Evaluating causal protective effect of dual GLP-1R/GIPR agonists on MASLD: A Mendelian randomization and...

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease globally, yet it lacks any approved pharmacological therapies. Dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists have shown clinical promise, but their causal effect on MASLD remains unestablished. This study uses genetic evidence to evaluate the causal role of dual GLP-1R/GIPR agonists on MASLD and to explore its underlying mechanisms.

Using a novel approach combining Mendelian randomization (MR) and Bayesian colocalization, we constructed a high-confidence genetic proxy for dual GLP-1R/GIPR agonists based on five genetic variants strongly associated with both mRNA expression and HbA1c levels. We then performed two-sample MR to assess the causal effect of this genetically proxied effect on MASLD and related metabolic risk abnormalities.

Genetically proxied dual GLP-1R/GIPR agonists was causally associated with a substantially reduced risk of MASLD (OR: 0.24, 95 % CI: 0.08-0.75, P = 0.01). This protective effect was accompanied by significant improvements in systemic metabolic health, including increased high-density lipoprotein cholesterol (Beta: 0.39, 95 % CI: 0.13-0.66, P = 3.40 × 10^-3), reduced triglycerides (Beta: -0.29, 95 % CI: -0.42 to -0.17, P = 1.57 × 10^-6), and enhanced insulin sensitivity (Beta: 0.89, 95 % CI: 0.36-1.42, P = 9.58 × 10^-4).

This study provides causal evidence that dual GLP-1R/GIPR agonists protects against MASLD. The mechanism likely involves broad improvements in lipid metabolism and insulin sensitivity. These findings offer strong genetic validation for this therapeutic strategy and provide a compelling rationale for its continued clinical development for the treatment of MASLD.