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

Abstract

Introduction4.2 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 methodsWe 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.ResultsWe 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)).ConclusionsMetformin 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.

Novel targets and therapies of metformin in dementia: old drug, new insights

“…The results from human studies have provided evidence that metformin prevents cognitive decline or dementia (Barbera et al, 2024;Doran et al, 2024). A cohort study utilizing UK primary healthcare records, involving 211,396 individuals, revealed that the use of metformin was linked to a reduced risk of dementia (adjusted HR = 0.86) and mild cognitive impairment (adjusted HR = 0.92) (Doran et al, 2024).…”

“…The results from human studies have provided evidence that metformin prevents cognitive decline or dementia (Barbera et al, 2024;Doran et al, 2024). A cohort study utilizing UK primary healthcare records, involving 211,396 individuals, revealed that the use of metformin was linked to a reduced risk of dementia (adjusted HR = 0.86) and mild cognitive impairment (adjusted HR = 0.92) (Doran et al, 2024). In a cohort study of 12,220 metformin users, including 12,220 early terminators and 29,126 routine users, discontinuation of metformin treatment was found to be associated with an increased incidence of dementia.…”