Stable HbA1c Levels Linked to Reduced Risk of Alzheimer's Disease and Related Dementias in Older Diabetics: JAMA

"In the cohort study of 374,021 older veterans with diabetes, higher HbA1c stability, indicated by more time spent within target HbA1c ranges, was linked to a reduced risk of ADRD. Additionally, when HbA1c levels fell outside the target range, spending more time below individualized HbA1c targets was associated with a higher risk of ADRD, even in individuals not on medications known to cause hypoglycemia," the researchers reported.

Individuals with diabetes often develop Alzheimer’s disease and related dementias. Factors such as hyperglycemia, hypoglycemia, and glycemic variability are linked to a higher risk of ADRD. Traditional glycemic metrics, like average glycated hemoglobin A1c (HbA1c), might not capture the complex and dynamic factors connecting diabetes to ADRD. The HbA1c time in range (TIR), a measure of glycemic control that reflects HbA1c stability within specific ranges over time, could provide new insights into how glucose levels over time relate to the incidence of ADRD.

Against the above background, Patricia C. Underwood, William F. Connell School of Nursing, Boston College, Boston, Massachusetts, and colleagues examine the association between HbA1c TIR and the incidence of ADRD in older veterans with diabetes.

The cohort study utilized administrative and healthcare utilization data from the Veterans Health Administration and Medicare, covering the period from January 1, 2004, to December 31, 2018. It included veterans aged 65 and older with diabetes who had at least four HbA1c tests during a 3-year baseline period starting between January 1, 2005, and December 31, 2014. Data analysis took place between July and December 2023.

Hemoglobin A1c TIR was calculated as the percentage of days during the baseline period when HbA1c levels were within individualized target ranges based on clinical characteristics and life expectancy, with higher HbA1c TIR considered more favorable. The study estimated the association between HbA1c TIR and the incidence of Alzheimer’s disease and related dementias. Additional models assessed ADRD incidence in participants who mostly fell above or below their HbA1c target ranges.

The study led to the following findings:

• The study included 374 021 veterans with diabetes (mean age, 73.2 years; 99% males). During follow-up of up to 10 years, 11% developed ADRD.
• Adjusted Cox proportional hazards regression models showed lower HbA1c TIR was associated with increased risk of incident ADRD (HbA1c TIR of 0 to <20% compared with ≥80%: hazard ratio, 1.19).
• The direction of out-of-range HbA1c levels was associated with incident ADRD.
• Having greater time below range (≥60%, compared with ≥60% TIR) was associated with significantly increased risk (hazard ratio, 1.23).
• Findings remained significant after excluding individuals with baseline use of medications associated with hypoglycemia risk (ie, insulin and sulfonylureas) or with hypoglycemia events.

The findings showed that in older adults with diabetes, greater HbA1c stability within individualized target ranges was linked to a reduced risk of Alzheimer’s disease and related dementias. Conversely, lower HbA1c TIR may help identify patients at higher risk for ADRD.

"These results underscore the advantages of using personalized HbA1c target ranges tailored to age, life expectancy, and comorbidities. Clinicians should collaborate with patients to maintain HbA1c stability, which can help lower the risk of ADRD in older adults with diabetes," the researchers concluded.

Reference:

Underwood PC, Zhang L, Mohr DC, et al. Glycated Hemoglobin A1c Time in Range and Dementia in Older Adults With Diabetes. JAMA Netw Open. 2024;7(8):e2425354. doi:10.1001/jamanetworkopen.2024.25354