Tight Control in Type 1 Diabetes No Cognitive Threat

BOSTON, May 3 -- Even if glucose levels plunge periodically in patients with type 1 diabetes, cognitive function stays on an even keel, researchers found.

Over 18 years, no evidence of a substantial long decline in mental ability was found in a large group of patients with type 1 diabetes, despite relatively high rates of severe hypoglycemia stemming from tight control, according to a report in the May 3 issue of the New England Journal of Medicine.

Forty percent of the cohort of more than 1,000 patients reported having had at least one hypoglycemic coma or seizure, said Alan M. Jacobson, M.D., of the Joslin Diabetes Center, Harvard Medical School here, and colleagues. Yet whether the patients belonged to a tight-control group in the study or a conventional-therapy group was not associated with a decline in cognitive function.

Long-standing concern about the effects of type 1 diabetes on cognitive ability has increased with the use of therapies designed to bring glucose levels close to the non-diabetic range and the attendant increased risk of severe hypoglycemia, Dr. Jacobson said.

To address this concern the researchers analyzed results from two interlocked studies over 18 years. From 1983 to 1989 1,441 patients (mean age 27) with type 1 diabetes were enrolled in the Diabetes Control and Complications Trial (DCCT) and were followed for six years with a comprehensive battery of cognitive tests.

Of these patients, 711 were randomly assigned to intensive therapy, including three or more insulin injections daily or subcutaneous infusion of insulin, guided by frequent self-monitoring of blood glucose, and a goal of preventing severe hypoglycemia.

The remaining 730 patients were assigned to conventional therapy with one or two insulin injections daily, no target glucose levels, and a goal of preventing hyperglycemia symptoms or frequent or severe hypoglycemia.

In 1993, at the end of 6.5 years, 1,375 of 1,428 surviving members volunteered to participate in an observational follow-up, known as the Epidemiology of Diabetes Interventions and Complications (EDIC) study and were followed for 12 years with the same battery of cognitive tests. Thus the two phases of the study amounted to 18 years of follow-up for these patients.

The cognitive tests, which required four to five hours to complete, included, for example, five subtests from the Wechsler Adult Intelligence Scale, four subtests form the Halstead-Reitan Neuropsychological Test Battery, subtests from the Wechsler Memory Scale, the Digit Vigilance Test, and the Verbal Fluency Test, among many others. Capillary blood glucose levels were routinely monitored immediately before testing and at the midpoint to rule out hypoglycemia during testing.

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 50 mg/dL or the symptoms were reversed by oral carbohydrate, injected glucagon, or IV glucose.

Cognitive ability 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 practice effects, the number of cognitive tests taken since the start of DCCT.

During the entire 18-year follow-up, a total of 1,355 episodes of coma or seizure were reported (896 in 262 patients in the intensive treatment group and 459 in 191 patients in the conventional treatment group). However, neither the original treatment assignment nor the cumulative number of hypoglycemic events influenced performance in any cognitive domain, the researchers reported.

Higher values of glycated hemoglobin were associated with moderate declines in psychomotor efficiency (P<0.001) and motor speed (P=0.001), but no other cognitive domain was affected, the researcher emphasized.

Referring to their earlier examination of the DCCT cohort, the researchers said that after an average follow-up of 6.5 years, they found that cognitive function was not affected by recurrent hypoglycemia.

In the EDIC study, after 18 years of follow-up of 85% of the available DCCT participants, no deleterious effects of previous intensive therapy or recurrent hypoglycemia were evident, despite the substantially longer exposure to diabetes and its glycemic changes, and the fact that the patients were now in a later phase of their lives.

These findings should be reassuring to patients for whom intensive therapy is strongly recommended, Dr. Jacobson said.

Despite the substantial strengths of this study, the researchers said, limitations included a lack of data for young children diagnosed with type 1diabetes before they entered the study.

Information was also lacking on the effect of intensive therapy on the elderly or those living for more than 30 years with diabetes.

Finally, the investigators said, these results from the selected DCCT cohort should be applied carefully to the total population of patients with type 1 diabetes.

The findings of this study, the researchers wrote, provide an important message about the cognitive safety of intensive diabetes therapy for those diagnosed with the disorder as adolescents or young adults.

Within the limits mentioned, they said, one can be confident that although acute hypoglycemic events can be dangerous at the time they occur, recurrent severe episodes associated with intensive diabetes therapy do not appear to have long-term adverse cognitive effects.

"This conclusion," the researchers said, "lends further support to the use of intensive diabetes therapy to reduce the long-term risks of retinopathic, nephropathic, neuropathic, and cardiovascular complications in type 1 diabetes."