Objective: Intensive glycemic control reduces risk of kidney, retinal,
and neurologic complications in type 1 diabetes (T1D), but whether it reduces
risk of lower extremity complications is unknown. We examined whether former intensive
versus conventional glycemic control among Diabetes Control and Complications
Trial (DCCT) participants with T1D reduced the long-term risk of diabetic foot
ulcers (DFU) and lower extremity amputations (LEA) in the subsequent
Epidemiology of Diabetes Interventions and Complications (EDIC) study.
Research Design and Methods: DCCT participants [n=1441] completed 6.5
years on average of intensive vs conventional diabetes treatment, after which
1408 were enrolled in EDIC and followed annually over 23 years for DFU and LEA
occurrences by physical examination. Multivariable Cox models estimated
associations of DCCT treatment assignment and time-updated exposures with DFU
Results: Intensive versus conventional glycemic control was associated
with a significant risk reduction for all DFU (Hazard Ratio [HR] 0.77, 95% CI
0.60 to 0.97), and a similar magnitude but nonsignificant risk reduction for first
recorded DFU (HR 0.78, 95% CI 0.59 to 1.03) and first LEA (HR 0.70, 95% CI 0.36
to 1.36). In adjusted Cox models, clinical neuropathy, lower sural nerve
conduction velocity and cardiovascular autonomic neuropathy were associated
with higher DFU risk; eGFR < 60 mL/min/1.73 m2, albuminuria, and
macular edema with higher LEA risk; and any retinopathy and greater time-weighted
mean DCCT/EDIC HbA1c with higher risk
of both outcomes (p<0.05).
Conclusions: Early intensive glycemic control decreases long-term DFU risk,
the most important antecedent in the causal pathway to LEA.
The DCCT/EDIC has been supported by cooperative agreement grants (1982-1993, 2012-2017, 2017-2022), and contracts (1982-2012) with the Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Disease (current grant numbers U01 DK094176 and U01 DK094157), and through support by the National Eye Institute, the National Institute of Neurologic Disorders and Stroke, the General Clinical Research Centers Program (1993-2007), and Clinical Translational Science Center Program (2006-present), Bethesda, Maryland, USA. Industry Contributions: Industry contributors have had no role in the DCCT/EDIC study but have provided free or discounted supplies or equipment to support participants’ adherence to the study: Abbott Diabetes Care (Alameda, CA), Animas (Westchester, PA), Bayer Diabetes Care (North America Headquarters, Tarrytown, NY), Becton, Dickinson and Company (Franklin Lakes, NJ), Eli Lilly (Indianapolis, IN), Extend Nutrition (St. Louis, MO), Insulet Corporation (Bedford, MA), Lifescan (Milpitas, CA), Medtronic Diabetes (Minneapolis, MN), Nipro Home Diagnostics (Ft. Lauderdale, FL), Nova Diabetes Care (Billerica, MA), Omron (Shelton, CT), Perrigo Diabetes Care (Allegan, MI), Roche Diabetes Care (Indianapolis, IN), and Sanofi-Aventis (Bridgewater, NJ).