• Che-Yuan Wu, Christa Wang, Refik Saskin, Baiju R Shah, Moira K Kapral, Krista L Lanctôt, Nathan Herrmann, Hugo Cogo-Moreira, Bradley J MacIntosh, Jodi D Edwards, and Walter Swardfager.
• Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
• J. Intern. Med. 2024 Jan 1; 295 (1): 687868-78.

BackgroundMetformin has been suggested to reduce dementia risk; however, most epidemiologic studies have been limited by immortal time bias or confounding due to disease severity.ObjectivesTo investigate the association of metformin initiation with incident dementia using strategies that mitigate these important sources of bias.MethodsResidents of Ontario, Canada ≥66 years newly diagnosed with diabetes from January 1, 2008 to December 31, 2017 entered this retrospective population-based cohort. To consider the indication for metformin monotherapy initiation, people with hemoglobin A1c of 6.5%-8.0% and estimated glomerular filtration rate ≥45 mL/min/1.73 m2 were selected. Using the landmark method to address immortal time bias, exposure was grouped into "metformin monotherapy initiation within 180 days after new diabetes diagnosis" or "no glucose-lowering medications within 180 days." To address disease latency, 1-year lag time was applied to the end of the 180-day landmark period. Incident dementia was defined using a validated algorithm for Alzheimer's disease and related dementias. Adjusted hazard ratios (aHR) and confidence intervals (CIs) were estimated from propensity-score weighted Cox proportional hazard models.ResultsOver mean follow-up of 6.77 years from cohort entry, metformin initiation within 180 days after new diabetes diagnosis (N = 12,331; 978 events; 65,762 person-years) showed no association with dementia risk (aHR [95% CI] = 1.05 [0.96-1.15]), compared to delayed or no glucose-lowering medication initiation (N = 22,369; 1768 events; 117,415 person-years).ConclusionEarly metformin initiation was not associated with incident dementia in older adults newly diagnosed with diabetes. The utility of metformin to prevent dementia was not supported.© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.

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