Longitudinal Trajectories of Biomarkers of Kidney Tubular Function in Type 1 Diabetes.

Introduction: Tubular biomarkers may shed insight into progression of kidney tubulointerstitial pathology complementary to traditional measures of glomerular function and damage. Methods: We examined trajectories of tubular biomarkers in the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC Study) of type 1 diabetes (T1D). Biomarkers were measured in a subset of 220 participants across 7 time points over 26 years. Measurements included the following: kidney injury molecule 1 (KIM-1), soluble tumor necrosis factor 1 (sTNFR1) in serum or plasma, epidermal growth factor (EGF), monocyte chemoattractant protein-1 (MCP1) in timed urine, and a composite tubular secretion score. We described biomarker trajectories and examined how these were affected by intensive glucose-lowering therapy and glycemia. Results: At baseline, participants had a mean age of 28 years, 45% were women, and 50% were assigned to intensive glucose-lowering therapy. The mean estimated glomerular filtration rate (eGFR) was 125 ml/min per 1.73 m2 and 90% of participants had a urinary albumin excretion rate (AER) <30 mg/24h. Mean changes in biomarkers over time (percent/decade) were: KIM-1: 27.3% (95% confidence interval [CI]: 21.4-33.5), sTNFR1: 16.9% (14.5-19.3), MCP1: 18.4% (8.9-28.8), EGF: -13.5% (-16.7 to -10.1), EGF-MCP1 ratio: -26.9% (-32.2 to -21.3), and tubular secretion score -0.9% (-1.8 to 0.0), versus -12.0% (CI: -12.9 to -11.1) for eGFR and 10.9% (2.5-20.1) for AER. Intensive versus conventional glucose-lowering therapy was associated with slower increase in sTNFR1 (relative difference in change: 0.94 [0.90-0.98]). Higher HbA1c was associated with faster increases in sTNFR1 (relative difference in change: 1.06 per 1% higher HbA1c [1.05-1.08]) and KIM-1 (1.09 [1.05-1.14]). Conclusion: Among participants with T1D and normal eGFR at baseline, kidney tubular biomarkers changed significantly over long-term follow-up. Hyperglycemia was associated with larger increases in serum or plasma sTNFR1 and KIM-1, when followed-up longitudinally.

Associations of Kidney Tubular Biomarkers With Incident Macroalbuminuria and Sustained Low eGFR in DCCT/EDIC.

OBJECTIVE: Tubulointerstitial injury contributes to diabetic kidney disease (DKD) progression. We tested tubular biomarker associations with DKD development in type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: We performed a case-cohort study examining associations of tubular biomarkers, measured across seven time points spanning ∼30 years, with incident macroalbuminuria ("severely elevated albuminuria," urinary albumin excretion rate (AER) ≥300 mg/day) and sustained low estimated glomerular filtration rate (eGFR) (persistent eGFR <60 mL/min/1.73 m2) in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. Biomarkers included KIM-1 and sTNFR1 in serum/plasma, MCP-1 and EGF in urine, and a composite tubular secretion score reflecting secreted solute clearance. We assessed biomarkers using single values, as mean values from consecutive time points, and as change over consecutive time points, each as time-updated exposures. RESULTS: At baseline, mean diabetes duration was 5.9 years, with mean HbA1c 8.9%, eGFR 125 mL/min/1.73 m2, and AER 16 mg/day. There were 4.8 and 3.5 cases per 1,000 person-years of macroalbuminuria and low eGFR, respectively. Assessed according to single biomarker values, KIM-1 was associated with risk of subsequent macroalbuminuria and low eGFR (hazard ratio [HR] per 20% higher biomarker 1.11 [95% CI 1.06, 1.16] and 1.12 [1.04, 1.21], respectively) and sTNFR1 was associated with subsequent macroalbuminuria (1.14 [1.03, 1.25]). Mean KIM-1 and EGF-to-MCP-1 ratio were associated with subsequent low eGFR. In slope analyses, increases in KIM-1 and sTNFR1 were associated with subsequent macroalbuminuria (per 20% biomarker increase, HR 1.81 [1.40, 2.34] and 1.95 [1.18, 3.21]) and low eGFR (2.26 [1.65, 3.09] and 2.94 [1.39, 6.23]). CONCLUSIONS: Serial KIM-1 and sTNFR1 are associated with incident macroalbuminuria and sustained low eGFR in T1D.

Intensive Glycemic Management Is Associated With Reduced Retinal Structure Abnormalities on Ocular Coherence Tomography in the DCCT/EDIC Study.

OBJECTIVE: To investigate quantitative and qualitative changes in retinal structure using optical coherence tomography (OCT) and their associations with systemic or other risk factors in individuals with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In the Epidemiology of Diabetes Interventions and Complications (EDIC) study, OCT images were obtained during study years 25-28 (2019-2022) in 937 participants; 54% and 46% were from the original intensive (INT) and conventional (CONV) glycemic management treatment groups, respectively. RESULTS: Average age for participants was 61 years old, diabetes duration 39 years, and HbA1c 7.6%. Participants originally in the CONV group were more likely to have disorganization of retinal inner layers (DRIL) (CONV 27.3% vs. INT 18.7%; P = 0.0003), intraretinal fluid (CONV 24.4% vs. INT 19.2%; P = 0.0222), and intraretinal cysts (CONV 20.8% vs. INT 16.6%; P = 0.0471). In multivariable models, sex, age, smoking, mean updated systolic blood pressure, and history of "clinically significant" macular edema (CSME) and of anti-VEGF treatment were independently associated with changes in central subfield thickness, while HbA1c, BMI, and history of CSME and of ocular surgery were associated with DRIL. Visual acuity (VA) decline was associated with significant thinning of all retinal subfields except for the central and inner nasal subfields. CONCLUSIONS: Early intensive glycemic management in T1D is associated with a decreased risk of DRIL. This important morphological abnormality was associated with a history of macular edema, a history of ocular surgery, and worse VA. This study reveals benefits of intensive glycemic management on the retina beyond features detected by fundus photographs and ophthalmoscopy.

Utility of the NIH Toolbox Cognition Battery in middle to older aged adults with longstanding type 1 diabetes: The DCCT/EDIC study.

Objective: Adults with type 1 diabetes (T1D) face an increased risk for cognitive decline and dementia. Diabetes-related and vascular risk factors have been linked to cognitive decline using detailed neuropsychological testing; however, it is unclear if cognitive screening batteries can detect cognitive changes associated with aging in T1D. Method: 1,049 participants with T1D (median age 59 years; range 43-74) from the Diabetes Control and Complications Trial (DCCT), and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study, completed the NIH Toolbox Cognition Battery (NIHTB-C) and Montreal Cognitive Assessment (MoCA). Neuropsychological assessments, depression, glycated hemoglobin levels (HbA1c), severe hypoglycemia, T1D complications, and vascular risk factors were assessed repeatedly over 32 years to determine associations with current NIHTB-C performance. Available cognitive data was clinically adjudicated to determine cognitive impairment status. Results: NIHTB-C scores had moderate associations (r = 0.36-0.53) with concurrently administered neuropsychological tests. In multivariate models, prior severe hypoglycemic episodes, depression symptoms, nephropathy, lower BMI, and higher HbA1c and LDL cholesterol were associated with poorer NIHTB-C Fluid Cognition Composite scores. The NIHTB-C adequately detected adjudicated cognitive impairment (Area Under the Curve = 0.86; optimal cut score ≤90). The MoCA performed similarly (Area Under the Curve = 0.83; optimal cut score ≤25). Conclusions: The NIHTB-C is sensitive to the cognitive effects of diabetes-related and vascular risk factors, correlated with neuropsychological testing, and accurately detects adjudicated cognitive impairment. These data support its use as a screening test in middle to older aged adults with T1D to determine if referral for detailed neuropsychological assessment is needed.

Relationships Between the Cumulative Incidences of Long-term Complications in Type 1 Diabetes: The DCCT/EDIC Study.

OBJECTIVE: To describe the relationships between the cumulative incidences of long-term complications in individuals with type 1 diabetes (T1D) and assess whether observed associations are independent of age, duration of diabetes, and glycemic levels. METHODS: Proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), reduced estimated glomerular filtration rate (eGFR), amputations, cardiovascular disease (CVD), and mortality were assessed in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study over ∼30 years. RESEARCH DESIGN AND RESULTS: The cumulative incidence of complications ranged from 3% (amputations) to 37% (CSME). There were large differences in the cumulative incidence of PDR between participants with versus without prior CSME (66% vs. 15%), reduced eGFR (59% vs. 29%), and amputation (68% vs. 32%); reduced eGFR with or without prior PDR (25% vs. 9%), amputation (48% vs. 13%), and CVD (30% vs. 11%); CVD with or without prior reduced eGFR (37% vs. 14%) and amputation (50% vs. 16%); and mortality with or without prior reduced eGFR (22% vs. 9%), amputation (35% vs. 8%), and CVD (25% vs. 8%). Adjusted for age, duration of T1D, and mean updated HbA1c, the complications and associations with higher risk included PDR with CSME (hazard ratio [HR] 1.88; 95% CI 1.42, 2.50), reduced eGFR (HR 1.41; 95% CI 1.01, 1.97), and CVD (HR 1.43; 95% CI 1.06, 1.92); CSME with higher risk of PDR (HR 3.94; 95% CI 3.18 4.89), reduced eGFR (HR 1.49; 95% CI 1.10, 2.01), and CVD (HR 1.35; 95% CI 1.03, 1.78); reduced eGFR with higher risk of CVD (HR 2.09; 95% CI 1.44, 3.03), and death (HR 3.40; 95% CI 2.35, 4.92); amputation(s) with death (HR 2.97; 95% CI 1.70, 2.90); and CVD with reduced eGFR (HR 1.59; 95% CI 1.08, 2.34) and death (HR 1.95; 95% CI 1.32, 2.90). CONCLUSIONS: Long-term micro- and macrovascular complications and mortality are highly correlated. Age, diabetes duration, and glycemic levels do not completely explain these associations.

Retinopathy During the First 5 Years of Type 1 Diabetes and Subsequent Risk of Advanced Retinopathy.

OBJECTIVE: To determine whether individuals with type 1 diabetes (T1D) who develop any retinopathy at any time prior to 5 years of diabetes duration have an increased subsequent risk for further progression of retinopathy or onset of proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), diabetes-related retinal photocoagulation, or anti-vascular endothelial growth factor injections. Additionally, to determine the influence of HbA1c and other risk factors in these individuals. RESEARCH DESIGN AND METHODS: Diabetic retinopathy (DR) was assessed longitudinally using standardized stereoscopic seven-field fundus photography at time intervals of 6 months to 4 years. Early-onset DR (EDR) was defined as onset prior to 5 years of T1D duration. Cox models assessed the associations of EDR with subsequent risk of outcomes. RESULTS: In unadjusted models, individuals with EDR (n = 484) had an increased subsequent risk of PDR (hazard ratio [HR] 1.51 [95% CI 1.12, 2.02], P = 0.006), CSME (HR 1.44 [1.10, 1.88], P = 0.008), and diabetes-related retinal photocoagulation (HR 1.48 [1.12, 1.96], P = 0.006) compared with individuals without EDR (n = 369). These associations remained significant when adjusted for HbA1c, but only the association with PDR remained significant after adjustment for age, duration of T1D, HbA1c, sex, systolic/diastolic blood pressure, pulse, use of ACE inhibitors, albumin excretion rate, and estimated glomerular filtration rate (HR 1.47 [95% CI 1.04, 2.06], P = 0.028). CONCLUSIONS: These data suggest that individuals with any sign of retinopathy within the first 5 years of T1D onset may be at higher risk of long-term development of advanced DR, especially PDR. Identification of early-onset DR may influence prognosis and help guide therapeutic management to reduce the risk of future visual loss in these individuals.

Optimal Frequency of Urinary Albumin Screening in Type 1 Diabetes.

OBJECTIVE: Kidney disease screening recommendations include annual urine testing for albuminuria after 5 years' duration of type 1 diabetes. We aimed to determine a simple, risk factor-based screening schedule that optimizes early detection and testing frequency. RESEARCH DESIGN AND METHODS: Urinary albumin excretion measurements from 1,343 participants in the Diabetes Control and Complications Trial and its long-term follow-up were used to create piecewise-exponential incidence models assuming 6-month constant hazards. Likelihood of the onset of moderately or severely elevated albuminuria (confirmed albumin excretion rate AER ≥30 or ≥300 mg/24 h, respectively) and its risk factors were used to identify individualized screening schedules. Time with undetected albuminuria and number of tests were compared with annual screening. RESULTS: The 3-year cumulative incidence of elevated albuminuria following normoalbuminuria at any time during the study was 3.2%, which was strongly associated with higher glycated hemoglobin (HbA1c) and AER. Personalized screening in 2 years for those with current AER ≤10 mg/24 h and HbA1c ≤8% (low risk [0.6% three-year cumulative incidence]), in 6 months for those with AER 21-30 mg/24 h or HbA1c ≥9% (high risk [8.9% three-year cumulative incidence]), and in 1 year for all others (average risk [2.4% three-year cumulative incidence]) was associated with 34.9% reduction in time with undetected albuminuria and 20.4% reduction in testing frequency as compared with annual screening. Stratification by categories of HbA1c or AER alone was associated with reductions of lesser magnitude. CONCLUSIONS: A personalized alternative to annual screening in type 1 diabetes can substantially reduce both the time with undetected kidney disease and the frequency of urine testing. ARTICLE HIGHLIGHTS: Kidney disease screening recommendations include annual urine testing for albuminuria after 5 years' duration of type 1 diabetes. We investigated simple screening schedules that optimize early detection and testing frequency. Personalized screening in 2 years for those with current AER ≤10 mg/24 h and HbA1c ≤8%, in 6 months for those with AER 21-30 mg/24 h or HbA1c ≥9%, and in 1 year for all others yielded 34.9% reduction in time with undetected albuminuria and 20.4% fewer evaluations compared with annual screening. A personalized alternative to annual screening in type 1 diabetes can substantially reduce both the time with undetected kidney disease and the frequency of urine testing.

Brain Structure Among Middle-aged and Older Adults With Long-standing Type 1 Diabetes in the DCCT/EDIC Study.

OBJECTIVE: Individuals with type 1 diabetes mellitus (T1DM) are living to ages when neuropathological changes are increasingly evident. We hypothesized that middle-aged and older adults with long-standing T1DM will show abnormal brain structure in comparison with control subjects without diabetes. RESEARCH DESIGN AND METHODS: MRI was used to compare brain structure among 416 T1DM participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study with that of 99 demographically similar control subjects without diabetes at 26 U.S. and Canadian sites. Assessments included total brain (TBV) (primary outcome), gray matter (GMV), white matter (WMV), ventricle, and white matter hyperintensity (WMH) volumes and total white matter mean fractional anisotropy (FA). Biomedical assessments included HbA1c and lipid levels, blood pressure, and cognitive assessments of memory and psychomotor and mental efficiency (PME). Among EDIC participants, HbA1c, severe hypoglycemia history, and vascular complications were measured longitudinally. RESULTS: Mean age of EDIC participants and control subjects was 60 years. T1DM participants showed significantly smaller TBV (least squares mean ± SE 1,206 ± 1.7 vs. 1,229 ± 3.5 cm3, P < 0.0001), GMV, and WMV and greater ventricle and WMH volumes but no differences in total white matter mean FA versus control subjects. Structural MRI measures in T1DM were equivalent to those of control subjects who were 4-9 years older. Lower PME scores were associated with altered brain structure on all MRI measures in T1DM participants. CONCLUSIONS: Middle-aged and older adults with T1DM showed brain volume loss and increased vascular injury in comparison with control subjects without diabetes, equivalent to 4-9 years of brain aging.

Type 1 diabetes and oral health: Findings from the Epidemiology of Diabetes Interventions and Complications (EDIC) study.

OBJECTIVE: To describe long-term oral health outcomes and examine associations between sociodemographic factors, clinical characteristics, and markers of diabetes control on tooth loss in participants with type 1 diabetes enrolled in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. RESEARCH DESIGN AND METHODS: Oral health outcomes related to tooth loss were reported at annual visits during EDIC years 22-26 (2015-2019). Generalized estimating equation models were used to assess the association of individual risk factors and tooth loss, over repeated time points. RESULTS: A total of 165 (17%) participants with type 1 diabetes reported 221 oral health outcomes related to tooth loss over a five-year period. After controlling for age and current tobacco use, the presence of diabetic peripheral neuropathy was significantly associated with an increased odds of tooth loss (OR = 1.88, 95% CI 1.24, 2.87) while higher mean HDL/LDL cholesterol ratio was significantly associated with a decreased odds of tooth loss (OR = 0.87, 95% CI = 0.79, 0.97). CONCLUSIONS: These findings suggest that diabetes-related complications, either resulting from or independent of poor glycemia, may be directly associated with oral health conditions, and support the need for individuals with type 1 diabetes and providers to implement lifestyle and medical interventions to reduce oral health risks.

Risk of Foot Ulcer and Lower-Extremity Amputation Among Participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study.

OBJECTIVE: Intensive glycemic control reduces the risk of kidney, retinal, and neurologic complications in type 1 diabetes (T1D), but whether it reduces the risk of lower-extremity complications is unknown. We examined whether former intensive versus conventional glycemic control among Diabetes Control and Complications Trial (DCCT) participants with T1D reduced the long-term risk of diabetic foot ulcers (DFUs) and lower-extremity amputations (LEAs) in the subsequent Epidemiology of Diabetes Interventions and Complications (EDIC) study. RESEARCH DESIGN AND METHODS: DCCT participants (n = 1,441) completed 6.5 years on average of intensive versus conventional diabetes treatment, after which 1,408 were enrolled in EDIC and followed annually over 23 years for DFU and LEA occurrences by physical examination. Multivariable Cox proportional hazard regression models estimated associations of DCCT treatment assignment and time-updated exposures with DFU or LEA. RESULTS: Intensive versus conventional glycemic control was associated with a significant risk reduction for all DFUs (hazard ratio 0.77 [95% CI 0.60, 0.97]) and a similar magnitude but nonsignificant risk reduction for first-recorded DFUs (0.78 [0.59, 1.03]) and first LEAs (0.70 [0.36, 1.36]). In adjusted Cox models, clinical neuropathy, lower sural nerve conduction velocity, and cardiovascular autonomic neuropathy were associated with higher DFU risk; estimated glomerular filtration rate <60 mL/min/1.73 m2, albuminuria, and macular edema with higher LEA risk; and any retinopathy and greater time-weighted mean DCCT/EDIC HbA1c with higher risk of both outcomes (P < 0.05). CONCLUSIONS: Early intensive glycemic control decreases long-term DFU risk, the most important antecedent in the causal pathway to LEA.

Utility of using electrocardiogram measures of heart rate variability as a measure of cardiovascular autonomic neuropathy in type 1 diabetes patients.

AIMS/INTRODUCTION: Cardiovascular autonomic neuropathy (CAN) is a predictor of cardiovascular disease and mortality. Cardiovascular reflex tests (CARTs) are the gold standard for the diagnosis of CAN, but might not be feasible in large research cohorts or in clinical care. We investigated whether measures of heart rate variability obtained from standard electrocardiogram (ECG) recordings provide a reliable measure of CAN. MATERIALS AND METHODS: Standardized CARTs (R-R response to paced breathing, Valsalva, postural changes) and digitized 12-lead resting ECGs were obtained concomitantly in Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications participants (n = 311). Standard deviation of normally conducted R-R intervals (SDNN) and the root mean square of successive differences between normal-to-normal R-R intervals (rMSSD) were measured from ECG. Sensitivity, specificity, probability of correct classification and Kappa statistics evaluated the agreement between ECG-derived CAN and CARTs-defined CAN. RESULTS: Participants with CARTs-defined CAN had significantly lower SDNN and rMSSD compared with those without CAN (P < 0.001). The optimal cut-off points of ECG-derived CAN were <17.13 and <24.94 ms for SDNN and rMSSD, respectively. SDNN plays a dominant role in defining CAN, with an area under the curve of 0.73, indicating fair test performance. The Kappa statistic for SDNN was 0.41 (95% confidence interval 0.30-0.51) for the optimal cut-off point, showing fair agreement with CARTs-defined CAN. Combining SDNN and rMSSD optimal cut-off points does not provide additional predictive power for CAN. CONCLUSIONS: These analyses are the first to show the agreement between indices of heart rate variability derived from ECGs and the gold standard CARTs, thus supporting potential use as a measure of CAN in clinical research and clinical care.

Comparison of central laboratory HbA1c measurements obtained from a capillary collection versus a standard venous whole blood collection in the GRADE and EDIC studies.

BACKGROUND: We compared HbA1c values obtained from capillary blood collection kits versus venous whole blood collections in study participants with type 1 or type 2 diabetes. METHODS: A total of 122 subjects, 64 with type 2 diabetes participating in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study and 58 with type 1 diabetes from the Epidemiology of Diabetes Interventions and Complications (EDIC) Study, participated in the validation study. Capillary tubes were filled by fingerstick by the participants on the same day as the collection of venous whole blood samples in EDTA-containing test tubes and were mailed to the central laboratory. HbA1c in all samples was measured with the same high-performance liquid chromatography. GRADE participants also completed a questionnaire on the ease of performing capillary collections. RESULTS: Participants from 22 clinical centers (GRADE n = 5, EDIC n = 17) were between 35 and 86 years of age, with 52% male and diverse race/ethnicities. Venous HbA1c results ranged between 5.4-11.9% (35.5-106.6 mmol/mol) with corresponding capillary results ranging between 4.2-11.9% (22.4-106.6 mmol/mol). The venous and capillary results were highly correlated (R2 = 0.993) and 96.7% differed by ≤0.2% (2.2 mmol/mol). Of participants surveyed, 69% indicated that the instructions and collection were easy to follow and 97% felt the collection method would be easy to do at home. CONCLUSIONS: The capillary blood HbA1c results compared well with the conventional venous whole blood results. The capillary kits can be employed in other studies to reduce interruption of critical data collection and potentially to augment clinical care when in-person visits are not possible.

Cognitive performance declines in older adults with type 1 diabetes: results from 32 years of follow-up in the DCCT and EDIC Study.

BACKGROUND: With improved treatment, individuals with type 1 diabetes are living longer but there is limited information on the effects of type 1 diabetes on cognitive ability as they become older adults. We followed up individuals with type 1 diabetes to identify independent risk factors for cognitive decline as people age. METHODS: 1051 participants with type 1 diabetes enrolled in the Diabetes Control and Complications Trial (DCCT) and its follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. Participants completed cognitive assessments at baseline (median age 27 years) and 2, 5, 18, and 32 years later (median age 59). HbA1c levels, frequency of severe hypoglycaemia, non-glycemic risk factors such as elevated blood pressure, and microvascular and macrovascular complications were assessed repeatedly. We examined the effects of these on measures of memory and psychomotor and mental efficiency. These studies are registered with clinicaltrials.gov, NCT00360815 (DCCT) and NCT00360893 (EDIC). FINDINGS: Over 32 years of follow-up, we found substantive declines in memory and psychomotor and mental efficiency. Between 18 and 32 years of follow-up, the decline in psychomotor and mental efficiency was five times larger than the change from baseline to year 18. Independent of the other risk factors and comorbidities, exposure to higher HbA1c levels, more episodes of severe hypoglycaemia, and elevated systolic blood pressure were associated with greater decrements in psychomotor and mental efficiency that was most notable by year 32 (p<0·0001). The combined effect of the presence of these three risk factors is the equivalent to an additional 9·4 years of age. INTERPRETATION: Cognitive function declines with ageing in type 1 diabetes. The association of glycaemia and blood pressure levels with cognitive decline suggests that better management might preserve cognitive function. FUNDING: United States National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease.

Risk Factors for Longitudinal Resting Heart Rate and Its Associations With Cardiovascular Outcomes in the DCCT/EDIC Study.

OBJECTIVE: Individuals with diabetes have higher resting heart rate compared with those without, which may be predictive of long-term cardiovascular disease (CVD) risk. Using data from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, we evaluated whether the beneficial effect of intensive versus conventional diabetes therapy on heart rate persisted, the factors mediating the differences in heart rate between treatment groups, and the effects of heart rate on future CVD risk. RESEARCH DESIGN AND METHODS: Longitudinal changes in heart rate, from annual electrocardiograms over 22 years of EDIC follow-up, were evaluated in 1,402 participants with type 1 diabetes. Linear mixed models were used to assess the effect of DCCT treatment group on mean heart rate over time, and Cox proportional hazards models were used to estimate the effect of heart rate on CVD risk during DCCT/EDIC. RESULTS: At DCCT closeout, 52% of participants were male and mean ± SD age was 33 ± 7 years, diabetes duration 12 ± 5 years, and HbA1c 7.4 ± 1.2% (intensive) and 9.1 ± 1.6% (conventional). Through EDIC, participants in the intensive group had significantly lower heart rate in comparison with the conventional group. While significant group differences in heart rate were fully attenuated by DCCT/EDIC mean HbA1c, higher heart rate predicted CVD and major adverse cardiovascular events independent of other risk factors. CONCLUSIONS: After 22 years of follow-up, former intensive versus conventional therapy remained significantly associated with lower heart rate, consistent with the long-term beneficial effects of intensive therapy on CVD. DCCT treatment group effects on heart rate were explained by differences in DCCT/EDIC mean HbA1c.

Moderation of the effect of glycemia on the risk of cardiovascular disease in type 1 diabetes: The DCCT/EDIC study.

AIMS: We assessed whether and to what extent established cardiovascular disease (CVD) risk factors moderate (enhance/reduce) the effect of hyperglycemia on CVD outcomes in the long-term follow-up of the Diabetes Control and Complications Trial type 1 diabetes (T1D) cohort (N = 1441). METHODS: Moderation of the effect of glycemia on subsequent risk of major adverse cardiovascular events (MACE: fatal or non-fatal myocardial infarction or stroke) and any-CVD (MACE plus confirmed angina, silent MI, revascularization, or congestive heart failure) was assessed separately using interaction terms between HbA1c and other risk factors in Cox proportional hazards models. RESULTS: Over a median follow-up of 29 years, there were 120 MACE cases and 239 any-CVD cases. Higher pulse, higher triglycerides, use of calcium channel blockers, and presence of neuropathy individually enhanced (p < 0.01) the effect of glycemia on any-CVD. Higher pulse and triglyceride levels, albumin excretion rate, hypertension, and no family history of type 2 diabetes enhanced (p < 0.01) the effect of glycemia on MACE. CONCLUSIONS: Such moderation analyses identify subgroups with increased CVD risk who might especially benefit from earlier and/or more intensive glycemic control. Interventions treating modifiable moderating factors may independently reduce the risk of CVD and also reduce the risk associated with a higher HbA1c.

An Observational Study of the Equivalence of Age and Duration of Diabetes to Glycemic Control Relative to the Risk of Complications in the Combined Cohorts of the DCCT/EDIC Study.

OBJECTIVE: This epidemiological analysis of the pooled Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort describes the equivalence of a 1-percentage point increase in HbA1c (such as from 7% to 8%) and years of additional age or duration of type 1 diabetes (T1D) relative to the risk of complications. RESEARCH DESIGN AND METHODS: Separate Cox proportional hazards models determined the number of additional years of age and/or duration of T1D that would result in the same increase in risk of microvascular (retinopathy, nephropathy, and neuropathy) and cardiovascular complications and mortality as a 1-percentage point increase in HbA1c. RESULTS: The risk of any cardiovascular disease associated with a 1-percentage point increase in HbA1c was equivalent to the risk associated with 4.3 (95% CI 2.7-5.9) additional years of age or 5.6 (95% CI 2.7-6.5) additional years' duration of T1D. The risk of estimated glomerular filtration rate <60 mL/min/1.73 m2 and/or end-stage renal disease associated with a 1-percentage point increase in HbA1c was equivalent to the risk associated with 12.1 (95% CI 8.3-15.9) additional years of age or 18.0 (95% CI 4.3-31.7) additional years' duration of T1D. The proliferative diabetic retinopathy risk associated with a 1-percentage point increase in HbA1c was equivalent to the risk associated with 6.4 (95% CI 5.3-7.4) additional years' duration of T1D, while for mortality risk, it was equivalent to the risk associated with 12.9 (95% CI 6.6-19.3) additional years of age. CONCLUSIONS: Our results help evaluate the impact of glycemia on advanced complications in a way that may be more interpretable to health care providers and individuals with T1D.

RISK FACTORS FOR HEARING IMPAIRMENT IN TYPE 1 DIABETES.

Objective: Studies have demonstrated that glycated hemoglobin (HbA1c) is a significant predictor of hearing impairment in type 1 diabetes. We identified additional factors associated with hearing impairment in participants with type 1 diabetes from the Diabetes Control and Complications Trial and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Methods: A total of 1,150 DCCT/EDIC participants were recruited for the Hearing Study. A medical history, physical measurements, and a self-administered hearing questionnaire were obtained. Audiometry was performed by study-certified personnel and assessed centrally. Logistic regression models assessed the association of risk factors and comorbidities with speech- and high-frequency hearing impairment. Results: Mean age was 55 ± 7 years, duration of diabetes 34 ± 5 years, and DCCT/EDIC HbA1c 7.9 ± 0.9% (63 mmol/mol). In multivariable models, higher odds of speech-frequency impairment were significantly associated with older age, higher HbA1c, history of noise exposure, male sex, and higher triglycerides. Higher odds of high-frequency impairment were associated with older age, male sex, history of noise exposure, higher skin intrinsic florescence (SIF) as a marker of tissue glycation, higher HbA1c, nonprofessional/nontechnical occupations, sedentary activity, and lower low-density-lipoprotein cholesterol. Among participants who previously completed computed tomography and carotid ultrasonography, coronary artery calcification (CAC) >0 and carotid intima-medial thickness were significantly associated with high-but not speech-frequency impairment. Conclusion: Consistent with previous reports, male sex, age, several metabolic factors, and noise exposure are independently associated with hearing impairment. The association with SIF further emphasizes the importance of glycemia-as a modifiable risk factor-over time. In addition, the macrovascular contribution of CAC is novel and important. Abbreviations: AER = albumin excretion rate; CAC = coronary artery calcification; CVD = cardiovascular disease; DCCT/EDIC = Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications; eGFR = estimated glomerular filtration rate; ETDRS = Early Treatment Diabetic Retinopathy Study; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; IMT = intima-media thickness; LDL = low-density lipoprotein; NHANES = National Health and Nutrition Examination Survey; OR = odds ratio; SIF = skin intrinsic fluorescence; T1D = type 1 diabetes.

Screening eye exams in youth with type 1 diabetes under 18 years of age: Once may be enough?

Case series and registry data suggest that diabetic retinopathy requiring treatment is rare in youth with type 1 diabetes (T1D) prior to 18 years of age. We evaluated this question in the standardized clinical trial setting by retrospectively reviewing diabetic retinopathy examinations from participants in the Diabetes Control and Complications Trial (DCCT) who were 13 to <18 years of age at randomization. Standardized stereoscopic 7-field fundus photographs were obtained every 6 months during DCCT (1983-1993). Photographs were graded centrally using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Transitions in diabetic retinopathy status over time were described. A total of 195 participants with median baseline glycated hemoglobin (HbA1c) of 9.3% (103 in the conventional and 92 in the intensive treatment groups) had an average of 5.3 diabetic retinopathy assessments during 2.3 years of follow-up (range 1-11) while under 18 years of age during the DCCT. No participant developed severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy and only one participant (in the intensive group) reached clinically significant macular edema (CSME) while less than 18 years of age. In this incident case, baseline characteristics included diabetes duration 9.3 years, HbA1c 10.3%, LDL 131 mg/dL, and mild non-proliferative diabetic retinopathy (35/35 ETDRS scale); CSME resolved without treatment. Similar analyses using age cut-offs of <19, 20, or 21 years showed a slight rise in diabetic retinopathy requiring treatment over late adolescence. Clinical trial evidence suggests that frequent eye exams may not be universally necessary in youth <18 years of age with T1D.

Mediation of the Effect of Glycemia on the Risk of CVD Outcomes in Type 1 Diabetes: The DCCT/EDIC Study.

OBJECTIVE: The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study has demonstrated the major role of hyperglycemia as a risk factor for clinical cardiovascular outcomes in type 1 diabetes (T1D). We assessed whether and to what extent the effect of glycemia is mediated by other established cardiovascular disease (CVD) risk factors. RESEARCH DESIGN AND METHODS: In the DCCT, 1,441 participants were randomized to receive either intensive or conventional diabetes therapy. The EDIC observational follow-up study enrolled 96% of the surviving DCCT cohort with 94% of the survivors still actively participating after more than 27 years of follow-up. Mediation of the effect of glycemia, as captured by HbA1c, on the subsequent CVD risk was quantified using the relative change in the CVD risk associated with HbA1c between models without and with the potential mediator. RESULTS: Adjusted for age, only a few factors (e.g., pulse, triglycerides, albumin excretion rate) explained more than 10% of the effect of glycemia on CVD risk when considered individually. In multivariable models, these traditional risk factors together mediated up to ∼50% of the effect of glycemia on the risk of CVD. However, the association between HbA1c and the risk of CVD remained highly significant even after adjustment for these risk factors. CONCLUSIONS: While HbA1c is associated with many traditional CVD risk factors, its association with these factors alone cannot explain its effects on risk of CVD. Consequently, aggressive management of traditional nonglycemic CVD risk factors, coupled with aggressive glycemic management, is indicated for individuals with type 1 diabetes.