Novel Insights into the Relationship Between Glucose-Lowering Drugs and Nonalcoholic Fatty Liver Disease and liver function: a Mendelian Randomization Study

Abstract

Objectives The potential risk of nonalcoholic fatty liver disease (NAFLD) and liver toxicity attributed to glucose-lowering medications is uncertain. The objective of this study was to explore the causal relationship between these factors through the implementation of a Mendelian randomization (MR) analysis. Methods Two-sample MR, summary-data-based MR (SMR), and colocalization analysis were utilized to investigate the association between ten drug reduce glucose targets (PPARG, DPP4, GLP1R, INSR, SLC5A2, ABCC8, KCNJ11, ETFDH, GPD2, and PRKAB1) to reduce NAFLD and liver function tests (LFTs) levels, including aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), alanine aminotransferase (ALT), and bilirubin. Results DPP4 is closely associated with GGT and ALT. PPARG is significantly associated with NAFLD and correlated with various liver enzymes GGT, AST, ALT, ALP, total bilirubin, and direct bilirubin. PRKAB1 is linked to total and direct bilirubin levels, while SLC5A2 is associated with total and direct bilirubin levels, ALP levels, and NAFLD risk. Limited evidence suggests that genetic variants in PRKAB1, GLP1R, INSR, GPD2, DPP4, and ABCC8/KCNJ11 are correlated with GGT, ALT, bilirubin, and NAFLD levels. Additional validation through SMR and colocalization analysis further confirmed the causal effects of these findings. Conclusions Specific glucose-lowering medications have been associated with an elevated risk of NAFLD and abnormal LFTs results, potentially offering innovative strategies for the management of NAFLD and LFTs abnormalities.