Incretin and amylin peptides explained: GLP-1, GIP, glucagon and amylin

The native hormones

GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) are incretins, gut hormones released after eating. Native GLP-1 is broken down by the enzyme DPP-4 within a couple of minutes, which is why every drug in this family has been engineered to last longer.

Glucagon, from the pancreas, raises blood glucose but also increases energy expenditure. Amylin is co-secreted with insulin and slows gastric emptying and contributes to satiety signalling.

First generation: stability

Exenatide, a copy of exendin-4 from Gila monster saliva, reached the market in 2005 as the first GLP-1 receptor agonist. Its natural resistance to DPP-4 made it viable.

Liraglutide took a different route: a modified human GLP-1 carrying a fatty acid that binds albumin and extends its half-life. Semaglutide refined that approach further.

Adding receptors

Tirzepatide combines GIP and GLP-1 receptor activity in one molecule. Retatrutide adds glucagon receptor activity, making it a triple agonist, and remains investigational.

The research question in each step is what the additional receptor contributes beyond the one before. Our incretin comparison pages set these steps side by side.

The amylin branch

Amylin analogues act through a different receptor family. Pramlintide, an approved short-acting analogue, uses proline substitutions to avoid the aggregation that makes native amylin unusable. Cagrilintide is an acylated, longer-acting analogue studied alongside semaglutide.

Evidence maturity differs widely

Semaglutide, liraglutide, exenatide, tirzepatide and pramlintide are approved medicines with large trial programmes. Retatrutide and cagrilintide are investigational. Our evidence scale puts each at the level the published data supports.