Patients

Between 1983 and 1989, a total of 1441 patients from 13 through 39 years of age with type 1 diabetes were enrolled in the DCCT. The DCCT study population consisted of two cohorts. Patients in the primary-prevention cohort had received a diagnosis of diabetes 1 to 5 years previously, had no retinopathy, and had a urinary albumin excretion rate of less than 40 mg per 24 hours. The secondary-intervention cohort consisted of patients who had had diabetes for 1 to 15 years, had nonproliferative retinopathy ranging from very mild to moderate, and had a urinary albumin excretion rate of 200 mg per 24 hours or less at baseline.

A total of 711 patients were randomly assigned to intensive therapy. Intensive therapy consisted of three or more insulin injections daily or subcutaneous infusion of insulin with an external pump, guided by frequent self-monitoring of blood glucose levels. The target preprandial blood glucose level was between 3.9 and 6.7 mmol per liter (70 and 120 mg per deciliter), the target glycated hemoglobin value (measured monthly) was within the nondiabetic range (<6.0%), and a goal of therapy was to prevent severe hypoglycemia. The remaining 730 patients were assigned to conventional therapy. These patients received one or two insulin injections daily; there were no target blood glucose levels, and the therapeutic goal was freedom from symptoms of hyperglycemia and from frequent or severe hypoglycemia.

During the 6.5-year DCCT follow-up, the median glycated hemoglobin values of the two treatment groups were maintained at a separation of 1.9 percentage points (7.1% in the intensive-treatment group and 9.0% in the conventional-treatment group). At the end of the DCCT, in 1993, intensive therapy was recommended for all patients, since it had been shown to be highly effective in reducing long-term complications of diabetes.1 Patients in the conventional-treatment group were given training in aspects of intensive therapy and were then returned to their own health care providers for diabetes care. In 1994, a total of 1375 (96%) of the 1428 surviving members volunteered to participate in the EDIC observational follow-up study.11 As previously reported, between-group differences in the median glycated hemoglobin values narrowed during the 12 years of the EDIC follow-up study to 0.2 percentage point (8.0% in the group that had previously received intensive treatment vs. 8.2% in the group previously receiving conventional treatment, P=0.03). In 2004, of the surviving eligible participants, 1144 (85%) were reevaluated with the cognitive-test battery.

Cognitive-Test Protocol

Cognitive testing, as originally described for the DCCT,5 was conducted at each site by personnel who were trained and certified by the DCCT/EDIC Central Neuropsychological Coding Unit. The test protocol, which required 4 to 5 hours to complete, included the following widely used, well-validated tests that were administered initially during the DCCT: five subtests (Similarities, Digit Span, Digit Symbol, Block Design, and Object Assembly) from the Wechsler Adult Intelligence Scale,12 four subtests (Category, Tactual Performance, Trail Making, and Finger Tapping) from the Halstead–Reitan Neuropsychological Test Battery,13 the Logical Memory and Visual Reproduction subtests from the Wechsler Memory Scale,14 the Digit Vigilance Test,15 the Grooved Pegboard Test,16 the Verbal Fluency Test,17 the Four-Word Short-Term Memory Test,18 the Symbol-Digit Learning Test,19 and the Embedded Figures Test.19 The tests were administered in a fixed order. Capillary blood glucose levels were routinely monitored immediately before the testing and at its midpoint to rule out the presence of hypoglycemia during testing. If a patient was found to have a blood glucose level at or below 3.9 mmol per liter (70 mg per deciliter), testing was stopped, the patient was given a snack, and after a wait of at least 15 minutes, testing was resumed when the reading returned to at least 5.0 mmol per liter (90 mg per deciliter).

The tests were scored by technicians at the Central Neuropsychological Coding Unit who were unaware of treatment assignment and other biomedical variables. The results were sent to the Data Coordinating Center, where the data were entered, verified, and edited for out-of-range values and other errors.

The compliance and performance of the patients during the testing session were rated systematically by the personnel administering the cognitive assessment. Information obtained from the patients was rated as “mostly accurate” to “completely accurate” for 97% of the patients. The testing staff also reported that 99% of the patients were “somewhat willing” to “very willing” to try their best throughout the testing session and that 94% of the patients had a “clear understanding” of the test instructions.

Cognitive Domains

During the DCCT, 24 test variables had been chosen a priori to be of particular diagnostic value when applied to patients with type 1 diabetes. For each of these 24 test variables, a standardized z score was calculated, with the mean and standard deviation from the baseline assessment of the DCCT cohort used as references.5 These standardized scores provided a unit-free measurement of the relative improvement (positive sign) or deterioration (negative sign) in performance as compared with the total group at baseline. To reduce the number of comparisons, the 24 standardized scores were grouped into eight cognitive domains consistent with standard neuropsychological assessment strategies.20 For each domain, the simple average of the standardized scores was used to represent the change from baseline, with equal weight assigned to each test.

Biomedical Evaluations

During the EDIC study, each patient underwent an annual examination that involved history taking, physical examination, an electrocardiogram, and laboratory tests, including tests for serum creatinine and glycated hemoglobin levels; the examination was conducted by the same methods used during the DCCT.21 As part of the history, the patients reported the presence of sensory symptoms of peripheral neuropathy. At entry to the DCCT, potential subjects were excluded if they had symptomatic sensory neuropathy. Data from the year in which cognitive testing was performed were used to characterize the level of symptomatic neuropathy at the time of the reevaluation. A criterion for inclusion in the DCCT was a best corrected visual acuity of 20/25 or better for the primary-prevention cohort and 20/32 or better for the secondary-intervention cohort. Best corrected visual acuity was measured at 4-year intervals during the EDIC study. The results of the visual acuity examination closest to the date of cognitive reevaluation were used to characterize the level of visual acuity at the time of cognitive reevaluation. Fasting lipid profiles were determined and 4-hour urine collections for measurement of albumin excretion and creatinine clearance rates were performed in alternate years during the EDIC study.11 Hypertension was defined as a systolic blood pressure of at least 140 mm Hg, a diastolic blood pressure of at least 90 mm Hg, previously documented hypertension, or the use of antihypertensive agents. Hypercholesterolemia was defined as a serum level of low-density lipoprotein (LDL) cholesterol of at least 130 mg per deciliter (3.4 mmol per liter) or the use of lipid-lowering agents. Renal insufficiency was defined as a centrally measured serum creatinine level of at least 2.0 mg per deciliter (177 μmol per liter), treatment with dialysis, or renal transplantation.

Glycated hemoglobin values were measured in a central laboratory by high-performance liquid chromatography21 quarterly during the DCCT and annually during the EDIC study. The time-weighted mean glycated hemoglobin value during the period of the DCCT and the 12 years of the EDIC study was computed, with each DCCT value weighted by one quarter of a year and each EDIC study value weighted by 1 year.

Psychiatric Symptoms

Psychiatric symptoms were assessed with the Symptom Checklist-90-Revised, which was administered annually during the DCCT and once during the EDIC study in the same year that the cognitive testing was performed.22,23 For this report, the depression scale was used to assess the effects of mood state on cognitive function.

Definition of Severe Hypoglycemia

During the DCCT, severe hypoglycemia was defined as any event, including seizure or coma, that required the assistance of another person and in which the blood glucose level was less than 2.8 mmol per liter (50 mg per deciliter) or the symptoms were subsequently reversed by oral carbohydrate, injected glucagon, or intravenous glucose.1 At quarterly visits, study coordinators asked about the occurrence of hypoglycemia since the last visit, and all such events were reported to the Data Coordinating Center as soon as possible after their occurrence. Twenty-seven percent of severe hypoglycemic episodes involved coma or seizure.9 During the EDIC study, severe hypoglycemic events that occurred in the 3 months before the annual visit were documented on the annual history form, and further details surrounding these events were recorded. For the purposes of this article, severe hypoglycemic events are limited to those leading to coma, seizure, or both.

Statistical Analysis

Demographic and clinical characteristics were compared with the use of the Wilcoxon rank-sum test to evaluate the differences between the treatment groups in ordinal and numeric variables.24 The contingency chi-square test was used for categorical variables; when the sample size was small, Fisher's exact test was used.24

Separate analysis-of-covariance models were used to assess the effects of treatment group (intensive vs. conventional), mean glycated hemoglobin values stratified according to thirds (<7.4%, 7.4 to 8.8%, or >8.8%), and frequency of severe hypoglycemia (zero, one to five, or more than five reported events) on the standardized quantitative score for each of the eight cognitive domains. Each model was adjusted for age at baseline, sex, years of education, length of follow-up, visual acuity, self-reported sensory loss due to peripheral neuropathy, and (to control for the effects of practice) the number of cognitive tests taken during the interval since the start of the DCCT. The results are presented as the average increase or decrease in the standardized score from the DCCT baseline within or between groups or the change per unit in a quantitative covariate. Nominally significant results (P<0.01) are reported.