Epidemiology of Diabetes Interventions and Complications (EDIC)

During the DCCT, the frequency of cardiovascular events was too low to determine whether the
interventions had significantly different effects. During EDIC, two measures of
atherosclerosis were employed, ultrasound measurement of carotid intima-media wall thickness
(IMT) and electron beam (or multidetector) computed tomography of the heart to measure
coronary artery calcification. The progression of IMT during EDIC was decreased in the former
intensive therapy group compared with the former conventional therapy group. Similarly, the
prevalence of coronary calcification was less in the former intensive treatment group. Both
measures were associated with level of glycemia, measured by HbA1c, during the DCCT,
independent of other established cardiovascular risk factors. The frequency of major CVD
clinical events (defined as any one of the following: fatal and non-fatal myocardial
infarctions and stroke, silent myocardial infarctions, angina confirmed by a positive stress
test or catheterization, and PTCA or CABG) has increased during EDIC. Preliminary analysis of
the clinical events has shown differences between the two DCCT treatment groups that support
a benefit of intensive therapy on clinical CVD outcomes, as previously demonstrated for
atherosclerosis. Collaboration with the Medical University of South Carolina, supported by an
NHLBI Program Project, has explored inflammatory, lipid, and hemorheologic risk factors for
micro- and macrovascular disease during EDIC.

The rate of mortality in the DCCT cohort has been low. The number of events has been too
small to provide a definitive assessment of the possible effects of the initial intensive
versus conventional therapy during DCCT on risk of mortality, or to assess the association of
other complications, principally nephropathy, on risk of mortality. However, projections over
the next 10 years suggest that an adequate number of deaths are expected to allow an
assessment of the effects of previous DCCT therapy, the history of glycemia and emergence of
other complications on the risk of mortality.

COLLABORATIONS- The DCCT/EDIC Research Group has sought to amplify the clinical science
opportunities afforded by the extensive clinical data collected during DCCT/EDIC. Four
important collaborations have extended and expanded our collection of data relevant to CVD.

1. Our collaborators at The Medical University of South Carolina (MUSC) have obtained 3
samples of specially preserved plasma at different time points from approximately 1000
EDIC participants for measurement of multiple risk factors, including nuclear magnetic
resonance lipoprotein profiles. Many of these assays have already been performed and
await correlation analyses with CVD events and their surrogates.

2. Our collaborators at University of Washington have received serum from 85-90% of the
participants every 2 years throughout the DCCT and EDIC for fractionation of
lipoproteins by gradient ultracentrifugation. One of the MUSC collaborators, now at
University of Oklahoma, has added characterization of apoproteins important in
lipoprotein metabolism.

3. In addition to the biochemical data generated by our collaborators at MUSC and the
University of Washington, a DCCT/EDIC Genetics Project has been initiated. (A proposal
for continuation of the genetics project will be submitted separately). Our
collaborators at the Hospital for Sick Children/University of Toronto have received DNA
from virtually all the participants and from 2918 first degree relatives, representing
87% of the relatives who were not available and did not refuse to provide their DNA
outright (25% of all relatives). Genetic analyses for genes influencing CVD are being
conducted by 3 approaches: population based association in the DCCT/EDIC probands with
candidate genes; "trios" analysis with probands and their parents and siblings; family
based associations with multiplex families in whom relatives have also been previously
clinically phenotyped for complications.

4. A collaboration with investigators located in several centers, including UCSF, that
focuses on urologic and sexual dysfunction in diabetes (Uro-EDIC) has yielded important
new insights.

In addition to the major, planned collaborations above, the DCCT/EDIC Research Group has made
its phenotypic data and saved samples available to outside investigators for almost a decade.
The DCCT/EDIC Research Group is also collaborating with the repositories recently established
by NIDDK to share phenotypic data, genetic samples, and other biologic samples, as available,
with external investigators.

Inclusion Criteria:

- A participant in the Diabetes Control and Complications Trial (DCCT)(N01-DK-6-2204-A).