Higher HbA1c Concentrations in Diabetes Linked With Greater Risk of Dementia

Chris Moran, PhD

Recently published findings from a large-scale study of individuals with diabetes showed that cumulative glycated hemoglobin (HbA1c) concentrations of 9% or more were associated with the greatest risk of dementia. Investigators noted that follow-up research is needed to examine whether the observational associations reported were causal and are seen in other groups.

The study, published in JAMA Neurology, included 253,211 individuals with type 2 diabetes, with a total of more than 4.6 million HbA1c measurements. Age-adjusted findings on the incidence of dementia showed that individuals with 75% or more of HbA1c measurements in the category of 6% to less than 7% had the lowest incidence of dementia (10.24 per 1000 person-years [PY]), while those with 75% or more in the range of 10% or greater had the greatest incidence of dementia (19.32 per 1000 PY).

Led by Chris Moran, PhD, associate professor, School of Public Health and Preventive Medicine, Monash University, patients were followed-up for a mean of 5.9 (standard deviation [SD], 4.5) years. Participants were categorized based on the percentage of their HbA1c measurements, recalculating each time a new value was captured. Amount of time exposed to the threshold were operationalized through a binary indicator of 50% of an individual’s HbA1c measures fell within the categories and a categorial variable representing the percentage of HbA1c measurements (reference group: <10%, 10% to <25%, 25% to <75%, or ≥75%).

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Majority exposure to HbA1c concentrations of 9% to less than 10% was associated with an increased hazard of dementia (aHR, 1.31; 95% CI, 1.15-1.51). Furthermore, the greatest hazard of dementia was observed in those with majority HbA1c measurements of 10% or more (aHR, 1.74; 95% CI, 1.62-1.86) compared with those less than 50% of measurements in that range. In sensitivity analyses, across all HbA1c ranges, having stable HbA1c (≥75% of all measurements within a particular range) was associated with a lower hazard of dementia than was having HbA1c measures that were less consistent (<75% in a particular range)(aHR, 0.86; 95% CI, 0.83-0.89).

Importantly, greater time spent within the glycemic targets proposed by most geriatrics guidelines, specifically those by the American Geriatrics Society and US Department of Veterans Affairs, for healthier older people, within the range of 6% to 7.9%, was associated with reduced dementia hazard. Investigators saw a decrease in the hazard of dementia by 1% (aHR, 0.99; 95% CI, 0.98-1.00) for every additional 10 percentage points of HbA1c from the 6% range replaced in the recommended 6% to less than 8% range. This hazard decreased by 3% (aHR, 0.97; 95% CI, 0.96-0.98) for every additional 10 percentage points spent in the 6% to less than 8% range instead of the 8% to 9% range. Similarly, the hazard decreased by 5% (aHR, 0.95% CI, 0.93-0.97) for points spent in the 6% to less than 8% range instead of the more than 9% range.

The study had several strengths, including "a high quality electronic health record with a low turnover rate, enabling us to capture multiple longitudinal HbA1c measurements, diabetes comorbidities, and incident dementia,” study authors wrote. "We reduced the risk of underlying changes in cognition driving changes in glycemic control by starting follow-up for any given time-updated exposure 3 years after the end of that exposure period."

REFERENCE
1. Moran C, Lacy ME, Whitmer RA, et al. Gylcemic control over multiple decades and dementia risk in people with type 2 diabetes. JAMA Neurol. Published online April 17, 2023. doi:10.1001/jamaneurol.2023.0697