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

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.