Association of metformin use with Alzheimer's disease in patients with newly diagnosed type 2 diabetes: a population-based nested case-control study

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.

Figure 1

Flowchart of the study participant selection process. NHIS-DM, the Korean National Health Insurance Service-diabetes mellitus; CVD, cerebrovascular disease; DM, diabetes mellitus; AD, Alzheimer’s disease.

Figure 2

Association between metformin use and Alzheimer’s disease risk according to diabetes mellitus (DM) duration and depression. Adjusted odds ratios with 95% confidence intervals for multivariable models evaluating associations between metformin use and incident Alzheimer’s disease. (A) Risk of Alzheimer’s disease associated with metformin use according to DM duration (B) Risk of Alzheimer’s disease associated with metformin use in patients with and without depression. Reference is metformin never-users, and the average cDDD per day is presented as quartiles. cDDDs cumulative defined daily doses; AOR, adjusted odds ratio; CI, confidence interval. *Analysis was adjusted for the following covariates: hypertension, ischemic heart disease, dyslipidemia, Charlson Comorbidity Index, Diabetes Complications Severity Index, depression, statin use, aspirin use, antiplatelet use, anticoagulant use, antihypertensive drug use, antiarrhythmic drug use, use of antidiabetic medications, fasting blood glucose levels, systolic blood pressure, diastolic blood pressure, total cholesterol levels, creatinine levels, body mass index, smoking status, alcohol consumption, and physical activity.