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Patricia A Cleary - One of the best experts on this subject based on the ideXlab platform.
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impact of excessive weight gain on cardiovascular outcomes in type 1 Diabetes results from the Diabetes Control and complications trial epidemiology of Diabetes interventions and complications dcct edic study
Diabetes Care, 2017Co-Authors: Jonathan Q Purnell, Patricia A Cleary, Bernard Zinman, Barbara H Braffett, Rose Gubitosiklug, G Ziegler, William I Sivitz, John P Bantle, John D BrunzellAbstract:OBJECTIVE Intensive treatment (INT) of type 1 Diabetes reduces the incidence of cardiovascular disease (CVD) events compared with conventional treatment (CONV), but it also results in more weight gain. Our objective was to examine whether excessive weight gain from INT of type 1 Diabetes is independently associated with subsequent CVD events. RESEARCH DESIGN AND METHODS Quartiles (Q) of weight gain in 1,213 participants aged 18 years and older at enrollment in the Diabetes Control and Complications Trial (DCCT) were determined within randomized treatment groups (INT vs. CONV) using change in BMI from baseline to the closeout DCCT visits. Effects of this weight gain on CVD risk factors and outcomes during an additional 20 years of observational follow-up were then determined. RESULTS The Q4 INT group experienced greater proportional weight gain (median change in BMI, 6.08 kg/m2), increases in CVD risk factors, and need for medications for hypertension and lipids compared with the Q1–3 INT and comparable CONV groups. Over a mean of 26 years of follow-up, the numbers of major and total CVD events were not statistically different in Q4 compared with Q1–3 of either the INT or CONV group. By year 14, however, the incident CVD event curve became significantly higher in the Q4 INT group than in the Q1–3 INT groups (P = 0.024) and was similar to that for the CONV group. CONCLUSIONS For the first 13 years after DCCT, INT for type 1 Diabetes reduced macrovascular events compared with CONV, even when excessive weight gain occurred. After this, total CVD events significantly increased in the Q4 INT group, becoming equivalent to those in the CONV group. Longer follow-up is needed to determine whether this trend continues and results in more major CVD events.
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association of cardiovascular risk factors and myocardial fibrosis with early cardiac dysfunction in type 1 Diabetes the Diabetes Control and complications trial epidemiology of Diabetes interventions and complications study
Diabetes Care, 2017Co-Authors: Patricia A Cleary, Jyeyu C Backlund, Anderson C Armstrong, Bharath Ambalevenkatesh, Evrim B Turkbey, Sirisha Donekal, Elzbieta Chamera, John M LachinAbstract:OBJECTIVE We investigated the association of cardiovascular risk factors and myocardial fibrosis with early cardiac dysfunction in type 1 Diabetes. RESEARCH DESIGN AND METHODS Participants with type 1 Diabetes aged 13–39 years without a known history of cardiovascular disease (CVD) (n = 1,441) were recruited into the Diabetes Control and Complications Trial (1983–1993) and subsequently followed in the Epidemiology of Diabetes Interventions and Complications study (1994 to present). Seven hundred fourteen participants underwent cardiac magnetic resonance (CMR) imaging (2007–2009) with late gadolinium enhancement sequences to assess ischemic and nonischemic scars and tagging sequences to evaluate circumferential strain. CMR-derived T1 mapping also was used to assess interstitial fibrosis. The influence of cardiovascular risk factors and myocardial scar on circumferential strain was assessed using linear regression. RESULTS Circumferential dysfunction was consistently associated with older age, male sex, smoking history, obesity, higher blood pressure, lower HDL cholesterol, and higher mean HbA1c. Participants with nonischemic scars (n = 16) had the worst circumferential function compared with those without scars (β ± SE 1.32 ± 0.60; P = 0.03). In sex-adjusted models, the correlation between T1 times and circumferential strain was not significant. In the fully adjusted models, a trend toward circumferential dysfunction in participants with nonischemic scars was found. Left ventricular ejection fraction was not associated with risk factors but was significantly lower if a myocardial scar was present. CONCLUSIONS Traditional CVD risk factors and elevated HbA1c levels are major factors related to early cardiac dysfunction in type 1 Diabetes. Nonischemic myocardial scar, possibly as a marker of chronic exposure to known risk factors, may predict early cardiac dysfunction mediated by diffuse myocardial fibrosis as seen in diabetic cardiomyopathy.
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effects of prior intensive insulin therapy and risk factors on patient reported visual function outcomes in the Diabetes Control and complications trial epidemiology of Diabetes interventions and complications dcct edic cohort
JAMA Ophthalmology, 2016Co-Authors: Rose Gubitosiklug, Patricia A Cleary, Barbara H Braffett, Wanjie Sun, Lloyd Paul Aiello, Arup Das, William V Tamborlane, Ronald KleinAbstract:Importance Preservation of vision in patients with Diabetes mellitus is critical. Interventions to improve glycemic Control through early intensive treatment of Diabetes reduce rates of severe retinopathy and preserve visual acuity. Objective To assess the effects of prior intensive insulin treatment and risk factors on patient-reported visual function in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. Design, Setting, and Participants Cohort study of 1184 participants with type 1 Diabetes from the DCCT/EDIC study (randomized clinical trial followed by an observational follow-up study) who completed the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) during EDIC years 17 through 20 (September 1, 2009, through April 30, 2014) in 28 institutions across the United States and Canada. Main Outcomes and Measures The primary outcome was the composite NEI-VFQ-25 score. Secondary outcomes were visual acuity (measured by the Early Treatment Diabetic Retinopathy Study protocol), retinopathy level (determined by masked grading of stereoscopic color fundus photographs), and NEI-VFQ-25 subscale scores. The composite NEI-VFQ-25 scale and its subscales were scored 0 to 100, corresponding to poor to excellent function, respectively. Results The overall average NEI-VFQ-25 score for 1184 DCCT/EDIC participants (mean [SD] age, 52.3 [6.9] years; 48% female) with a 30-year duration of Diabetes was high (all participants: median, 91.7; interquartile range [IQR], 89.7-96.9; intensive treatment [n = 605]: median, 94.7; IQR, 91.0-97.2; conventional treatment [n = 579]: median, 94.0; IQR, 88.4-96.1; P = .006 for intensive vs conventional). After adjustment for sex, age, hemoglobin A 1c level, and retinopathy level at DCCT baseline, the former intensive treatment group had a significant, albeit modest, improvement in overall NEI-VFQ-25 score compared with the former conventional Diabetes treatment group (median difference, −1.0; 95% CI, −1.7 to −0.3; P = .006). This beneficial treatment effect was fully attributed to the prior glycemic Control in DCCT (explained treatment effect: 100%). Those with visual acuity worse than 20/100 reported the largest decline in visual function (median difference, −21.0; 95% CI, −40.5 to −1.6; P = .03). Conclusions and Relevance In the DCCT/EDIC cohort, patient-reported visual function remains high in both treatment groups, comparable to previous reports of overall health-related quality of life. Intensive Diabetes therapy modestly improved NEI-VFQ-25 score 30 years after the start of the DCCT, the benefit underestimated owing to more nonparticipants from the conventional treatment group. Visual acuity had the greatest effect on patient-reported visual function from among all risk factors. Trial Registration clinicaltrials.gov Identifiers:NCT00360815andNCT00360893
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relationship of urologic complications with health related quality of life and perceived value of health in men and women with type 1 Diabetes the Diabetes Control and complications trial epidemiology of interventions and complications dcct edic cohort
Diabetes Care, 2015Co-Authors: Alan M Jacobson, Patricia A Cleary, Barbara H Braffett, Rodney L. Dunn, Hunter Wessells, Mary E. Larkin, Aruna V. SarmaAbstract:OBJECTIVE Limited information exists about the influence of urologic complications on health-related quality of life (HRQOL) in patients with type 1 Diabetes. RESEARCH DESIGN AND METHODS We studied 664 men and 580 women from the Diabetes Control and Complications Trial/Epidemiology of Interventions and Complications Study: mean ages were 51.6 ± 6.6 and 50.6 ± 7.2 years and duration of Diabetes was 29.5 ± 4.8 and 29.8 ± 5.1 years, respectively. We assessed associations of sexual dysfunction, lower urinary tract symptoms (LUTS), and, in women, urinary incontinence (UI) with general quality of life (SF-36), perceived value of health (EuroQol-5), Diabetes-related quality of life (Diabetes Quality of Life Scale [DQOL]), and psychiatric symptoms (Symptom Checklist 90-R). RESULTS In both men and women, urologic complications adversely affected HRQOL and psychiatric symptoms, even after accounting for history of depression leading to treatment. Multivariable analyses accounting for the presence of diabetic retinopathy, neuropathy, and nephropathy also revealed substantial independent effects. In men, for example, the odds (95% CI) of a low DQOL score (≤25th percentile) were 3.01 (1.90–4.75) times greater with erectile dysfunction and 2.65 (1.68–4.18) times greater with LUTS and in women, 2.04 (1.25–3.35) times greater with sexual dysfunction and 2.71 (1.72–4.27) times greater with UI/LUTS combined compared with men and women without such complications. Similar effects were observed for the other measures. CONCLUSIONS Sexual dysfunction and urinary complications with type 1 Diabetes are associated with decreased quality of life and perceived value of health and with higher levels of psychiatric symptoms, even after accounting for other Diabetes complications and depression treatment.
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effect of glycemic treatment and microvascular complications on menopause in women with type 1 Diabetes in the Diabetes Control and complications trial epidemiology of Diabetes interventions and complications dcct edic cohort
Diabetes Care, 2014Co-Authors: Catherine Kim, Patricia A Cleary, Barbara H Braffett, David M. Nathan, Rodney L. Dunn, Hunter Wessells, Catherine C. Cowie, Mary E. Larkin, Patricia Gatcomb, Aruna V. SarmaAbstract:Objective We examined the impact of intensive vs. conventional Diabetes treatment upon menopause among women with type 1 Diabetes in the Diabetes Control and Complications Trial (DCCT), a randomized Controlled trial of intensive Diabetes treatment, and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Research Design and Methods In a secondary analysis of women in DCCT/EDIC (n=657), outcomes were the cumulative incidences of natural menopause and surgical menopause. Cox regression analyses were used to examine associations with treatment group, time-varying estimates of hemoglobin A1c (HbA1c), insulin dosage, body mass index (BMI), and microvascular complications (retinopathy, nephropathy, and neuropathy). Results By EDIC year 18, after an average of 28 years of follow-up, 240 (38%) women had experienced natural menopause and 115 (18%) women had experienced surgical menopause. Age at natural menopause was similar in the intensive vs. conventional groups (49.9 vs. 49.0 years, p=0.28), and age at surgical menopause was similar in the intensive vs. conventional groups (40.8 vs. 42.0 years, p=0.31). In multivariable models, treatment group, HbA1c, and microvascular complications were not associated with risk of natural or surgical menopause. Each 10 unit/day increase in insulin dosage decreased risk of natural menopause (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.75, 0.98) and each kg/m2 increase in BMI increased risk of surgical menopause (HR 1.08, 95% CI 1.00, 1.16). Conclusions In the DCCT/EDIC, intensive vs. conventional treatment group and HbA1c level were not associated with menopause risk. Greater insulin dose was associated with lower menopause risk.
John M Lachin - One of the best experts on this subject based on the ideXlab platform.
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understanding metabolic memory the prolonged influence of glycemia during the Diabetes Control and complications trial dcct on future risks of complications during the study of the epidemiology of Diabetes interventions and complications edic
Diabetes Care, 2021Co-Authors: John M Lachin, David M. NathanAbstract:The Diabetes Control and Complications Trial (DCCT, 1983–1993) showed that intensive therapy (mean HbA1c 7.2%) compared with conventional therapy (mean HbA1c 9.0%) markedly reduced the risks of retinopathy, nephropathy, and neuropathy, and these reductions in complications were entirely attributable, statistically, to the difference in mean HbA1c levels. The DCCT cohort has been followed in the Epidemiology of Diabetes Interventions and Complications (EDIC) study (1994 to date). Early in EDIC, mean HbA1c levels in the former intensively and conventionally treated groups converged. Nevertheless, the beneficial effects of DCCT intensive versus conventional therapy on microvascular complications not only persisted but increased during EDIC. The differences in complications during EDIC were wholly explained, statistically, by differences between groups in HbA1c levels during DCCT. These observations give rise to the concept of metabolic memory. Subsequent similar findings from the UKPDS gave rise to a similar concept, which they called the legacy effect. In this report, we present the evidence to support metabolic memory as both a biological and epidemiological phenomenon and discuss potential underlying mechanisms. We also compare metabolic memory and the legacy effect and conclude that the two are likely biologically similar, with comparable effects on long-term outcomes. The long-term influence of metabolic memory on the risk of micro- and macrovascular complications supports the implementation of intensive therapy, with the goal of maintaining near-normal levels of glycemia, as early and as long as safely possible in order to limit the risk of complications.
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refractive error and retinopathy outcomes in type 1 Diabetes the Diabetes Control and complications trial epidemiology of Diabetes interventions and complications study
Ophthalmology, 2021Co-Authors: Dean P Hainsworth, John M Lachin, Lloyd Paul Aiello, Xiaoyu Gao, Ionut Bebu, Arup Das, Lisa Olmos De Koo, Andrew J Barkmeier, William V Tamborlane, Diabetes ControlAbstract:Purpose To determine the relationship between refractive error and diabetic retinopathy (DR). Design Clinical trial. Participants Type I Diabetes individuals with serial refractive error and DR stage measurements over 30 years in the Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study. Methods Stage of DR was measured every 6 months from standard fundus photographs, and refractive error was measured annually during the 6.5 years of DCCT; then, both were staggered every fourth year during EDIC with the full cohort measured at EDIC years 4 and 10. Outcomes of DR were 2- or 3-step progression, presence of proliferative DR (PDR), clinically significant macular edema (CSME), diabetic macular edema (DME), or ocular surgery. Myopia, emmetropia, and hyperopia were defined as a spherical equivalent of ≤−0.5, >−0.5 and Main Outcome Measures For each outcome separately, Cox proportional hazard (PH) models assessed the association between the refractive error status and the subsequent risk of that outcome, both without and with adjustment for potential risk factors. Results Hyperopia was associated with a higher risk of 2-step progression (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.05–1.59), 3-step progression (HR, 1.35; 95% CI, 1.05–1.73), and PDR (HR, 1.40; 95% CI, 1.02–1.92) compared with emmetropia in unadjusted models. These associations remained significant after adjustment for DCCT treatment group, cohort, age, sex, smoking, duration of Diabetes, systolic and diastolic blood pressures, pulse, low-density lipoprotein, high-density lipoprotein, triglycerides, albumin excretion rate, and DCCT/EDIC mean updated hemoglobin A1c (HbA1c) (2-step progression: HR, 1.28; 95% CI, 1.03–1.58; 3-step progression: HR, 1.30; 95% CI, 1.00–1.68; PDR: HR, 1.38; 95% CI, 1.00–1.90). Myopia was not associated with any of the 5 DR outcomes in the unadjusted models and only marginally associated with 2-step progression (HR, 1.11; 95% CI, 1.00–1.24) in the adjusted models. Conclusions Myopia is not associated with DR progression risk. Hyperopia is an independent risk factor for 2-step and 3-step DR progression and PDR.
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risk factors for diabetic peripheral neuropathy and cardiovascular autonomic neuropathy in the Diabetes Control and complications trial epidemiology of Diabetes interventions and complications dcct edic study
Diabetes, 2020Co-Authors: Barbara H Braffett, John M Lachin, Rose Gubitosiklug, James W Albers, Eva L Feldman, Catherine L Martin, Neil H White, Trevor J Orchard, Maria F Lopesvirella, Rodica PopbusuiAbstract:The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study demonstrated that intensive glucose Control reduced the risk of developing diabetic peripheral neuropathy (DPN) and cardiovascular autonomic neuropathy (CAN). We evaluated multiple risk factors and phenotypes associated with DPN and CAN in this large, well-characterized cohort of participants with type 1 Diabetes, followed for >23 years. DPN was defined by symptoms, signs, and nerve conduction study abnormalities in ≥2 nerves; CAN was assessed using standardized cardiovascular reflex tests. Generalized estimating equation models assessed the association of DPN and CAN with individual risk factors measured repeatedly. During DCCT/EDIC, 33% of participants developed DPN and 44% CAN. Higher mean HbA1c was the most significant risk factor for DPN, followed by older age, longer duration, greater height, macroalbuminuria, higher mean pulse rate, β-blocker use, and sustained albuminuria. The most significant risk factor for CAN was older age, followed by higher mean HbA1c, sustained albuminuria, longer duration of type 1 Diabetes, higher mean pulse rate, higher mean systolic blood pressure, β-blocker use, estimated glomerular filtration rate <60 mL/min/1.73 m2, higher most recent pulse rate, and cigarette smoking. These findings identify risk factors and phenotypes of participants with diabetic neuropathy that can be used in the design of new interventional trials and for personalized approaches to neuropathy prevention.
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association of cardiovascular risk factors and myocardial fibrosis with early cardiac dysfunction in type 1 Diabetes the Diabetes Control and complications trial epidemiology of Diabetes interventions and complications study
Diabetes Care, 2017Co-Authors: Patricia A Cleary, Jyeyu C Backlund, Anderson C Armstrong, Bharath Ambalevenkatesh, Evrim B Turkbey, Sirisha Donekal, Elzbieta Chamera, John M LachinAbstract:OBJECTIVE We investigated the association of cardiovascular risk factors and myocardial fibrosis with early cardiac dysfunction in type 1 Diabetes. RESEARCH DESIGN AND METHODS Participants with type 1 Diabetes aged 13–39 years without a known history of cardiovascular disease (CVD) (n = 1,441) were recruited into the Diabetes Control and Complications Trial (1983–1993) and subsequently followed in the Epidemiology of Diabetes Interventions and Complications study (1994 to present). Seven hundred fourteen participants underwent cardiac magnetic resonance (CMR) imaging (2007–2009) with late gadolinium enhancement sequences to assess ischemic and nonischemic scars and tagging sequences to evaluate circumferential strain. CMR-derived T1 mapping also was used to assess interstitial fibrosis. The influence of cardiovascular risk factors and myocardial scar on circumferential strain was assessed using linear regression. RESULTS Circumferential dysfunction was consistently associated with older age, male sex, smoking history, obesity, higher blood pressure, lower HDL cholesterol, and higher mean HbA1c. Participants with nonischemic scars (n = 16) had the worst circumferential function compared with those without scars (β ± SE 1.32 ± 0.60; P = 0.03). In sex-adjusted models, the correlation between T1 times and circumferential strain was not significant. In the fully adjusted models, a trend toward circumferential dysfunction in participants with nonischemic scars was found. Left ventricular ejection fraction was not associated with risk factors but was significantly lower if a myocardial scar was present. CONCLUSIONS Traditional CVD risk factors and elevated HbA1c levels are major factors related to early cardiac dysfunction in type 1 Diabetes. Nonischemic myocardial scar, possibly as a marker of chronic exposure to known risk factors, may predict early cardiac dysfunction mediated by diffuse myocardial fibrosis as seen in diabetic cardiomyopathy.
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impact of c peptide preservation on metabolic and clinical outcomes in the Diabetes Control and complications trial
Diabetes, 2014Co-Authors: John M Lachin, Paula Mcgee, Jerry P. PalmerAbstract:The Diabetes Control and Complications Trial established that a stimulated C-peptide concentration ≥0.2 nmol/L at study entry among subjects with up to a 5-year Diabetes duration is associated with favorable metabolic and clinical outcomes over the subsequent 7 years of follow-up. Herein we further examine the association of both fasting and stimulated C-peptide numerical values with outcomes. In the intensive treatment group, for a 50% higher stimulated C-peptide on entry, such as from 0.10 to 0.15 nmol/L, HbA 1c decreased by 0.07% (0.8 mmol/mol; P = 0.0003), insulin dose decreased by 0.0276 units/kg/day ( P P P = 0.0010), all in unadjusted analyses. Other than HbA 1c , these effects remained significant after adjusting for the HbA 1c on entry. While C-peptide was not significantly associated with the incidence of nephropathy, it was strongly associated with the albumin excretion rate. The fasting C-peptide had weaker associations with outcomes. As C-peptide decreased to nonmeasurable concentrations, the outcomes changed in a nearly linear manner, with no threshold or breakpoint. While preservation of stimulated C-peptide at ≥0.2 nmol/L has clinically beneficial outcomes, so also does an increase in the concentration of C-peptide across the range of values.
Saul Genuth - One of the best experts on this subject based on the ideXlab platform.
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the Diabetes Control and complications trial epidemiology of Diabetes interventions and complications study 30th anniversary presentations
Diabetes Care, 2014Co-Authors: Bernard Zinman, Saul Genuth, David M. NathanAbstract:The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) both recognized the seminal contributions of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, by scheduling a dedicated DCCT/EDIC symposium in their respective programs “The DCCT/EDIC study: 30 years of progress and contributions.” We are very grateful that both organizations provided the DCCT/EDIC Research Group this important opportunity to highlight our advances and contributions to improving the health and quality of life of people with type 1 Diabetes (T1D). What …
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Diabetes Control and complications trial epidemiology of Diabetes interventions and complications study at 30 years advances and contributions
Diabetes, 2013Co-Authors: David M. Nathan, Patricia A Cleary, John M Lachin, Rose Gubitosiklug, Saul Genuth, M. Bayless, Gayle M. Lorenzi, Bernard ZinmanAbstract:The Diabetes Control and Complications Trial (DCCT) (1) and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (EDIC) Study (2), are celebrating the 30th anniversary since the start of the DCCT and 20th since the reporting of the DCCT primary results (3). During the past three decades, our understanding of the relationship between metabolic Control and complications and the treatment of type 1 Diabetes (T1D) has been transformed by the results of DCCT/EDIC. Most importantly, the long-term prospects for patients have dramatically improved with the adoption of intensive therapy designed to achieve near-normal glycemia as the standard of care of T1D. In this Perspective, we present an overview of the major scientific advances provided by the DCCT/EDIC Research Group, the resulting changes in therapy that have improved long-term outcomes in patients with T1D worldwide, and the challenges that remain. ### Background and rationale. After the introduction of insulin therapy in 1922, type 1 Diabetes (T1D) was transformed from a uniformly fatal disease to a chronic degenerative one (4). During the 1930–1960s, the development of chronic complications affecting the eyes, kidneys, peripheral and autonomic nervous system, and a substantially increased risk of cardiovascular disease (CVD) were observed in patients who had survived >20 years with the disease (5). The origin of these newly discovered complications was debated vigorously, and theories to explain them abounded (4,6). The debate led to two opposing philosophies of Diabetes treatment: one in which treatment to achieve glucose concentrations as low as possible was endorsed and another in which glycemic levels were thought to be inconsequential, at least with regard to the pathogenesis of long-term complications (7,8). Although the debate regarding the so-called glucose hypothesis was vigorous, it was largely academic, since objective means of measuring long-term glycemia and of achieving near-normal glycemia did not …
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haptoglobin genotype and the rate of renal function decline in the Diabetes Control and complications trial epidemiology of Diabetes interventions and complications study
Diabetes, 2013Co-Authors: Trevor J Orchard, Patricia A Cleary, John M Lachin, Saul Genuth, Wanjie Sun, Paula Mcgee, Andrew D. Paterson, Philip Raskin, Yefim Anbinder, Andrew P. LevyAbstract:Many patients with type 1 Diabetes develop renal disease despite moderately good metabolic Control, suggesting other risk factors may play a role. Recent evidence suggests that the haptoglobin (HP) 2-2 genotype, which codes for a protein with reduced antioxidant activity, may predict renal function decline in type 1 Diabetes. We examined this hypothesis in 1,303 Caucasian participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. HP genotype was determined by polyacrylamide gel electrophoresis. Glomerular filtration rate was estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and albumin excretion based on timed urine samples. Participants were followed up for a mean of 22 years. HP genotype was significantly associated with the development of sustained estimated glomerular filtration rate (GFR) <60 mL/min/1.73 m2 and with end-stage renal disease (ESRD), with HP 2-2 having greater risk than HP 2-1 and 1-1. No association was seen with albuminuria. Although there was no treatment group interaction, the associations were only significant in the conventional treatment group, where events rates were much higher. We conclude that the HP genotype is significantly associated with the development of reduced GFR and ESRD in the DCCT/EDIC study.
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effect of glycemic exposure on the risk of microvascular complications in the Diabetes Control and complications trial revisited
Diabetes, 2008Co-Authors: John M Lachin, Bernard Zinman, Saul Genuth, David M. Nathan, Brandy N RutledgeAbstract:OBJECTIVE— The Diabetes Control and Complications Trial ( Diabetes 44:968–983, 1995) presented statistical models suggesting that subjects with similar A1C levels had a higher risk of retinopathy progression in the conventional treatment group than in the intensive treatment group. That analysis has been cited to support the hypothesis that specific patterns of glucose variation, in particular postprandial hyperglycemia, contribute uniquely to an increased risk of microvascular complications above and beyond that explained by the A1C level. RESEARCH DESIGN AND METHODS— We performed statistical evaluations of these models and additional analyses to assess whether the original analyses were flawed. RESULTS— Statistically, we show that the original results are an artifact of the assumptions of the statistical model used. Additional analyses show that virtually all (96%) of the beneficial effect of intensive versus conventional therapy on progression of retinopathy is explained by the reductions in the mean A1C levels, similarly for other outcomes. Furthermore, subjects within the intensive and conventional treatment groups with similar A1C levels over time have similar risks of retinopathy progression, especially after adjusting for factors in which they differ. CONCLUSIONS— A1C explains virtually all of the difference in risk of complications between the intensive and conventional groups, and a given A1C level has similar effects within the two treatment groups. While other components of hyperglycemia, such as glucose variation, may contribute to the risk of complications, such factors can only explain a small part of the differences in risk between intensive and conventional therapy over time.
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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
Diabetes, 2006Co-Authors: Patricia A Cleary, Bernard Zinman, Trevor J Orchard, Saul Genuth, Wanjie Sun, Jyeyu C Backlund, Nathan D Wong, Robert Detrano, Alan M Jacobson, John M LachinAbstract: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.
Vincent M Monnier - One of the best experts on this subject based on the ideXlab platform.
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glycation and carboxymethyllysine levels in skin collagen predict the risk of future 10 year progression of diabetic retinopathy and nephropathy in the Diabetes Control and complications trial and epidemiology of Diabetes interventions and complications participants with type 1 Diabetes
Diabetes, 2005Co-Authors: Saul Genuth, Patricia A Cleary, Wanjie Sun, David R Sell, William Dahms, William I Sivitz, John I Malone, Vincent M MonnierAbstract:Several mechanistic pathways linking hyperglycemia to Diabetes complications, including glycation of proteins and formation of advanced glycation end products (AGEs), have been proposed. We investigated the hypothesis that skin collagen glycation and AGEs predict the risk of progression of microvascular disease. We measured glycation products in the skin collagen of 211 Diabetes Control and Complications Trial (DCCT) volunteers in 1992 who continued to be followed in the Epidemiology of Diabetes Interventions and Complications study for 10 years. We determined whether the earlier measurements of glycated collagen and AGE levels correlated with the risk of progression of retinopathy and nephropathy from the end of the DCCT to 10 years later. In multivariate analyses, the combination of furosine (glycated collagen) and carboxymethyllysine (CML) predicted the progression of retinopathy (χ2 = 59.4, P < 0.0001) and nephropathy (χ2 = 18.2, P = 0.0001), even after adjustment for mean HbA1c (A1C) (χ2 = 32.7, P < 0.0001 for retinopathy) and (χ2 = 12.8, P = 0.0016 for nephropathy). The predictive effect of A1C vanished after adjustment for furosine and CML (χ2 = 0.0002, P = 0.987 for retinopathy and χ2 = 0.0002, P = 0.964 for nephropathy). Furosine explained more of the variation in the 10-year progression of retinopathy and nephropathy than did CML. These results strengthen the role of glycation of proteins and AGE formation in the pathogenesis of retinopathy and nephropathy. Glycation and subsequent AGE formation may explain the risk of these complications associated with prior A1C and provide a rational basis for the phenomenon of “metabolic memory” in the pathogenesis of these Diabetes complications.
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skin collagen glycation glycoxidation and crosslinking are lower in subjects with long term intensive versus conventional therapy of type 1 Diabetes relevance of glycated collagen products versus hba1c as markers of diabetic complications dcct skin collagen ancillary study group Diabetes Control and complications trial
Diabetes, 1999Co-Authors: Vincent M Monnier, Patricia A Cleary, John M Lachin, Oliver M Bautista, David Kenny, David R Sell, John Fogarty, William Dahms, Saul GenuthAbstract:The relationships between long-term intensive Control of glycemia and indicators of skin collagen glycation (furosine), glycoxidation (pentosidine and N(epsilon)-[carboxymethyl]-lysine [CML]), and crosslinking (acid and pepsin solubility) were examined in 216 patients with type 1 Diabetes from the primary prevention and secondary intervention cohorts of the Diabetes Control and Complications Trial. By comparison with conventional treatment, 5 years of intensive treatment was associated with 30-32% lower furosine, 9% lower pentosidine, 9-13% lower CML, 24% higher acid-soluble collagen, and 50% higher pepsin-soluble collagen. All of these differences were statistically significant in the subjects of the primary prevention cohort (P
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skin collagen glycation glycoxidation and crosslinking are lower in subjects with long term intensive versus conventional therapy of type 1 Diabetes relevance of glycated collagen products versus hba1c as markers of diabetic complications dcct skin collagen ancillary study group Diabetes Control and complications trial
Diabetes, 1999Co-Authors: Vincent M Monnier, Patricia A Cleary, John M Lachin, Oliver M Bautista, David Kenny, David R Sell, John Fogarty, William Dahms, Saul GenuthAbstract:The relationships between long-term intensive Control of glycemia and indicators of skin collagen glycation (furosine), glycoxidation (pentosidine and N(epsilon)-[carboxymethyl]-lysine [CML]), and crosslinking (acid and pepsin solubility) were examined in 216 patients with type 1 Diabetes from the primary prevention and secondary intervention cohorts of the Diabetes Control and Complications Trial. By comparison with conventional treatment, 5 years of intensive treatment was associated with 30-32% lower furosine, 9% lower pentosidine, 9-13% lower CML, 24% higher acid-soluble collagen, and 50% higher pepsin-soluble collagen. All of these differences were statistically significant in the subjects of the primary prevention cohort (P < 0.006-0.001) and also of the secondary intervention cohort (P < 0.015-0.001) with the exception of CML and acid-soluble collagen. Age- and duration-adjusted collagen variables were significantly associated with the HbA1c value nearest the biopsy and with cumulative prior HbA1c values. Multiple logistic regression analyses with six nonredundant collagen parameters as independent variables and various expressions of retinopathy, nephropathy, and neuropathy outcomes as dependent variables showed that the complications were significantly associated with the full set of collagen variables. Surprisingly, the percentage of total variance (R2) in complications explained by the collagen variables ranged from 19 to 36% with the intensive treatment and from 14 to 51% with conventional treatment. These associations generally remained significant even after adjustment for HbA1c, and, most unexpectedly, in conventionally treated subjects, glycated collagen was the parameter most consistently associated with diabetic complications. Continued monitoring of these subjects may determine whether glycation products in the skin, and especially the early Amadori product (furosine), have the potential to be predictors of the future risk of developing complications, and perhaps be even better predictors than glycated hemoglobin (HbA1c).
David M. Nathan - One of the best experts on this subject based on the ideXlab platform.
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understanding metabolic memory the prolonged influence of glycemia during the Diabetes Control and complications trial dcct on future risks of complications during the study of the epidemiology of Diabetes interventions and complications edic
Diabetes Care, 2021Co-Authors: John M Lachin, David M. NathanAbstract:The Diabetes Control and Complications Trial (DCCT, 1983–1993) showed that intensive therapy (mean HbA1c 7.2%) compared with conventional therapy (mean HbA1c 9.0%) markedly reduced the risks of retinopathy, nephropathy, and neuropathy, and these reductions in complications were entirely attributable, statistically, to the difference in mean HbA1c levels. The DCCT cohort has been followed in the Epidemiology of Diabetes Interventions and Complications (EDIC) study (1994 to date). Early in EDIC, mean HbA1c levels in the former intensively and conventionally treated groups converged. Nevertheless, the beneficial effects of DCCT intensive versus conventional therapy on microvascular complications not only persisted but increased during EDIC. The differences in complications during EDIC were wholly explained, statistically, by differences between groups in HbA1c levels during DCCT. These observations give rise to the concept of metabolic memory. Subsequent similar findings from the UKPDS gave rise to a similar concept, which they called the legacy effect. In this report, we present the evidence to support metabolic memory as both a biological and epidemiological phenomenon and discuss potential underlying mechanisms. We also compare metabolic memory and the legacy effect and conclude that the two are likely biologically similar, with comparable effects on long-term outcomes. The long-term influence of metabolic memory on the risk of micro- and macrovascular complications supports the implementation of intensive therapy, with the goal of maintaining near-normal levels of glycemia, as early and as long as safely possible in order to limit the risk of complications.
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effect of glycemic treatment and microvascular complications on menopause in women with type 1 Diabetes in the Diabetes Control and complications trial epidemiology of Diabetes interventions and complications dcct edic cohort
Diabetes Care, 2014Co-Authors: Catherine Kim, Patricia A Cleary, Barbara H Braffett, David M. Nathan, Rodney L. Dunn, Hunter Wessells, Catherine C. Cowie, Mary E. Larkin, Patricia Gatcomb, Aruna V. SarmaAbstract:Objective We examined the impact of intensive vs. conventional Diabetes treatment upon menopause among women with type 1 Diabetes in the Diabetes Control and Complications Trial (DCCT), a randomized Controlled trial of intensive Diabetes treatment, and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Research Design and Methods In a secondary analysis of women in DCCT/EDIC (n=657), outcomes were the cumulative incidences of natural menopause and surgical menopause. Cox regression analyses were used to examine associations with treatment group, time-varying estimates of hemoglobin A1c (HbA1c), insulin dosage, body mass index (BMI), and microvascular complications (retinopathy, nephropathy, and neuropathy). Results By EDIC year 18, after an average of 28 years of follow-up, 240 (38%) women had experienced natural menopause and 115 (18%) women had experienced surgical menopause. Age at natural menopause was similar in the intensive vs. conventional groups (49.9 vs. 49.0 years, p=0.28), and age at surgical menopause was similar in the intensive vs. conventional groups (40.8 vs. 42.0 years, p=0.31). In multivariable models, treatment group, HbA1c, and microvascular complications were not associated with risk of natural or surgical menopause. Each 10 unit/day increase in insulin dosage decreased risk of natural menopause (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.75, 0.98) and each kg/m2 increase in BMI increased risk of surgical menopause (HR 1.08, 95% CI 1.00, 1.16). Conclusions In the DCCT/EDIC, intensive vs. conventional treatment group and HbA1c level were not associated with menopause risk. Greater insulin dose was associated with lower menopause risk.
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self reported autoimmune disease by sex in the Diabetes Control and complications trial epidemiology of Diabetes interventions and complications dcct edic study
Diabetes Care, 2014Co-Authors: Elizabeth Buschur, Patricia A Cleary, Barbara H Braffett, Aruna V. Sarma, Rodney L. Dunn, Hunter Wessells, Massimo Pietropaolo, Catherine C. Cowie, Mary E. Larkin, David M. NathanAbstract:People with type 1 Diabetes have an increased risk for autoimmune thyroid disease, which is more common in women than in men according to at least one (1) but not all (2) studies. Exposures unique to women, such as pregnancy, exogenous estrogen, and menopause, have been linked to other autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus (3). However, studies examining such exposures in women with type 1 Diabetes are unavailable. Because the incidence of type 1 Diabetes is increasing worldwide, it is important to determine the factors associated with comorbid conditions (4). We analyzed participants ( n = 1,324) in the Diabetes Control and Complications Trial (DCCT), a randomized trial of intensive insulin therapy, and its follow-up, Epidemiology of Diabetes Interventions and Complications (EDIC). With the use of Cox regression models, we estimated hypothyroid risk associated with sex, age, DCCT treatment group, Diabetes duration, microvascular complications, and hemoglobin A1c (HbA1c). Among women, we further examined parity, menopause, and estrogen use. We also report the cumulative …
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the Diabetes Control and complications trial epidemiology of Diabetes interventions and complications study 30th anniversary presentations
Diabetes Care, 2014Co-Authors: Bernard Zinman, Saul Genuth, David M. NathanAbstract:The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) both recognized the seminal contributions of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, by scheduling a dedicated DCCT/EDIC symposium in their respective programs “The DCCT/EDIC study: 30 years of progress and contributions.” We are very grateful that both organizations provided the DCCT/EDIC Research Group this important opportunity to highlight our advances and contributions to improving the health and quality of life of people with type 1 Diabetes (T1D). What …
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the Diabetes Control and complications trial epidemiology of Diabetes interventions and complications study at 30 years overview
Diabetes Care, 2014Co-Authors: David M. NathanAbstract:OBJECTIVE The Diabetes Control and Complications Trial (DCCT) was designed to test the glucose hypothesis and determine whether the complications of type 1 Diabetes (T1DM) could be prevented or delayed. The Epidemiology of Diabetes Interventions and Complications (EDIC) observational follow-up determined the durability of the DCCT effects on the more-advanced stages of Diabetes complications including cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS The DCCT (1982-1993) was a Controlled clinical trial in 1,441 subjects with T1DM comparing intensive therapy (INT), aimed at achieving levels of glycemia as close to the nondiabetic range as safely possible, with conventional therapy (CON), which aimed to maintain safe asymptomatic glucose Control. INT utilized three or more daily insulin injections or insulin pump therapy guided by self-monitored glucose. EDIC (1994-present) is an observational study of the DCCT cohort. RESULTS The DCCT followed >99% of the cohort for a mean of 6.5 years and demonstrated a 35-76% reduction in the early stages of microvascular disease with INT, with a median HbA1c of 7%, compared with CONV, with a median HbA1c of 9%. The major adverse effect of INT was a threefold increased risk of hypoglycemia, which was not associated with a decline in cognitive function or quality of life. EDIC showed a durable effect of initial assigned therapies despite a loss of the glycemic separation (metabolic memory) and demonstrated that the reduction in early-stage complications during the DCCT translated into substantial reductions in severe complications and CVD. CONCLUSIONS DCCT/EDIC has demonstrated the effectiveness of INT in reducing the long-term complications of T1DM and improving the prospects for a healthy life span.