Background: Type 2 diabetes (T2D) is a well-established risk factor for dementia. However, the role of glycaemic control in the development of dementia has been less well substantiated. Metformin, a first-line anti-diabetes drug, has been suggested as a promising disease-modifying agent for dementia, but the evidence of its beneficial effect has been partial and inconsistent.
Methods: A series of large-scale cohort studies were conducted based on the UK Clinical Practice Research Datalink (CPRD) between 1987 and 2018. Time-varying Cox proportional hazards model was adopted to estimate associations of longitudinal HbA1c levels and diabetic complications with dementia incidence among T2D patients. Risk of dementia incidence was then compared between patients initially treated with metformin and those initially treated with sulfonylureas or patients receiving no anti-diabetes drugs during registration.
Results: During a median of six years follow-up, 28,627 incident dementia cases were observed among 457,902 T2D patients. Patients with recorded hypoglycaemia or microvascular complications had higher risk of dementia compared to those without such complications (HR=1.30 [95% CI: 1.22-1.39] or 1.10 [95% CI: 1.06-1.14]). Time-varying HbA1c was associated with increased dementia risk (HR=1.08, 95% CI: 1.07-1.09 per 1% HbA1c increment). Both conventional Cox regression and propensity score weighting analysis showed metformin initiators had lower risk of dementia compared with sulfonylurea initiators (HR=0.91 [95% CI: 0.87-0.95] and 0.88 [95% CI: 0.81-0.96]) or patients receiving no anti-diabetes drugs (HR=0.86 [95% CI: 0.83-0.90] and 0.94 [95% CI: 0.90-0.99]). HbA1c and diabetic complications during follow-up only partially mediated the inverse metformin-dementia association.
Conclusions: This thesis highlights the importance of effective glycaemic management in maintaining cognitive health among diabetes patients and provides evidence on a beneficial effect of metformin for dementia prevention. Metformin may reduce dementia risk beyond its effect on diabetes control, thus has the potential of being repurposed for dementia prevention in the general population.