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Tight Control No Help for Cognitive Loss in Diabetes

Sep 30, 2011

Tight glucose control won’t mitigate the cognitive effects of type 2 diabetes, an ACCORD subanalysis found.

Lenore J. Launer, PhD, of the National Institute on Aging in Bethesda, Md., and colleagues found that, intensive treatment aiming for hemoglobin A1c under 6% did reduce brain atrophy over 40 months compared with standard management (P=0.0007).

But cognitive scores over 40 months showed no advantage over treatment to the conventional 7% to 7.9% goal (P=0.2997), they reported.

These results from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Memory in Diabetes (MIND) substudy matched the overall lack of benefit for cardiovascular outcomes with tight control of glucose, blood pressure, or lipids. The trial even suggested harm from 19% excess mortality with tight glucose control at five years.

Launer’s group wrote, altogether, “our findings do not support the use of intensive therapy to reduce the adverse effects of diabetes on the brain in patients with similar characteristics to those of our participants.” This comes on the heels of a study suggesting that poor diabetes control, particularly after meals, may play a role in dementia and Alzheimer’s disease risk.

One small pilot study reported earlier this month suggested that pumping aerosolized insulin deep into the nose in an attempt to boost brain levels could delay progression of Alzheimer’s. However, dysglycemia might not be the only or best target, Geert Jan Biessels, PhD, of the University Medical Center in Utrecht, the Netherlands, noted in an accompanying commentary.

In type 2 diabetes, “glucose dysmetabolism co-occurs with many factors that might adversely affect the brain,” he wrote. “At present it is still unclear whether dysglycemia is a key factor in accelerated cognitive decline and dementia in type 2 diabetes.”

Another possibility is that three years of treatment in this kind of advanced diabetes population may not have been enough to see an effect, commented Richard Bergenstal, MD, of the International Diabetes Center at Park Nicollet in Minneapolis.

“This link between diabetes and increased cognitive impairment and dementia is unquestionable, but what intervention to take to try to reduce this is really still in question,” he said online in Lancet Neurology

The ACCORD MIND study included 2,977 patients randomized to intensive or standard glycemic management who took cognitive tests at baseline, and at 20 and 40 months of follow up. For the primary cognitive outcome, Digit Symbol Substitution Test (DSST) score declined in both treatment groups.

A trend for less worsening in the intensive group appeared at 20 months with a small difference in the means between groups of 0.53 compared with the baseline score of 52.55 in both groups (P=0.0756). But any trend disappeared by 40 months (difference in means 0.32, P=0.2997).

Other cognitive tests — Rey Auditory Verbal Learning Test, Stroop test, and Mini-Mental State Examination — showed no trends for a treatment effect at any point.

Total brain volume declined by 13.0 cm3 with intensive management compared with 17.7 cm3 in the control group over 40 months in the 614 patients with repeat MRI in the substudy (baseline 927.5 cm3 in both), which was a significant difference at the P=0.0007 level.

That kind of structural change would be expected to lead to earlier loss of function and possibly dementia, Launer’s group noted.

For a population with an average age of 62, it’s reasonable to think that structural changes would precede any clinical or cognitive effects, they suggested. But the group again cautioned that “this difference does not support the use of intensive treatment to reduce brain atrophy in view of the effects of this intervention in the main ACCORD trial: raised mortality, no overall benefit on cardiovascular disease events, an increase in hypoglycemic events, and weight gain.”

Indeed, more abnormal white matter showed up with intensive treatment (P=0.0156), though this appeared largely restricted to patients under age 60.

Practice Pearls:
  • Explain that tight glucose control (aiming for hemoglobin A1c under 6%) did not reduce cognitive decline at 40 months significantly in type 2 diabetes patients compared with standard management according to a substudy of the ACCORD trial.
  • Note that intensive treatment did reduce brain atrophy over 40 months compared with standard management.

Launer LJ, et al “Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): A randomised open-label substudy” Lancet Neurol 2011; DOI: 10.1016/S1474-4422(11)70188-0.