Oxyntomodulin
/ Endogenous 37-residue dual GLP-1 + glucagon receptor agonist; cleavage product of proglucagonALIAS · OXM · Oxyntomodulin · Glucagon-37
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Tier 3 for the native peptide. Oxyntomodulin is a foundational dual GLP-1 + glucagon receptor agonist - the endogenous proof-of-concept whose pharmacology informed the engineered dual and triple receptor agonists currently in late-stage development (mazdutide, survodutide, retatrutide). The native peptide itself has not been advanced past small Phase 2 trials.
Oxyntomodulin is a 37-residue peptide produced by intestinal L-cell processing of the proglucagon precursor - the first 29 residues are identical to glucagon (which is generated by alternative pancreatic processing of the same precursor), with an additional 8-residue C-terminal extension. This structural relationship gives oxyntomodulin balanced agonism at both the GLP-1 receptor (GLP-1R) and the glucagon receptor (GCGR), with relative potency in the low-nanomolar range at each.
The dual-agonism pharmacology engages the GLP-1 axis for incretin and satiety effects while simultaneously activating glucagon-receptor signalling for energy expenditure (lipolysis, hepatic glucose handling, brown adipose activation). Preclinical and early human data suggested that the combination produces greater weight loss for a given degree of glycaemic effect than GLP-1 monoagonism - the rationale that motivated mazdutide (a long-acting OXM analog), survodutide (Boehringer Ingelheim BI 456906), and retatrutide (Eli Lilly LY3437943, a GLP-1/GIP/GCGR triple agonist).
Native oxyntomodulin shares the rapid DPP-4 inactivation that limits GLP-1's plasma half-life, motivating engineered analogs with extended duration of action.
Tier 3. Two small Phase 2 studies of subcutaneous native oxyntomodulin in obesity (Cohen 2003 acute infusion in JCEM; Wynne 2005 four-week subcutaneous in Diabetes) showed appetite suppression, reduced food intake, and modest weight loss versus saline. No Phase 3 development of the native peptide. The clinical translation runs through engineered dual agonists - mazdutide is in Phase 3 in China (approved for obesity in China 2025), survodutide and retatrutide are in Phase 3 globally.
Acute and subacute infusion of native oxyntomodulin in research participants has been associated with nausea (the dominant gastrointestinal effect, shared with GLP-1 analogs) and modest blood-pressure changes. No long-term safety database for the native peptide. The dual-agonism class concern of glucagon-receptor activation increasing endogenous glucose production has not produced clinically meaningful hyperglycaemia in studies of carefully balanced engineered analogs but remains a design parameter for the class.
Regulatory status
- FDA status:
- Not FDA-approved
Vendor-sold 'oxyntomodulin' research peptide is the native 37-residue form, with native (~12 minute) plasma half-life. It is not interchangeable with mazdutide, survodutide, or retatrutide - those are engineered analogs with substantially extended duration of action and different receptor-balance pharmacology.
The 'optimal GLP-1:GCGR balance' for metabolic disease remains an open scientific question - native oxyntomodulin is roughly equipotent at both receptors, while engineered analogs vary the ratio deliberately.