AT EASD 2015

STOCKHOLM (FRONTLINE MEDICAL NEWS) – 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 potentially help prevent such cognitive decline.

In the large observational study, hemoglobin A1c levels in excess of 10% increased the rate of dementia by 23%-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 of less than 6%.

“An HbA1c between 6% and 7% was associated with a lower [HR, 0.82; 95% confidence interval, 0.86-0.91; P <.001] risk of any dementia compared to the reference, but as HbA1c increased and was above 10% [HR, 1.23; 95% CI, 1.11-1.35; P <.001] the risk was higher for individuals,” Dr. Aidin Rawshani reported at the annual meeting of the European Association for the Study of Diabetes.

For the study, Dr. Rawshani and his colleagues at the Institute of Medicine at the University of Gothenburg (Sweden) identified all individuals with type 2 diabetes (2DM) who were registered 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 those who later developed Alzheimer’s or vascular, unspecified, or any dementia.

Over a mean follow-up of 4.8 years, accounting for 1.7 million person-years, there were 353,214 individuals with 2DM without dementia at enrollment into the registry. Of these, 13,159 were reported to have any dementia, with 3,499 and 3,377 having Alzheimer’s disease or vascular dementia.

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 both time-dependent and time-variable predictors.

The study population was divided into six groups according to baseline HbA1c: <6% (n = 118,433); 6% to <7% (n = 117,397); 7% to <8% (n = 49,049); 8% to <9% (n = 23,143); 9% to <10% (n = 9,096); ≥10% (n = 8,354). Over half (55%-60%) of subjects were men, the mean age was approximately 68 years, and the duration of diabetes ranged from 4 to 10 years.

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 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 as a continuous variable showed that there was no dementia risk at an HbA1c of 6.7% but that it increased substantially thereafter. Dementia risk also was found to increase with increasing age, diastolic blood pressure, high-density-lipoprotein cholesterol, and low-density-lipoprotein cholesterol, he said.

Looking at time-updated covariates, individuals who developed microalbuminuria (HR, 1.22; 95% CI, 1.15-1.29; P <.001) or macroalbuminuria (HR, 1.39; 95% CI, 1.29-1.50; P <.001) had a higher risk for dementia than those without albuminuria.

A higher risk for dementia also was seen in patients who did not perform any daily physical activity versus those who did, with a HR of 2.21 (95% CI, 2.05-2.38; P <.001).

Comorbid stroke increased the risk for dementia by 43% (HR, 1.43; 95% CI, 1.34-1.53; P <.001), with little risk increase for comorbid atrial fibrillation (HR, 1.11; 95% CI, 1.04-1.18; P <.003) or coronary heart disease (HR, 1.02; 95% CI, 1.02-1.16; P <.009).

Conversely, the use of statins (HR, 0.87; 95% CI, 0.82-0.92; P <.001) and antihypertensive medication (HR, 0.69; 95% CI, 0.64-0.73; P <.001) was associated with lower dementia risk.

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%.

“Our conclusion is that higher HbA1c levels are associated with an increased risk of dementia among persons with type 2 diabetes,” Dr. Rawshani said.

“The conclusion is interesting,” Dr. Naveed Sattar, professor of metabolic medicine at the Institute of Cardiovascular and Medical Sciences, University of Glasgow (Scotland), said in an interview. Dr. Sattar, who was not involved in the study, said that, while interesting, there was no mention that the very lowest blood glucose levels also were linked to an increased risk. There was a J-shaped curve, he observed.

“In people who have very low blood glucose levels, below guideline levels, I suspect that there are other reasons that they are sick and they’re hemoglobin A1c is low because of this and that then leads to dementia.” Dr. Sattar observed. He added that perhaps it was not necessarily the hyperglycemia causing dementia, it was more likely a case of reverse causality.

“The study showed clearly that high BMI, high LDL, and high blood pressure were also associated with more dementia,” Dr. Sattar said. “And, it also showed that being on antihypertensives and cholesterol-lowering tablets gives you a low risk of dementia,” he added. “So the things we are doing in diabetes to keep blood pressure down, smoking down, cholesterol down, are working and, together with keeping hemoglobin in the normal range, should help to lower the risk of dementia. That’s epidemiology, and we now need the trials to prove it, but it’s going to be very, very tough.”

Dr. Rawshani did not report having any disclosures. Dr. Sattar said that he had no disclosures relevant to his comments.