Intensive glycemic lowering did not significantly affect cognition at 40 months in older adults with type 2 diabetes participating in the Action to Control Cardiovascular Risk in Diabetes study.
There were differences in brain structure, however, suggesting that structural changes occur prior to cognitive changes, said Lenore J. Launer, Ph.D., of the National Institute on Aging, Bethesda, Md., and her associates (Lancet Neurol. 2011 [doi:10.1016/S1474-4422[11]70188-0]).
The MIND (Memory in Diabetes) study was a substudy of 2,977 ACCORD participants who had been randomly assigned to receive either intensive glycemic treatment targeting hemoglobin A1c to less than 6.0% or standard treatment targeting HbA1c to 7.0%-7.9%. They were also assigned to either intensive or standard lipid- and blood pressure–lowering treatment arms. The intensive glucose-lowering intervention was stopped early, in February 2008, because it was associated with a significant 22% increased cardiovascular mortality. Participants in that group were switched to standard glycemic treatment, and the lipid and blood pressure arms of the study were continued. No significant cardiovascular benefit was seen with intensive glucose lowering during the period it was studied (N. Engl. J. Med. 2008;358:2545-59).
The MIND study – believed to be the first-ever randomized study to examine the effect of intensive glucose lowering on cognition and brain structure in older people with type 2 diabetes – began in August 2003, 34 months into ACCORD, and continued until December 2005. Of the total 2,794 MIND patients who had at least 20-month and 40-month follow-up, 614 underwent successful brain magnetic resonance imaging (MRI).
The patients had a mean age of 62.5 years at study start, and the separation in median HbA1c achieved between the intensive and standard treatment groups – 6.6% vs. 7.5% – was similar to that of the overall ACCORD study population. At the time the intensive treatment intervention was stopped, the MIND study patients in that group had received treatment for a median of 39 months, and those in the MRI substudy had received 35 months of intensive treatment.
Scores on the primary end point DSST (Digit Symbol Substitution Test), a measure of psychomotor speed that requires reasoning and working memory, declined in both the intensive and standard treatment groups. At 20 months, the difference between the two groups approached statistical significance (P = .076), but by 40 months the difference was attenuated and not significant (P = .23).
Other measures of cognition, the RAVLT (Rey Auditory Verbal Learning Test) and the Stroop test of executive function, also changed similarly in the intensive and standard treatment groups. There were small increases in mean RAVLT scores between groups, but no significant difference between them. Performance on the Stroop test improved slightly in the intensive treatment group and declined slightly in the standard treatment group, but there was no difference between treatments.
"Overall, there is no evidence in this patient group, which had long-standing type 2 diabetes, a high risk of cardiovascular disease, and a mean of 62 years, that an intensive glycemic treatment strategy provides benefit to cognitive function," Dr. Launer and her associates commented.
Differences were seen in brain structure, however. At 40 months, the intensive treatment group had significantly greater total brain volume (TBV), compared with the standard treatment group. Although TBV declined in both groups, the TBV of the intensive treatment group declined less, by 0.41%/year, compared with 0.57%/year. Abnormal white matter (AWM) tissue volume was significantly greater in the intensive treatment group at 40 months (geometric mean 1.89 vs. 1.71 cm3), but this effect seems to be restricted to patients younger than 60 years, they noted.
There was no evidence that measures of peripheral edema or weight gain could explain the differences in TBV or AWM between groups.
"There was a significant but small difference in TBV favoring the intensive strategy. However, 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," the investigators commented.
"Taking the cognitive and MRI findings together, it is reasonable to postulate that, in this age group, structural changes in the brain happen before cognitive changes and that over time cognitive differences between treatment groups would emerge," Dr. Launer and her associates said, noting that ongoing follow-up should be able to establish whether that is the case.
Dr. Launer and all but one of her 21 coauthors declared that they had no conflicts of interest. Dr. Hertzel C. Gerstein, the principal investigator for the overall ACCORD trial, declared that that he has received consulting fees, institutional grant support, and/or lecture fees from numerous pharmaceutical companies including Sanofi-Aventis, GlaxoSmithKline, Eli Lilly, Novo Nordisk, AstraZeneca, and Bristol-Myers Squibb.