STOCKHOLM—Data from the Swedish National Diabetes Registry add to evidence that high blood glucose levels increase the risk for dementia in individuals with type 2 diabetes and imply that better glycemic control might help prevent cognitive decline.
In a large observational study presented at the Annual Meeting of the European Association for the Study of Diabetes, hemoglobin A1c (HbA1c) levels in excess of 10% increased the rate of dementia by 23% to 77%, depending on the time-fixed or time-updated statistical analysis performed, with hazard ratios (HRs) of 1.23 and 1.77, respectively, compared with a reference HbA1c level of less than 6%.
“An HbA1c [level] between 6% and 7% was associated with a lower risk of any dementia [HR, 0.82], compared to the reference, but as HbA1c increased and was above 10%, the risk was higher for individuals [HR, 1.23],” said Aidin Rawshani, MD, a researcher at the University of Gothenburg in Sweden.
Aidin Rawshani, MD
An Analysis of Epidemiologic Data
For the study, Dr. Rawshani and his colleagues identified all individuals with type 2 diabetes who were included in the Swedish National Diabetes Registry between 2003 and 2012 and who did not have dementia at enrollment. Data on individuals’ socioeconomic status, hospital admissions, outpatient visits, and deaths were then obtained from four Swedish databases and ICD-10 codes to identify people who later developed Alzheimer’s disease or vascular, unspecified, or any dementia.
There were 353,214 individuals with type 2 diabetes without dementia at enrollment into the registry. Of these participants, 13,159 were reported to have any dementia. In all, 3,499 people had Alzheimer’s disease, and 3,377 people had vascular dementia. Mean follow-up was 4.8 years, which represented 1.7 million person-years.
Cox regression analysis was used to assess the association between dementia and glycemic control, as well as other pertinent patient characteristics, risk factors, complications and comorbidities, and medication use. All covariates were modeled as time-dependent and time-variable predictors.
The study population was categorized into six groups according to baseline HbA1c level. A total of 118,433 people had a level less than 6%, 117,397 people had a level of 6% to less than 7%, 49,049 people had a level of 7% to less than 8%, 23,143 people had a level of 8% to less than 9%, 9,096 people had a level of 9% to less than 10%, and 8,354 people had a level of 10% or more. More than half (55% to 60%) of subjects were men, the mean age was approximately 68, and the duration of diabetes ranged from four to 10 years.
Statins Reduced Dementia Risk
Dr. Rawshani reported that the crude event rate for any dementia was 7.25 cases per 1,000 person-years for the lowest (<6%) and 8.47 cases per 1,000 person-years for the highest (≥10%) levels of HbA1c. The crude event rates for the other HbA1c categories were 7.91, 8.75, 9.13, and 8.71 per 1,000 person-years, respectively.
Modeling HbA1c level as a continuous variable showed that there was no increased dementia risk at an HbA1c level of 6.7%, but that the risk increased substantially at higher levels. Dementia risk also increased with increasing age, diastolic blood pressure, high-density-lipoprotein cholesterol, and low-density-lipoprotein cholesterol, said Dr. Rawshani.
When the researchers examined time-updated covariates, they found that individuals who developed microalbuminuria or macroalbuminuria had a higher risk for dementia than those without albuminuria (HR, 1.22 and HR, 1.39, respectively). A higher risk for dementia also was seen in patients who did not perform any daily physical activity versus those who did (HR, 2.21).
Comorbid stroke increased the risk for dementia by 43% (HR, 1.43), with little risk increase for comorbid atrial fibrillation (HR, 1.11) or coronary heart disease (HR, 1.02). Conversely, the use of statins and antihypertensive medication were associated with lower dementia risk (HR, 0.87 and HR, 0.69, respectively).
The respective Cox analysis–predicted survival rates at 10 years for the patients who did and did not develop dementia during follow-up were 40% and 70%, respectively. “Our conclusion is that higher HbA1c levels are associated with an increased risk of dementia among persons with type 2 diabetes,” Dr. Rawshani said.
A Case of Reverse Causality?
“The conclusion is interesting,” said Naveed Sattar, MD, Professor of Metabolic Medicine at the Institute of Cardiovascular and Medical Sciences in the University of Glasgow in an interview.The investigators did not mention, however, that the lowest blood glucose levels also were linked to an increased risk of dementia, said Dr. Sattar. The results had a J-shaped curve, he added.
“In people who have very low blood glucose levels, below guideline levels, I suspect that there are other reasons that they are sick,” Dr. Sattar continued. “Their HbA1c is low because of this, and that then leads to dementia.” Perhaps the hyperglycemia did not cause dementia, he added, it was more likely a case of reverse causality.