DCCT/EDIC: No cognitive impairment from tight blood glucose control in type 1 diabetes

Susan Jeffrey

June 20, 2006

Washington, DC - A new analysis of data from the landmark Diabetes Control and Complications Trial and the ongoing follow-up Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) shows no increase in cognitive impairment over time associated with vigilant control of blood glucose to near-normal levels in patients with type 1 diabetes[1].

Tight control means more hypoglycemic episodes, with attendant confusion, irrational behavior, convulsions, and unconsciousness, researchers point out. The concern had been that the reduction in diabetic complications seen with tight control—including less retinopathy, neuropathy, and cardiovascular and renal disease—might come at the price of some impairment in cognitive function.

"Over the average of 18 years of follow-up, neither prior treatment group nor exposure to recurrent severe hypoglycemia led to decreases in cognitive functioning on any of the eight cognitive domains," the study's principal investigator, Dr Alan M Jacobsen (Joslin Diabetes Center and professor of psychiatry at Harvard Medical School, Boston, MA), told meeting attendees here. "Because of the length of follow-up and extensive cognitive testing, this study strongly supports the safety of intensive diabetes therapy," he concluded.

The results were presented at the American Diabetes Association 2006 Scientific Sessions.

Normalizing blood glucose

Primary results of the DCCT trial changed the management of diabetes, replacing the pattern of one or two injections of insulin per day with a regimen of several injections, titrated to match food intake, and supported with the use by patients of glucose monitors in an effort to reduce swings in blood glucose and keep levels as close as possible to normal.

DCCT was a multicenter, randomized trial comparing intensive therapy using an insulin pump or with three or more daily insulin injections with conventional diabetes treatment consisting of one or two insulin injections per day in 1441 people with type 1 diabetes[2]. The trial ran from 1983 to 1993, with an average of follow-up of 6.5 years. Substantial reductions were seen in the development and progression of microvascular complications and in peripheral neuropathy with the intensive treatment, Jacobsen noted.

EDIC is an observational follow-up study, including 1059 of the original DCCT participants, 537 patients initially randomized to intensive therapy and 522 who received conventional therapy. Follow-up in EDIC is now at 12 additional years and is funded to continue until 2016.

Previous data from EDIC proved that progression of retinopathy, nephropathy, neuropathy, and, more recently, cardiovascular events[3] are all reduced by prior intensive therapy, Jacobsen noted. However, it was clear from both phases of the study that intensive therapy increases therisk for hypoglycemic events ranging from mild to severe, defined as hypoglycemia resulting in coma or seizure.

"When the DCCT was initiated, there were serious concerns raised about the anticipated increase in severe hypoglycemic episodes and the impact on cognitive functioning," Jacobsen said. Case reports had suggested that severe hypoglycemia could lead to brain-structure changes and cognitive dysfunction.

Cognitive testing was incorporated into the DCCT trial to address these concerns. Although there was a threefold increase seen in recurrent severe hypoglycemic events with intensive therapy during DCCT, there were no differences in cognition between the groups or any effects of recurrent hypoglycemic events on cognition at that point, Jacobsen said.

This new analysis provides data on an additional 12 years of follow-up, for a total of 18 years. At the close of DCCT, all patients were switched to intensive management. Blood glucose levels went up somewhat over time in the group originally receiving intensive treatment and down in the group initially randomized to conservative management, to meet more or less in the middle at hemoglobin A1 cs of about 7.8%.

Over follow-up, more patients in the group originally randomized to intensive therapy reported having had a severe hypoglycemic event, with some reporting more than five of these events. However, the majority of patients in both groups reported no episode of severe hypoglycemia.

Distribution of severe hypoglycemic events from DCCT entry to EDIC year 12 (18-year follow-up)

End point Intensive group Conservative management
No severe hypoglycemic event 325 366
1 to 5 severe hypoglycemic events 210 171
>5 severe hypoglycemic events 48 16

All of the patients were evaluated using the same neuropsychological testing employed during the trial, assessing abilities in eight cognitive domains, including problem solving, learning, immediate memory, delayed recall, spatial information processing, attention, psychomotor efficiency, and motor speed.

After adjusting for age, sex, years of education, length of follow-up, and the number of cognitive tests taken, researchers found no effect associated with severe hypoglycemic events in any domain. "In some instances, it actually appears that the patients who had the most episodes had the least deterioration," Jacobsen noted. "In others, the reverse is true, but none of these differences are statistically significant across any of these domains."

Higher hemoglobin A1c levels,an indication of poorer glucose control over time, were associated with a modest decline in motor speed and psychomotor efficiency, the authors note, but no other cognitive domain was affected.


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