Long-Term Use of Metformin Is Associated With Reduced Risk of Cognitive Impairment With Alleviation of Cerebral Small Vessel Disease Burden in Patients With Type 2 Diabetes.

Zhenjie Teng,Yining Xiao,Huifang Chen,Qianqian Qi,Jing Feng,Xiaohua Xie,Yanhong Dong,Peiyuan Lv,Wenhui Zhang,Nan Meng

doi:10.3389/fnagi.2021.773797

Abstract

Objective: Type 2 diabetes (T2D) is a risk factor for cognitive impairment and cerebral small vessel disease (CSVD). The relation of metformin use and cognitive impairment or CSVD is not clear. The objective of this study was to investigate the cross-sectional effects of long-term use of metformin on total CSVD burden and cognitive function in patients with T2D.Methods: A total of 234 participants with T2D from the memory clinic in Hebei General Hospital were enrolled in this retrospective study. Duration of metformin use and dosage were recorded. Along with cerebral magnetic resonance imaging (MRI) examination, Mini-Mental State Examination (MMSE) was also performed to assess their cognitive status. We determined the validated total CSVD score (ranging from 0–4) by combining four markers of CSVD that were visually rated. We used binary logistic regression analysis, ordinal logistic regression analysis and mediation analysis to assess the relation of long-term use of metformin with CSVD burden and cognitive function.Results: Binary logistic regression analysis showed long-term use of metformin was associated with reducing the risk of cognitive impairment (OR: 0.446; 95% Confidence Interval (CI): 0.249 to 0.800; P = 0.007), after adjustment of potential confounders, such as total CSVD burden score, age, HbA1c, hypertension, history of stroke, homocysteine, body mass index, TG and HDL-C. Ordinal logistic regression analysis suggested that long-term use of metformin was associated with alleviation of total CSVD burden score (OR: 0.583; 95% CI: 0.359 to 0.943; P = 0.027), after adjusting for age, HbA1c, hypertension, history of stroke, homocysteine, body mass index, TG and HDL-C. Mediation analysis showed significant mediation by the presence of severe CSVD burden score for long-term use of metformin in relation to cognitive impairment.Conclusion: Long-term use of metformin was associated with lower rates of cognitive impairment and lower total CSVD burden score in patients with T2D. A proportion of the relation between long-term use of metformin and cognitive impairment may be attributable to alleviation of CSVD burden.

Highlights

MATERIALS AND METHODSCognitive impairment is a growing problem, which can range in severity from mild cognitive impairment to dementia
All individuals were divided into cognitive impairment (CI) (n = 101) group and no cognitive impairment (NCI) (n = 133) group according to cognitive function assessment
Conclusions did not change when the possible interaction between long-term use of metformin and Cerebral small vessel disease (CSVD) burden score was taken into account. In this cross-sectional study, we investigated the association of long-term use of metformin with total CSVD burden and cognitive function in patients with Type 2 diabetes (T2D)

Summary

Introduction

MATERIALS AND METHODSCognitive impairment is a growing problem, which can range in severity from mild cognitive impairment to dementia. Recent studies have revealed that blood-brain barrier (BBB) dysfunction and endothelial cell dysfunction seem to be pivotal factors contributing to the pathogenesis of CSVD (Ihara and Yamamoto, 2016; Wardlaw et al, 2019). Factors, such as oxidative stress, inflammation, hypoxia, and hypoperfusion may lead to BBB and endothelial dysfunction (Grochowski et al, 2018; Low et al, 2019; Zanon et al, 2021), which is worse in patients with cognitive impairment (Nation et al, 2019)

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