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1.  HbA1c and Coronary Heart Disease Risk Among Diabetic Patients 
Diabetes Care  2014;37(2):428-435.
OBJECTIVE
Clinical trials to date have not provided definitive evidence regarding the effects of glucose lowering with coronary heart disease (CHD) risk among diabetic patients.
RESEARCH DESIGN AND METHODS
We prospectively investigated the association of HbA1c at baseline and during follow-up with CHD risk among 17,510 African American and 12,592 white patients with type 2 diabetes.
RESULTS
During a mean follow-up of 6.0 years, 7,258 incident CHD cases were identified. The multivariable-adjusted hazard ratios of CHD associated with different levels of HbA1c at baseline (<6.0 [reference group], 6.0–6.9, 7.0–7.9, 8.0–8.9, 9.0–9.9, 10.0–10.9, and ≥11.0%) were 1.00, 1.07 (95% CI 0.97–1.18), 1.16 (1.04–1.31), 1.15 (1.01–1.32), 1.26 (1.09–1.45), 1.27 (1.09–1.48), and 1.24 (1.10–1.40) (P trend = 0.002) for African Americans and 1.00, 1.04 (0.94–1.14), 1.15 (1.03–1.28), 1.29 (1.13–1.46), 1.41 (1.22–1.62), 1.34 (1.14–1.57), and 1.44 (1.26–1.65) (P trend <0.001) for white patients, respectively. The graded association of HbA1c during follow-up with CHD risk was observed among both African American and white diabetic patients (all P trend <0.001). Each one percentage increase of HbA1c was associated with a greater increase in CHD risk in white versus African American diabetic patients. When stratified by sex, age, smoking status, use of glucose-lowering agents, and income, this graded association of HbA1c with CHD was still present.
CONCLUSIONS
The current study in a low-income population suggests a graded positive association between HbA1c at baseline and during follow-up with the risk of CHD among both African American and white diabetic patients with low socioeconomic status.
doi:10.2337/dc13-1525
PMCID: PMC4179505  PMID: 24130365
2.  Acute Metabolic Effects of Exenatide in Patients With Type 1 Diabetes With and Without Residual Insulin to Oral and Intravenous Glucose Challenges 
Diabetes Care  2013;37(1):210-216.
OBJECTIVE
Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the gastrointestinal tract. Treatment with GLP-1 analogs has proven to be of clinical use for patients with type 2 diabetes. Patients with type 1 diabetes, particularly those with residual β-cell function, may also respond to treatment, but the acute metabolic effects of GLP-1 analogs on these patients in reaction to both oral and intravenous glucose challenges are not well understood.
RESEARCH DESIGN AND METHODS
Seventeen patients with type 1 diabetes, half of whom had residual insulin production, underwent two mixed-meal tolerance tests (MMTTs) and two intravenous glucose tolerance tests (IVGTTs), with and without pretreatment with exenatide. No exogenous bolus insulin was administered for the studies. Glucose excursions, insulin secretion rates (ISRs), and levels of glucagon, endogenous GLP-1, and gastric inhibitory polypeptide were measured after the meal or glucose loads.
RESULTS
During the MMTT, glucose levels were suppressed with exenatide in patients with or without residual insulin production (P = 0.0003). Exenatide treatment did not change the absolute ISR, but the ISR to glucose levels were increased (P = 0.0078). Gastric emptying was delayed (P = 0.0017), and glucagon was suppressed (P = 0.0015). None of these hormonal or glucose changes were detected during the IVGTT with exenatide administration.
CONCLUSIONS
Exenatide showed a significant antidiabetogenic effect prior to an oral meal in patients with type 1 diabetes involving glucagon suppression and gastric emptying, while preserving increased insulin secretion. GLP-1 analogs may be useful as an adjunctive treatment in type 1 diabetes.
doi:10.2337/dc13-1169
PMCID: PMC3968447  PMID: 23939544
3.  Real-Time Support of Pediatric Diabetes Self-Care by a Transport Team 
Diabetes Care  2013;37(1):81-87.
OBJECTIVE
The study seeks to improve access for underserved patients via novel integration of Pedi-Flite (a critical care transport team) and to validate whether this safely enhances diabetes care and effectively expands the endocrine workforce.
RESEARCH DESIGN AND METHODS
The study retrospectively analyzed pager service use in a cohort of established diabetic patients (n = 979) after inception of Pedi-Flite support. Outcomes included incidence and severity of recurrent diabetic ketoacidosis (DKA) and cost savings generated from reduced referrals to the emergency department (ED) and on-call endocrinologist. We generated descriptive statistics to characterize the study population and ED visits for DKA and constructed logistic regression models to examine associations of pager use and likelihood of ED visitation and nonelective inpatient admission from an ED for DKA.
RESULTS
Pager users comprised 30% of the patient population. They were younger but had more established diabetes than nonusers. While pager users were 2.75 times more likely than nonusers to visit the ED for DKA (P < 0.0001), their visits were less likely to lead to inpatient admissions (odds ratio 0.58; P < 0.02). More than half (n = 587) of all calls to the pager were resolved without need for further referral. Estimates suggest that 439 ED visits and 115 admissions were avoided at a potential cost savings exceeding 760,000 USD.
CONCLUSIONS
Integration of a transport service provides a novel, cost-effective approach to reduce disparities in diabetes care. Advantages include scalability, applicability to other disease areas and settings, and low added costs. These findings enrich an emerging evidence base for telephonic care-management models supported by allied health personnel.
doi:10.2337/dc13-1041
PMCID: PMC3968448  PMID: 23959568
7.  Cost-Effectiveness of MODY Genetic Testing: Translating Genomic Advances Into Practical Health Applications 
Diabetes Care  2013;37(1):202-209.
OBJECTIVE
To evaluate the cost-effectiveness of a genetic testing policy for HNF1A-, HNF4A-, and GCK-MODY in a hypothetical cohort of type 2 diabetic patients 25–40 years old with a MODY prevalence of 2%.
RESEARCH DESIGN AND METHODS
We used a simulation model of type 2 diabetes complications based on UK Prospective Diabetes Study data, modified to account for the natural history of disease by genetic subtype to compare a policy of genetic testing at diabetes diagnosis versus a policy of no testing. Under the screening policy, successful sulfonylurea treatment of HNF1A-MODY and HNF4A-MODY was modeled to produce a glycosylated hemoglobin reduction of −1.5% compared with usual care. GCK-MODY received no therapy. Main outcome measures were costs and quality-adjusted life years (QALYs) based on lifetime risk of complications and treatments, expressed as the incremental cost-effectiveness ratio (ICER) (USD/QALY).
RESULTS
The testing policy yielded an average gain of 0.012 QALYs and resulted in an ICER of 205,000 USD. Sensitivity analysis showed that if the MODY prevalence was 6%, the ICER would be ∼50,000 USD. If MODY prevalence was >30%, the testing policy was cost saving. Reducing genetic testing costs to 700 USD also resulted in an ICER of ∼50,000 USD.
CONCLUSIONS
Our simulated model suggests that a policy of testing for MODY in selected populations is cost-effective for the U.S. based on contemporary ICER thresholds. Higher prevalence of MODY in the tested population or decreased testing costs would enhance cost-effectiveness. Our results make a compelling argument for routine coverage of genetic testing in patients with high clinical suspicion of MODY.
doi:10.2337/dc13-0410
PMCID: PMC3867988  PMID: 24026547
8.  Diabetic Retinopathy and Other Ocular Findings in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study 
Diabetes Care  2013;37(1):17-23.
OBJECTIVE
To evaluate whether intensive treatment (INT) with the goal of achieving blood glucose levels as close to the nondiabetic range as safely possible reduced the risk of onset and progression of diabetic retinopathy (DR) in subjects with type 1 diabetes (T1D) compared with conventional therapy (CON).
RESEARCH DESIGN AND METHODS
The Diabetes Control and Complications Trial (DCCT) (1982–1993) was a multicenter, controlled clinical trial comparing INT with CON for onset and progression of DR. The Epidemiology of Diabetes Interventions and Complications (EDIC) study (1994–present) is an observational follow-up of the DCCT cohort.
RESULTS
Of the 1,441 DCCT subjects, 726 had no DR (primary prevention cohort) and 715 had mild DR (secondary intervention cohort) at baseline. Subjects were followed for a mean of 6.5 years. INT median HbA1c was 7% compared with CON median of 9%. INT reduced the adjusted mean risk for the development of DR by 76% and slowed progression of DR by 54% compared with CON. Following DCCT, the HbA1c levels in the original INT and CON groups converged (year 8, INT 7.98%; CON 8.07%); nevertheless, the groups continued to have a durable effect of initial assigned therapy with significantly lower incidence of further DR progression in the INT group (hazard reduction 53–56%). Severe retinal outcomes and procedures to treat them were reduced by 50% in the original INT group.
CONCLUSIONS
INT delays the onset and slows the progression of DR. Furthermore, the early effects of metabolic control continue to accrue over many years despite subsequent comparable glycemic control (metabolic memory). These results emphasize the need for optimizing glycemic control as early as possible in patients with diabetes.
doi:10.2337/dc13-2251
PMCID: PMC3867989  PMID: 24356593
10.  The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study at 30 Years: Summary and Future Directions 
Diabetes Care  2013;37(1):44-49.
OBJECTIVE
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study continues to address knowledge gaps in our understanding of type 1 diabetes and the effects of intensive therapy on its long-term complications.
RESEARCH DESIGN AND METHODS
During the DCCT (1982–1993), a controlled clinical trial of 1,441 subjects with type 1 diabetes, and the EDIC (1994–present), an observational study of the DCCT cohort, core data collection has included medical history questionnaires, surveillance health exams, and frequent laboratory and other evaluations for microvascular and macrovascular disease. Numerous collaborations have expanded the outcome data with more detailed investigations of cardiovascular disease, cognitive function, neuropathy, genetics, and potential biological pathways involved in the development of complications.
RESULTS
The longitudinal follow-up of the DCCT/EDIC cohort provides the opportunity to continue monitoring the durability of intensive treatment as well as to address lingering questions in type 1 diabetes research. Future planned analyses will address the onset and progression of microvascular triopathy, evidence-based screening for retinopathy and nephropathy, effects of glycemic variability and nonglycemic risk factors on outcomes, long-term impact of intensive therapy on cognitive decline, and health economics. Three new proposed investigations include an examination of residual C-peptide secretion and its impact, prevalence of hearing impairment, and evaluation of gastrointestinal dysfunction.
CONCLUSIONS
With the comprehensive data collection and the remarkable participant retention over 30 years, the DCCT/EDIC continues as an irreplaceable resource for understanding type 1 diabetes and its long-term complications.
doi:10.2337/dc13-2148
PMCID: PMC3867991  PMID: 24356597
11.  The Association Between Different A1C-Based Measures of Glycemia and Risk of Cardiovascular Disease Hospitalization 
Diabetes Care  2013;37(1):167-172.
OBJECTIVE
We tested whether average monthly glycemic burden (AMGB), a marker of hyperglycemia that is a function of the extent and duration that A1C exceeded 7%, indicated greater risk of cardiovascular disease (CVD) than traditional A1C measures.
RESEARCH DESIGN AND METHODS
Using a case-control design, we studied 2,456 members of Kaiser Permanente Northwest with type 2 diabetes: 1,228 who experienced a CVD hospitalization, matched on age, sex, and duration of diabetes to 1,228 patients who were not hospitalized for CVD. We calculated AMGB from diabetes diagnosis until CVD hospitalization as a function of the difference between each actual or interpolated A1C measurement and 7%, resulting in an area under the curve estimate of hyperglycemic exposure, adjusted for number of months of observation. We used conditional logistic regression to compare the association between several A1C-based measures of glycemia and CVD, controlling for clinical characteristics and comorbidities.
RESULTS
AMGB was associated with increased CVD risk of 29% (odds ratio 1.29 [95% CI 1.16–1.44]; P < 0.001), while mean A1C was associated with a 22% risk increase (1.22 [1.09–1.37]; P < 0.001). A1C ever exceeding 7% was associated with increased CVD risk of 39% (1.39 [1.08–1.79]; P = 0.010). No model with a glycemia measure provided substantially more information than an identical model without a glycemia measure.
CONCLUSIONS
AMGB demonstrated somewhat greater CVD risk than mean A1C, but its clinical usefulness may be limited. A1C ever rising above 7% (53 mmol/mol) was a simple predictor of CVD risk that may have important clinical ramifications for newly diagnosed patients.
doi:10.2337/dc13-1300
PMCID: PMC3867992  PMID: 23990520
12.  Early Progressive Renal Decline Precedes the Onset of Microalbuminuria and Its Progression to Macroalbuminuria 
Diabetes Care  2013;37(1):226-234.
OBJECTIVE
Progressive decrease in the glomerular filtration rate (GFR), or renal decline, in type 1 diabetes (T1D) is observed in patients with macroalbuminuria. However, it is unknown whether this decline begins during microalbuminuria (MA) or normoalbuminuria (NA).
RESEARCH DESIGN AND METHODS
The study group (second Joslin Kidney Study) comprises patients with T1D and NA (n = 286) or MA (n = 248) who were followed for 4–10 years (median 8 years). Serial measurements (median 6, range 3–16) of serum creatinine and cystatin C were used jointly to estimate GFR (eGFRcr-cys) and assess its trajectories during follow-up.
RESULTS
Renal decline (progressive eGFRcr-cys loss of at least 3.3% per year) occurred in 10% of the NA and 35% of the MA (P < 0.001). In both groups, the strongest determinants of renal decline were baseline serum concentrations of uric acid (P < 0.001) and tumor necrosis factor receptor 1 or 2 (TNFR-1 or -2, P < 0.001). Other significant risk factors included baseline HbA1c, age/diabetes duration, and systolic blood pressure. Relative impacts of these determinants were similar in NA and MA. Renal decline was not associated with sex or baseline serum concentration of TNF-α, IL-6, IL-8, IP-10, MCP-1, VCAM, ICAM, Fas, or FasL.
CONCLUSIONS
Renal decline in T1D begins during NA and it is determined by multiple factors, similar to MA. Thus, this early decline is the primary disease process leading to impaired renal function in T1D. Changes in albumin excretion rate, such as the onset of MA or its progression to macroalbuminuria, are either caused by or develop in parallel to the early renal decline.
doi:10.2337/dc13-0985
PMCID: PMC3867993  PMID: 23939543
13.  Kidney Disease and Related Findings in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study 
Diabetes Care  2013;37(1):24-30.
OBJECTIVE
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.
RESULTS
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.
CONCLUSIONS
In the DCCT/EDIC, INT resulted in clinically important, durable reductions in the risks of microalbuminuria, macroalbuminuria, impaired GFR, and hypertension.
doi:10.2337/dc13-2113
PMCID: PMC3867994  PMID: 24356594
14.  Islet Transplantation Stabilizes Hemostatic Abnormalities and Cerebral Metabolism in Individuals With Type 1 Diabetes 
Diabetes Care  2013;37(1):267-276.
OBJECTIVE
Islets after kidney transplantation have been shown to positively affect the quality of life of individuals with type 1 diabetes (T1D) by reducing the burden of diabetes complications, but fewer data are available for islet transplantation alone (ITA). The aim of this study was to assess whether ITA has a positive impact on hemostatic and cerebral abnormalities in individuals with T1D.
RESEARCH DESIGN AND METHODS
Prothrombotic factors, platelet function/ultrastructure, and cerebral morphology, metabolism, and function have been investigated over a 15-month follow-up period using ELISA/electron microscopy and magnetic resonance imaging, nuclear magnetic resonance spectroscopy, and neuropsychological evaluation (Profile of Mood States test and paced auditory serial addition test) in 22 individuals with T1D who underwent ITA (n = 12) or remained on the waiting list (n = 10). Patients were homogeneous with regard to metabolic criteria, hemostatic parameters, and cerebral morphology/metabolism/function at the time of enrollment on the waiting list.
RESULTS
At the 15-month follow-up, the group undergoing ITA, but not individuals with T1D who remained on the waiting list, showed 1) improved glucose metabolism; 2) near-normal platelet activation and prothrombotic factor levels; 3) near-normal cerebral metabolism and function; and 4) a near-normal neuropsychological test.
CONCLUSIONS
ITA, despite immunosuppressive therapy, is associated with a near-normalization of hemostatic and cerebral abnormalities.
doi:10.2337/dc13-1663
PMCID: PMC3867995  PMID: 24026546
15.  Correlates of Treatment Patterns Among Youth With Type 2 Diabetes 
Diabetes Care  2013;37(1):64-72.
OBJECTIVE
To describe treatment regimens in youth with type 2 diabetes and examine associations between regimens, demographic and clinical characteristics, and glycemic control.
RESEARCH DESIGN AND METHODS
This report includes 474 youth with a clinical diagnosis of type 2 diabetes who completed a SEARCH for Diabetes in Youth study visit. Diabetes treatment regimen was categorized as lifestyle alone, metformin monotherapy, any oral hypoglycemic agent (OHA) other than metformin or two or more OHAs, insulin monotherapy, and insulin plus any OHA(s). Association of treatment with demographic and clinical characteristics (fasting C-peptide [FCP], diabetes duration, and self-monitoring of blood glucose [SMBG]), and A1C was assessed by χ2 and ANOVA. Multiple linear regression models were used to evaluate independent associations of treatment regimens and A1C, adjusting for demographics, diabetes duration, FCP, and SMBG.
RESULTS
Over 50% of participants reported treatment with metformin alone or lifestyle. Of the autoantibody-negative youth, 40% were on metformin alone, while 33% were on insulin-containing regimens. Participants on metformin alone had a lower A1C (7.0 ± 2.0%, 53 ± 22 mmol/mol) than those on insulin alone (9.2 ± 2.7%, 77 ± 30 mmol/mol) or insulin plus OHA (8.6 ± 2.6%, 70 ± 28 mmol/mol) (P < 0.001). These differences remained significant after adjustment (7.5 ± 0.3%, 58 ± 3 mmol/mol; 9.1 ± 0.4%, 76 ± 4 mmol/mol; and 8.6 ± 0.4%, 70 ± 4 mmol/mol) (P < 0.001) and were more striking in those with diabetes for ≥2 years (7.9 ± 2.8, 9.9 ± 2.8, and 9.8 ± 2.6%). Over one-half of those on insulin-containing therapies still experience treatment failure (A1C ≥8%, 64 mmol/mol).
CONCLUSIONS
Approximately half of youth with type 2 diabetes were managed with lifestyle or metformin alone and had better glycemic control than individuals using other therapies. Those with longer diabetes duration in particular commonly experienced treatment failures, and more effective management strategies are needed.
doi:10.2337/dc13-1124
PMCID: PMC3867996  PMID: 24026554
16.  Metabolomics Reveals Broad-Scale Metabolic Perturbations in Hyperglycemic Mothers During Pregnancy 
Diabetes Care  2013;37(1):158-166.
OBJECTIVE
To characterize metabolites across the range of maternal glucose by comparing metabolomic profiles of mothers with high and low fasting plasma glucose (FPG).
RESEARCH DESIGN AND METHODS
We compared fasting serum from an oral glucose tolerance test at ∼28 weeks’ gestation from 67 Northern European ancestry mothers from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study with high (>90th percentile) FPG with 50 mothers with low (<10th percentile) FPG but comparable BMI. Metabolic data from biochemical analyses of conventional clinical metabolites, targeted mass spectrometry (MS)-based measurement of amino acids, and nontargeted gas chromatography/MS were subjected to per-metabolite analyses and collective pathway analyses using Unipathway annotation.
RESULTS
High-FPG mothers had a metabolic profile consistent with insulin resistance including higher triglycerides, 3-hydroxybutyrate, and amino acids including alanine, proline, and branched-chain amino acids (false discovery rate [FDR]-adjusted P < 0.05). Lower 1,5-anhydroglucitol in high-FPG mothers suggested recent hyperglycemic excursions (FDR-adjusted P < 0.05). Pathway analyses indicated differences in amino acid degradation pathways for the two groups (FDR-adjusted P < 0.05), consistent with population-based findings in nonpregnant populations. Exploratory analyses with newborn outcomes indicated positive associations for maternal triglycerides with neonatal sum of skinfolds and cord C-peptide and a negative association between maternal glycine and cord C-peptide (P < 0.05).
CONCLUSIONS
Metabolomics reveals perturbations in metabolism of major macronutrients and amino acid degradation pathways in high- versus low-FPG mothers.
doi:10.2337/dc13-0989
PMCID: PMC3867997  PMID: 23990511
17.  Differential Associations of Oral Glucose Tolerance Test–Derived Measures of Insulin Sensitivity and Pancreatic β-Cell Function With Coronary Artery Calcification and Microalbuminuria in Type 2 Diabetes 
Diabetes Care  2013;37(1):124-133.
OBJECTIVE
We evaluated relationships of oral glucose tolerance testing (OGTT)–derived measures of insulin sensitivity and pancreatic β-cell function with indices of diabetes complications in a cross-sectional study of patients with type 2 diabetes who are free of overt cardiovascular or renal disease.
RESEARCH DESIGN AND METHODS
A subset of participants from the Penn Diabetes Heart Study (n = 672; mean age 59 ± 8 years; 67% male; 60% Caucasian) underwent a standard 2-h, 75-g OGTT. Insulin sensitivity was estimated using the Matsuda Insulin Sensitivity Index (ISI), and β-cell function was estimated using the Insulinogenic Index. Multivariable modeling was used to analyze associations between quartiles of each index with coronary artery calcification (CAC) and microalbuminuria.
RESULTS
The Insulinogenic Index and Matsuda ISI had distinct associations with cardiometabolic risk factors. The top quartile of the Matsuda ISI had a negative association with CAC that remained significant after adjusting for traditional cardiovascular risk factors (Tobit ratio −0.78 [95% CI −1.51 to −0.05]; P = 0.035), but the Insulinogenic Index was not associated with CAC. Conversely, the highest quartile of the Insulinogenic Index, but not the Matsuda ISI, was associated with lower odds of microalbuminuria (OR 0.52 [95% CI 0.30–0.91]; P = 0.022); however, this association was attenuated in models that included duration of diabetes.
CONCLUSIONS
Lower β-cell function is associated with microalbuminuria, a microvascular complication, while impaired insulin sensitivity is associated with higher CAC, a predictor of macrovascular complications. Despite these pathophysiological insights, the Matsuda ISI and Insulinogenic Index are unlikely to be translated into clinical use in type 2 diabetes beyond established clinical variables, such as obesity or duration of diabetes.
doi:10.2337/dc12-1880
PMCID: PMC3867998  PMID: 23949560
18.  The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study at 30 Years: Overview 
Diabetes Care  2013;37(1):9-16.
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.
doi:10.2337/dc13-2112
PMCID: PMC3867999  PMID: 24356592
19.  Neuropathy and Related Findings in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study 
Diabetes Care  2013;37(1):31-38.
OBJECTIVE
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.2337/dc13-2114
PMCID: PMC3868000  PMID: 24356595
21.  Update on Cardiovascular Outcomes at 30 Years of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study 
Diabetes Care  2013;37(1):39-43.
OBJECTIVE
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.2337/dc13-2116
PMCID: PMC3868002  PMID: 24356596

Results 1-25 (3535)