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

Nov 2, 2024Liver international : official journal of the International Association for the Study of the Liver

Genetic Support for Targeting GLP-1 and GIP Receptors to Treat and Prevent Fatty Liver Disease

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Abstract

Circulating 2-hour GLP-1 and GIP concentrations are associated with a lower risk of metabolic dysfunction-associated steatotic liver disease (MASLD).

Higher levels of circulating GLP-1 and GIP during an oral glucose tolerance test show protective effects against MASLD.
The odds ratio for the protective effect of GLP-1 on MASLD risk is 0.168, while GIP shows an odds ratio of 0.331.
GIP receptor expression significantly reduces MASLD risk, with an odds ratio of 0.671.
GLP1R expression has a minimal causal effect on MASLD risk compared to GIPR expression.
Mediation analysis indicates that GIPR expression protects against MASLD, independent of type 2 diabetes or body mass index.

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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 = 0.168 [95% CI 0.033-0.839], p = 0.030; OR = 0.331 [95% CI 0.222-0.494], p = 6.31 × 10). 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). 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. GLP-1GIP -8 -4

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.

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

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