The Epidemiology of Diabetes Interventions and Complications (EDIC) is a multicenter longitudinal observational study of the Diabetes Control and Complications Trial (DCCT) cohort. One of the major objectives of EDIC is to study the development and progression of atherosclerotic cardiovascular disease in type 1 diabetes. In this study, we evaluated the role of cardiovascular risk factors and antecedent therapy in the DCCT on carotid intima-media wall thickness (IMT) in type 1 diabetes. At ~18 months after the end of the DCCT, high-resolution B-mode ultrasonography was used to assess the carotid arteries of 1,325 patients with type 1 diabetes, 19–51 years of age, with duration of diabetes ranging from 6.3 to 26.1 years. An age- and sex-matched nondiabetic population (n = 153) was studied with the same protocol. The ultrasound protocol was carried out in 28 EDIC clinics by centrally trained and certified sonographers using one of three scanning systems. Determination of IMT from videotaped images was performed by a single reader at the Central Ultrasound Reading Unit. Univariate associations with greater IMT were strongest for older age and longer diabetes duration, greater waist-to-hip ratio (men only), higher blood pressure, higher LDL cholesterol, and smoking. The DCCT therapy group (intensive versus conventional) and HbA1c, measured at the time of the ultrasound or the mean HbA1c during the DCCT, were not significantly related to IMT. Multivariate analyses suggest that age, height, smoking, and BMI were the major predictors of common carotid IMT, whereas age, smoking, and LDL cholesterol predicted internal carotid IMT. There were significant differences between the IMT values of the internal carotid artery in the EDIC male cohort and similarly aged male nondiabetic control subjects. There were no significant differences between the IMT values in the EDIC female cohort and similarly aged female nondiabetic control subjects. At this point in the planned 10-year follow-up of the DCCT cohort, neither intensive therapy nor HbA1c level appears to influence the early signs of atherosclerosis. Traditional risk factors, including age, smoking, and LDL cholesterol, were related to IMT. As the cohort is only now entering the age interval during which rapid progression and clinical expression of atherosclerosis are expected, further follow-up will help to determine the role of hyperglycemia, and its interaction with other risk factors, on the development of atherosclerosis.
To describe the beneficial long-term effects of an average of 6.5 years of intensive diabetes therapy (INT) in type 1 diabetes on measures of atherosclerosis, cardiac structure and function, and clinical cardiovascular events observed in the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) study.
RESEARCH DESIGN AND METHODS
The DCCT was a randomized clinical trial of 1,441 participants assigned to receive INT or conventional therapy (CON). It was conducted between 1983–1993 with an average follow-up of 6.5 years. EDIC (1994–present) is an observational follow-up of the DCCT cohort. Cardiovascular events have been recorded throughout. During EDIC common carotid intima-media thickness (IMT) was measured with ultrasound, coronary artery calcification with computed tomography, and cardiac structure and function with cardiac magnetic resonance imaging.
DCCT INT and lower levels of HbA1c during DCCT/EDIC were associated with thinner carotid IMT, less coronary calcification, and a lower incidence of clinical cardiovascular events including myocardial infarction, stroke, and cardiac death. While there were no significant differences in cardiac structure and function between the former INT and CON groups, they were significantly associated with higher HbA1c during DCCT/EDIC.
DCCT INT and the attendant 6.5 years of lower HbA1c had long-term salutary effects on the development and progression of atherosclerosis and cardiovascular disease during the subsequent follow-up during EDIC.
Cardiovascular disease causes severe morbidity and mortality in type 1 diabetes, although the specific risk factors and whether chronic hyperglycemia has a role are unknown. We examined the progression of carotid intima–media thickness, a measure of atherosclerosis, in a population with type 1 diabetes.
As part of the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the long-term follow-up of the Diabetes Control and Complications Trial (DCCT), 1229 patients with type 1 diabetes underwent B-mode ultrasonography of the internal and common carotid arteries in 1994–1996 and again in 1998–2000. We assessed the intima–media thickness in 611 subjects who had been randomly assigned to receive conventional diabetes treatment during the DCCT and in 618 who had been assigned to receive intensive diabetes treatment.
At year 1 of the EDIC study, the carotid intima–media thickness was similar to that in an age- and sex-matched nondiabetic population. After six years, the intima–media thickness was significantly greater in the diabetic patients than in the controls. The mean progression of the intima–media thickness was significantly less in the group that had received intensive therapy during the DCCT than in the group that had received conventional therapy (progression of the intima–media thickness of the common carotid artery, 0.032 vs. 0.046 mm; P=0.01; and progression of the combined intima–media thickness of the common and internal carotid arteries, −0.155 vs. 0.007; P=0.02) after adjustment for other risk factors. Progression of carotid intima–media thickness was associated with age, and the EDIC base-line systolic blood pressure, smoking, the ratio of low-density lipoprotein to high-density lipoprotein cholesterol, and urinary albumin excretion rate and with the mean glycosylated hemoglobin value during the mean duration (6.5 years) of the DCCT.
Intensive therapy during the DCCT resulted in decreased progression of intima–media thickness six years after the end of the trial.
Intensive diabetes therapy of type 1 diabetes (T1DM) reduces diabetes complications but can be associated with excess weight gain, central obesity, and dyslipidemia.
The purpose of this study was to determine if excessive weight gain with diabetes therapy of T1DM is prospectively associated with atherosclerotic disease.
Methods and Results
Subjects with T1DM (97% Caucasian, 45% female, mean age 35 years) randomly assigned to intensive (INT) or conventional (CONV) diabetes treatment during the Diabetes Control and Complications Trial (DCCT) underwent intima-media thickness (IMT) (n=1015) and coronary artery calcium (CAC) score (n=925) measurements during follow-up in the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. INT subjects were classified by quartile of BMI change during the DCCT. Excess gainers (4th quartile, including CONV subjects meeting this threshold) maintained greater BMI and waist circumference (WC), needed more insulin, had greater IMT (+5%, P<0.001 EDIC year 1, P=0.003 EDIC year 6), and trended towards greater CAC scores (OR 1.55, CI 0.97 – 2.49, P=0.07) than minimal gainers. DCCT subjects meeting metabolic syndrome criteria for WC and blood pressure had greater IMT in both EDIC years (P =0.02 to <0.001); those meeting HDL criteria had greater CAC scores (OR 1.6 and CI 1.1 – 2.4, P=0.01) during follow-up. Increasing frequency of a family history of diabetes, hypertension, and hyperlipidemia was associated with greater IMT thickness with INT but not CONV.
Excess weight gain in DCCT is associated with sustained increases in central obesity, insulin resistance, dyslipidemia and blood pressure, as well as more extensive atherosclerosis during EDIC.
diabetes mellitus; carotid intima media thickness; coronary artery calcium; imaging; obesity
The Diabetes Control and Complications Trial (DCCT) demonstrated the powerful impact of glycemic control on the early manifestations of microvascular complications. Contemporary prospective data on the evolution of macrovascular and late microvascular complications of type 1 diabetes are limited. The Epidemiology of Diabetes Interventions and Complications (EDIC) study is a multicenter, longitudinal, observational study designed to use the well-characterized DCCT cohort of >1,400 patients to determine the long-term effects of prior separation of glycemic levels on micro- and macrovascular outcomes.
RESEARCH DESIGN AND METHODS
Using a standardized annual history and physical examination, 28 EDIC clinical centers that were DCCT clinics will follow the EDIC cohort for 10 years. Annual evaluation also includes resting electrocardiogram, Doppler ultrasound measurements of ankle/arm blood pressure, and screening for nephropathy. At regular intervals, a timed 4-h urine is collected, lipid profiles are obtained, and stereoscopic fundus photographs are taken. In addition, dual B-mode Doppler ultrasound scans of the common and internal carotid arteries will be performed at years 1 and 6 and at study end.
Written informed consent was obtained from 96% of the DCCT subjects. The participants, compared with nonparticipants, tended to have better glycemic control at the completion of the DCCT and were more likely to have their diabetes care provided by DCCT personnel. The EDIC baseline measurement stratified by sex delineates multiple cardiovascular disease risk factor differences such as age (older in men), waist-to-hip ratio (higher in men), HDL cholesterol (lower in men), hypertension (more prevalent in men), and maximum intimal-medial thickness of common and internal carotid arteries (thicker in men). Of the original conventional treatment group, 69% have changed to continuous subcutaneous insulin infusion or multiple daily injections. Although the mean HbA1c difference between the intensive and conventional treatment groups narrowed at EDIC years 1 and 2, HbA1c remained significantly lower in the intensive group. Of all expected clinic visits, 95% were completed, and the quality of EDIC data is very similar to that observed in the DCCT.
Although obvious problems exist in extended follow-up studies of completed clinical trials, these are balanced by the value of continued systematic observation of the DCCT cohort. In contrast to other epidemiologic studies, EDIC will provide 1) definitive data on type 1 as distinct from type 2 diabetes; 2) reliance on prospective rather than on cross-sectional analysis; 3) long-term follow-up in a large population; 4) consistent use of objective, reliable measures of outcomes and glycemia; and 5) observation of patients from before the onset of complications.
Plasma homocysteine (tHcy) has been positively associated with carotid intima-media thickness (IMT) in non-diabetic populations and in a few cross-sectional studies of diabetic patients. We investigated cross-sectional and prospective associations of a single measure of tHcy with common and internal carotid IMT over a 6-year period in type 1 diabetes.
RESEARCH DESIGN AND METHODS
tHcy levels were measured once, in plasma obtained in 1997-1999 from patients (n=599) in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the observational follow-up of the Diabetes Control and Complications Trial (DCCT). Common and internal carotid IMT were determined twice, in EDIC “Year 6” (1998-2000) and “Year 12” (2004-2006), using B-mode ultra-sonography.
After adjustment, plasma tHcy [median (interquartile range): 6.2 (5.1, 7.5) μmol/L] was significantly correlated with age, diastolic blood pressure, renal dysfunction, and smoking (all p<0.05). In an unadjusted model only, increasing quartiles of tHcy correlated with common and internal carotid IMT, again at both EDIC time-points (p<0.01). However, multivariate logistic regression revealed no significant associations between increasing quartiles of tHcy and the 6-year change in common and internal carotid IMT (highest vs. lowest quintile) when adjusted for conventional risk factors.
In a type 1 diabetes cohort from the EDIC study, plasma tHcy measured in samples drawn in 1997-1999 was associated with measures of common and internal carotid IMT measured both one and seven years later, but not with IMT progression between the two time-points. The data do not support routine measurement of tHcy in people with Type 1 diabetes.
High cholesterol levels in circulating immune complexes (IC), surrogate markers of modified LDL, are associated with increased carotid intima-media thickness (IMT) and cardiovascular events in type 1 diabetes. Different modifications of LDL are involved in IC formation, but which of these are predictive of vascular events is not known. Therefore, we measured oxidized LDL (oxLDL), advanced glycation end products–modified LDL (AGE-LDL), and malondialdehyde-modified LDL (MDA-LDL) in IC and determined their relationship with increased carotid IMT and compared the strength of the association with that observed with conventional risk factors.
RESEARCH DESIGN AND METHODS
Levels of oxLDL, AGE-LDL, and MDA-LDL were measured in circulating IC isolated from sera of 479 patients of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort, collected at baseline. Internal and common carotid IMT were measured 8 and 14 years later by DCCT/EDIC.
OxLDL, AGE-LDL, and MDA-LDL levels in circulating IC were significantly correlated with diabetes duration, BMI, and lipid and blood pressure, but not with age. Multivariate logistic regression models indicated that individuals in the highest versus lowest quartile of oxLDL and AGE-LDL in IC had a 6.11-fold [confidence interval (CI) 2.51–14.8] and a 6.4-fold (CI 2.53–16.2) increase in the odds of having high carotid IMT, respectively, after adjusting for conventional risk factors. Parallel analyses resulted in odds ratios of 2.62 (CI 1.24, 5.55) for LDL-C, 1.45 (CI 0.69, 3.03) for diastolic blood pressure, and 2.33 (CI 1.09, 4.99) for A1C.
OxLDL and AGE-LDL in circulating IC were significantly associated with progression and increased levels of carotid IMT in type 1 diabetes.
Type 1 diabetes (T1DM) is associated with increased risk of macrovascular complications. We examined longitudinal associations of serum conventional lipids and nuclear magnetic resonance (NMR)-determined lipoprotein subclasses with carotid intima-media thickness (IMT) in adults with T1DM (n=455) enrolled in the Diabetes Control and Complications Trial (DCCT). Data on serum lipids and lipoproteins were collected at DCCT baseline (1983–89) and were correlated with common and internal carotid IMT determined by ultrasonography during the observational follow-up of the DCCT, the Epidemiology of Diabetes Interventions and Complications (EDIC) study, at EDIC ‘Year 1’ (199–1996) and EDIC ‘Year 6’ (1998–2000). This article contains data on the associations of DCCT baseline lipoprotein profiles (NMR-based VLDL & chylomicrons, IDL/LDL and HDL subclasses and ‘conventional’ total, LDL-, HDL-, non-HDL-cholesterol and triglycerides) with carotid IMT at EDIC Years 1 and 6, stratified by gender. The data are supplemental to our original research article describing detailed associations of DCCT baseline lipids and lipoprotein profiles with EDIC Year 12 carotid IMT (Basu et al. in press) .
Lipids and lipoproteins; Carotid intima-media thickness; Type 1 diabetes; AER, Albumin Excretion Rate; BMI, Body Mass Index; CVD, CardioVascular Disease; DCCT, Diabetes Control and Complications Trial; EDIC, Epidemiology of Diabetes Interventions and Complications; IMT, Intima-Media Thickness; NMR-LSP, Nuclear Magnetic Resonance-determined Lipoprotein Subclass Profiles; T1DM, Type 1 Diabetes Mellitus.
OBJECTIVE—Because endothelial cell dysfunction and inflammation are key contributors to the development of complications in type 1 diabetes, we studied risk factors related to endothelial dysfunction and inflammation (C-reactive protein and fibrinogen, soluble vascular cell adhesion molecule-1, intracellular adhesion molecule-1, and E-selectin, and fibrinolytic markers) in a subgroup of patients from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Intervention and Complications (EDIC) study cohort.
RESEARCH DESIGN AND METHODS—We determined which of these risk factors or clusters thereof are associated with the presence of and subsequent development of nephropathy and macrovascular complications (reflected by carotid intima-media thickness [IMT]).
RESULTS—After adjustment for conventional risk factors (age, sex, DCCT treatment group, diabetes duration, A1C, systolic blood pressure, waist-to-hip ratio, total and HDL cholesterol, and smoking status), fibrinogen remained strongly associated with progression of internal and common carotid IMT (P < 0.01) and soluble E-selectin had a strong association with nephropathy (P < 0.01).
CONCLUSIONS—The best predictor for IMT progression in the DCCT/EDIC cohort was plasma fibrinogen, and the levels of soluble E-selectin discriminate patients with albuminuria better than conventional risk factors.
Intensive diabetes treatment reduces the risk of developing albuminuria in individuals with type 1 diabetes. Effects on the long-term clinical course of kidney disease remain to be defined. We aimed to compare the long-term effects of intensive versus conventional treatment on incident albuminuria.
For this long-term follow-up study of the Diabetes Control and Complications Trial (DCCT) we assessed the effect of intensive diabetes treatment on albuminuria during 18 years after the completion of the trial. During the DCCT (1983–1993), 1441 participants with type 1 diabetes were randomly assigned to receive either intensive treatment (with the goal of achieving levels of glycaemia as close to the non-diabetic range as safely possible) or conventional treatment (aimed at prevention of symptoms of hyperglycaemia and hypoglycaemia). At the end of the DCCT, all participants were instructed in intensive treatment, and all participants were invited to join the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. Mean HbA1c during the EDIC study was similar in the two groups of patients who differed in their treatment assignment during the DCCT. Albumin excretion rate was measured every other year during the EDIC study. Microalbuminuria was defined as an albumin excretion rate of 30 mg per 24 h or higher on two consecutive study visits and macroalbuminuria as an albumin excretion rate of 300 mg per day or higher. We estimated glomerular filtration rate from annual serum creatinine measurements throughout DCCT and the EDIC study. The DCCT is registered with ClinicalTrials.gov, number NCT00360815, and the EDIC study, with number NCT00360893.
During years 1–18 of EDIC, we noted 191 new cases of microalbuminuria (71 in the group receiving intensive treatment during DCCT and 120 in the group receiving conventional treatment during DCCT; risk reduction 45%, 95% CI 26–59) and 117 new cases of macroalbuminuria (31 intensive, 86 conventional; 61%, 41–74). At year 17–18 of EDIC, the prevalence of albumin excretion rate of 30 mg per 24 h or higher was 18·4% in participants assigned to intensive treatment during the DCCT, compared with 24·9% in participants assigned to conventional treatment (p=0·02). During years 1–18 of EDIC, we recorded 84 cases of sustained estimated glomerular filtration rate lower than 60 mL/min per 1·73m2 (31 intensive, 53 conventional; risk reduction 44%, 95% CI 12–64).
In individuals with type 1 diabetes, intensive diabetes treatment yields durable renal benefits that persist for at least 18 years after its application. Ultimately, such benefits should result in fewer patients requiring renal replacement therapy.
National Institute of Diabetes and Digestive and Kidney Disease.
The Diabetes Control and Complications Trial (DCCT) demonstrated the benefits of intensive treatment of diabetes in reducing glycemic levels and slowing the progression of diabetic nephropathy. The DCCT cohort has been examined annually for another 8 years as part of the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study, During the EDIC study, glycemic levels no longer differed substantially between the 2 original treatment groups.
To determine the long-term effects of intensive vs conventional diabetes treatment during the DCCT on kidney function during the EDIC study.
Design, Setting, and Participants
Observational study begun in 1993 (following DCCT closeout) in 28 medical centers in the United States and Canada. Participants were 1349 (of 1375) EDIC volunteers who had kidney evaluation at years 7 or 8.
Main Outcome Measures
Development of microalbuminuria, clinical-grade albuminuria, hypertension, or increase in serum creatinine level.
Results were analyzed by intention-to-treat analyses, comparing the 2 original DCCT treatment groups. New cases of microalbuminuria occurred during the EDIC study in 39 (6.8%) of the participants originally assigned to the intensive-treatment group vs 87 (15.8%) of those assigned to the conventional-treatment group, for a 59% (95% confidence interval [CI], 39% -73%) reduction in odds, adjusted for baseline values, compared with a 59% (95% CI, 36%-74%) reduction at the end of the DCCT (P<.001 for both comparisons). New cases of clinical albuminuria occurred in 9 (1.4%) of the participants in the original intensive-treatment group vs 59 (9.4%) of those in the original conventional-treatment group, representing an 84% reduction in odds (95% Cl, 67%-92%), compared with a reduction of 57% (95% CI, -1 % to +81%) at the end of the DCCT. Fewer cases of hypertension (prevalence at year 8, 29.9% vs 40.3%; P<.001) developed in the original intensive-treatment group. Significantly fewer participants reached a serum creatinine level of 2 mg/dL or greater in the intensive-treatment vs the conventional-treatment group (5 vs 19, P=.004), but there were no differences in mean log clearance values. Although small numbers of patients required dialysis and/or transplantation, fewer patients experienced either of these outcomes in the intensive group (4 vs 7, P=.36).
The persistent beneficial effects on albumin excretion and the reduced incidence of hypertension 7 to 8 years after the end of the DCCT suggest that previous intensive treatment of diabetes with near-normal glycemia during the DCCT has an extended benefit in delaying progression of diabetic nephropathy.
Intensive diabetes therapy reduces the prevalence of coronary calcification and progression of atherosclerosis and the risk of cardiovascular disease (CVD) events in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. The effects of intensive therapy on measures of cardiac function and structure and their association with glycemia have not been explored in type 1 diabetes (T1DM). We assess whether intensive treatment compared with conventional treatment during the DCCT led to differences in these parameters during EDIC. After 6.5 years of intensive versus conventional therapy in the DCCT, and 15 years of additional follow-up in EDIC, left ventricular (LV) indices were measured by cardiac magnetic resonance (CMR) imaging in 1,017 of the 1,371 members of the DCCT cohort. There were no differences between the DCCT intensive versus conventional treatment in end diastolic volume (EDV), end systolic volume, stroke volume (SV), cardiac output (CO), LV mass, ejection fraction, LV mass/EDV, or aortic distensibility (AD). Mean DCCT/EDIC HbA1c over time was associated with EDV, SV, CO, LV mass, LV mass/EDV, and AD. These associations persisted after adjustment for CVD risk factors. Cardiac function and remodeling in T1DM assessed by CMR in the EDIC cohort was associated with prior glycemic exposure, but there was no effect of intensive versus conventional treatment during the DCCT on cardiac parameters.
Over 90% of modified LDL in circulation is associated to specific antibodies circulating as part of immune complexes (IC); however, few studies have examined their relationship with cardiovascular disease.
We report the relationship between circulating concentrations of IC of oxidized LDL (oxLDL-IC), malondialdehyde-LDL (MDA-LDL-IC) and advanced glycation end products-LDL (AGE-LDL-IC) and progression of atherosclerosis over a 12 year period in 467 individuals with type 1 diabetes who participated in the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) study. OxLDL-IC, AGE-LDL-IC and MDA-LDL-IC levels were measured at DCCT closeout. Internal carotid intima-medial thickness (IMT) was measured at EDIC follow-up years 1, 6 and 12.
OxLDL-IC, AGE-LDL-IC and MDA-LDL-IC levels were significantly correlated with age, lipid levels, blood pressure levels and albumin excretion rates. Levels of oxLDL, AGE-LDL and MDA-LDL in isolated LDL-IC were highly inter-correlated (r=0.66 to 0.84, p<0.0001). After adjusting for cardiovascular risk factors individuals in the upper quartile of oxLDL-IC had a 2.98fold increased odds (CI: 1.34, 6.62) of having IMT ≥ 1.00 mm and had a 5.13-fold increased odds (CI: 1.98, 13.3) of having significant IMT progression, relative to those in the lowest quartile. Parallel odds ratios for AGE-LDL-IC were 2.95 (CI: 1.37, 6.34) and 3.50 (CI: 1.38, 8.86), while results for MDA-LDL-IC were 1.76 (0.87, 3.56) and 2.86 (1.20, 6.81).
Our study indicates that high levels of oxLDL-IC and AGE-LDL-IC are important predictors of carotid intima-medial thickening in patients with type 1 diabetes.
modified LDL; subclinical atherosclerosis; carotid artery intima-media thickness; type 1 diabetes
The Epidemiology of Diabetes Interventions and Complications (EDIC) study, a prospective observational follow-up of the Diabetes Control and Complications Trial (DCCT) cohort, reported persistent benefit of prior intensive therapy on retinopathy and nephropathy in type 1 diabetes. We evaluated the effects of prior intensive insulin therapy on the prevalence and incidence of cardiac autonomic neuropathy (CAN) in former DCCT intensive (INT) and conventional (CONV) therapy subjects13-to-14 (13/14) years after DCCT closeout.
Methods and Results
DCCT autonomic measures (R-R variation with paced breathing, Valsalva ratio, postural blood pressure changes, and autonomic symptoms) were repeated in 1,226 EDIC subjects in EDIC year 13/14. Logistic regression models were used to calculate the odds of incident CAN by DCCT treatment group after adjusting for DCCT baseline covariates, duration in the DCCT, and quantitative autonomic measures at DCCT closeout. In EDIC year 13/14, the prevalence of CAN using the DCCT composite definition was significantly lower in former INT group vs. former CONV group (28.9 vs. 35.2%; P = 0.018). Adjusted R-R variation was significantly greater in former DCCT INT vs. former CONV group (29.9 vs.25.9, P < 0.001). Prior DCCT intensive therapy reduced the risks of incident CAN by 31% [odds ratio(95% CI) 0.69 (0.51–0.93)] and of incident abnormal R-R variation by 30% [odds ratio(95%CI) 0.70 (0.51–0.96)] in EDIC year 13/14.
Although CAN prevalence increased in both groups, the incidence was significantly lower in former INT group compared to former CONV group. The benefits of former intensive therapy extend to measures of CAN up to 14 years after DCCT closeout.
type 1 diabetes mellitus; cardiac autonomic neuropathy; nervous system autonomic; intensive glucose control; metabolic memory
Type 1 diabetes mellitus is associated with early atherosclerosis and enhanced cardiovascular mortality. The relationship between carotid IMT (cIMT), a marker of subclinical atherosclerosis and left ventricular (LV) mass, an independent predictor of cardiovascular morbidity has not been previously studied in type 1 diabetics.
The Epidemiology of Diabetes Interventions and Complications (EDIC) study is a multicenter observational study designed to follow up the Diabetes Control and Complications Trial (DCCT) cohort. LV mass was measured with cardiac MRI at EDIC year 15 and common cIMT was assessed using B-mode ultrasound at EDIC year 12. Multivariable linear regression models were used to assess the relationship between cIMT at year 12 and LV mass at year 15.
A total of 889 participants had both cardiac MRI and cIMT measures available for these analyses. At EDIC year 15, the mean age of the participants was 49 (±7) years; mean diabetes duration was 28 (±5) years and 52% were males. Spearman correlation coefficient (r) between LV mass and cIMT was 0.33 (p<0.0001). After adjusting for basic covariates (machine, reader, age and gender), a significant association between LV mass and cIMT (estimate 2.0 g/m2 per 0.1 mm cIMT increment, p < 0.0001) was observed. This association was diminished by the addition of systolic blood pressure in particular 1.15 g/m2 per 0.1 mm cIMT increment, p<0.0001) and to a lessor extent other cardiovascular disease (CVD) risk factors. The relationship observed between LV mass and cIMT was stronger (HOW MUCH) in patients with shorter diabetes duration.
In a well characterized population with type 1 diabetes, cIMT was an independent predictor of higher LV mass. These findings suggest a common pathway, possibly mediated by blood pressure dependent mechanisms, for vascular and myocardial structural change in T1DM.
To describe the development and progression of neuropathy and related findings among patients with type 1 diabetes who participated in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study.
RESEARCH DESIGN AND METHODS
The main diabetic peripheral neuropathy (DPN) outcome was assessed using clinical symptoms, signs, and nerve conduction study results during DCCT and repeated in EDIC year 13/14. Cardiovascular autonomic neuropathy (CAN) was assessed by R-R response to paced breathing, Valsalva ratio, and blood pressure response to standing during DCCT and in EDIC years 13/14 and 16/17. Additionally, symptoms reflecting neuropathic pain and autonomic function (including hypoglycemia awareness) were collected yearly in EDIC using standardized questionnaires; peripheral neuropathy was also assessed annually using the Michigan Neuropathy Screening Instrument. Assessments of genitourinary function were collected at EDIC year 10.
Intensive therapy during the DCCT significantly reduced the risk of DPN and CAN at DCCT closeout (64% and 45%, respectively, P < 0.01). The prevalence and incidence of DPN and CAN remained significantly lower in the DCCT intensive therapy group compared with the DCCT conventional therapy group through EDIC year 13/14.
The persistent effects of prior intensive therapy on neuropathy measures through 14 years of EDIC largely mirror those observed for other diabetes complications. DCCT/EDIC provides important information on the influence of glycemic control, and the clinical course of diabetic neuropathy, and, most important, on how to prevent neuropathy in type 1 diabetes.
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 ~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 HbA1c (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.
We recently reported strong associations between eight skin collagen AGEs and two solubility markers from skin biopsies obtained at DCCT study closeout and the long-term progression of microvascular disease in EDIC, despite adjustment for mean glycemia. Herein we investigated the hypothesis that some of these AGEs (fluorescence to be reported elsewhere) correlate with long-term subclinical cardiovascular disease (CVD) measurements, i.e. coronary artery calcium score (CAC) at EDIC year 7–9 (n = 187), change of carotid intima-media thickness (IMT) from EDIC year 1 to year 6 and 12 (n = 127), and cardiac MRI outcomes at EDIC year 15–16 (n = 142).
Skin collagen AGE measurements obtained from stored specimens were related to clinical data from the DCCT/EDIC using Spearman correlations and multivariable logistic regression analyses.
Spearman correlations showed furosine (early glycation) was associated with future mean CAC (p < 0.05) and CAC >0 (p = 0.39), but not with CAC score <100 vs. >100. Glucosepane and pentosidine crosslinks, methylglyoxal hydroimidazolones (MG-H1) and pepsin solubility (inversely) correlated with IMT change from year 1 to 6(all P < 0.05). Left ventricular (LV) mass (cMRI) correlated with MG-H1, and inversely with pepsin solubility (both p < 0.05), while the ratio LV mass/end diastolic volume correlated with furosine and MG-H1 (both p < 0.05), and highly with CML (p < 0.01). In multivariate analysis only furosine (p = 0.01) was associated with CAC. In contrast IMT was inversely associated with lower collagen pepsin solubility and positively with glucosepane,
In type 1 diabetes, multiple AGEs are associated with IMT progression in spite of adjustment for A1c implying a likely participatory role of glycation and AGE mediated crosslinking on matrix accumulation in coronary arteries. This may also apply to functional cardiac MRI outcomes, especially left ventricular mass. In contrast, early glycation measured by furosine, but not AGEs, was associated with CAC score, implying hyperglycemia as a risk factor in calcium deposition perhaps via processes independent of glycation.
Trial registration: Registered at Clinical trial reg. nos. NCT00360815 and NCT00360893, http://www.clinicaltrials.gov
AGEs; A1c; DCCT/EDIC; Coronary artery calcium; Intima media thickening; Cardiac indices
Preservation of visual acuity in patients with diabetes is critical to preserve VQOL. Interventions to improve glycemic control through early intensive treatment of diabetes reduce rates of severe retinopathy and preserve VA.
To assess the effect of prior intensive treatment and risk factors on visual quality of life (VQOL) in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) cohort.
Randomized controlled clinical trial followed by an observational follow-up study.
28 institutions across the United States and Canada.
1184 DCCT/EDIC participants with type 1 diabetes completed the National Eye Institute (NEI) Visual Functioning Questionnaire (VFQ) during EDIC years 17-20, up to thirty years after the start of the DCCT.
Main Outcome Measures
The 25-item NEI-VFQ was administered. Visual acuity (VA) was measured by the Early Treatment of Diabetic Retinopathy Study (ETDRS) protocol and the presence and severity of retinopathy and macular edema were detected by masked grading of stereoscopic color fundus photographs using the ETDRS retinopathy severity scheme. The composite VQOL and subscales were scored on a scale of 0 to 100 corresponding to poor to excellent function, respectively. Quantile regression was used to assess the treatment/risk factor effect on median QOL score, owing to the ordinal scoring and a skewed distribution.
The overall average VQOL for DCCT/EDIC participants with a 30 year duration of diabetes was high (median 91.7, interquartile (IQR), 89.7-96.9). After adjustment for gender, age, HbA1c, and retinopathy level at DCCT baseline, the former intensive (INT) treatment group had a significant, albeit modest, improvement in overall VQOL compared to the former conventional (CONV) diabetes treatment group (median difference −1.0 [−1.7, −0.3], p=0.0058). This beneficial treatment effect was fully attributed to the prior glycemic control in DCCT (explained treatment effect: 100%). Those with VA worse than 20/100 reported the lowest VQOL score.
Conclusions and Relevance
In the DCCT/EDIC cohort, VQOL remains high in both treatment groups. Intensive diabetes therapy modestly improved VQOL 30 years after the start of the DCCT. VA had the greatest impact on VQOL from among all risk factors.
To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at near-normal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy.
Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome.
After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conventional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; P<.001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (P<.001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT.
The persistent difference in diabetic retinopathy between former intensive and conventional therapy (“metabolic memory”) continues for at least 10 years but may be waning.
To examine the long-term effects of type 1 diabetes treatment, metabolic control, and complications on health-related quality of life (HRQOL).
RESEARCH DESIGN AND METHODS
A total of 1,441 participants, initially 13–39 years of age, were followed for an average of 23.5 years as part of the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study. The Diabetes Quality-of-Life questionnaire (DQOL) was administered annually during DCCT and every other year during EDIC. Biomedical data, including HbA1c levels, exposure to severe hypoglycemia, intercurrent psychiatric events, and development of diabetes complications were collected at regular intervals throughout the follow-up.
Mean total DQOL scores were not significantly different between the former DCCT intensive and conventional treatment groups (DCCT baseline, 78 ± 8 vs. 78 ± 9; EDIC year 17, 75 ± 11 vs. 74 ± 11). Over the course of the study, a drop of ≥5 points in DQOL score from DCCT baseline maintained on two successive visits occurred in 755 individuals and was associated with increased HbA1c, albumin excretion rate, mean blood pressure, BMI, and occurrence of hypoglycemic events requiring assistance. Lower DQOL scores after 23.5 years of follow-up were associated with prior development of retinopathy (P = 0.0196), nephropathy (P = 0.0019), and neuropathy (P < 0.0001) as well as self-reported chest pain (P = 0.0004), decreased vision in both eyes (P = 0.0005), painful paresthesias (P < 0.0001), recurrent urinary incontinence (P = 0.0001), erectile dysfunction (P < 0.0001), and history of psychiatric events (P < 0.0001).
Among DCCT/EDIC participants, worsening metabolic control, serious diabetes complications and their associated symptoms, and development of psychiatric conditions led to decreased HRQOL.
Kidney disease manifests clinically as elevated albumin excretion rate (AER), impaired glomerular filtration rate (GFR), or both, and is a cause of substantial morbidity and mortality in type 1 diabetes (T1D). The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study tested whether intensive diabetes therapy (INT) aimed at lowering glucose concentrations as close as safely possible to the normal range reduces the risks of kidney disease and other diabetes complications.
RESEARCH DESIGN AND METHODS
In the DCCT, 1,441 participants with T1D were randomly assigned to INT or conventional diabetes therapy (CON) for a mean duration of 6.5 years. Subsequently, participants have been followed for 18 years in the ongoing observational EDIC. Standardized longitudinal measurements of AER, estimated GFR, and blood pressure were made throughout the DCCT/EDIC.
During the DCCT, INT reduced the risks of incident microalbuminuria (AER ≥40 mg/24 h) and macroalbuminuria (AER ≥300 mg/24 h) by 39% (95% CI 21–52%) and 54% (29–74%), respectively. During EDIC years 1–8, participants previously assigned to DCCT INT continued to experience lower rates of incident microalbuminuria and macroalbuminuria, with risk reductions of 59% (39–73%) and 84% (67–92%), respectively. Beneficial effects of INT on the development of impaired GFR (sustained estimated GFR <60 mL/min/1.73 m2) and hypertension became evident during combined DCCT/EDIC follow-up, with risk reductions of 50% (18–69%) and 20% (6–21%), respectively, compared with CON.
In the DCCT/EDIC, INT resulted in clinically important, durable reductions in the risks of microalbuminuria, macroalbuminuria, impaired GFR, and hypertension.
The purpose of this report is to summarize and integrate the findings of the Diabetes Control and Complications Trial (DCCT), a randomized controlled clinical trial, and the succeeding observational follow-up of the DCCT cohort in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, regarding the effects of intensive treatment on the microvascular complications of type 1 diabetes mellitus. The DCCT proved that intensive treatment reduced the risks of retinopathy, nephropathy, and neuropathy by 35% to 90% compared with conventional treatment. The absolute risks of retinopathy and nephropathy were proportional to the mean glycosylated hemoglobin (HbA1c) level over the follow-up period preceding each event Intensive treatment was most effective when begun early, before complications were detectable. These risk reductions, achieved at a median HbA1c level difference of 9.1 % for conventional treatment vs 7.3% for intensive treatment have been maintained through 7 years of EDIC, even though the difference in mean HbA1c levels of the 2 former randomized treatment groups was only 0.4% at 1 year (P<.001) (8.3% in the former conventional treatment group vs 7.9% in the former intensive treatment group), continued to narrow, and became statistically nonsignificant by 5 years (8.1 % vs 8.2%, P=.09). The further rate of progression of complications from their levels at the end of the DCCT remains less in the former intensive treatment group. Thus, the benefits of 6.5 years of intensive treatment extend well beyond the period of its most intensive implementation. Intensive treatment should be started as soon as is safely possible after the onset of type 1 diabetes mellitus and maintained thereafter, aiming for a practicable target HbA1c level of 7.0% or less.
Skin collagen Long Wavelength Fluorescence (LWF) is widely used as a surrogate marker for accumulation of advanced glycation end-products. Here we determined the relationship of LWF with glycemia, skin fluorescence, and the progression of complications during EDIC in 216 participants from the DCCT.
LW-1 and collagen-linked fluorescence (CLF) were measured by either High Performance Liquid Chromatography (HPLC) with fluorescence detection (LW-1) or total fluorescence of collagenase digests (CLF) in insoluble skin collagen extracted from skin biopsies obtained at the end of the DCCT (1993). Skin intrinsic fluorescence (SIF) was noninvasively measured on volar forearm skin at EDIC year 16 by the SCOUT DS instrument.
LW-1 levels significantly increased with age and diabetes duration (P < 0.0001) and significantly decreased by intensive vs. conventional glycemic therapy in both the primary (P < 0.0001) and secondary (P < 0.037) DCCT cohorts. Levels were associated with 13–16 year progression risk of retinopathy (>3 sustained microaneurysms, P = 0.0004) and albumin excretion rate (P = 0.0038), the latter despite adjustment for HbA1c. Comparative analysis for all three fluorescent measures for future risk of subclinical macrovascular disease revealed the following significant (P < 0.05) associations after adjusting for age, diabetes duration and HbA1c: coronary artery calcium with SIF and CLF; intima-media thickness with SIF and LW-1; and left ventricular mass with LW-1 and CLF.
LW-1 is a novel risk marker that is robustly and independently associated with the future progression of microvascular disease, intima-media thickness and left ventricular mass in type 1 diabetes.
Trial registration NCT00360815 and NCT00360893 at clinicaltrials.gov
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-016-0343-3) contains supplementary material, which is available to authorized users.
Glycation; Skin autofluorescence; HbA1c; Retinopathy; Nephropathy; Neuropathy
We assessed whether epigenetic histone posttranslational modifications are associated with the prolonged beneficial effects (metabolic memory) of intensive versus conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term Epidemiology of Diabetes Interventions and Complications (EDIC) study. We performed chromatin immunoprecipitation linked to promoter tiling arrays to profile H3 lysine-9 acetylation (H3K9Ac), H3 lysine-4 trimethylation (H3K4Me3), and H3K9Me2 in blood monocytes and lymphocytes obtained from 30 DCCT conventional treatment group subjects (case subjects: mean DCCT HbA1c level >9.1% [76 mmol/mol] and progression of retinopathy or nephropathy by EDIC year 10 of follow-up) versus 30 DCCT intensive treatment subjects (control subjects: mean DCCT HbA1c level <7.3% [56 mmol/mol] and without progression of retinopathy or nephropathy). Monocytes from case subjects had statistically greater numbers of promoter regions with enrichment in H3K9Ac (active chromatin mark) compared with control subjects (P = 0.0096). Among the patients in the two groups combined, monocyte H3K9Ac was significantly associated with the mean HbA1c level during the DCCT and EDIC (each P < 2.2E-16). Of note, the top 38 case hyperacetylated promoters (P < 0.05) included >15 genes related to the nuclear factor-κB inflammatory pathway and were enriched in genes related to diabetes complications. These results suggest an association between HbA1c level and H3K9Ac, and a possible epigenetic explanation for metabolic memory in humans.