Metformin Use and Subsequent Alzheimer’s Disease Incidence in Patients With Newly Diagnosed Type 2 Diabetes: a Population-based Nested Case-control Study

Abstract Background: Metformin reduces insulin resistance, which may be shared pathophysiology between diabetes mellitus (DM) and Alzheimer’s disease (AD). Thus, it has been hypothesized that metformin may be effective against AD; however, evidence of metformin effects on AD development remains insufficient and conflicting. We investigated Alzheimer’s disease risk in patients with newly diagnosed type 2 diabetes mellitus treated with metformin.Methods: This retrospective, observational, nested case-control study included enrolled patients with newly diagnosed type 2 diabetes mellitus in the Korean National Health Insurance Service diabetes mellitus cohort (2002–2017). Among 70,499 DM patients who were dementia-free at the time of DM diagnosis, 1,675 AD cases identified were matched to 8,375 controls by age, sex, and DM onset and duration. Association of AD with metformin use were analyzed using multivariable conditional logistic regression analyses adjusted for comorbidities and cardiometabolic risk profile. Results: Metformin use was associated with an increased adjusted odds ratio (AOR) of AD (1.50; 95% CI, 1.23–1.83). The strength of the association increased with the cumulative daily defined dose per day in metformin users. The risk was more pronounced among patients with a longer duration of DM (1.48; 95% CI, 1.14 to 1.91, for a DM duration of 5–9 years; 2.18; 95% CI, 1.41 to 3.39 for a duration greater than 10 years), while no statistical significance was found in the patients with DM duration less than 5 years (AOR 0.88; 95%CI 0.54–1.43). Furthermore, the risk of AD was significantly higher in DM patients with depression (AOR 2.05; 1.02–4.12). Conclusions: Given the huge number of patients with DM who are taking metformin worldwide, a double-blinded, prospective study is required to determine the long-term cognitive safety of metformin.