Hypoglycemic episodes severe enough for hospital admission or an emergency department visit are associated with an increased risk of dementia among older patients with type 2 diabetes, according to study results published in the April 15 issue of JAMA. "This adds to the evidence base that we already have—we know that having too low of a blood sugar level is associated with harm," said lead author Rachel A. Whitmer, PhD, Kaiser Permanente, Division of Research, Oakland, CA. "We really need to think about balance."

The study shows that dementia risk greatly increases with each additional hypoglycemic episode in this group of patients, whose mean age was 74 years. Patients with one severe episode were 26% more likely to develop dementia, those with a history of two episodes had an 80% increased risk, and those with three episodes had a 94% increased risk.

Increased risk of dementia was present whether patients were treated with insulin alone, oral agents alone, or both, Dr. Whitmer said. "We also looked at all forms of dementia and there was nothing to say hypoglycemia is more linked to Alzheimer's disease than other dementias but I will say that most cases of dementia were AD in this population," she added.

This cohort study included 16,667 type 2 diabetes patients in the Kaiser Permanente database treated beginning in 1980. Mean patient age at baseline was 51 years. Data on treatment and hypoglycemic episodes was collected for 22 years until 2002, and researchers looked for cases of dementia occurring in these patients between 2003 and 2007.

"This study is very good and very provocative. I think it is an alarm," said Nir Barzilai, MD, director, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY. "The problem is that in diabetes treatment, until recently there hasn't been a study that showed what happens when we treat elderly patients. We all give our elderly patients whatever is available."

Some agents, like metformin, are contraindicated in patients over age 85 and elderly patients are at increased risk for hypoglycemia when treated with longer-acting secretagogues, Dr. Barzilai said.

The mechanism by which severe hypoglycemic episodes may cause dementia remain unknown. "The brain is exposed to entirely different glucose and insulin levels than the periphery. In the neurons, the levels are about a third of what they are in plasma," Dr. Barzilai said. "But the brain is also more resistant to changes in the plasma levels."

Dr. Whitmer and colleagues will continue to follow the study patients and plan to conduct brain imaging studies to help determine what the link between low blood sugar and dementia is. "We really want to understand," she said.