September 28, 2011 — Intensive lowering of blood glucose in patients with type 2 diabetes does not provide an edge in terms of cognition, a new study suggests.
However, it is too early to abandon the approach of targeting abnormal glycemic levels to prevent cognitive decline in patients with diabetes, said lead author Lenore J. Launer, PhD, from the Intramural Research Program, National Institute on Aging, Bethesda, Maryland. "The clinical implications are that people with diabetes should follow whatever the recommendations are now until we do further research."
There was a trend, however, toward preservation of total brain volume with intensive management. Although the study did not show a difference between standard and more intensive glucose-lowering treatment, this may have been because the patients, with a mean age of just older than 60 years, may have been too young, the authors speculate.
The study, a subanalysis of the previously published Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was published online September 28 in Lancet Neurology.
ACCORD Memory in Diabetes Subset
The ACCORD study was a randomized, multicenter trial that tested the effect of 2 therapeutic strategies to control blood glucose, blood pressure, and lipid concentrations in patients with type 2 diabetes and an unfavorable cardiovascular risk profile. Patients were randomly assigned to receive either intensive glycemic treatment targeting HbA1c levels of less than 6.0% (42 mmol/mol) or standard glycemic treatment targeting HbA1c levels of 7.0% to 7.9% (53 - 63 mmol/mol). They also received diabetes education, glucose-monitoring equipment, and antidiabetic drugs.
Those patients in the intensive glycemic group were started on 2 or more classes of drugs with doses intensified or a new drug class added monthly if HbA1c concentrations were 6.0% (42 mmol/mol) or greater, or if more than 50% of glucose readings were greater than 5.6 mmol/L. The standard glycemic treatment group was intensified if HbA1c was 8% (64 mmol/mol) or greater, or more than 50% of glucose readings were greater than 7.8 mmol/L.
The intensive intervention was stopped early in February 2008 when an increased risk for mortality (hazard ratio, 1.22) was reported, and participants were moved to the standard treatment group.
The current report focuses on a subset of 2977 ACCORD patients in the current Memory in Diabetes study. At baseline, 20 months, and 40 months, researchers carried out a battery of cognitive tests on these patients, including the Digit Symbol Substitution Test (DSST), which assesses psychomotor speed and requires reasoning and working memory; the Rey Auditory Verbal Learning Test, which measures memory; and the Stroop test, which assesses executive function.
Age a Factor?
The researchers found that intensive glucose lowering did not benefit cognition. The DSST scores had significantly declined in both groups, and while at 20 months the between-group difference in DSST scores approached statistical significance, at 40 months, the difference was not significant.
A subset of 632 participants was included in a magnetic resonance imaging (MRI) substudy. At baseline and at 40 months, researchers measured total brain volume and abnormal white matter tissue volume.
At the end of the study, the intensive treatment group had significantly greater total brain volume compared with the standard treatment group. Although total volume declined in both groups, it declined less in the intensive group than in the standard group, at 13.0 cm3 (0.41%) per year compared with 17.7 cm3 (0.57%) per year.
The age of the study participants might help explain the study results: They were 10 or 15 years younger than those enrolled in most other studies that find that "diabetes is bad for the brain," said Dr. Launer. "These people are just now approaching the period where there probably is a more accelerated change in the function and structure of their brain, although already at this age we found that their brain volumes were sort of similar to people who are 15 years older."
Treatment differences might have been more apparent if the intervention had been given during a period when participants were experiencing more rapid decline in cognition, she said.
The trial raises the question of how best to design early prevention trials, as most studies now include patients older than 70 years. Although researchers now have a good "fix" on what outcome measures should be, "we don't really have a good fix on doing these trials on people who are not yet at a stage of significant increased risk for dementia."
If it is not lack of glycemic control that is accelerating cognitive decline, what else could be doing this? People with diabetes often have other disorders, including high blood pressure, microvascular disease and macrovascular disease, all of which can contribute to cognitive decline, said Dr. Launer.
Too Early to Discard the Glycemic Connection
Asked to comment, Geert Jan Biessels, MD, PhD, from the Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, the Netherlands, who also wrote an accompanying editorial, said he agreed that dysglycemia cannot be discarded as a treatment target.
"In my view, the cognitive outcome measure that was used in this study is probably not a very good proxy for dementia," he said in an email. "Based on this study, it remains uncertain if treatment for dysglycemia can prevent accelerated cognitive decline and dementia."
Addressing whether an older patient population subjected to intensive glucose-lowering treatment may have had a different outcome, Dr. Biessels said that the mean rate of cognitive decline is higher in older people, and more important, the proportion of those with abnormal accelerated decline is higher. "In my view, we should try to prevent the latter. The question is, of course, whether a treatment in older individuals, who are closer to the time that dementia becomes clinically manifest, might be too late."
Dr. Biessels also said that the more severe cognitive decline that occurs at a later age is "almost certainly" related to a different process than cognitive decline that occurs earlier.
"Diabetes is associated with modest cognitive decrements, which do not progress rapidly over time," he said. "On the other hand, diabetes doubles the rate of accelerated cognitive decline and dementia. This accelerated decline is due to different processes than the modest decrements, in most cases a combination of Alzheimer-type pathology and vascular damage. At present, we do not know the exact cause of the modest decrements, but it is probably a combination of metabolic and vascular changes, leading to subtle cerebral atrophy and vascular abnormalities on MRI."
This leaves 2 options, he said. One is that the increased dementia risk is a result of the effects of a dementia process on top of other damage: Preexisting damage already draws on the reserve capacity of the brain, so less dementia-type pathology is needed for dementia symptoms to develop. The second option is that diabetes accelerates the processes that lead to dementia. "At present, we do not know if option 1, 2, or both, are correct," he said.
In his editorial, Dr. Biessels said that despite the largely negative results, ACCORD Memory in Diabetes is still an important study, as it is the first large, randomized trial to target cognition and abnormalities on brain MRI in people older than 55 years with type 2 diabetes. In addition, its recordings of cognitive and MRI outcome were meticulous, and loss to follow-up was low.
The study was supported by the National Institute on Aging and the National Heart, Lung, and Blood Institute. Coauthor Hertzel C. Gerstein has received consulting fees from Sanofi-Aventis, GlaxoSmithKline, Eli Lilly, Novo, Nordisk, AstraZeneca, Bristol-Myers Squibb, Roche, Merck, Bayer and Janssen-Ortho, and other support. The other authors have disclosed no relevant financial relationships.
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