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Effect of Glycemic Exposure on the Risk of Microvascular Complications in the Diabetes Control and Complications Trial—Revisited John M. Lachin 1 , Saul Genuth 2 , David M. Nathan 3 , Bernard Zinman 4 , Brandy N. Rutledge 1 and for the DCCT/EDIC Research Group * 1 The Biostatistics Center, The George Washington University, Rockville, Maryland 2 Case Western Reserve University, Cleveland, Ohio 3 Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 4 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada Address correspondence and reprint requests to John M. Lachin, The Biostatistics Center, 6110 Executive Blvd., Rockville, MD 20852. E-mail: jml{at}biostat.bsc.gwu.edu Abstract 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. AER, albumin excretion rate DCCT, Diabetes Control and Complications Trial MBG, mean blood glucose PH, proportional hazards Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 25 January 2008. DOI: 10.2337/db07-1618. Clinical trial registry no. NCT00360815, clinicaltrials.gov. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-1618 . * * A complete list of investigators and members of the DCCT/EDIC Research Group appears in N Engl J Med 356:1842–1852, 2007. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted January 2, 2008. Received November 16, 2007. DIABETES

The Hemoglobin Glycation Index Is Not an Independent Predictor of the Risk of Microvascular Complications in the Diabetes Control and Complications Trial John M. Lachin 1 , Saul Genuth 2 , David M. Nathan 3 and Brandy N. Rutledge 1 1 The Biostatistics Center, George Washington University, Rockville, Maryland 2 Case Western Reserve University, Cleveland, Ohio 3 Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts Address correspondence and reprint requests to John M. Lachin, The Biostatistics Center, 6110 Executive Blvd., Rockville, MD 20852. E-mail: jml{at}biostat.bsc.gwu.edu Abstract 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. AER, albumin excretion rate AGE, advanced glycation end product DCCT, Diabetes Control and Complications Trial HGI, hemoglobin glycation index MBG, mean blood glucose Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 14 March 2007. DOI: 10.2337/db07-0028. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted February 19, 2007. Received January 8, 2007. DIABETES

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 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 Stephen K. Van Den Eeden , PHD 1 , Aruna V. Sarma , PHD 2 , Brandy N. Rutledge , PHD 3 , Patricia A. Cleary , MS 3 , John W. Kusek , PHD 4 , Leroy M. Nyberg , MD 4 , Kevin T. McVary , MD 5 , Hunter Wessells , MD 6 and for the DCCT/EDIC Research Group * 1 Division of Research, Kaiser Permanente, Northern California Region, Oakland, California; 2 Departments of Epidemiology and Urology, University of Michigan, Ann Arbor, Michigan; 3 The Biostatistics Center, The George Washington University, Rockville, Maryland; 4 National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; 5 Department of Urology, Northwestern University, Chicago, Illinois; 6 Department of Urology, University of Washington School of Medicine and Harborview Medical Center, Seattle, Washington. Corresponding author: Stephen K. Van Den Eeden, stephen.vandeneeden{at}kp.org . Abstract 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. Footnotes ↵ *A complete list of investigators and members of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study group appears in the New England Journal of Medicine 2005;353:2643–2653. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received December 14, 2007. Accepted January 13, 2009. © 2009 by the American Diabetes Association.

OBJECTIVE: This multicenter study examined the impact of albumin excretion rate (AER) on the course of estimated glomerular filtration rate (eGFR) and the incidence of sustained eGFR <60 ml/min/1.73 m² in type 1 diabetes up to year 14 of the Epidemiology of Diabetes Interventions and Complications (EDIC) study (mean duration of 19 years in the Diabetes Control and Complications Trial [DCCT]/EDIC). RESEARCH DESIGN AND METHODS: Urinary albumin measurements from 4-h urine collections were obtained from participants annually during the DCCT and every other year during the EDIC study, and serum creatinine was measured annually in both the DCCT and EDIC study. GFR was estimated from serum creatinine using the abbreviated Modification of Diet in Renal Disease equation. RESULTS: A total of 89 of 1,439 subjects developed an eGFR <60 ml/min/1.73 m² (stage 3 chronic kidney disease on two or more successive occasions (sustained) during the DCCT/EDIC study (cumulative incidence 11.4%). Of these, 20 (24%) had AER <30 mg/24 h at all prior evaluations, 14 (16%) had developed microalbuminuria (AER 30-300 mg/24 h) before they reached stage 3 chronic kidney disease, and 54 (61%) had macroalbuminuria (AER >300 mg/24 h) before they reached stage 3 chronic kidney disease. Macroalbuminuria is associated with a markedly increased rate of fall in eGFR (5.7%/year vs. 1.2%/year with AER <30 mg/24 h, P < 0.0001) and risk of eGFR <60 ml/min/1.73 m² (adjusted hazard ratio 15.3, P < 0.0001), whereas microalbuminuria had weaker and less consistent effects on eGFR. CONCLUSIONS: Macroalbuminuria was a strong predictor of eGFR loss and risk of developing sustained eGFR <60 ml/min/1.73 m². However, screening with AER alone would have missed 24% of cases of sustained impaired eGFR.

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.

Sexual Dysfunction in Women With Type 1 Diabetes Long-term findings from the DCCT/ EDIC study cohort Paul Enzlin , PHD 1 , 2 , Raymond Rosen , PHD 3 , 4 , Markus Wiegel , PHD 3 , 4 , Jeanette Brown , MD 5 , Hunter Wessells , MD 6 , Patricia Gatcomb , RN, CDE 7 , Brandy Rutledge , PHD 8 , Ka-Ling Chan , MS 8 , Patricia A. Cleary , MS 8 and the DCCT/EDIC Research Group * 1 Department of Psychiatry, Katholieke Universiteit Leuven & University Hospitals Gasthuisberg, Leuven, Belgium; 2 Department of Obstetrics and Gynaecology, Institute for Family and Sexuality Studies, Katholieke Universiteit Leuven & University Hospitals Gasthuisberg, Leuven, Belgium; 3 New England Research Institutes, Watertown, Massachusetts; 4 Robert Wood Johnson Medical School, University of Medicine & Dentistry, Piscataway, New Jersey; 5 Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco Women's Health Clinical Research Center, San Francisco, California; 6 Department of Urology, University of Washington, Seattle, Washington; 7 Yale University School of Medicine, New Haven, Connecticut; 8 The Biostatistics Center, The George Washington University, Rockville, Maryland. Corresponding author: Paul Enzlin, paul.enzlin{at}uz.kuleuven.ac.be Abstract 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. Footnotes ↵ *A complete list of participants in the DCCT/EDIC Research Group can be found in Arch Ophthalmol 2008;126:1707–1715. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received August 15, 2008. Accepted February 2, 2009. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. © 2009 by the American Diabetes Association.

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 greater-than-or-equal8). 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.

Background. We aimed to define the relative importance of renal and endocrine changes in tenofovir disoproxil fumarate (TDF)–related bone toxicity. Methods. In a study of daily TDF/emtricitabine (FTC) preexposure prophylaxis (PrEP) in human immunodeficiency virus (HIV)–uninfected young men who have sex with men, we measured changes from baseline in blood and urine markers of the parathyroid hormone (PTH)–vitamin D–fibroblast growth factor 23 (FGF23) axis, creatinine, and renal tubular reabsorption of phosphate (TRP). We explored the relationship of those variables to changes in bone mineral density (BMD). Tenofovir-diphosphate (TFV-DP) in red blood cells was used to categorize participants into high and low drug exposure groups. Results. There were 101 participants, median age 20 years (range 15 to 22). Compared with low drug exposure, high-exposure participants showed increase from baseline in PTH and decline in FGF23 by study week 4, with no differences in creatinine, phosphate, or TRP. At 48 weeks, the median (interquartile range) percent decline in total hip BMD was greater in those with high- compared to low- exposure (−1.59 [2.77] vs +1.54 [3.34] %, respectively; P = .001); in high-exposure participants, this correlated with week 4 TFV-DP (inversely; r = −0.60, P = .002) and FGF23 (directly; r = 0.42; P = .039) but not other variables. Conclusions. These findings support the short-term renal safety of TDF/FTC PrEP in HIV-seronegative young men and suggest that endocrine disruption (PTH-FGF23) is a primary contributor to TDF-associated BMD decline in this age group. Clinical Trials Registration. NCT01769469.

Background. The study goal was to determine the effect of vitamin D (VITD) supplementation on tubular reabsorption of phosphate (TRP), parathyroid hormone (PTH), bone alkaline phosphatase (BAP), and C-telopeptide (CTX) in youth infected with human immunodeficiency virus (HIV) receiving and not receiving combination antiretroviral therapy (cART) containing tenofovir disoproxil fumarate (TDF). Methods. This randomized, double-blind, placebo-controlled multicenter trial enrolled HIV-infected youth 18—25 years based on stable treatment with cART containing TDF (n = 118) or no TDF (noTDF; n = 85), and randomized within those groups to vitamin D3, 50 000 IU (n = 102) or placebo (n = 101), administered at 0, 4, and 8 weeks. Outcomes included change in TRP, PTH, BAP, and CTX from baseline to week 12 by TDF/noTDF; and VITD/placebo. Results. At baseline, VITD and placebo groups were similar except those on TDF had lower TRP and higher PTH and CTX. At week 12, 95% in the VITD group had sufficient serum 25-hydroxy vitamin D (25-OHD; ≥20 ng/mL), increased from 48% at baseline, without change in placebo (P < .001). PTH decreased in the TDF group receiving VITD (P = .031) but not in the noTDF group receiving VITD, or either placebo group. The decrease in PTH with VITD in those on TDF occurred with insufficient and sufficient baseline 25-OHD (mean PTH change, -7.9 and -6.2 pg/mL; P = .031 and .053, respectively). Conclusions. In youth on TDF, vitamin D3 supplementation decreased PTH, regardless of baseline 25-OHD concentration. Clinical Trials Registration. NCT00490412.