 1 diabetes. At year 10 of the EDIC study, 652 female participants were invited to complete a validated self-report measure of sexual function, standardized history and physical examinations, laboratory testing, and mood assessment. RESULTS Of the sexually active women with type 1 diabetes in the EDIC study, 35% met criteria for female sexual dysfunction (FSD). Women with FSD reported loss of libido (57%); problems with orgasm (51%), lubrication (47%), and arousal (38%); and pain (21%). Univariate analyses revealed a positive association between FSD and age (P = 0.0041), marital status (P = 0.0016), menopausal status (P = 0.0019), microvasculopathy (P = 0.0092), and depression (P = 0.0022). However, in a multivariate analysis, only depression (P = 0.004) and marital status (P = 0.003) were significant predictors of FSD. CONCLUSIONS FSD is common in women with type 1 diabetes and affects all aspects of sexual function and satisfaction. Depression is the major predictor of sexual dysfunction in women with type 1 diabetes. These findings suggest that women with type 1 diabetes should be routinely queried about the presence of sexual dysfunction and possible co-association with depression.

The effect of intensive diabetes treatment on resting heart rate in type 1 diabetes: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study

OBJECTIVE—Cardiovascular disease is a major cause of morbidity and mortality in individuals with type 1 diabetes. Resting heart rate (RHR) is a risk factor for cardiovascular disease in the general population, and case-control studies have reported a higher RHR in individuals with type 1 diabetes. In individuals with type 1 diabetes, there is a positive correlation between A1C and RHR; however, no prospective studies have examined whether a causal relationship exists between A1C and RHR. We hypothesized that intensive diabetes treatment aimed to achieve normal A1C levels has an effect on RHR in individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS—A total of 1,441 individuals with type 1 diabetes who participated in the Diabetes Control and Complications Trial (DCCT) had their RHR measured biennially by an electrocardiogram during the DCCT and annually for 10 years during the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study. RESULTS—During the DCCT, intensive treatment was associated with lower mean RHR than conventional treatment, both in adolescents (69.0 vs. 72.0 bpm [95% CI 62.8–75.7 and 65.7–78.9, respectively], P = 0.013) and adults (66.8 vs. 68.2 [65.3–68.4 and 66.6–69.8, respectively], P = 0.0014). During follow-up in the EDIC, the difference in RHR between the treatment groups persisted for at least 10 years (P < 0.0001). CONCLUSIONS—Compared with conventional therapy, intensive diabetes management is associated with lower RHR in type 1 diabetes. The lower RHR with intensive therapy may explain, in part, its effect in reducing cardiovascular disease, recently demonstrated in type 1 diabetes.

Effect of Intensive Glycemic Therapy on Erectile Function in Men With Type 1 Diabetes

PURPOSE We determined whether intensive glycemic therapy reduces the risk of erectile dysfunction in men with type 1 diabetes enrolled in the Diabetes Control and Complications Trial. MATERIALS AND METHODS The Diabetes Control and Complications Trial randomized 761 men with type 1 diabetes to intensive or conventional glycemic therapy at 28 sites between 1983 and 1989, of whom 366 had diabetes for 1 to 5 years and no microvascular complications (primary prevention cohort), and 395 had diabetes for 1 to 15 years with nonproliferative retinopathy or microalbuminuria (secondary intervention cohort). Subjects were treated until 1993, and followed in the Epidemiology of Diabetes Interventions and Complications study. In 2003 we conducted an ancillary study using a validated assessment of erectile dysfunction in 571 men (80% participation rate), 291 in the primary cohort and 280 in the secondary cohort. RESULTS Of the participants 23% reported erectile dysfunction. The prevalence was significantly lower in the intensive vs conventional treatment group in the secondary cohort (12.8% vs 30.8%, p = 0.001) but not in the primary cohort (17% vs 20.3%, p = 0.49). The risk of erectile dysfunction in primary and secondary cohorts was directly associated with mean HbA1c during the Diabetes Control and Complications Trial, and Epidemiology of Diabetes Interventions and Complications combined. Age, peripheral neuropathy and lower urinary tract symptoms were other risk factors. CONCLUSIONS A period of intensive therapy significantly reduced the prevalence of erectile dysfunction 10 years later among those men in the secondary intervention cohort but not in the primary prevention cohort. Higher HbA1c was significantly associated with risk in both cohorts. These findings provide further support for early implementation of intensive insulin therapy in young men with type 1 diabetes.

The Hemoglobin Glycation Index Is Not an Independent Predictor of the Risk of Microvascular Complications in the Diabetes Control and Complications Trial

The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy aimed at improved glucose control markedly reduced the risk of diabetes complications compared with conventional therapy. The principal determinant of risk was the history of glycemia. Recently, McCarter et al. (Diabetes Care 27:1259–1264, 2004) have presented analyses of the publicly available DCCT data using their hemoglobin glycation index (HGI), which is computed as the difference between the observed HbA1c (A1C) and that predicted from the level of blood glucose. In their analyses, the HGI level was a significant predictor of progression of retinopathy and nephropathy in the DCCT, which the authors claimed to support the hypothesis that the biological propensity for glycation, so-called biological variation in glycation, is another mechanism that determines risk of complications. However, we have criticized these analyses and conclusions because, from statistical principles, the glycation index must be positively correlated with the A1C level and thus may simply be a surrogate for A1C. Herein, we present the statistical properties of the glycation index to document its high correlation with A1C. We then replicate the analyses of McCarter et al. using both the HGI and the A1C together. Analyses show conclusively that the glycation index is not an independent risk factor for microvascular complications and that the effect of the glycation index on risk is wholly explained by the associated level of A1C. The HGI should not be used to estimate risk of complications or to guide therapy.

Effect of Intensive Glycemic Control and Diabetes Complications on Lower Urinary Tract Symptoms in Men With Type 1 Diabetes : Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study

OBJECTIVE Although diabetes is known to result in lower urinary tract symptoms (LUTS) in men, it remains unclear if glycemic control can mitigate urinary symptoms. We studied how diabetic characteristics are related to LUTS in the men who completed the urological assessment component (UroEDIC) of the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study of the Diabetes Control and Complications Trial (DCCT) participants. RESEARCH DESIGN AND METHODS Study participants were men who completed the UroEDIC questionnaire at the year 10 DCCT/EDIC follow-up examination, which included data on genitourinary tract function and the American Urological Association Symptom Index (AUASI). Analyses were conducted to assess how treatment arm and diabetes characteristics were associated with LUTS using logistic regression. RESULTS Of the 591 men who completed the AUASI questions, nearly 20% (n = 115) had AUASI scores in the moderate to severe category for LUTS (AUASI score ≥8). No associations were observed between LUTS and treatment arm, or A1C levels at the DCCT baseline or end-of-study or at the year 10 EDIC (UroEDIC) examination. Of the diabetes complications studied, only erectile dysfunction at the UroEDIC examination was associated with LUTS. CONCLUSIONS These data from the UroEDIC cohort do not support the assumption that intensive glycemic control results in decreased lower urinary tract symptom severity in men with type 1 diabetes. This result may be due to a true lack of effect, or it may be due to other factors, for example, the relatively young age of the cohort.

The Effect of Intensive Glycemic Control and Diabetic Complications on Lower Urinary Tract Symptoms (LUTS) in Men with Type 1 Diabetes: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study

OBJECTIVE Although diabetes is known to result in lower urinary tract symptoms (LUTS) in men, it remains unclear if glycemic control can mitigate urinary symptoms. We studied how diabetic characteristics are related to LUTS in the men who completed the urological assessment component (UroEDIC) of the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study of the Diabetes Control and Complications Trial (DCCT) participants. RESEARCH DESIGN AND METHODS Study participants were men who completed the UroEDIC questionnaire at the year 10 DCCT/EDIC follow-up examination, which included data on genitourinary tract function and the American Urological Association Symptom Index (AUASI). Analyses were conducted to assess how treatment arm and diabetes characteristics were associated with LUTS using logistic regression. RESULTS Of the 591 men who completed the AUASI questions, nearly 20% (n = 115) had AUASI scores in the moderate to severe category for LUTS (AUASI score ≥8). No associations were observed between LUTS and treatment arm, or A1C levels at the DCCT baseline or end-of-study or at the year 10 EDIC (UroEDIC) examination. Of the diabetes complications studied, only erectile dysfunction at the UroEDIC examination was associated with LUTS. CONCLUSIONS These data from the UroEDIC cohort do not support the assumption that intensive glycemic control results in decreased lower urinary tract symptom severity in men with type 1 diabetes. This result may be due to a true lack of effect, or it may be due to other factors, for example, the relatively young age of the cohort.

Risk Factors for Urinary Incontinence Among Women With Type 1 Diabetes: Findings From the Epidemiology of Diabetes Interventions and Complications Study

OBJECTIVES To determine risk factors for, and long-term effects of, glycemic control on urinary incontinence among women with type 1 diabetes enrolled in the Epidemiology of Diabetes Interventions and Complications study. METHODS The Diabetes Control and Complications Trial (1982-1993) cohort follow-up, Epidemiology of Diabetes Interventions and Complications trial, began in 1994. In 2004, the female participants (n = 550) completed a self-administered questionnaire on incontinence. Our primary outcome was weekly or greater incontinence, overall and by type. Multivariate regression models were used to determine independent predictors of weekly urinary incontinence, both overall and by type. RESULTS Overall, 38% of women reported any incontinence and 17% reported weekly or greater incontinence. An increasing body mass index (odds ratio 1.1, 95% confidence interval 1.1-1.2) was significantly associated with weekly incontinence, overall and by type. Advancing age and >/=2 urinary tract infections in the previous year were associated with weekly urge incontinence (odds ratio 1.4, 95% confidence interval 1.0-2.0 per 5 years, and odds ratio 4.9, 95% confidence interval 1.8-13.5, respectively). Weaker evidence was seen for increased risk with age for overall weekly incontinence (22% per 5 years, P = .06) and stress incontinence (21% per 5 years, P = .08). CONCLUSIONS Urinary incontinence is common among women with type 1 diabetes and the risk factors, including advancing age, increased weight, and previous urinary tract infection, are important. Weight reduction and the treatment of urinary tract infections might have the additional benefit of preventing incontinence or reducing its severity.

Urinary Incontinence Among Women With Type 1 Diabetes—How Common is it?

PURPOSE We compared the prevalence, level of bother and effect on daily activities of urinary incontinence among women with type 1 diabetes enrolled in the Epidemiology of Diabetes Interventions and Complications study to a population based sample of women with normal glucose. MATERIALS AND METHODS We performed a cross-sectional analysis of women with type 1 diabetes and normal glucose tolerance using 2 study populations. The Diabetes Control and Complications Trial cohort followup, Epidemiology of Diabetes Interventions and Complications, began in 1994. In 2004 women participants (550) completed a self-administered questionnaire on urinary incontinence. Our primary outcome was weekly or greater incontinence, overall and by type. Prevalence of urinary incontinence was compared to a subgroup of women with normal glucose in the 2001 to 2002 National Health and Nutrition Examination Survey (NHANES). RESULTS Overall 65% of women with type 1 diabetes reported any urinary incontinence (17% reported weekly incontinence). Nearly 40% of these women were greatly bothered by their incontinence and 9% believed it affected their day-to-day activities. Women with type 1 diabetes had a nearly 2-fold greater prevalence of weekly urge incontinence compared to those without diabetes in the NHANES cohort (8.8% vs 4.5%, p = 0.01). CONCLUSIONS Urinary incontinence is common in women with type 1 diabetes and the prevalence of weekly urge incontinence is far greater compared to that in women with normal glucose levels. Moreover, the prevalence of urinary incontinence in women with type 1 diabetes was greater than that of neuropathy, retinopathy and nephropathy. These findings highlight the importance of screening for urinary incontinence among women with type 1 diabetes. Studies examining factors associated with urinary incontinence in women with type 1 diabetes are warranted.

ORIGINAL RESEARCH—MEN'S SEXUAL HEALTH: Sexual Dysfunction and Symptom Impact in Men with Long-Standing Type 1 Diabetes in the DCCT/EDIC Cohort

INTRODUCTION Male sexual dysfunction is a common complication of diabetes (DM), but the relative impact of erectile dysfunction (ED), orgasmic dysfunction (OD), and/or decreased libido (DL) on global sexual bother has not been assessed. AIM To assess the relationship between ED, OD, and DL and overall sexual satisfaction in men with type 1 DM, and determine which form of dysfunction causes the most bother. METHODS The study cohort consisted of 713 men with type 1 DM who completed the Diabetes Control and Complication Trial and then participated in the follow-up Epidemiology of Diabetes Interventions and Complications Study. In year 10 of EDIC, 583 (83%) completed a validated instrument assessing ED, OD, and DL and the bother these conditions cause. Statistical tests determined the concordance of function and bother in each domain, and the impact of each domain on overall sexual satisfaction. MAIN OUTCOME MEASURES Patient-reported outcomes using responses to individual items of the International Index of Erectile Function (IIEF). RESULTS ED was present in 34%, OD in 20%, and DL in 55%. When correlated with overall sexual satisfaction, ED had the highest weighted kappa (0.84, 95% confidence interval [CI] = 0.80-0.87), while OD (0.57, 95% CI = 0.51-0.63) and DL (0.55, 95%CI = 0.48-0.62) were considerably lower. Furthermore, the single item assessing confidence in getting and keeping an erection had the strongest correlation with overall sexual bother as well as specific erectile bother. CONCLUSIONS ED, OD, and DL are highly prevalent in men with long-standing type I diabetes. All three sexual dysfunctions cause bother in men with DM, but ED causes more general sexual bother and likely has a greater overall impact on quality of life. Our data underscore the importance of asking men with DM about their sexual function and point to the need for further research to investigate disorders of orgasm and desire.