Metformin, Other Antidiabetic Drugs, and Risk of Alzheimer's Disease

A Population-Based Case-Control Study

Patrick Imfeld, MSc; Michael Bodmer, MD; Susan S. Jick, DSc; Christoph R. Meier, PhD

Disclosures

J Am Geriatr Soc. 2012;60(5):916-921. 

In This Article

Abstract and Introduction

Abstract

Objectives To explore the risk of developing Alzheimer's disease (AD) in individuals with diabetes mellitus treated with metformin or other antidiabetic drugs.
Design Case–control study.
Setting The United Kingdom–based General Practice Research Database (GPRD), a well-established primary care database.
Participants Seven thousand eighty-six individuals aged 65 and older with an incident diagnosis of AD identified between 1998 and 2008 and the same number of matched controls without dementia. Matching criteria were age, sex, general practice, calendar time, and years of history in the database.
Measurements Comparison of previous use of metformin or other antidiabetic drugs between cases and controls and calculation of corresponding odds ratios (ORs) with 95% confidence intervals (CIs), using conditional logistic regression. Risk estimates were stratified according to duration of use and adjusted for potential confounders.
Results As compared with nonusers, long-term users of 60 or more metformin prescriptions were at greater risk of developing AD (adjusted OR (AOR) = 1.71, 95% CI = 1.12–2.60), but there was no consistent trend with increasing number of prescriptions. Long-term use of other antidiabetic drugs such as sulfonylureas (AOR = 1.01, 95% CI = 0.72–1.42), thiazolidinediones (AOR = 0.87, 95% CI = 0.31–2.40), or insulin (AOR = 1.01, 95% CI = 0.58–1.73) was not related to an altered risk of developing AD.
Conclusion Long-term use of sulfonylureas, thiazolidinediones, or insulin was not associated with an altered risk of developing AD. There was a suggestion of a slightly higher risk of AD in long-term users of metformin.

Introduction

Evidence from epidemiological studies suggests that individuals with diabetes mellitus (DM) are at greater risk of developing Alzheimer's disease (AD),[1–4] although not consistently in all studies.[5–7] Studies on the association between antidiabetic medication and the risk of AD are scarce. In the Rotterdam Study, individuals with DM treated with insulin had a substantially greater risk of developing AD.[3] By contrast, a more-recent neuropathological study reported that individuals treated with both insulin and oral antidiabetic drugs had a significantly lower neuritic plaque density than individuals without DM.[8]

To the knowledge of the authors of the current study, data on metformin and the risk of AD exist only from in vitro studies or animal models. A recent study reported that metformin reduced phosphorylation of tau protein in cortical neurons of mice.[9] Metformin was also found to improve impaired neuronal insulin signaling and AD-related neuropathological changes in another recent in vitro study.[10] These findings suggest that metformin may play a role in reducing the risk of AD, although the authors of another study found metformin to increase the generation of β-amyloid (Aβ) protein,[11] indicating that its use may promote the development of AD.

The association between use of sulfonylureas or thiazolidinediones and the risk of developing AD has not been reported in published observational studies.

The current study examined the association between DM and use of antidiabetic drugs, in particular metformin, and the risk of developing AD in a large population-based case–control analysis.

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