Association of Metformin with the Risk of Dementia: A Population-Based Retrospective Cohort Study in Taiwan

Abstract

Background: Diabetes is rapidly increasing in developing and industrializing nations, primarily due to type 2 diabetes (T2DM). With the global prevalence of diabetes steadily increasing, estimates suggest that by 2045, nearly 548 million people will be living with the disease worldwide. Alzheimer’s disease (AD), recognized as the primary contributor to dementia in aging populations, exhibits an escalating prevalence that parallels the demographic shifts toward older age groups worldwide. This progressive neurodegenerative disorder has emerged as a critical public health challenge, with epidemiological patterns closely tracking the trajectory of population aging across industrialized and developing nations. This study investigates whether metformin may help reduce the risk of dementia. Previous studies from various countries have explored the association between metformin use and dementia risk; however, the findings have been inconsistent. Therefore, we conducted this study to examine whether the observed protective effect of metformin also applies to the Taiwanese (Han Chinese) population, potentially providing valuable insights into ethnic or regional differences in drug response. Methods: We conducted a retrospective cohort study using data from the Longitudinal Health Insurance Database 2000 (LHID2000), including 2 million individuals from 2000 to 2013. Patients with T2DM aged ≥40 years who initiated metformin between 2000 and 2005 formed the exposed group, while those starting other second-line antidiabetic medications formed the non-exposed group. Propensity score matching was used to control for age, sex, index date, and major comorbidities. Incident dementia (2007–2013) was identified using relevant ICD-9-CM codes. Adjusted hazard ratios were estimated using Cox regression with time-dependent covariates. Results: The metformin-exposed cohort demonstrated a risk reduction for dementia incidence relative to the comparator group (adjusted HR 0.472, 95% CI = 0.328–0.679). This protective association remained robust in sex-stratified analyses and age-stratified subgroups. Temporal analysis further revealed a duration-dependent risk attenuation, with extended therapeutic exposure correlating with progressive dementia risk decrement. Conclusions: Our findings suggest that metformin use may be associated with a lower risk of developing dementia in individuals with type 2 diabetes mellitus.