Metformin and the Risk of Dementia Introduction
Dementia can be caused by vascular etiology or neurodegenerative disease (Alzheimer’s disease). It is a syndrome characterized by deterioration in memory and loss of daily self-care ability.
It affects mainly the older people but may also happen in the younger generation.
The World Health Organization (2017) has recognized the growing incidence of dementia in the world population and estimated that the number of people with dementia is currently around 47 million in the world and each year nearly 10 million new cases will add into the growing pool of patients (www.who.int/mediacentre/factsheets/fs362/en/).
A call for actions and research priorities to reduce the global burden of dementia has been advocated following the First World Health Organization Ministerial Conference on Global Action Against Dementia summoned in March 2015 [1].
Elevated blood glucose may impair cerebral function and patients with diabetes have an increased risk of dementia [2].
The link between diabetes and dementia is probably multifactorial and mechanisms may involve inflammation, oxidative stress, atherosclerosis, amyloid-β deposition, brain insulin resistance with hyper-insulinemia, advanced glycation end-products (AGEs) and dysregulation of lipid metabolism [3,4].
Metformin is now considered the first-line therapy
for type 2 diabetes mellitus. It reduces blood glucose level by reducing hepatic gluconeogenesis and increasing muscular glucose uptake through activation of the 5’-adenosine monophosphate-activated protein kinase (AMPK) [5].
In patients with type 2 diabetes mellitus, in addition to its glucose lowering effect, metformin has also been shown to reduce the risk of atherosclerotic events and cancers and have an anti-aging effect [6].
Studies evaluating the effect of metformin on the risk of dementia are still rare. Four population-based observational studies can be found in the literature,
three from Taiwan using the administrative database of the National Health Insurance (NHI) and one from the UK using the General Practice Research Database.
The first study by Hsu et al. from Taiwan showed that users of metformin only (n=1864, hazard ratio 0.76, 95% confidence interval 0.58-0.98) and users of metformin plus sulfonylureas (n=9257, hazard ratio 0.65, 95% confidence interval 0.56-0.74) had lower risk of dementia while compared to diabetes patients without taking any antidiabetic drugs (n=10519) [7].
The second study from Taiwan by Cheng et al. enrolled new-onset type 2 diabetes patients who had been using single oral antidiabetic drug of metformin, sulfonylureas and thiazolidinediones (TZDs), respectively [8].
When metformin users were treated as the referent group, the risk of dementia was significantly higher for users of TZDs but not for users of sulfonylureas [8].
The third study from Taiwan by Kuan et al. published recently compared 4651 metformin users and a comparable number of non-users matched on propensity score (PS) [9].
They showed a significantly higher risk in metformin users with an adjusted hazard ratio of 1.66 (95% confidence interval 1.35-2.04). The UK study by Imfeld et al. showed an increased risk of dementia associated with metformin use (odds ratio 1.71, 95% confidence interval 1.12-2.60) by using a matched case-control design including 7086 incident cases of Alzheimer’s disease and 7086 controls without dementia [10].
In a recent meta-analysis evaluating the impact of insulin sensitizers on the incidence of dementia, Ye et al. showed a statistical trend of risk reduction associated with the use of either TZDs (relative risk 0.75, 95% confidence interval 0.56-1.00, P=0.050) or metformin (relative risk 0.79, 95% confidence interval 0.62-1.01, P=0.064) [11].
Conflicting findings in the effect of metformin on cognitive function were also observed between a follow-up study conducted in Singapore and a small clinical study conducted in Australia. Ng et al. compared the cognitive function of 204 metformin users versus 161 non-users of diabetes patients recruited from the population-based Singapore Longitudinal Aging Study [12].
They showed that metformin use was associated with a lower risk of cognitive impairment (odds ratio 0.49, 95% confidence interval 0.25-0.95). In the Australian clinical study, Moore et al. showed that, among subgroup participants with diabetes (n=104, 35 metformin users and 91 non-users), worse cognitive performance was observed in metformin users (odds ratio 2.23, 95% confidence interval 1.05-4.75) [13].
Because metformin is widely used in a large number of diabetes patients, the conflicting findings of metformin on dementia risk and cognitive function warrant more in-depth research to clarify whether it can be beneficial or harmful.
Therefore, the present study aimed at investigating the risk of dementia associated with metformin use in type 2 diabetes patients with careful consideration of potential bias and confounding commonly encountered in pharmacoepidemiological studies using existing administrative databases.
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