Abstract
Oxyntomodulin (OXM), an endogenous proglucagon-derived peptide with dual glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) agonism, provides a physiological precedent for contemporary multi-receptor pharmacology. Recognition that GCGR signaling regulates not only hepatic glucose production but also amino acid turnover, lipid metabolism, substrate oxidation, and energy expenditure prompted the development of engineered GLP-1R/GCGR co-agonists, including cotadutide, mazdutide, survodutide, and pemvidutide. Retatrutide extends this strategy by integrating GIPR, GLP-1R, and GCGR agonism within a single long-acting peptide and has produced substantial improvements in body weight, glycemic control, and cardiometabolic parameters in phase 2 and phase 3 trials. This review examines the evolutionary and structural relationships of the proglucagon–Class B1 GPCR system, OXM biosynthesis and receptor pharmacology, the mechanistic rationale for therapeutic GCGR agonism, and the molecular and clinical development of dual and triple agonists. We further address receptor balance, the GIPR agonism–antagonism paradox, and the unresolved attribution of clinical effects to individual receptor components. Finally, we propose an Activity–Exposure–Context framework for interpreting polyagonist pharmacology and discuss prospective enteroinsular phenotyping using standardized mixed-meal testing as a testable strategy to investigate interindividual variability in therapeutic response.