NEW YORK – Studies continue to examine approaches that might reduce the well-known increased risk for cognitive decline and dementia in people with type 2 diabetes.
A combination of hyperglycemia, insulin resistance, oxidative stress, and other diabetes-related factors appears to play a part in the cognitive impairment associated with type 2 diabetes, said Dr. Jeff D. Williamson, chief of gerontology and geriatric medicine and director of the Kulynych Brain Research Center at Wake Forest University in Winston-Salem, N.C.
Dr. Jeff Williamson
But, to date, there hasn’t been much success in intervening in type 2 diabetes patients to affect cognitive outcomes.
"Brain disease is prevalent in type 2 diabetes, and the risk for progression to dementia is high. There’s really no evidence that intensive medication can change that rate, at least at this point, but there may be some evidence that behavioral interventions are effective," Dr. Williamson said at the annual advanced postgraduate course held by the American Diabetes Association.
He advised that "monitoring cognitive function should take its place alongside lipid monitoring, kidney function monitoring, and eye monitoring in your assessments of patients coming through. Diabetes education may be adapted in people who are showing cognitive frailty, and we really need more work to show what works best in this population, but we certainly know that they are going to need more backup strategies."
Pathways to dementia
Diabetes interacts with the brain through two primary pathways: neuronal factors, including advanced glycated end products (with the apt acronym AGES), altered metabolism of neurotransmitters, and hypoglycemia; and vascular factors, including hypertension, endothelial damage, infarction, white-matter lesions, and disruption of the blood-brain barrier.
Both pathways contribute to inflammation, oxidative stress, and altered energy metabolism, which in turn lead to small- and large-vessel disease in the case of vascular damage factors, and to cortical atrophy in the case of neuronal degeneration. The end result of these processes may be vascular or Alzheimer’s type cognitive impairment and dementia, Dr. Williamson said.
Imaging studies conducted as part of the ACCORD-Memory in Diabetes Study (ACCORD-MIND, a substudy of the ACCORD [Action to Control Cardiovascular Risk in Diabetes] Study), showed increased white-matter lesions and brain atrophy in some people with type 2 diabetes, he noted.
In addition, a 2011 study, which Dr. Williamson coauthored, found that postmenopausal women with type 2 diabetes had deficits in verbal knowledge and verbal memory relative to similar women with no diabetes. Deficits in fine motor speed, a marker of cognitive impairment, also were more common in women with longer diabetes duration. Insulin use, indicative of diabetes severity, was associated with greater cognitive deficits, whereas oral medications were associated with better relative cognitive function.
Similarly, a 2009 systematic review and meta-analysis detected significant relative risks (RRs) associated with all diabetes types and all dementia types (RR, 1.47), Alzheimer’s disease (RR, 1.39), and vascular dementia (RR, 2.38).
Disappointing results
As in the parent trial, the ACCORD-MIND trial investigators found that an intensive glucose control intervention did not affect patients’ scores on the Digital Symbol Substitution Test, the primary endpoint. Among the nearly 3,000 patients randomized in that study, those assigned to intensive glucose control had significantly greater total brain volume than did patients assigned to standard control, but no difference in cognitive outcomes.
"Combined with the unfavorable effects on other ACCORD outcomes, MIND findings do not support using intensive therapy to reduce the adverse effects of diabetes on the brain in patients similar to MIND participants," they wrote.
The fact that there was a reduction in the rate of brain volume loss in the intensive glucose control arm, however, gives hope to the investigators that there might be a "legacy" effect for a slower decline in cognitive function with better control over longer follow-up, Dr. Williamson said.
Researchers are now focusing on the Look AHEAD (Action for Health in Diabetes) study on the question of whether lifestyle interventions might be able to accomplish what drugs could not in ACCORD. Alternatively, it may be possible that the type of drug treatment is more important than a specific numeric target, he said.
Dr. Williamson reported having no financial disclosures.