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OBJECTIVE To describe the relationships between the cumulative incidences of long-term complications in individuals with type 1 diabetes (T1D) and assess whether observed associations are independent of age, duration of diabetes, and glycemic levels. METHODS Proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), reduced estimated glomerular filtration rate (eGFR), amputations, cardiovascular disease (CVD), and mortality were assessed in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study over ∼30 years. RESEARCH DESIGN AND RESULTS The cumulative incidence of complications ranged from 3% (amputations) to 37% (CSME). There were large differences in the cumulative incidence of PDR between participants with versus without prior CSME (66% vs. 15%), reduced eGFR (59% vs. 29%), and amputation (68% vs. 32%); reduced eGFR with or without prior PDR (25% vs. 9%), amputation (48% vs. 13%), and CVD (30% vs. 11%); CVD with or without prior reduced eGFR (37% vs. 14%) and amputation (50% vs. 16%); and mortality with or without prior reduced eGFR (22% vs. 9%), amputation (35% vs. 8%), and CVD (25% vs. 8%). Adjusted for age, duration of T1D, and mean updated HbA1c, the complications and associations with higher risk included PDR with CSME (hazard ratio [HR] 1.88; 95% CI 1.42, 2.50), reduced eGFR (HR 1.41; 95% CI 1.01, 1.97), and CVD (HR 1.43; 95% CI 1.06, 1.92); CSME with higher risk of PDR (HR 3.94; 95% CI 3.18 4.89), reduced eGFR (HR 1.49; 95% CI 1.10, 2.01), and CVD (HR 1.35; 95% CI 1.03, 1.78); reduced eGFR with higher risk of CVD (HR 2.09; 95% CI 1.44, 3.03), and death (HR 3.40; 95% CI 2.35, 4.92); amputation(s) with death (HR 2.97; 95% CI 1.70, 2.90); and CVD with reduced eGFR (HR 1.59; 95% CI 1.08, 2.34) and death (HR 1.95; 95% CI 1.32, 2.90). CONCLUSIONS Long-term micro- and macrovascular complications and mortality are highly correlated. Age, diabetes duration, and glycemic levels do not completely explain these associations.

OBJECTIVE Intensive glycemic control reduces the risk of kidney, retinal, and neurologic complications in type 1 diabetes (T1D), but whether it reduces the 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 (DFUs) and lower-extremity amputations (LEAs) in the subsequent Epidemiology of Diabetes Interventions and Complications (EDIC) study. RESEARCH DESIGN AND METHODS DCCT participants (n = 1,441) completed 6.5 years on average of intensive versus conventional diabetes treatment, after which 1,408 were enrolled in EDIC and followed annually over 23 years for DFU and LEA occurrences by physical examination. Multivariable Cox proportional hazard regression models estimated associations of DCCT treatment assignment and time-updated exposures with DFU or LEA. RESULTS Intensive versus conventional glycemic control was associated with a significant risk reduction for all DFUs (hazard ratio 0.77 [95% CI 0.60, 0.97]) and a similar magnitude but nonsignificant risk reduction for first-recorded DFUs (0.78 [0.59, 1.03]) and first LEAs (0.70 [0.36, 1.36]). In adjusted Cox models, clinical neuropathy, lower sural nerve conduction velocity, and cardiovascular autonomic neuropathy were associated with higher DFU risk; estimated glomerular filtration rate CONCLUSIONS Early intensive glycemic control decreases long-term DFU risk, the most important antecedent in the causal pathway to LEA.

Objective To describe the relationships between the cumulative incidences of long-term complications in individuals with type 1 diabetes (T1D), and assess whether observed associations are independent of age, duration of diabetes, and glycemic levels. Methods Proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), reduced eGFR, amputations, cardiovascular disease (CVD) and mortality were assessed in DCCT/EDIC over ~30 years. Results The cumulative incidence of complications ranged from 3% (amputations) to 37% (CSME). There were large differences in the cumulative incidence of: PDR between participants with versus without prior CSME (66% vs. 15%), reduced eGFR (59% vs. 29%) and amputation (68% vs. 32%); reduced eGFR with/without prior PDR (25% vs. 9%), amputation (48% vs. 13%), and CVD (30% vs. 11%); CVD with/without prior reduced eGFR (37% vs. 14%) and amputation (50% vs. 16%); and mortality with/without prior reduced eGFR (22% vs. 9%), amputation (35% vs. 8%) and CVD (25% vs. 8%). Adjusted for age, duration of T1D, and mean updated HbA1c, the complications and associations with higher risk included: PDR with CSME (HR=1.88, 95%CI:[1.42,2.50]), reduced eGFR (HR=1.41, [1.01,1.97]), and CVD (HR=1.43, [1.06,1.92]); CSME with higher risk of PDR (HR=3.94, [3.18,4.89]), reduced eGFR (HR=1.49, [1.10,2.01]), and CVD (HR=1.35, [1.03,1.78]); reduced eGFR with higher risk of CVD (HR=2.09, [1.44,3.03]) and death (HR=3.40, [2.35,4.92]); amputation(s) with death (HR=2.97, [1.70,2.90]); and CVD with reduced eGFR (HR=1.59, [1.08,2.34]) and death (HR=1.95, [1.32,2.90]). Conclusions Long term micro- and macrovascular complications and mortality are highly correlated. Age, diabetes duration, and glycemic levels do not completely explain these associations.

The lower risk of cardiovascular disease (CVD) among women compared with men in the general population may be diminished among those with diabetes.To evaluate cardiometabolic risk factors and their management in association with CVD events in women vs men with type 1 diabetes enrolled in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study.This cohort study used data obtained during the combined DCCT (randomized clinical trial, conducted 1983-1993) and EDIC (observational study, conducted 1994 to present) studies through April 30, 2018 (mean [SD] follow-up, 28.8 [5.8] years), at 27 clinical centers in the US and Canada. Data analyses were performed between July 2021 and April 2022.During the DCCT phase, patients were randomized to intensive vs conventional diabetes therapy.Cardiometabolic risk factors and CVD events were assessed via detailed medical history and focused physical examinations. Blood and urine samples were assayed centrally. CVD events were adjudicated by a review committee. Linear mixed models and Cox proportional hazards models evaluated sex differences in cardiometabolic risk factors and CVD risk over follow-up.A total of 1441 participants with type 1 diabetes (mean [SD] age at DCCT baseline, 26.8 [7.1] years; 761 [52.8%] men; 1390 [96.5%] non-Hispanic White) were included. Over the duration of the study, compared with men, women had significantly lower body mass index (BMI, calculated as weight in kilograms divided by height in meters squared; β = -0.43 [SE, 0.16]; P = .006), waist circumference (β = -10.56 cm [SE, 0.52 cm]; P .001), blood pressure (systolic: β = -5.77 mm Hg [SE, 0.35 mm Hg]; P .001; diastolic: β = -3.23 mm Hg [SE, 0.26 mm Hg]; P .001), and triglyceride levels (β = -10.10 mg/dL [SE, 1.98 mg/dL]; P .001); higher HDL cholesterol levels (β = 9.36 mg/dL [SE, 0.57 mg/dL]; P .001); and similar LDL cholesterol levels (β = -0.76 mg/dL [SE, 1.22 mg/dL]; P = .53). Women, compared with men, achieved recommended targets more frequently for blood pressure (ie,130/80 mm Hg: 90.0% vs 77.4%; P .001) and triglycerides (ie,150 mg/dL: 97.3% vs 90.5%; P .001). However, sex-specific HDL cholesterol targets (ie, ≥50 mg/dL for women, ≥40 mg/dL for men) were achieved less often (74.3% vs 86.6%; P .001) and cardioprotective medications were used less frequently in women than men (ie, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker: 29.6% [95% CI, 25.7%-33.9%] vs 40.0% [95% CI, 36.1%-44.0%]; P = .001; lipid-lowering medication: 25.3% [95% CI, 22.1%-28.7%] vs 39.6% [95% CI, 36.1%-43.2%]; P .001). Women also had significantly higher pulse rates (mean [SD], 75.2 [6.8] beats per minute vs 71.8 [6.9] beats per minute; P .001) and hemoglobin A1c levels (mean [SD], 8.3% [1.0%] vs 8.1% [1.0%]; P = .01) and achieved targets for tighter glycemic control less often than men (ie, hemoglobin A1c7%: 11.2% [95% CI, 9.3%-13.3%] vs 14.0% [95% CI, 12.0%-16.3%]; P = .03).These findings suggest that despite a more favorable cardiometabolic risk factor profile, women with type 1 diabetes did not have a significantly lower CVD event burden than men, suggesting a greater clinical impact of cardiometabolic risk factors in women vs men with diabetes. These findings call for conscientious optimization of the control of CVD risk factors in women with type 1 diabetes.

Objective: To describe the prevalence and clinical correlates of functional limitations in middle-aged and older adults with long-standing type 1 diabetes. Research Design and Methods: Functional limitations were assessed for 1,094 participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, a multi-center, longitudinal, observational follow-up of participants with type 1 diabetes randomly assigned to intensive or conventional diabetes therapy during the Diabetes Control and Complications Trial (DCCT). The primary outcome measure was a score . Results: Fifty-three percent of participants were male. The mean age was 59.5±6.8 years and mean diabetes duration was 37.9±4.9 years. The prevalence of SPPB score Conclusions: Almost half of the middle-aged and older adults with long-standing type 1 diabetes reported functional limitations, which were associated with higher HbA1c and BMI, general psychological distress, and cardiac autonomic neuropathy. Future research is needed to determine if these findings are generalizable.

Objective: Individuals with type 1 diabetes (T1DM) are living to ages when neuropathological changes are increasingly evident. We hypothesized that middle-aged and older adults with long-standing T1DM will show abnormal brain structure in comparison to non-diabetic controls. Research Design and Methods: Magnetic resonance imaging (MRI) was used to compare brain structure among 416 T1DM participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study with 99 demographically similar non-diabetic controls at 26 U.S. and Canadian sites. Assessments included total brain (TBV, primary outcome), gray matter (GMV), white matter (WMV), ventricle and white matter hyperintensity (WMH) volumes and white matter fractional anisotropy (FA). Biomedical assessments included HbA1c and lipid levels, blood pressure, and cognitive assessments of memory and psychomotor and mental efficiency (PME). Among EDIC participants, HbA1c, severe hypoglycemia history, and vascular complications were measured longitudinally. Results: Mean age of EDIC participants and controls was 60 years. T1DM participants showed significantly smaller TBV (1206 ± 1.7 vs. 1229 ± 3.5 cm3, p Conclusions: Middle-aged and older adults with T1DM showed brain volume loss and increased vascular injury in comparison to non-diabetic controls, equivalent to 4 to 9 years of brain aging.

Objective: We evaluated blinded continuous glucose monitoring (CGM) profiles in a subset of adults with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study to characterize the frequency of glycemic excursions and contributing factors. Research Design and Methods: CGM-derived metrics were compared for daytime and nighttime periods using blinded CGM for a minimum of 6.5 days (average 11.9 days) and correlated with HbA1c levels, routine use of diabetes devices, and other characteristics in 765 participants. Results: Participants were 58.9±6.5 years of age with diabetes duration 36.8±4.9 years and HbA1c 7.8±1.2%; 58% used insulin pumps and 27% used personal, unblinded CGM. Compared to daytime, nighttime mean sensor glucose was lower, % time in range 70-180 mg/dL (TIR) was similar and hypoglycemia more common. Over the entire recording period, only 9% of the 765 participants achieved >70% TIR and only 28% achieved Conclusions: In adults with long-standing type 1 diabetes, short-term blinded CGM profiles revealed frequent clinically-significant hypoglycemia (

OBJECTIVE We evaluated blinded continuous glucose monitoring (CGM) profiles in a subset of adults with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study to characterize the frequency of glycemic excursions and contributing factors. RESEARCH DESIGN AND METHODS CGM-derived metrics were compared for daytime and nighttime periods using blinded CGM for a minimum of 6.5 days (average 11.9 days) and correlated with HbA1c levels, routine use of diabetes devices, and other characteristics in 765 participants. RESULTS Participants were 58.9 ± 6.5 years of age with diabetes duration 36.8 ± 4.9 years and HbA1c 7.8 ± 1.2%; 58% used insulin pumps, and 27% used personal, unblinded CGM. Compared with daytime, nighttime mean sensor glucose was lower, percent time in range 70–180 mg/dL (TIR) was similar, and hypoglycemia was more common. Over the entire recording period, only 9% of the 765 participants achieved >70% TIR and only 28% achieved CONCLUSIONS In adults with long-standing type 1 diabetes, short-term blinded CGM profiles revealed frequent clinically significant hypoglycemia (

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 or LEA. 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 Conclusions: Early intensive glycemic control decreases long-term DFU risk, the most important antecedent in the causal pathway to LEA.