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What are the implications of the REAL.FR study for endocrinologists?
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This study, because of its design, cannot really give us any new or useful information concerning the risk of developing dementia or Alzheimer’s disease in patients with diabetes. The study looked at a cohort of patients with dementia, of whom about 10% are said to have diabetes either because there was a stated history of diabetes or the patient was receiving diabetic medication. It does not address the issue of the relative likelihood of having dementia or Alzheimer’s disease if a patient has diabetes or does not. The average age at enrollment into the study was 76 years for patients with diabetes; they may represent ‘survivors’ and therefore be unrepresentative of diabetes as a whole.
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I do not find their conclusion convincing that the rate of decline of cognitive function is slower in patients with diabetes. A significant proportion of the overall cohort died during the study — 25 in first year, 31 in second, 17 in third and 21 in fourth — but the researchers did not state what proportion of deaths were in patients with diabetes; one cannot discount the possibility that a greater proportion of patients with diabetes died and, if so, it is likely that the surviving patients are the less affected, with less cognitive decline. Also, they lost track of a lot of the patients because they were ‘institutionalized.’
Several studies have shown that high long-term HbA1c levels can be associated with mental decline. This study does not provide any data relating to glycemic control, which the researchers acknowledged, so we do not know what effect, if any, glycemic control had on the results.
Another point is that the dementia in patients with diabetes may have a greater vascular (ischemic) element than in patients without diabetes. There is no specific test for Alzheimer’s disease per se, and patients with diabetes are known to have a greater likelihood of small vessel disease than those without diabetes, so the cause of their dementia could be subtly different, and that difference in cause could affect the rate of cognitive decline.
Laurence Kennedy, MD, is Chairman of the Endocrinology, Diabetes and Metabolism Department at Cleveland Clinic.
Study had unexpected findings, flaws
This study has numerous flaws leading to skepticism of its unexpected findings. It will not affect my clinical approach to patient care. For example, could the finding be related to the higher rate of statin use in the diabetic population? It was not reported, but there were twice as many people with a diagnosis of hyperlipidemia in the diabetes group vs. the remainder of the population, which would have led to at least twice as many individuals on statins. At the time, most experts were recommending statins for all patients with type 2 diabetes, so it is likely the difference in statin use was highly significant.
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Likewise, the diabetic group had significantly more hypertension, which would lead to more angiotensin-converting enzyme inhibitor and angiotensin receptor blocker use, a trend that would again be enhanced by the additional indication for these agents for microalbuminuria and cardiac protection in diabetes. Other possible diabetes interventions could explain the finding, including hyperglycemic drug therapy, increased physical activity, diet changes, aspirin (unlikely) or insulin.
Other reports conflict with these data. There is evidence that the rate of progression is influenced by a variety of comorbidities that are much more common in those with diabetes. Additionally, there is evidence that inflammatory factors and markers such as C-reactive protein and interleukin-6 are associated with increased rate of progression. Many of these factors are more common in diabetes and insulin resistance; the same is true for oxidative stress. In other words, there are many reasons to expect the increased rate of Alzheimer’s disease progression in diabetes and almost no good explanations for a decreased progression.
Andrew Ahmann, MD, is Director of the Harold Schnitzer Diabetes Health Center at Oregon Health & Science University.