The Diabetes Control and Complications Trial (DCCT, 1983-1993) compared intensive therapy aimed at near normal glycemia versus conventional therapy with no specific glucose targets in 1441 subjects with type 1 diabetes (T1DM). In 1993, after a mean follow-up of 6.5 yrs, the study showed conclusively that intensive therapy reduced the risks of retinopathy, nephropathy, and neuropathy by 35-76%, and that hyperglycemia was a primary determinant of complications. We also described potential adverse effects of intensive therapy;assessed its effects on cardiovascular disease (CVD) risk factors, neurocognition and quality of life;and projected the lifetime health-economic impact. DCCT intensive therapy was then adopted world- wide as standard-of-care for T1DM. The Epidemiology of Diabetes Interventions and its Complications (EDIC, 1994-present) is the observational follow-up study of the DCCT cohort, with 95% of those surviving actively participating. Most outcomes are evaluated annually. CVD events and deaths are carefully documented and adjudicated. EDIC has notably discovered that the early beneficial effects of intensive treatment on complications have persisted for over 10 years despite the similar HbA1c levels during EDIC in the two groups, termed metabolic memory. Remarkably, former intensive therapy also greatly reduced the risk of CVD events. DCCT/EDIC collaborators have also conducted numerous ancillary studies, with separate funding, most recently including measurement of cardiac function on cardiac MRI and measurement of biomarkers of oxidative stress and inflammation as determinants of complications. The overarching goals for the next 5 years are to follow at least 90% of the surviving cohort;to describe accurately the study-long effects of glycemia (HbA1c) and other established and putative risk factors on diabetes complications and the metabolic memory effects of prior DCCT intensive therapy;and to expand knowledge regarding T1DM and its complications by supporting collaborations for new research funding applications to maximally utilize the cohort, phenotypic data set, and collected biologic and genetic samples. The specific scientific aims are to 1) evaluate effects of risk factors, biomarkers and glycemia on risk of clinical CVD;2) assess the long-term changes in CVD risk factors;3) describe effects of DCCT intensive versus conventional therapy on mortality;4) evaluate risk factors for severe retinopathy/nephropathy;5) assess effects of diurnal glycemic variation on complications;and 6) conduct eight new research projects involving new measurements and analyses.

Public Health Relevance

Patients with T1DM (1,500,000 in the US) are at risk of microvascular and cardiovascular complications that are a major cause of morbidity, mortality and health care cost. The DCCT/EDIC is continuing to describe the long term benefits of intensive therapy on increasingly more severe manifestations of these complications, and to explore the mechanisms by which hyperglycemia and nonglycemic factors lead to an increased risk of these adverse complications, potentially affording a future lifetime free of complications and normal life expectancy for future generations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01DK094157-02
Application #
8437871
Study Section
Special Emphasis Panel (ZDK1-GRB-2 (O4))
Program Officer
Leschek, Ellen W
Project Start
2011-09-30
Project End
2017-06-30
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$6,225,381
Indirect Cost
$628,157
Name
Case Western Reserve University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Lachin, John M; Bebu, Ionut; Bergenstal, Richard M et al. (2017) Response to Comment on Lachin et al. Association of Glycemic Variability in Type 1 Diabetes With Progression of Microvascular Outcomes in the Diabetes Control and Complications Trial. Diabetes Care 2017;40:777-783. Diabetes Care 40:e165-e166
Sandholm, Niina; Van Zuydam, Natalie; Ahlqvist, Emma et al. (2017) The Genetic Landscape of Renal Complications in Type 1 Diabetes. J Am Soc Nephrol 28:557-574
Palmer, Melody R; Holt, Sarah K; Sarma, Aruna V et al. (2017) Longitudinal Patterns of Occurrence and Remission of Erectile Dysfunction in Men With Type 1 Diabetes. J Sex Med 14:1187-1194
Soliman, Elsayed Z; Backlund, Jye-Yu C; Bebu, Ionut et al. (2017) Electrocardiographic Abnormalities and Cardiovascular Disease Risk in Type 1 Diabetes: The Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Diabetes Care 40:793-799
de Boer, Ian H; Gao, Xiaoyu; Bebu, Ionut et al. (2017) Biomarkers of tubulointerstitial damage and function in type 1 diabetes. BMJ Open Diabetes Res Care 5:e000461
Hammad, Samar M; Baker, Nathaniel L; El Abiad, Jad M et al. (2017) Increased Plasma Levels of Select Deoxy-ceramide and Ceramide Species are Associated with Increased Odds of Diabetic Neuropathy in Type 1 Diabetes: A Pilot Study. Neuromolecular Med 19:46-56
Bebu, Ionut; Braffett, Barbara H; Pop-Busui, Rodica et al. (2017) The relationship of blood glucose with cardiovascular disease is mediated over time by traditional risk factors in type 1 diabetes: the DCCT/EDIC study. Diabetologia 60:2084-2091
Armstrong, Anderson C; Ambale-Venkatesh, Bharath; Turkbey, Evrim et al. (2017) 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 40:405-411
Purnell, Jonathan Q; Braffett, Barbara H; Zinman, Bernard et al. (2017) 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 40:1756-1762
Gubitosi-Klug, Rose A; Braffett, Barbara H; White, Neil H et al. (2017) Risk of Severe Hypoglycemia in Type 1 Diabetes Over 30 Years of Follow-up in the DCCT/EDIC Study. Diabetes Care 40:1010-1016

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