Oxyntomodulin, GLP-1, and Glucagon All Cut Food Intake Equally — But Combining Them Didn't Help More

Double-blinded, randomized, crossover study in 15 healthy young men. Each participant received five 4-hour liquid meal tests during infusion of saline, GLP-1, glucagon, oxyntomodulin, or GLP-1+glucagon on separate occasions. Researchers measured resting energy expenditure (oxygen uptake), gastric emptying, composite appetite scores, and ad libitum food intake.

Oxyntomodulin activates both GLP-1 and glucagon receptors, and the drug industry has bet heavily on dual-agonists (like survodutide) that mimic this. This study challenges a key assumption: that activating both receptors simultaneously produces additive benefits. The finding that GLP-1+glucagon was no better than either alone at reducing food intake suggests oxyntomodulin's weight-loss mechanism may not be simply the sum of its receptor activities — there may be something else at play.

The pharmaceutical industry has invested billions in dual GLP-1/glucagon agonists (like survodutide, efinopegdutide, and mazdutide) based on the theory that hitting both receptors simultaneously produces superior metabolic effects. This study's finding that combining GLP-1 and glucagon infusions didn't produce additive appetite suppression complicates that narrative. It suggests the clinical benefits of dual agonists may come from mechanisms beyond simple receptor co-activation — perhaps from receptor interactions, timing, or downstream signaling differences.

Small sample size (n=15) of only young, lean, healthy men — results may differ in obese individuals or women. Acute infusion study (4 hours) may not reflect chronic effects relevant to weight management. The doses tested may not have been optimal to demonstrate additive effects. Only one dose combination of GLP-1+glucagon was tested.