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Taken together, the figure highlights a key mechanistic principle underlying the therapeutic rationale for multi-agonist strategies: while GLP-1R monotherapy achieves meaningful metabolic and hepatic benefits exclusively through indirect, systemic pathways, the addition of GIPR and - most importantly - GCGR co-agonism introduces complementary and increasingly direct hepatic mechanisms, providing the pharmacological basis for the superior efficacy observed with dual and triple agonists in MASLD/MASH