Drug risks associated with sarcopenia: a real-world and GWAS study

Abstract

Introduction: Drug-induced sarcopenia has not received adequate attention. Meanwhile, there is growing recognition of the importance of effective pharmacovigilance in evaluating the benefits and risks of medications.

Aims: The primary aim of this study is to investigate the potential association between drug use and sarcopenia through an analysis of adverse event reports from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and to evaluate the genetic factors contributing to drug-induced sarcopenia using summary-data-based Mendelian randomization (SMR).

Methods: We obtained reports of adverse drug reactions from FAERS. Primary outcomes included sarcopenia and potential sarcopenia. We calculated the Proportional reporting ratio (PRR) to assess the risk of specific adverse events associated with various drugs, applying chi-square tests for statistical significance. Additionally, we used SMR based on Genome-wide association study (GWAS) to evaluate the potential associations between drug target genes of some significant medications and sarcopenia outcomes. The outcome data for sarcopenia included metrics as hand grip strength and appendicular lean mass (ALM).

Results: A total of 55 drugs were identified as inducing potential sarcopenia, and 3 drugs were identified as inducing sarcopenia. The top 5 drugs causing a potential risk of sarcopenia were levofloxacin (PRR = 9.96, χ² = 1057), pregabalin (PRR = 7.20, χ² = 1023), atorvastatin (PRR = 4.68, χ² = 903), duloxetine (PRR = 4.76, χ² = 527) and venlafaxine (PRR = 5.56, χ² = 504), and the 3 drugs that had been proved to induced sarcopenia included metformin (PRR = 7.41, χ² = 58), aspirin (PRR = 5.93, χ² = 35), and acetaminophen (PRR = 4.73, χ² = 25). We identified electron-transfer flavoprotein dehydrogenase (ETFDH) and protein Kinase AMP-Activated Non-Catalytic Subunit Beta 1 (PRKAB1) as the primary drug target genes for metformin, while Prostaglandin-endoperoxide Synthase 1 (PTGS1) and Prostaglandin-endoperoxide Synthase 2 (PTGS2) were considered the primary action target genes for aspirin and acetaminophen according to DrugBank database. SMR showed that the expression abundance of ETFDH was negatively correlated with right hand grip strength (blood: OR = 1.01, p-value = 1.27e-02; muscle: OR = 1.01, p-value = 1.42e-02) and negatively correlated with appendicular lean mass (blood: OR = 1.03, p-value = 7.73e-08; muscle: OR = 1.03, p-value = 1.67e-07).

Conclusions: We find that metformin, aspirin, and acetaminophen are specifically noted for their potential to induce sarcopenia based on the analyses conducted. We perform signal mining for drug-associated sarcopenia events based on real-world data and provides certain guidance for the safe use of medications to prevent sarcopenia.

Keywords: Drug safety; ETFDH; Mendelian randomization; Metformin; Pharmacovigilance; Sarcopenia.

Fig. 1

Sunburst chart created based on the drugs’ anatomical system subgroups, treatment subgroups, and ATC codes. The width of each slice represents the relative PRR, with larger slices indicating stronger signals

Fig. 2

Forest plot illustrating the genetic effects of ETFDH on the outcomes