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Collectively, these findings provide a mechanistic rationale for developing multi-target agonists: GLP-1R appears to provide the most potent and direct anti-MASLD and anti-fibrotic effects in the liver, while GIPR and GCGR offer complementary benefits for glucose and lipid metabolism, with GIPR also exhibiting superior cardiovascular protection
It suggests that even well-designed compounds with plausible mechanisms and positive animal data may not translate to human benefit
In the SURMOUNT-5 head-to-head trial ( N Engl J Med , May 2025), tirzepatide produced 20.2% average weight loss compared to 13.7% with semaglutide over 72 weeks a 47% greater relative reduction
The first GLP-1RA was discovered in the Gila monster, a desert-dwelling lizard capable of consuming up to half its body weight in a single meal while maintaining stable blood glucose levels
