Metformin and Dementia Risk: A Systematic Review with Respect to Time Related Biases

Jiahui Dai; Kayleen Deanna Ports; Maria M Corrada; Andrew O Odegaard; Joan O'Connell; Luohua Jiang

doi:10.3233/ADR-220002

Metformin and Dementia Risk: A Systematic Review with Respect to Time Related Biases

J Alzheimers Dis Rep. 2022 Aug 3;6(1):443-459. doi: 10.3233/ADR-220002. eCollection 2022.

Authors

Jiahui Dai¹, Kayleen Deanna Ports¹, Maria M Corrada^{1

2

3}, Andrew O Odegaard¹, Joan O'Connell⁴, Luohua Jiang¹

Affiliations

¹ Department of Epidemiology & Biostatistics, University of California Irvine, Irvine, CA, USA.
² Department of Neurology, University of California Irvine, Irvine, CA, USA.
³ Institute for Memory Impairments and Neurological Disorders (UCI MIND), University of California Irvine, Irvine, CA, USA.
⁴ Centers for American Indian and Alaska Native Health, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Abstract

Background: When studying drug effects using observational data, time-related biases may exist and result in spurious associations. Numerous observational studies have investigated metformin and dementia risk, but have reported inconsistent findings, some of which might be caused by unaddressed time-related biases. Immortal time bias biases the results toward a "protective" effect, whereas time-lag and time-window biases can lead to either a "detrimental" or "protective" effect.

Objective: To conduct a systematic review examining time-related biases in the literature on metformin and dementia.

Methods: The electronic databases PubMed, Web of Science, and ProQuest were searched for the terms "Metformin" AND ("dementia" OR "Alzheimer's Disease" OR "cognitive impairment"). These databases were searched from inception through 09/24/2021. Only English language articles and human research were eligible.

Results: Seventeen studies were identified: thirteen cohort studies, two case-control studies, and two nested case-control studies. Eleven (64.7%) studies reported a reduced risk of dementia associated with metformin use; two (11.8%) suggested metformin increased dementia risk, while four (23.5%) concluded no significant associations. Eight (61.5%) of thirteen cohort studies had immortal time bias or did not clearly address it. Fifteen (88.2%) of seventeen reviewed studies had time-lag bias or did not clearly address it. Two (50.0%) of four case-control studies did not explicitly address time-window bias. The studies that addressed most biases concluded no associations between metformin and dementia risk.

Conclusion: None of the reviewed studies clearly addressed relevant time-related biases, illustrating time-related biases are common in observational studies investigating the impact of anti-diabetic medications on dementia risk.

Keywords: Bias; case-control studies; cohort studies; dementia; metformin.