Genetic Evidence for GLP‐1 and GIP Receptors as Targets for Treatment and Prevention of MASLD/MASH

ABSTRACT Background and Aims Glucagon‐like peptide‐1 receptor (GLP1R) agonists and glucose‐dependent insulinotropic polypeptide receptor (GIPR) agonists may help treat metabolic dysfunction‐associated steatotic liver disease (MASLD) and metabolic dysfunction‐associated steatohepatitis (MASH). However, their definitive effects are still unclear. Our study aims to clarify this uncertainty. Methods We utilised conventional Mendelian randomisation (MR) analysis to explore potential causal links between plasma GLP‐1/GIP concentrations and MASLD and its related traits. Next, we conducted drug‐target MR analysis using highly expressed tissue data to assess the effects of corresponding drug perturbation on these traits. Finally, mediation analysis was performed to ascertain whether the potential causal effect is direct or mediated by other MASLD‐related traits. Results Circulating 2‐h GLP‐1 and GIP concentrations measured during an oral glucose tolerance test showed hepatoprotective effects on MASLD risk (OR GLP‐1 = 0.168 [95% CI 0.033–0.839], p = 0.030; OR GIP = 0.331 [95% CI 0.222–0.494], p = 6.31 × 10 −8 ). GLP1R expression in the blood had a minimal causal effect on MASLD risk, whereas GIPR expression significantly affected MASLD risk (OR = 0.671 [95% CI 0.531–0.849], p = 9.07 × 10 −4 ). Expression levels of GLP1R or GIPR in the blood significantly influenced MASLD‐related clinical traits. Mediation analysis revealed that GIPR expression protected against MASLD, even after adjusting for type 2 diabetes or body mass index. Conclusions GLP‐1/GIP receptor agonists offer promise in lowering MASLD/MASH risk. GIP receptor agonists can exert direct and indirect effects on MASLD mediated by weight reduction or glycemic control improvement.