Survodutide (revision 5)

Survodutide (development code BI 456906) is an investigational peptide that agonises both the glucagon receptor and the GLP-1 receptor. It is under phase 3 evaluation for obesity and has been studied in metabolic dysfunction-associated steatohepatitis. It is not approved for use in any indication.^[1]

Unlike the GIP/GLP-1 pairing of tirzepatide, the glucagon/GLP-1 pairing sets two opposing glycaemic effects against each other deliberately. Glucagon-receptor agonism raises hepatic glucose output and energy expenditure; GLP-1 agonism lowers glucose and food intake. The design intent is to capture the energy-expenditure and hepatic-fat effects of the former while the latter dominates the net glycaemic balance.^[1]

Reported phase 2 weight reduction reached approximately 19% at 46 weeks at the highest dose studied. The hepatic programme is of independent interest, since glucagon-receptor agonism reduces liver fat by a mechanism that GLP-1 agonism does not share.^[2]

Survodutide is a 29-residue acylated peptide derived from the glucagon sequence, with substitutions conferring GLP-1-receptor activity and a fatty-acid chain for albumin binding. Its natural template is oxyntomodulin, a product of proglucagon processing that is a weak agonist at both receptors — the existence of which is why the combination was thought physiologically coherent rather than merely chemically possible.^[1][3]

The potency ratio is the central design variable. Too much glucagon activity relative to GLP-1 activity raises fasting glucose; too little forfeits the energy-expenditure benefit that motivated the design. This is a fixed intramolecular property, so the balance must hold across the whole dose range rather than at one point in it.

Reported in vitro ratios place survodutide closer to balanced than the triple agonist retatrutide, though as always such ratios are assay-dependent and are not comparable across publications.^[2]