Exploring the Relationship Between Atorvastatin and Memory Loss: A Comprehensive Analysis Integrating Real-World Pharmacovigilance and Mendelian Randomization

Abstract

Background and objective: Atorvastatin is a drug widely used to prevent cardiovascular and cerebrovascular diseases. Current observational studies suggest that atorvastatin may be associated with cognitive dysfunction (especially memory loss). However, some studies have suggested that dyslipidemia may be an important factor in cognitive dysfunction. The purpose of this study was to perform a pharmacovigilance analysis using real-world data from the US Food and Drug Administration's Adverse Event Reporting System (FAERS) to assess whether memory loss is an adverse effect of atorvastatin and to further clarify its causality through Mendelian randomization (MR).

Methods: We extracted real-world data from the FAERS database (Quarter 1 2004 to Quarter 1 2023). Disproportionality analysis methods and measures of association such as the reporting odds ratio (OR), proportional reporting ratio, Bayesian confidence interval progressive neural network, and polynomial Gamma Poisson distribution reduction were used to assess whether memory loss was an adverse effect of atorvastatin. In addition, we used MR to evaluate causality in depth.

Results: In the pharmacovigilance analysis of atorvastatin, we extracted four datasets of clinical symptoms associated with memory loss from the FAERS database [Amnesia (n = 1196), Memory impairment (n = 840), Transient global amnesia (n = 38), and Retrograde amnesia (n = 9)]. The reporting OR, proportional reporting ratio, Bayesian confidence interval progressive neural network, and Gamma Poisson distribution reduction all showed positive results for amnesia, transient global amnesia, and retrograde amnesia, while the reporting OR and Bayesian confidence interval progressive neural network also showed positive results for memory disorders. Thus, memory loss was a frequent side effect of atorvastatin. The MR analyses were used to further evaluate the association between statins and memory loss. The results of the MR analysis (statins and memory loss) are as follows: Ivw (mre) (β = 0.11 [OR = 1.11], P = 0.01 < 0.05) and the OR and β directions of MR-Egger and weighted mode were the same. The results of the MR analysis (statins and mitochondrial DNA copy number) are as follows: Ivw(mre) (β = -0.03 [OR = 0.96], P < 0.01) and the OR and β direction of MR-Egger and weighted mode are the same. The results of the MR analysis (DNA copy number and memory loss) are as follows: Ivw(β = - 0.06 [OR = 0.94], P = 0.04 < 0.05) and the OR and β direction of MR-Egger and weighted mode were the same. The pleiotropy test did not find horizontal diversity in our results.

Conclusions: This study suggests that memory loss is a notable adverse event associated with atorvastatin and provides evidence indicating a potential causal relationship between atorvastatin and memory loss. We also found that statins may further affect memory by affecting mitochondrial function. Therefore, in the clinical use of atorvastatin, it is important to carefully monitor the changes in cognitive function of patients. Second, a pharmacovigilance analysis combined with MR was used in this study to provide a new approach for the study of adverse drug reactions. This comprehensive analysis method helps to evaluate the safety of drugs and the risk of adverse reactions more comprehensively and provides doctors with a more accurate clinical decision-making basis.

Fig. 1

Broken line of the reporting year (atorvastatin-memory loss). y  Number of reports

Fig. 2

Memory loss onset time-medication date (days [d]). y  Number of reports

Fig. 3

Mendelian randomization (MR) association between statin medication and memory loss. CI confidence interval, OR odds ratio, Snp  single nucleotide polymorphism

Fig. 4

Mendelian randomization (MR) association between low-density lipoprotein and memory loss. CI confidence interval, OR odds ratio, Snp single nucleotide polymorphism

Fig. 5

Mendelian randomization (MR) association between statin medication and the mitochondrial DNA copy number. CI confidence interval, OR odds ratio, Snp single nucleotide polymorphism

Fig. 6

Mendelian randomization (MR) association between the mitochondrial DNA copy number and memory loss. CI confidence interval, OR odds ratio, Snp  single nucleotide polymorphism