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Incident dementia risk among patients with type 2 diabetes receiving metformin versus alternative oral glucose-lowering therapy: an observational cohort study using UK primary healthcare records

Doran, William; Tunnicliffe, Louis; Muzambi, Rutendo; Rentsch, Christopher T; Bhaskaran, Krishnan; Smeeth, Liam; Brayne, Carol; ... Warren-Gash, Charlotte; + view all (2024) Incident dementia risk among patients with type 2 diabetes receiving metformin versus alternative oral glucose-lowering therapy: an observational cohort study using UK primary healthcare records. BMJ Open Diabetes Research and Care , 12 (1) , Article e003548. 10.1136/bmjdrc-2023-003548. Green open access

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Abstract

INTRODUCTION: 4.2 million individuals in the UK have type 2 diabetes, a known risk factor for dementia and mild cognitive impairment (MCI). Diabetes treatment may modify this association, but existing evidence is conflicting. We therefore aimed to assess the association between metformin therapy and risk of incident all-cause dementia or MCI compared with other oral glucose-lowering therapies (GLTs). RESEARCH DESIGN AND METHODS: We conducted an observational cohort study using the Clinical Practice Research Datalink among UK adults diagnosed with diabetes at ≥40 years between 1990 and 2019. We used an active comparator new user design to compare risks of dementia and MCI among individuals initially prescribed metformin versus an alternative oral GLT using Cox proportional hazards regression controlling for sociodemographic, lifestyle and clinical confounders. We assessed for interaction by age and sex. Sensitivity analyses included an as-treated analysis to mitigate potential exposure misclassification. RESULTS: We included 211 396 individuals (median age 63 years; 42.8% female), of whom 179 333 (84.8%) initiated on metformin therapy. Over median follow-up of 5.4 years, metformin use was associated with a lower risk of dementia (adjusted HR (aHR) 0.86 (95% CI 0.79 to 0.94)) and MCI (aHR 0.92 (95% CI 0.86 to 0.99)). Metformin users aged under 80 years had a lower dementia risk (aHR 0.77 (95% CI 0.68 to 0.85)), which was not observed for those aged ≥80 years (aHR 0.95 (95% CI 0.87 to 1.05)). There was no interaction with sex. The as-treated analysis showed a reduced effect size compared with the main analysis (aHR 0.90 (95% CI 0.83 to 0.98)). CONCLUSIONS: Metformin use was associated with lower risks of incident dementia and MCI compared with alternative GLT among UK adults with diabetes. While our findings are consistent with a neuroprotective effect of metformin against dementia, further research is needed to reduce risks of confounding by indication and assess causality.

Type: Article
Title: Incident dementia risk among patients with type 2 diabetes receiving metformin versus alternative oral glucose-lowering therapy: an observational cohort study using UK primary healthcare records
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1136/bmjdrc-2023-003548
Publisher version: http://dx.doi.org/10.1136/bmjdrc-2023-003548
Language: English
Additional information: © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.
Keywords: Dementia, Diabetes Mellitus, Type 2, Electronic Health Records, Metformin, Adult, Humans, Female, Middle Aged, Male, Diabetes Mellitus, Type 2, Metformin, Cohort Studies, Hypoglycemic Agents, Glucose, Dementia, Primary Health Care, United Kingdom
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine > MRC Unit for Lifelong Hlth and Ageing
URI: https://discovery.ucl.ac.uk/id/eprint/10186748
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