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Long-Term Cognitive Sequelae of Severe Hypoglycemia

Tight glycemic control leads to frequent episodes of severe hypoglycemia but produces no measurable cognitive deficit even 18 years later.

The Diabetes Control and Complications Trial (DCCT) showed that tight management of glycemic control in type 1 diabetes delays the onset and progression of neuropathy, retinopathy, and nephropathy compared with standard care. The benefits required frequent and intensive insulin therapy, which led to three times as many episodes of severe hypoglycemia, defined as episodes leading to a seizure or coma. One-third of those in the intensive therapy group had between one and five episodes during the 5-year DCCT trial.

Now, researchers report longer-term follow-up with this cohort. At the conclusion of the original trial, all subjects were advised to maintain tight glycemic control and both groups had similar success over the following 12 years (glycated hemoglobin levels, 8.0% vs. 8.2% in the intensive and conventional treatment groups, respectively). Subjects underwent extensive cognitive testing at enrollment in DCCT and at a mean of 18 years later, at a mean age of 45.

Even the subjects who had more than five episodes of severe hypoglycemia had no significant cognitive decline in 24 realms tested. Those who had worse glycemic control (glycated hemoglobin level >8.8%) showed significant impairments in psychomotor efficiency and motor speed compared with those with tighter control (glycated hemoglobin level <7.4%), though they fared similarly well across six other cognitive domains tested.

Comment: These findings demonstrate that although tight glycemic control causes more episodes of severe hypoglycemia, these episodes do not have demonstrable cognitive sequelae; in fact, this level of control was associated with better performance in certain cognitive domains. Patients’ main cognitive concerns, however, usually center on the risks for stroke and dementia. Even after 18 years, most participants in this study are still too young to have faced these endpoints. As we learn more about the complex relationship between vascular processes and dementia (N Engl J Med 2003; 348:1215), this cohort should cast light on whether tight glycemic control lowers the risks for both stroke and dementia. Subjects originally randomized to tight control have had the benefit of this approach for an additional 5 years (akin to the "staggered-start" design in neuroprotection trials), and their outcomes may help answer these critical questions in the future.

— Daniel Press, MD

Dr. Press is a Staff Neurologist, Beth Israel Deaconess Medical Center, and Assistant Professor of Neurology, Harvard Medical School, Boston.

Published in Journal Watch Neurology June 12, 2007

Citation(s):

Jacobson AM et al. Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med 2007 May 3; 356:1842-52.

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