From Oxyntomodulin to Retatrutide: A Translational Review of Metabolic Polyagonism
5 affiliations
- 1Unidad de Remisión de Diabetes Mellitus (URDM), Carrera de Médico Cirujano, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Estado de Mexico, Mexico
- 2Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Ciudad de Mexico 07360, Mexico
- 3Centro Internacional de Simulación y Entrenamiento en Soporte Vital Iztacala (CISESVI), Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Estado de Mexico, Mexico
- 4Laboratorio de Genética y Oncología Molecular, Carrera de Médico Cirujano, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Estado de Mexico, Mexico
- 5Unidad de Biomedicina (UBIMED), Carrera de Médico Cirujano, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Estado de Mexico, Mexico
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, receptor-specific causal attribution, and the unresolved limitations of translating molecular pharmacology into durable clinical benefit. 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.
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BibTeX
@article{saldivarceron2026from,
title = {{From Oxyntomodulin to Retatrutide: A Translational Review of Metabolic Polyagonism}},
author = {Héctor Iván Saldívar-Cerón and Daniela Maldonado-Trejo and Quetzal Chavez-Castañeda and Ana Lorena Mercado-Guzmán and Angela de Jesús León-Barrita and Isela Alejandra López-García and Alejandra Hernández-Solís and Andrés Moranchel Ramírez-Mendoza and Daniela Alejandra Terrazas-Delgado and Ari Evelyn Castañeda-Ramírez and Efrén Quiñones-Lara and Brenda Ofelia Jay-Jímenez and Glustein Pozo-Molina and Sonia León-Cabrera},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219654},
url = {https://www.mdpi.com/1422-0067/27/21/9654},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - From Oxyntomodulin to Retatrutide: A Translational Review of Metabolic Polyagonism
AU - Héctor Iván Saldívar-Cerón
AU - Daniela Maldonado-Trejo
AU - Quetzal Chavez-Castañeda
AU - Ana Lorena Mercado-Guzmán
AU - Angela de Jesús León-Barrita
AU - Isela Alejandra López-García
AU - Alejandra Hernández-Solís
AU - Andrés Moranchel Ramírez-Mendoza
AU - Daniela Alejandra Terrazas-Delgado
AU - Ari Evelyn Castañeda-Ramírez
AU - Efrén Quiñones-Lara
AU - Brenda Ofelia Jay-Jímenez
AU - Glustein Pozo-Molina
AU - Sonia León-Cabrera
PY - 2026
DA - 2026/10/28
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219654
UR - https://www.mdpi.com/1422-0067/27/21/9654
AB - 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, receptor-specific causal attribution, and the unresolved limitations of translating molecular pharmacology into durable clinical benefit. 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.
SN - 1422-0067
ER -