medwireNews: US research confirms a significant relationship between the time older men with diabetes spend within their target range for glycated hemoglobin (HbA1c) and their risk for Alzheimer’s disease and related dementias (ADRD), even after adjusting for hypoglycemia.
“These results suggest that in addition to preventing hypoglycemia, maintaining higher HbA1c TIR [time in range] over time may decrease dementia incidence,” report Paul Conlin (Veterans Affairs Boston Healthcare System, Massachusetts, USA) and co-workers in JAMA Network Open.
The team used information for 374,021 individuals aged at least 65 years who were registered in the Veterans Health Administration and Medicare database between January 2004 and December 2018. Overall, 99% of the participants were men, the mean age at baseline was 73.2 years, and 87% were White.
The participants all had results for at least four HbA1c tests between the baseline period of 2005 and 2014, during which time their target range was determined based on their life expectancy, diabetes complications, and comorbidities.
The average baseline HbA1c level was 7.0% (8.6 mmol/L). Overall, 25.2% of patients had a target range of 6.0–7.0% (7.0–8.6 mmol/L), 34.4% a range of 7.0–8.0% (8.6–10.1 mmol/L), 33.4% a range of 7.5–8.5% (9.4–10.9 mmol/L), and 7.4% a range of 8.0–9.0% (10.1–11.7 mmol/L).
After up to 10 years of follow-up, 11% of participants had developed ADRD, the investigators report.
Initial analysis indicated that, compared with individuals with a TIR of at least 80%, those with a shorter TIR had a significantly increased risk for ADRD, ranging from a hazard ratio (HR) of 1.19 for those with a TIR of 60% to less than 80% and a HR of 1.59 for those with a TIR of less than 20%.
And these increased risks remained (HRs=1.07–1.19) after adjusting for a raft of covariates including age, sex, race, hypoglycemia events, diabetes complications, statin use, average HbA1c over the baseline period, hypertension, smoking, and a history of heart or cerebrovascular disease, the researchers emphasize.
The significant relationship between HbA1c TIR and incident ADRD persisted in a sensitivity analysis excluding participants who were at risk for, or experienced, hypoglycemia during the baseline period, based on use of insulin or sulfonylureas, or documented hypoglycemia events.
In addition, there were significant associations between average HbA1c at baseline and ADRD, with increased risks found for men with an average HbA1c below 6.0% (<7.0 mmol/L, HR=1.16) and for those with a mean HbA1c of 8.0–8.9% (10.1–11.6 mmol/L), 9.0–9.9% (11.7–13.2 mmol/L), or above 10.0% (>13.3 mmol/L), with HRs of 1.10, 1.29, and 1.66, respectively.
The researchers also investigated the impact of time below range or above range in men whose HbA1c levels were out of range more than 60% of the time. Compared with men who had TIR of at least 60%, men who spent 60% or more time below their target were a significant 1.48 and 1.23 times more likely to develop ADRD before and after adjustment, respectively. There was also a significant increased risk for ADRD in men who spent 60% or greater time above their target range but this was lost after adjustment.
The investigators believe the relationship between time below range and ADRD is “clinically relevant” and indicates “that in older adults with diabetes, the stability of ambient glucose levels over time may be as important as the level per se.”
They suggest: “Investigating this hypothesis is an area that warrants further investigation.”
Conlin and co-authors conclude: “These results affirm the benefits of applying personalized HbA1c target ranges based on age, life expectancy, and comorbidities.
“Clinicians should work with patients to ensure HbA1c stability to reduce ADRD risk in older adults with diabetes.”
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