Glycemic Control over Multiple Decades and Dementia Risk in People with Type 2 Diabetes

Importance: The levels of glycemic control associated with the lowest risk of dementia in people with type 2 diabetes are unknown. This knowledge is critical to inform patient-centered glycemic target setting. Objective: To examine the associations between cumulative exposure to various ranges of glycated hemoglobin (HbA_1c) concentrations with dementia risk across sex and racial and ethnic groups and the association of current therapeutic glycemic targets with dementia risk. Design, Setting, and Participants: This cohort study included members of the Kaiser Permanente Northern California integrated health care system with type 2 diabetes who were aged 50 years or older during the study period from January 1, 1996, to September 30, 2015. Individuals with fewer than 2 HbA_1cmeasurements during the study period, prevalent dementia at baseline, or less than 3 years of follow-up were excluded. Data were analyzed from February 2020 to January 2023. Exposures: Time-updated cumulative exposure to HbA_1cthresholds. At each HbA_1cmeasurement, participants were categorized based on the percentage of their HbA_1cmeasurements that fell into the following categories: less than 6%, 6% to less than 7%, 7% to less than 8%, 8% to less than 9%, 9% to less than 10%, and 10% or more of total hemoglobin (to convert percentage of total hemoglobin to proportion of total hemoglobin, multiply by 0.01). Main Outcomes and Measures: Dementia diagnosis was identified using International Classification of Diseases, Ninth Revision codes from inpatient and outpatient encounters. Cox proportional hazards regression models estimated the association of time-varying cumulative glycemic exposure with dementia, adjusting for age, race and ethnicity, baseline health conditions, and number of HbA_1cmeasurements. Results: A total of 253211 participants were included. The mean (SD) age of participants was 61.5 (9.4) years, and 53.1% were men. The mean (SD) duration of follow-up was 5.9 (4.5) years. Participants with more than 50% of HbA_1cmeasurements at 9% to less than 10% or 10% or more had greater risk of dementia compared with those who had 50% or less of measurements in those categories (HbA_1c9% to <10%: adjusted hazard ratio [aHR], 1.31 [95% CI, 1.15-1.51]; HbA_1c≥10%: aHR, 1.74 [95% CI, 1.62-1.86]). By contrast, participants with more than 50% of HbA_1cconcentrations less than 6%, 6% to less than 7%, or 7% to less than 8% had lower risk of dementia (HbA_1c<6%: aHR, 0.92 [95% CI, 0.88-0.97]; HbA_1c6% to <7%: aHR, 0.79 [95% CI, 0.77-0.81]; HbA_1c7% to <8%: aHR, 0.93 [95% CI, 0.89-0.97]). Conclusions and Relevance: In this study dementia risk was greatest among adults with cumulative HbA_1cconcentrations of 9% or more. These results support currently recommended relaxed glycemic targets for older people with type 2 diabetes.