Abstract
BACKGROUND: People with diabetes have elevated dementia risk. Optimal glycemic treatment targets for dementia risk reduction among individuals initiating metformin monotherapy are unknown. METHODS: We used Danish health registry data to identify metformin monotherapy initiators aged 50+ in Northern Denmark during 2000-2018. We examined the relation between early glycemic control, HbA1c reduction magnitude, and their combination with incident dementia using standard hazard models and propensity-score based restricted and weighted models, which better address confounding and mimic a clinical trial. We explored effects by age, calendar year of metformin initiation, and presence of cardiovascular disease. RESULTS: Among 46,332 metformin initiators (median age 65 years), 83% achieved an HbA1c level <7% (<53 mmol/mol) within one year after metformin initiation and 1,432 (3.2%) developed dementia over a median 5.6 years of follow-up. Both standard and propensity-score restricted/weighted analyses suggested elevated dementia risk at achieved HbA1c levels >7% (>53 mmol/mol), but little difference in dementia risk among those achieving tight (HbA1c of 6.5% to <7%/48 to <53 mmol/mol) or very tight glycemic control (HbA1c of 6% to <6.5%/42 to <48 mmol/mol or <6%/<42 mmol/mol). While P values for interaction were non-significant, point estimates suggested benefits of early glycemic control on dementia risk were limited to persons without established cardiovascular disease and take years to manifest. CONCLUSION: Our findings support established recommendations for early glycemic control (i.e., HbA1c <7%/<53 mmol/mol) in type 2 diabetes for dementia risk reduction, with little evidence of benefit for pursuing lower targets (i.e. <6.5%/<48 mmol/mol, <6%/<42mmol/mol).