Utility of the NIH Toolbox Cognition Battery in middle to older aged adults with longstanding type 1 diabetes: The DCCT/EDIC study.

Objective: Adults with type 1 diabetes (T1D) face an increased risk for cognitive decline and dementia. Diabetes-related and vascular risk factors have been linked to cognitive decline using detailed neuropsychological testing; however, it is unclear if cognitive screening batteries can detect cognitive changes associated with aging in T1D. Method: 1,049 participants with T1D (median age 59 years; range 43-74) from the Diabetes Control and Complications Trial (DCCT), and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study, completed the NIH Toolbox Cognition Battery (NIHTB-C) and Montreal Cognitive Assessment (MoCA). Neuropsychological assessments, depression, glycated hemoglobin levels (HbA1c), severe hypoglycemia, T1D complications, and vascular risk factors were assessed repeatedly over 32 years to determine associations with current NIHTB-C performance. Available cognitive data was clinically adjudicated to determine cognitive impairment status. Results: NIHTB-C scores had moderate associations (r = 0.36-0.53) with concurrently administered neuropsychological tests. In multivariate models, prior severe hypoglycemic episodes, depression symptoms, nephropathy, lower BMI, and higher HbA1c and LDL cholesterol were associated with poorer NIHTB-C Fluid Cognition Composite scores. The NIHTB-C adequately detected adjudicated cognitive impairment (Area Under the Curve = 0.86; optimal cut score ≤90). The MoCA performed similarly (Area Under the Curve = 0.83; optimal cut score ≤25). Conclusions: The NIHTB-C is sensitive to the cognitive effects of diabetes-related and vascular risk factors, correlated with neuropsychological testing, and accurately detects adjudicated cognitive impairment. These data support its use as a screening test in middle to older aged adults with T1D to determine if referral for detailed neuropsychological assessment is needed.

Physical Function in Middle-aged and Older Adults With Type 1 Diabetes: Long-term Follow-up of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study.

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 multicenter, 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 <10 on the Short Physical Performance Battery (SPPB). The secondary outcome, self-reported functional limitation, was assessed by written questionnaire. Logistic regression models were used to assess associations of both outcomes with demographic and clinical factors (glycemic and nonglycemic factors, micro- and macrovascular complications, DCCT cohort, and treatment assignment). RESULTS: Participants were 53% male, with mean ± SD age 59.5 ± 6.8 years and diabetes duration 37.9 ± 4.9 years. The prevalence of SPPB score <10 was 21%. The prevalence of self-reported functional limitations was 48%. While DCCT treatment assignment was not associated with physical function outcomes measured ∼25 years after the end of the DCCT, the time-weighted mean DCCT/EDIC HbA1c was associated with both outcomes. Other clinical factors associated with both outcomes in multivariable analyses were BMI, general psychological distress, and cardiac autonomic neuropathy. 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 whether these findings are generalizable.

Brain Structure Among Middle-aged and Older Adults With Long-standing Type 1 Diabetes in the DCCT/EDIC Study.

OBJECTIVE: Individuals with type 1 diabetes mellitus (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 with control subjects without diabetes. RESEARCH DESIGN AND METHODS: MRI was used to compare brain structure among 416 T1DM participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study with that of 99 demographically similar control subjects without diabetes 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 total white matter mean 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 control subjects was 60 years. T1DM participants showed significantly smaller TBV (least squares mean ± SE 1,206 ± 1.7 vs. 1,229 ± 3.5 cm3, P < 0.0001), GMV, and WMV and greater ventricle and WMH volumes but no differences in total white matter mean FA versus control subjects. Structural MRI measures in T1DM were equivalent to those of control subjects who were 4-9 years older. Lower PME scores were associated with altered brain structure on all MRI measures in T1DM participants. CONCLUSIONS: Middle-aged and older adults with T1DM showed brain volume loss and increased vascular injury in comparison with control subjects without diabetes, equivalent to 4-9 years of brain aging.

Risk factors for lower bone mineral density in older adults with type 1 diabetes: a cross-sectional study.

BACKGROUND: Type 1 diabetes is associated with lower bone mineral density (BMD) and increased fracture risk, but little is known regarding the effects of diabetes-related factors on BMD. We assessed whether these factors are associated with lower hip BMD among older adults with type 1 diabetes. METHODS: This cross-sectional study was embedded in a long-term observational study, the Epidemiology of Diabetes Interventions and Complications study (EDIC), a cohort of participants with type 1 diabetes, who were originally enrolled in the Diabetes Control and Complications Trial (DCCT), and were followed-up for more than 30 years at 27 sites in the USA and Canada. All active EDIC participants were eligible except if they were pregnant, weighed above the dual-energy x-ray absorptiometry (DXA) scanner limit, had an implanted neurostimulator, or were not willing to participate. The primary study outcome was total hip BMD. Hip, spine, and radius BMD and trabecular bone score (TBS) were measured with DXA at an annual EDIC visit (2017-19). Time-weighted mean HbA1c, kidney disease, and peripheral neuropathy were measured annually during EDIC, and retinopathy was measured every 4 years. Skin intrinsic fluorescence, a measure of advanced glycation end products (AGEs), and cardiac autonomic neuropathy were assessed once (2009-10) during EDIC. FINDINGS: 1147 of the 1441 participants who were enrolled in the DCCT trial remained active EDIC participants at the start of this cross-sectional study. Between Sept 20, 2017, and Sept 19, 2019, 1094 of 1147 participants were screened for the EDIC Skeletal Health study. 1058 participants completed at least one of a set of DXA scans and were included in the analysis. 47·8% were women and 52·2% were men, 96·6% were White and 3·4% were of other race or ethnicity. The mean age of participants was 59·2 years (SD 6·7). Higher mean HbA1c, higher skin intrinsic fluorescence, and kidney disease (but not retinopathy or neuropathy) were independently associated with a lower total hip BMD. Total hip BMD differed by -10·7 mg/cm2 (95% CI -19·6 to -1·7) for each 1% increase in mean HbA1c, -20·5 mg/cm2 (-29·9 to -11·0) for each 5 unit higher skin intrinsic fluorescence, and -51·7 mg/cm2 (-80·6 to -22·7) in the presence of kidney disease. Similar associations were found for femoral neck and ultra-distal radius BMD, but not for lumbar spine BMD or TBS. INTERPRETATION: Poorer glycaemic control, AGE accumulation, and kidney disease are independent risk factors for lower hip BMD in older adults with type 1 diabetes. Maintenance of glycaemic control and prevention of kidney disease might reduce bone loss and ultimately fractures in this population. Osteoporosis screening might be particularly important in people with these risk factors. Further research to identify AGE blockers could benefit skeletal health. FUNDING: National Institute of Diabetes and Digestive and Kidney Disease.

Type 1 diabetes and oral health: Findings from the Epidemiology of Diabetes Interventions and Complications (EDIC) study.

OBJECTIVE: To describe long-term oral health outcomes and examine associations between sociodemographic factors, clinical characteristics, and markers of diabetes control on tooth loss in participants with type 1 diabetes enrolled in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. RESEARCH DESIGN AND METHODS: Oral health outcomes related to tooth loss were reported at annual visits during EDIC years 22-26 (2015-2019). Generalized estimating equation models were used to assess the association of individual risk factors and tooth loss, over repeated time points. RESULTS: A total of 165 (17%) participants with type 1 diabetes reported 221 oral health outcomes related to tooth loss over a five-year period. After controlling for age and current tobacco use, the presence of diabetic peripheral neuropathy was significantly associated with an increased odds of tooth loss (OR = 1.88, 95% CI 1.24, 2.87) while higher mean HDL/LDL cholesterol ratio was significantly associated with a decreased odds of tooth loss (OR = 0.87, 95% CI = 0.79, 0.97). CONCLUSIONS: These findings suggest that diabetes-related complications, either resulting from or independent of poor glycemia, may be directly associated with oral health conditions, and support the need for individuals with type 1 diabetes and providers to implement lifestyle and medical interventions to reduce oral health risks.

Continuous Glucose Monitoring in Adults With Type 1 Diabetes With 35 Years Duration From the DCCT/EDIC Study.

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 <1% of observations of <54 mg/dL. Indeed, participants with the highest percentage of hypoglycemia had the lowest HbA1c levels. However, use of insulin pumps and CGM decreased the percent time at <54 mg/dL. CONCLUSIONS: In adults with long-standing type 1 diabetes, short-term blinded CGM profiles revealed frequent clinically significant hypoglycemia (<54 mg/dL) during the night and more time in hyperglycemia during the day. The small subset of participants using routine CGM and insulin pumps had fewer hypoglycemic and hyperglycemic excursions and lower HbA1c levels. Thus, strategies to lower meal-stimulated hyperglycemia during the day and prevent hypoglycemia at night are relevant clinical goals in older patients with type 1 diabetes.

Cognitive performance declines in older adults with type 1 diabetes: results from 32 years of follow-up in the DCCT and EDIC Study.

BACKGROUND: With improved treatment, individuals with type 1 diabetes are living longer but there is limited information on the effects of type 1 diabetes on cognitive ability as they become older adults. We followed up individuals with type 1 diabetes to identify independent risk factors for cognitive decline as people age. METHODS: 1051 participants with type 1 diabetes enrolled in the Diabetes Control and Complications Trial (DCCT) and its follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. Participants completed cognitive assessments at baseline (median age 27 years) and 2, 5, 18, and 32 years later (median age 59). HbA1c levels, frequency of severe hypoglycaemia, non-glycemic risk factors such as elevated blood pressure, and microvascular and macrovascular complications were assessed repeatedly. We examined the effects of these on measures of memory and psychomotor and mental efficiency. These studies are registered with clinicaltrials.gov, NCT00360815 (DCCT) and NCT00360893 (EDIC). FINDINGS: Over 32 years of follow-up, we found substantive declines in memory and psychomotor and mental efficiency. Between 18 and 32 years of follow-up, the decline in psychomotor and mental efficiency was five times larger than the change from baseline to year 18. Independent of the other risk factors and comorbidities, exposure to higher HbA1c levels, more episodes of severe hypoglycaemia, and elevated systolic blood pressure were associated with greater decrements in psychomotor and mental efficiency that was most notable by year 32 (p<0·0001). The combined effect of the presence of these three risk factors is the equivalent to an additional 9·4 years of age. INTERPRETATION: Cognitive function declines with ageing in type 1 diabetes. The association of glycaemia and blood pressure levels with cognitive decline suggests that better management might preserve cognitive function. FUNDING: United States National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease.

An Observational Study of the Equivalence of Age and Duration of Diabetes to Glycemic Control Relative to the Risk of Complications in the Combined Cohorts of the DCCT/EDIC Study.

OBJECTIVE: This epidemiological analysis of the pooled Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort describes the equivalence of a 1-percentage point increase in HbA1c (such as from 7% to 8%) and years of additional age or duration of type 1 diabetes (T1D) relative to the risk of complications. RESEARCH DESIGN AND METHODS: Separate Cox proportional hazards models determined the number of additional years of age and/or duration of T1D that would result in the same increase in risk of microvascular (retinopathy, nephropathy, and neuropathy) and cardiovascular complications and mortality as a 1-percentage point increase in HbA1c. RESULTS: The risk of any cardiovascular disease associated with a 1-percentage point increase in HbA1c was equivalent to the risk associated with 4.3 (95% CI 2.7-5.9) additional years of age or 5.6 (95% CI 2.7-6.5) additional years' duration of T1D. The risk of estimated glomerular filtration rate <60 mL/min/1.73 m2 and/or end-stage renal disease associated with a 1-percentage point increase in HbA1c was equivalent to the risk associated with 12.1 (95% CI 8.3-15.9) additional years of age or 18.0 (95% CI 4.3-31.7) additional years' duration of T1D. The proliferative diabetic retinopathy risk associated with a 1-percentage point increase in HbA1c was equivalent to the risk associated with 6.4 (95% CI 5.3-7.4) additional years' duration of T1D, while for mortality risk, it was equivalent to the risk associated with 12.9 (95% CI 6.6-19.3) additional years of age. CONCLUSIONS: Our results help evaluate the impact of glycemia on advanced complications in a way that may be more interpretable to health care providers and individuals with T1D.

Screening eye exams in youth with type 1 diabetes under 18 years of age: Once may be enough?

Case series and registry data suggest that diabetic retinopathy requiring treatment is rare in youth with type 1 diabetes (T1D) prior to 18 years of age. We evaluated this question in the standardized clinical trial setting by retrospectively reviewing diabetic retinopathy examinations from participants in the Diabetes Control and Complications Trial (DCCT) who were 13 to <18 years of age at randomization. Standardized stereoscopic 7-field fundus photographs were obtained every 6 months during DCCT (1983-1993). Photographs were graded centrally using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Transitions in diabetic retinopathy status over time were described. A total of 195 participants with median baseline glycated hemoglobin (HbA1c) of 9.3% (103 in the conventional and 92 in the intensive treatment groups) had an average of 5.3 diabetic retinopathy assessments during 2.3 years of follow-up (range 1-11) while under 18 years of age during the DCCT. No participant developed severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy and only one participant (in the intensive group) reached clinically significant macular edema (CSME) while less than 18 years of age. In this incident case, baseline characteristics included diabetes duration 9.3 years, HbA1c 10.3%, LDL 131 mg/dL, and mild non-proliferative diabetic retinopathy (35/35 ETDRS scale); CSME resolved without treatment. Similar analyses using age cut-offs of <19, 20, or 21 years showed a slight rise in diabetic retinopathy requiring treatment over late adolescence. Clinical trial evidence suggests that frequent eye exams may not be universally necessary in youth <18 years of age with T1D.