Metformin and Risk of Alzheimer's Disease Among Community-Dwelling People With Diabetes: A National Case-Control Study

Abstract

Context: Type 2 diabetes has been linked with an increased risk of Alzheimer's disease (AD). Studies on the association between metformin use and AD have reported conflicting results.

Objective: To investigate whether metformin use modifies the association between diabetes and incident, clinically verified AD.

Design: Nested case-control study.

Setting: All community-dwelling people in Finland.

Participants: Cases were all community-dwelling Finns with AD diagnosed from 2005 to 2011 and with diabetes diagnosed ≥ 3 years before AD (n = 9862). Cases were matched with up to 2 control persons by age, sex, and diabetes duration (n = 19 550).

Main outcome measure: Cumulative metformin exposure was determined from reimbursed dispensings over a 10- to 16-year period. Adjusted odds ratios (aORs) were calculated using conditional logistic regression to estimate associations, with adjustment for potential confounders.

Results: A total of 7225 (73.3%) cases and 14528 (74.3%) controls received metformin at least once. Metformin use (ever use) was not associated with incident AD (aOR 0.99; 95% confidence interval [CI], 0.94-1.05). The adjusted odds of AD were lower among people dispensed metformin for ≥ 10 years (aOR 0.85; 95% CI, 0.76-0.95), those dispensed cumulative defined daily doses (DDDs) of < 1825-3650 (aOR 0.91; 95% CI, 0.84-0.98) and > 3650 DDDs (aOR 0.77; 95% CI, 0.67-0.88), and among persons dispensed an average of 2 g metformin daily (aOR 0.89; 95% CI, 0.82-0.96).

Conclusion: In this large national sample we found no evidence that metformin use increases the risk of AD. Conversely, long-term and high-dose metformin use was associated with a lower risk of incident AD in older people with diabetes.

Keywords: Alzheimer’s disease; Finland; biguanide; dementia; diabetes; metformin.