Early glycemic control and subsequent risk of incident dementia among new metformin users

People with diabetes have elevated dementia risk. Optimal glycemic treatment targets for dementia risk reduction among individuals initiating metformin monotherapy are unknown.

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.

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.

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).