GLP-1/Glucagon
Co-agonists

GLP-1/glucagon co-agonists are engineered peptides designed to activate both the GLP-1 receptor and the glucagon receptor with a single molecule. The concept originates with oxyntomodulin, the natural gut peptide with modest activity at both receptors. In 2009, researchers led by Richard DiMarchi and Matthias Tschöp described optimised co-agonist peptides that reduced body weight and improved metabolic markers in obese rodents, launching a drug class that is now in late-stage clinical development.

The rationale is complementary pharmacology: GLP-1 receptor activation reduces food intake and counters the hyperglycaemic effect of glucagon, while glucagon receptor activation may raise energy expenditure and promote hepatic fat oxidation. Candidates studied in clinical research include survodutide, mazdutide, pemvidutide, efinopegdutide and the discontinued cotadutide, with several molecules in phase 3 trials for obesity and metabolic dysfunction-associated steatohepatitis. These co-agonists are not approved by the FDA or EMA. For researchers, the class provides a framework for exploring receptor balance, hepatic lipid metabolism and energy expenditure.

Co-agonists are typically based on the glucagon or oxyntomodulin backbone, with substitutions that tune relative potency at each receptor, along with fatty acid acylation for extended half-life. At the GLP-1 receptor, they activate Gs-cAMP signalling in beta cells and satiety circuits, enhancing glucose-dependent insulin secretion, slowing gastric emptying and reducing food intake. At the hepatic glucagon receptor, they stimulate cAMP signalling that increases fatty acid oxidation, reduces de novo lipogenesis and alters amino acid metabolism. Glucagon signalling may also increase energy expenditure, though the mechanism in humans is debated. The ratio of receptor activities is the central design variable, balancing hepatic effects against glycaemic risk.