If you have spent any time reading about the newer incretin compounds, you have probably seen the shorthand: semaglutide is a GLP-1 agonist, tirzepatide is a dual GLP-1 / GIP agonist, and retatrutide is a triple GLP-1 / GIP / glucagon agonist. That's accurate, but it glosses over the more interesting question: what does each receptor actually do, and why does adding more of them matter?
GLP-1 receptor
The GLP-1 receptor is the one most research has focused on for the longest. In animal models and isolated tissue, GLP-1 receptor activation slows gastric emptying, increases glucose-dependent insulin secretion, and acts centrally on appetite circuits. Compounds that bind it well, like semaglutide, produce the weight and glycemic effects the field is best characterized for.
GIP receptor
GIP is the other major incretin hormone, and for years it was thought to be clinically uninteresting because GIP receptor agonism alone produced underwhelming results. The shift came with the realization that GIP receptor activity appears to amplify GLP-1's metabolic effects rather than work independently. Tirzepatide's dual activity is widely thought to be why it outperformed pure GLP-1 agonists in head-to-head readouts.
Glucagon receptor
Glucagon is the receptor that surprises people. Glucagon raises blood glucose, so on the surface adding glucagon agonism to a weight-loss compound looks backward. The reasoning is energy expenditure: glucagon receptor activation increases hepatic energy turnover and lipid mobilization. The bet behind retatrutide is that pairing glucagon agonism with strong GLP-1 / GIP coverage can drive weight effects beyond what incretin pathways alone produce, without the glycemic penalty glucagon would carry on its own.
Whether that bet holds up in larger trials is still an open question, but it is the reason researchers care about the triple-agonist profile as a distinct class rather than just a stronger GLP-1.