The Course of Visual Recovery after Optic Neuritis: Experience of the Optic Neuritis Treatment Trial.

PURPOSE: To define the time course of visual recovery after optic neuritis and factors predictive of this course in the patients enrolled in the Optic Neuritis Treatment Trial. METHODS: The cohort for this study consisted of the 438 patients who completed the 6-month follow-up visit. Visual acuity was measured at baseline and at seven follow-up visits during the first 6 months. Factors predictive of recovery were evaluated with univariate and multivariate statistical tests. RESULTS: Visual recovery was rapid in all three treatment groups. In almost all patients, regardless of treatment group and initial severity of visual loss, improvement began within the first month. Among the 278 patients with baseline visual acuity of 20/ 50 or worse, all patients improved at least one line of visual acuity, and all except six improved at least three lines, during the 6-month follow-up period. Baseline visual acuity was the best predictor of the 6-month visual acuity outcome (P = 0.0001). Older age was statistically associated with a slightly worse outcome (P = 0.02), but this appeared to be of no clinical importance. CONCLUSIONS: In most patients with optic neuritis, visual recovery is rapid. The only factor of value in predicting the visual outcome is initial severity of visual loss. However, even when initial loss is severe, visual recovery is still good in most patients. Patients not following the usual course of visual recovery should be considered atypical. For such patients, further investigation in regard to etiology of the visual loss may be appropriate.

Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality.

IMPORTANCE: Whether mortality in type 1 diabetes mellitus is affected following intensive glycemic therapy has not been established. OBJECTIVE: To determine whether mortality differed between the original intensive and conventional treatment groups in the long-term follow-up of the Diabetes Control and Complications Trial (DCCT) cohort. DESIGN, SETTING, AND PARTICIPANTS: After the DCCT (1983-1993) ended, participants were followed up in a multisite (27 US and Canadian academic clinical centers) observational study (Epidemiology of Diabetes Control and Complications [EDIC]) until December 31, 2012. Participants were 1441 healthy volunteers with diabetes mellitus who, at baseline, were 13 to 39 years of age with 1 to 15 years of diabetes duration and no or early microvascular complications, and without hypertension, preexisting cardiovascular disease, or other potentially life-threatening disease. INTERVENTIONS AND EXPOSURES: During the clinical trial, participants were randomly assigned to receive intensive therapy (n = 711) aimed at achieving glycemia as close to the nondiabetic range as safely possible, or conventional therapy (n = 730) with the goal of avoiding symptomatic hypoglycemia and hyperglycemia. At the end of the DCCT, after a mean of 6.5 years, intensive therapy was taught and recommended to all participants and diabetes care was returned to personal physicians. MAIN OUTCOMES AND MEASURES: Total and cause-specific mortality was assessed through annual contact with family and friends and through records over 27 years' mean follow-up. RESULTS: Vital status was ascertained for 1429 (99.2%) participants. There were 107 deaths, 64 in the conventional and 43 in the intensive group. The absolute risk difference was -109 per 100,000 patient-years (95% CI, -218 to -1), with lower all-cause mortality risk in the intensive therapy group (hazard ratio [HR] = 0.67 [95% CI, 0.46-0.99]; P = .045). Primary causes of death were cardiovascular disease (24 deaths; 22.4%), cancer (21 deaths; 19.6%), acute diabetes complications (19 deaths; 17.8%), and accidents or suicide (18 deaths; 16.8%). Higher levels of glycated hemoglobin (HbA1c) were associated with all-cause mortality (HR = 1.56 [95% CI, 1.35-1.81 per 10% relative increase in HbA1c]; P < .001), as well as the development of albuminuria (HR = 2.20 [95% CI, 1.46-3.31]; P < .001). CONCLUSIONS AND RELEVANCE: After a mean of 27 years' follow-up of patients with type 1 diabetes, 6.5 years of initial intensive diabetes therapy was associated with a modestly lower all-cause mortality rate when compared with conventional therapy. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00360815 and NCT00360893.

Epicardial and intra-thoracic adipose tissue and cardiovascular calcifications in type 1 diabetes (T1D) in epidemiology of diabetes Interventions and Complications (EDIC): A pilot study.

Objective: Coronary artery, aortic valve, and descending aorta calcification (CAC, AVC, DAC) are manifestations of atherosclerosis, and cardiac epicardial adipose tissue (EAT) indicates heart adiposity. This study explored the association between cardiac adipose tissue and cardiovascular calcification in participants with long-standing T1D. Methods: EAT and intra-thoracic adipose tissue (IAT) were measured in 100 T1D subjects with cardiac computed tomography (CT) scans in the EDIC study. Volume analysis software was used to measure fat volumes. Spearman correlations were calculated between CAC, AVC, DAC with EAT, and IAT. Associations were evaluated using multiple linear and logistic regression models. Results: Participants ranged in age from 32 to 57. Mean EAT, and IAT were 38.5 and 50.8 mm3, respectively, and the prevalence of CAC, AVC, and DAC was 43.6 %, 4.7 %, and 26.8 %, respectively. CAC was positively correlated with age (p-value = 0.0001) and EAT (p-value = 0.0149) but not with AVC and DAC; IAT was not associated with calcified lesions. In models adjusted for age and sex, higher levels of EAT and IAT were associated with higher CAC (p-value < 0.0001 for both) and higher AVC (p-values of 0.0111 and 0.0053, respectively), but not with DAC. The associations with CAC remained significant (p-value < 0.0001) after further adjustment for smoking, systolic blood pressure, BMI, and LDL, while the associations with AVC did not remain significant. Conclusion: In participants with T1D, higher EAT and IAT levels are correlated with higher CAC scores. EAT and IAT were not independently correlated with DAC or AVC.

Diabetes Risk Factors and Bone Microarchitecture as Assessed by High-Resolution Peripheral Quantitative Computed Tomography in Adults With Long-Standing Type 1 Diabetes.

OBJECTIVE: To determine whether type 1 diabetes and its complications are associated with bone geometry and microarchitecture. RESEARCH DESIGN AND METHODS: This cross-sectional study was embedded in a long-term observational study. High-resolution peripheral quantitative computed tomography (HR-pQCT) scans of the distal radius and distal and diaphyseal tibia were performed in a subset of 183 participants with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study and 94 control participants without diabetes. HbA1c, skin advanced glycation end products (AGEs), and diabetes-related complications were assessed in EDIC participants with >30 years of follow-up. RESULTS: Compared with control participants (aged 60 ± 8 years, 65% female), EDIC participants (aged 60 ± 7 years, diabetes duration 38 ± 5 years, 51% female) had lower total bone mineral density (BMD) at the distal radius (-7.9% [95% CI -15.2%, -0.6%]; P = 0.030) and distal tibia (-11.3% [95% CI -18.5%, -4.2%]; P = 0.001); larger total area at all sites (distal radius 4.7% [95% CI 0.5%, 8.8%; P = 0.030]; distal tibia 5.9% [95% CI 2.1%, 9.8%; P = 0.003]; diaphyseal tibia 3.4% [95% CI 0.8%, 6.1%; P = 0.011]); and poorer radius trabecular and cortical microarchitecture. Estimated failure load was similar between the two groups. Among EDIC participants, higher HbA1c, AGE levels, and macroalbuminuria were associated with lower total BMD. Macroalbuminuria was associated with larger total area and lower cortical thickness at the distal radius. Higher HbA1c and AGE levels and lower glomerular filtration rate, peripheral neuropathy, and retinopathy were associated with deficits in trabecular microarchitecture. CONCLUSIONS: Type 1 diabetes is associated with lower BMD, larger bone area, and poorer trabecular microarchitecture. Among participants with type 1 diabetes, suboptimal glycemic control, AGE accumulation, and microvascular complications are associated with deficits in bone microarchitecture and lower BMD.

Myocardial structure, function, and scar in patients with type 1 diabetes mellitus.

BACKGROUND: We report relationships between cardiovascular disease risk factors and myocardial structure, function, and scar in patients with type 1 diabetes mellitus in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. METHODS AND RESULTS: Cardiac magnetic resonance was obtained in 1017 patients with type 1 diabetes mellitus. Gadolinium cardiac magnetic resonance was also obtained in 741 patients. The mean age was 49±7 years; 52% were men; and mean duration of diabetes mellitus was 28±5 years. Associations of cardiovascular disease risk factors with cardiac magnetic resonance parameters were examined with linear and logistic regression models. History of macroalbuminuria was positively associated with left ventricular mass (by 14.8 g), leading to a significantly higher ratio of left ventricular mass to end-diastolic volume (by 8%). Mean hemoglobin A(1c) levels over the preceding 22 years were inversely associated with end-diastolic volume (-3.0 mL per unit mean hemoglobin A(1c) percent) and stroke volume (-2.3 mL per unit mean hemoglobin A(1c) percent) and positively related to the ratio of elevated left ventricular mass to end-diastolic volume (0.02 g/mL per unit). The overall prevalence of myocardial scar was 4.3% by cardiac magnetic resonance and 1.4% by clinical adjudication of myocardial infarction. Both mean hemoglobin A(1c) (odds ratio, 1.5 [95% confidence interval, 1.0-2.2] per unit) and macroalbuminuria (odds ratio, 3.5 [95% confidence interval, 1.2-9.9]) were significantly associated with myocardial scar and traditional cardiovascular disease risk factors. CONCLUSIONS: In addition to traditional cardiovascular disease risk factors, elevated mean hemoglobin A(1c) and macroalbuminuria were significantly associated with alterations in left ventricular structure and function. The prevalence of myocardial scar was 4.3% in this subcohort of DCCT/EDIC participants with relatively preserved renal function. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00360893 and NCT00360815.

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.

Left Ventricular Structure, Tissue Composition, and Aortic Distensibility in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications.

Alterations in myocardial structure, function, tissue composition (e.g., fibrosis) may be associated with metabolic syndrome (MetS). This study aimed to determine the relation of MetS and its individual components to markers of cardiovascular disease in patients with type 1 Diabetes Mellitus (T1DM). A total of 978 subjects of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications T1DM cohort (age: 49 ± 7 years, 47% female, DM duration 28 ± 5 years) underwent cardiovascular magnetic resonance. In a subset of 200 patients, myocardial tissue composition was measured with cardiovascular magnetic resonance T1 mapping after contrast administration. MetS was defined as T1DM plus 2 other abnormalities based on the American Heart Association/National Cholesterol Education Program criteria. MetS was present in 34.1% of subjects. After adjustment for age, height, scanner, study cohort, gender, smoking, mean glycated hemoglobin levels, history of macroalbuminuria and end-stage renal disease, left ventricle mass was greater by 12.3 g, end-diastolic volume was higher by 5.4 ml, and mass to end-diastolic volume ratio was higher by 5% in patients with MetS versus those without MetS (p <0.001 for all). Myocardial T1 times were lower by 29 ms in patients with MetS than those without (p <0.001). Elevated waist circumference showed the strongest associations with left ventricle mass (+10.1 g), end-diastolic volume (+6.7 ml), and lower myocardial T1 times (+31 ms) in patients with MetS compared with those without (p <0.01). In conclusion, in a large cohort of patients with T1DM, 34.1% of subjects met MetS criteria. MetS was associated with adverse myocardial structural remodeling and change in myocardial tissue composition.

Physical Function in Middle-aged and Older Adults With Type 1 Diabetes: Long-term Follow-up of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study.

OBJECTIVE: To describe the prevalence and clinical correlates of functional limitations in middle-aged and older adults with long-standing type 1 diabetes. RESEARCH DESIGN AND METHODS: Functional limitations were assessed for 1,094 participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, a multicenter, longitudinal, observational follow-up of participants with type 1 diabetes randomly assigned to intensive or conventional diabetes therapy during the Diabetes Control and Complications Trial (DCCT). The primary outcome measure was a score <10 on the Short Physical Performance Battery (SPPB). The secondary outcome, self-reported functional limitation, was assessed by written questionnaire. Logistic regression models were used to assess associations of both outcomes with demographic and clinical factors (glycemic and nonglycemic factors, micro- and macrovascular complications, DCCT cohort, and treatment assignment). RESULTS: Participants were 53% male, with mean ± SD age 59.5 ± 6.8 years and diabetes duration 37.9 ± 4.9 years. The prevalence of SPPB score <10 was 21%. The prevalence of self-reported functional limitations was 48%. While DCCT treatment assignment was not associated with physical function outcomes measured ∼25 years after the end of the DCCT, the time-weighted mean DCCT/EDIC HbA1c was associated with both outcomes. Other clinical factors associated with both outcomes in multivariable analyses were BMI, general psychological distress, and cardiac autonomic neuropathy. CONCLUSIONS: Almost half of the middle-aged and older adults with long-standing type 1 diabetes reported functional limitations, which were associated with higher HbA1c and BMI, general psychological distress, and cardiac autonomic neuropathy. Future research is needed to determine whether these findings are generalizable.

Biochemical Markers of Bone Turnover in Older Adults With Type 1 Diabetes.

CONTEXT: Type 1 diabetes (T1D) is characterized by high fracture risk, yet little is known regarding diabetes-related mechanisms or risk factors. OBJECTIVE: Determine whether glycemic control, advanced glycation end products (AGEs), and microvascular complications are associated with bone turnover markers among older T1D adults. DESIGN: Cross-sectional. SETTING: Epidemiology of Diabetes Interventions and Complications study (6 of 27 clinical centers). PARTICIPANTS: 232 T1D participants followed for >30 years. EXPOSURES: Glycemic control ascertained as concurrent and cumulative hemoglobin A1c (HbA1c); kidney function, by estimated glomerular filtration rates (eGFR); and AGEs, by skin intrinsic fluorescence. MAIN OUTCOME MEASURES: Serum procollagen 1 intact N-terminal propeptide (PINP), bone-specific alkaline phosphatase (bone ALP), serum C-telopeptide (sCTX), tartrate-resistant acid phosphatase 5b (TRACP5b), and sclerostin. RESULTS: Mean age was 59.6 ±â€…6.8 years, and 48% were female. In models with HbA1c, eGFR, and AGEs, adjusted for age and sex, higher concurrent HbA1c was associated with lower PINP [ß -3.4 pg/mL (95% CI -6.1, -0.7), P = 0.015 for each 1% higher HbA1c]. Lower eGFR was associated with higher PINP [6.9 pg/mL (95% CI 3.8, 10.0), P < 0.0001 for each -20 mL/min/1.73 m2 eGFR], bone ALP [1.0 U/L (95% CI 0.2, 1.9), P = 0.011], sCTX [53.6 pg/mL (95% CI 32.6, 74.6), P < 0.0001], and TRACP5b [0.3 U/L (95% CI 0.1, 0.4), P = 0.002]. However, AGEs were not associated with any bone turnover markers in adjusted models. HbA1c, eGFR, and AGEs were not associated with sclerostin levels. CONCLUSIONS: Among older adults with T1D, poor glycemic control is a risk factor for reduced bone formation, while reduced kidney function is a risk factor for increased bone resorption and formation.

Risk factors for lower bone mineral density in older adults with type 1 diabetes: a cross-sectional study.

BACKGROUND: Type 1 diabetes is associated with lower bone mineral density (BMD) and increased fracture risk, but little is known regarding the effects of diabetes-related factors on BMD. We assessed whether these factors are associated with lower hip BMD among older adults with type 1 diabetes. METHODS: This cross-sectional study was embedded in a long-term observational study, the Epidemiology of Diabetes Interventions and Complications study (EDIC), a cohort of participants with type 1 diabetes, who were originally enrolled in the Diabetes Control and Complications Trial (DCCT), and were followed-up for more than 30 years at 27 sites in the USA and Canada. All active EDIC participants were eligible except if they were pregnant, weighed above the dual-energy x-ray absorptiometry (DXA) scanner limit, had an implanted neurostimulator, or were not willing to participate. The primary study outcome was total hip BMD. Hip, spine, and radius BMD and trabecular bone score (TBS) were measured with DXA at an annual EDIC visit (2017-19). Time-weighted mean HbA1c, kidney disease, and peripheral neuropathy were measured annually during EDIC, and retinopathy was measured every 4 years. Skin intrinsic fluorescence, a measure of advanced glycation end products (AGEs), and cardiac autonomic neuropathy were assessed once (2009-10) during EDIC. FINDINGS: 1147 of the 1441 participants who were enrolled in the DCCT trial remained active EDIC participants at the start of this cross-sectional study. Between Sept 20, 2017, and Sept 19, 2019, 1094 of 1147 participants were screened for the EDIC Skeletal Health study. 1058 participants completed at least one of a set of DXA scans and were included in the analysis. 47·8% were women and 52·2% were men, 96·6% were White and 3·4% were of other race or ethnicity. The mean age of participants was 59·2 years (SD 6·7). Higher mean HbA1c, higher skin intrinsic fluorescence, and kidney disease (but not retinopathy or neuropathy) were independently associated with a lower total hip BMD. Total hip BMD differed by -10·7 mg/cm2 (95% CI -19·6 to -1·7) for each 1% increase in mean HbA1c, -20·5 mg/cm2 (-29·9 to -11·0) for each 5 unit higher skin intrinsic fluorescence, and -51·7 mg/cm2 (-80·6 to -22·7) in the presence of kidney disease. Similar associations were found for femoral neck and ultra-distal radius BMD, but not for lumbar spine BMD or TBS. INTERPRETATION: Poorer glycaemic control, AGE accumulation, and kidney disease are independent risk factors for lower hip BMD in older adults with type 1 diabetes. Maintenance of glycaemic control and prevention of kidney disease might reduce bone loss and ultimately fractures in this population. Osteoporosis screening might be particularly important in people with these risk factors. Further research to identify AGE blockers could benefit skeletal health. FUNDING: National Institute of Diabetes and Digestive and Kidney Disease.

Coronary Artery Disease Events and Carotid Intima-Media Thickness in Type 1 Diabetes in the DCCT/EDIC Cohort.

Background Carotid artery intima-media thickness (IMT) is associated with the risk of subsequent cardiovascular events in the general population. This association has not been established in type 1 diabetes. Methods and Results We studied if carotid IMT is associated with the risk of a first coronary artery disease event in participants with type 1 diabetes in the EDIC (Epidemiology of Diabetes Interventions and Complications) study, the long-term observational follow-up of the DCCT (Diabetes Control and Complications Trial). Between 1994 and 1996, common carotid artery and internal carotid artery IMT were measured with high-resolution ultrasound in 1309 study participants with a mean age of 35 years and diabetes duration of 13.8 years; 52% were men. Cox proportional hazards models evaluated the association of standardized common carotid artery IMT and internal carotid artery IMT with subsequent cardiovascular events over the next 17 years. Models were adjusted for age, sex, mean hemoglobin A1c levels, and traditional cardiovascular risk factors. Associations of common carotid artery IMT with subsequent CAD were significant after adjustment for imaging device, sex, and age (hazard ratio [HR], 1.23 per 0.09 mm [95% CI, [1.04-1.45]; P=0.0141), but did not remain significant after further adjustment for traditional risk factors and hemoglobin A1c (HR, 1.14 per 0.09 mm [95% CI, 0.97-1.33]; P=0.1206). No significant associations with subsequent coronary artery disease events were seen for internal carotid artery IMT. Conclusions In the DCCT/EDIC cohort with type 1 diabetes, common carotid artery IMT, but not internal carotid artery IMT, is weakly associated with subsequent coronary artery events, an association eliminated after adjusting for coexistent traditional cardiovascular risk factors. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00360815 and NCT00360893.

The Association of Coronary Artery Calcification With Subsequent Incidence of Cardiovascular Disease in Type 1 Diabetes: The DCCT/EDIC Trials.

OBJECTIVES: This study sought to determine the relationship between coronary artery calcium (CAC) scores and subsequent cardiovascular disease (CVD) events in DCCT (Diabetes Control and Complications Trial)/EDIC (Epidemiology of Diabetes Interventions and Complications) participants. BACKGROUND: The CAC score has been validated for improved risk stratification in general populations; however, this association has not been well studied in type 1 diabetes (T1DM). METHODS: Computed tomography (CT) to measure CAC was performed in 1,205 DCCT/EDIC participants at a mean of 42.8 years of age during EDIC years 7 to 9, after the end of DCCT. This study analyzed the association between CAC and time to the first subsequent CVD event or to the first major adverse cardiac event (MACE), a follow-up of 10 to 13 years. CAC was categorized as: 0, >0 to 100, >100 to 300, or >300 Agatston units. RESULTS: Of 1,156 participants at risk for subsequent CVD, 105 had an initial CVD event (8.5 per 1,000 patient-years); and of 1,187 participants at risk for MACE, 51 had an initial MACE event (3.9 per 1,000 patient-years). Event rates among those with scores of zero (n = 817 [70.7%]) were very low for CVD (5.6 per 1,000 patient years). CAC scores >100 to 300 (hazard ratio [HR]: 4.17, 5.40) and >300 (HR: 6.06, 6.91) were associated with higher risks of CVD and MACE, respectively, compared to CAC of 0 (p < 0.0001). CAC scores >0 to 100 were nominally associated with CVD (HR: 1.71; p = 0.0415) but not with MACE (HR: 1.11; p = 0.8134). Similar results were observed when also adjusted for mean HbA1c and conventional CVD risk factors. The increment in the AUC due to CAC was modest. CONCLUSIONS: CAC scores >100 Agatston units were significantly associated with an increased risk of the subsequent occurrence of CVD and MACE in DCCT/EDIC cohort. (Diabetes Control and Complications Trial [DCCT]; NCT00360815; Epidemiology of Diabetes Interventions and Complications [EDIC]; NCT00360893).

Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.

BACKGROUND: Intensive diabetes therapy aimed at achieving near normoglycemia reduces the risk of microvascular and neurologic complications of type 1 diabetes. We studied whether the use of intensive therapy as compared with conventional therapy during the Diabetes Control and Complications Trial (DCCT) affected the long-term incidence of cardiovascular disease. METHODS: The DCCT randomly assigned 1441 patients with type 1 diabetes to intensive or conventional therapy, treating them for a mean of 6.5 years between 1983 and 1993. Ninety-three percent were subsequently followed until February 1, 2005, during the observational Epidemiology of Diabetes Interventions and Complications study. Cardiovascular disease (defined as nonfatal myocardial infarction, stroke, death from cardiovascular disease, confirmed angina, or the need for coronary-artery revascularization) was assessed with standardized measures and classified by an independent committee. RESULTS: During the mean 17 years of follow-up, 46 cardiovascular disease events occurred in 31 patients who had received intensive treatment in the DCCT, as compared with 98 events in 52 patients who had received conventional treatment. Intensive treatment reduced the risk of any cardiovascular disease event by 42 percent (95 percent confidence interval, 9 to 63 percent; P=0.02) and the risk of nonfatal myocardial infarction, stroke, or death from cardiovascular disease by 57 percent (95 percent confidence interval, 12 to 79 percent; P=0.02). The decrease in glycosylated hemoglobin values during the DCCT was significantly associated with most of the positive effects of intensive treatment on the risk of cardiovascular disease. Microalbuminuria and albuminuria were associated with a significant increase in the risk of cardiovascular disease, but differences between treatment groups remained significant (P< or =0.05) after adjusting for these factors. CONCLUSIONS: Intensive diabetes therapy has long-term beneficial effects on the risk of cardiovascular disease in patients with type 1 diabetes.

The effect of intensive glycemic treatment on coronary artery calcification in type 1 diabetic participants of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study.

The Epidemiology of Diabetes Interventions and Complications (EDIC) study, an observational follow-up of the Diabetes Control and Complications Trial (DCCT) type 1 diabetes cohort, measured coronary artery calcification (CAC), an index of atherosclerosis, with computed tomography (CT) in 1,205 EDIC patients at approximately 7-9 years after the end of the DCCT. We examined the influence of the 6.5 years of prior conventional versus intensive diabetes treatment during the DCCT, as well as the effects of cardiovascular disease risk factors, on CAC. The prevalences of CAC >0 and >200 Agatston units were 31.0 and 8.5%, respectively. Compared with the conventional treatment group, the intensive group had significantly lower geometric mean CAC scores and a lower prevalence of CAC >0 in the primary retinopathy prevention cohort, but not in the secondary intervention cohort, and a lower prevalence of CAC >200 in the combined cohorts. Waist-to-hip ratio, smoking, hypertension, and hypercholesterolemia, before or at the time of CT, were significantly associated with CAC in univariate and multivariate analyses. CAC was associated with mean HbA(1c) (A1C) levels before enrollment, during the DCCT, and during the EDIC study. Prior intensive diabetes treatment during the DCCT was associated with less atherosclerosis, largely because of reduced levels of A1C during the DCCT.

Electrocardiographic Abnormalities and Cardiovascular Disease Risk in Type 1 Diabetes: The Epidemiology of Diabetes Interventions and Complications (EDIC) Study.

OBJECTIVE: We examined the association between the prevalence and incidence of electrocardiographic (ECG) abnormalities and the development of cardiovascular disease (CVD) in patients with type 1 diabetes, among whom these ECG abnormalities are common. RESEARCH DESIGN AND METHODS: We conducted a longitudinal cohort study involving 1,306 patients with type 1 diabetes (mean age 35.5 ± 6.9 years; 47.7% female) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study. ECG abnormalities were defined by the Minnesota Code ECG classification as major, minor, or no abnormality. CVD events were defined as the first occurrence of myocardial infarction, stroke, confirmed angina, coronary artery revascularization, congestive heart failure, or death from any CVD. RESULTS: During a median follow-up of 19 years, 155 participants (11.9%) developed CVD events. In multivariable Cox proportional hazard models adjusted for demographics and potential confounders, the presence of any major ECG abnormalities as a time-varying covariate was associated with a more than twofold increased risk of CVD events (hazard ratio [HR] 2.10 [95% CI 1.26, 3.48] vs. no abnormality/normal ECG, and 2.19 [1.46, 3.29] vs. no major abnormality). Also, each visit (year) at which the diagnosis of major ECG abnormality was retained was associated with a 30% increased risk of CVD (HR 1.30 [95% CI 1.14, 1.48]). The presence of minor ECG abnormalities was not associated with a significant increase in CVD risk. CONCLUSIONS: The presence of major ECG abnormalities is associated with an increased risk of CVD in patients with type 1 diabetes. This suggests a potential role for ECG screening in patients with type 1 diabetes to identify individuals at risk for CVD.

Significance of Epicardial and Intrathoracic Adipose Tissue Volume among Type 1 Diabetes Patients in the DCCT/EDIC: A Pilot Study.

INTRODUCTION: Type 1 diabetes (T1DM) patients are at increased risk of coronary artery disease (CAD). This pilot study sought to evaluate the relationship between epicardial adipose tissue (EAT) and intra-thoracic adipose tissue (IAT) volumes and cardio-metabolic risk factors in T1DM. METHOD: EAT/IAT volumes in 100 patients, underwent non-contrast cardiac computed tomography in the Diabetes Control and Complications Trial /Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study were measured by a certified reader. Fat was defined as pixels' density of -30 to -190 Hounsfield Unit. The associations were assessed using-Pearson partial correlation and linear regression models adjusted for gender and age with inverse probability sample weighting. RESULTS: The weighted mean age was 43 years (range 32-57) and 53% were male. Adjusted for gender, Pearson correlation analysis showed a significant correlation between age and EAT/IAT volumes (both p<0.001). After adjusting for gender and age, participants with greater BMI, higher waist to hip ratio (WTH), higher weighted HbA1c, elevated triglyceride level, and a history of albumin excretion rate of equal or greater than 300 mg/d (AER≥300) or end stage renal disease (ESRD) had significantly larger EAT/IAT volumes. CONCLUSION: T1DM patients with greater BMI, WTH ratio, weighted HbA1c level, triglyceride level and AER≥300/ESRD had significantly larger EAT/IAT volumes. Larger sample size studies are recommended to evaluate independency.

Progression of Electrocardiographic Abnormalities in Type 1 Diabetes During 16 Years of Follow-up: The Epidemiology of Diabetes Interventions and Complications (EDIC) Study.

BACKGROUND: The electrocardiogram (ECG) is an objective tool for cardiovascular disease (CVD) risk assessment. METHODS AND RESULTS: We evaluated distribution of ECG abnormalities and risk factors for developing new abnormalities in 1314 patients with type 1 diabetes (T1D) from the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Annual ECGs were centrally read. ECG abnormalities were classified as major and minor according to the Minnesota ECG Classification. At EDIC year 1 (baseline), 356 (27.1%) of the participants had at least 1 ECG abnormality (major or minor) whereas 26 (2%) had at least one major abnormality. During 16 years of follow-up, 1016 (77.3%) participants developed at least 1 new ECG abnormality (major or minor), whereas 172 (13.1%) developed at least 1 new major abnormality. Independent risk factors for developing new major ECG abnormalities were: age, current smoking, increased systolic blood pressure, and higher glycosylated hemoglobin (hazard ratio [HR] [95% CI]: 1.04 [1.02-1.06] per 1-year increase, 1.75 [1.22-2.53], 1.03 [1.01-1.05] per 1 mm Hg increase, and 1.16 [1.04-1.29] per 10% increase, respectively). Independent risk factors for developing any new ECG abnormalities (major or minor) were age and systolic blood pressure (HR [95% CI]: 1.02 [1.01-1.03] per 1-year increase and 1.01 [1.00-1.02] per 1 mm Hg increase, respectively). CONCLUSIONS: New ECG abnormalities commonly occur in the course of T1D, consistent with the recognized increasing risk for CVD as patients age. Advanced age, increased systolic blood pressure, smoking, and higher HbA1c are independent risk factor for developing major ECG abnormalities, which underscores the importance of tight glucose control in T1D in addition to management of common CVD risk factors.

Haptoglobin 2-2 genotype and the risk of coronary artery disease in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study (DCCT/EDIC).

AIMS/HYPOTHESIS: Haptoglobin(Hp) 2-2 genotype has been shown to increase coronary artery disease (CAD) risk in numerous type 2 diabetes studies but in only one type 1 diabetes cohort. We assessed the association of Hp2-2 with incident CAD over 26years of follow-up in 1303 Caucasian participants of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. METHODS: DCCT randomized volunteers with type 1 diabetes to intensive versus conventional therapy within two cohorts: 'primary prevention' with 1-5years diabetes duration and 'secondary intervention' with 1-15years diabetes duration and early retinopathy, with or without albuminuria, but no advanced complications. CAD was defined as myocardial infarction (MI) or death judged to be from CAD, silent MI, angina, coronary revascularization, or congestive heart failure due to CAD. RESULTS: In the entire DCCTcohort, Hp2-2 was not significantly associated with incident CAD or MI. However, in pre-specified exploratory subgroup analyses, an increased MI risk was suggested in the secondary cohort for those with Hp2-2. CONCLUSIONS/INTERPRETATION: The analysis does not statistically confirm an overall association between Hp 2-2 and incident CAD, however, some suggestions of associations were observed in secondary analyses.

Aortic distensibility in type 1 diabetes.

OBJECTIVE: To evaluate the relationship between long-term glycemia, traditional cardiovascular disease (CVD) risk factors, and ascending aortic stiffness in type 1 diabetes. RESEARCH DESIGN AND METHODS: Eight hundred seventy-nine subjects in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study were evaluated. The stiffness/distensibility of the ascending thoracic aorta (AA) was measured with magnetic resonance imaging. Associations of AA distensibility and CVD risk factors, mean HbA1c, and cardiovascular complications including macroalbuminuria were assessed using multivariate linear regression models. RESULTS: The mean age of the subjects was 50 ± 7 years (47% women, mean diabetes duration of 28 years). Over 22 years of follow-up, 27% of participants had cardiovascular complications. After adjusting for gender and cohort, AA distensibility was lower with increasing age, mean systolic blood pressure, LDL, and HbA1c measured over an average of 22 years (-26.3% per 10 years, -11.0% per 10 mmHg SBP, -1.8% per 10 mg/dL of LDL, and -9.3% per unit mean HbA1c [%], respectively). Patients with macroalbuminuria had 25% lower AA distensibility compared with those without (P < 0.0001). Lower AA distensibility also was associated with greater ratio of left ventricular mass to volume (-3.4% per 0.1 g/mL; P < 0.0001). CONCLUSIONS: Our findings indicate strong adverse effects of hypertension, chronic hyperglycemia and macroalbuminuria on AA stiffness in type 1 diabetes in the DCCT/EDIC cohort.