Abstract
Metformin reduces insulin resistance, which constitutes a pathophysiological connection of diabetes with Alzheimer’s disease (AD), but the evidence of metformin on AD development was still insufficient and conflicting. We investigated AD risk in patients with newly diagnosed type 2 DM treated with metformin. This retrospective, observational, nested case–control study included patients with newly diagnosed type 2 DM obtained from the Korean National Health Insurance Service DM cohort (2002–2017). Among 70,499 dementia-free DM patients, 1675 AD cases were matched to 8375 controls for age, sex, and DM onset and duration. The association between AD and metformin was analyzed by multivariable regression analyses, adjusted for comorbidities and cardiometabolic risk profile. Metformin use was associated with an increased odds of AD (adjusted odds ratio [AOR] 1.50; 95% CI 1.23–1.83). The risk of AD was higher in patients with a longer DM duration. Furthermore, AD risk was significantly high in DM patients with depression (AOR 2.05; 95% CI 1.02–4.12). Given the large 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.
Highlights
Metformin reduces insulin resistance, which constitutes a pathophysiological connection of diabetes with Alzheimer’s disease (AD), but the evidence of metformin on AD development was still insufficient and conflicting
One study in the UK showed that long-term metformin use is associated with an increased risk of AD10, and an Australian one found that metformin-induced vitamin B 12 deficiency was related to impaired cognitive performance in diabetes mellitus (DM) patients[11]
In a national longitudinal nested case–control study, we evaluated 1675 AD cases and 8375 controls matched by age, sex, time of DM onset, and DM duration
Summary
Metformin reduces insulin resistance, which constitutes a pathophysiological connection of diabetes with Alzheimer’s disease (AD), but the evidence of metformin on AD development was still insufficient and conflicting. One study in the UK showed that long-term metformin use is associated with an increased risk of AD10, and an Australian one found that metformin-induced vitamin B 12 deficiency was related to impaired cognitive performance in DM patients[11]. A population-based cohort study in Taiwan showed that metformin exposure in type 2 DM patients may be a risk factor for neurodegenerative diseases, including dementia and Parkinson’s. It could not be conclusively established that metformin use, and not DM duration/severity, showed a significant relationship with an increased risk of AD. To address the possibility of diagnostic misclassification, we conducted a validation study, and to account for confounders by indication, we assessed cardiometabolic risk profile and prescription registry data of patients with newly diagnosed type 2 DM, assumed to be homogeneous in disease severity
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