GLP-1, GIP, Glucagon, Amylin: The Four Gut Hormones Behind the New Drugs
Every headline drug in metabolic medicine is built from the same short list of hormones. Here is what each one does, and why companies keep combining them.
If you have read this month’s clinical-trial news, you have met the whole cast already: retatrutide works on three receptors, zenagamtide on two, tirzepatide on two others. Behind the drug names is a surprisingly short list of hormones. Learn the four that matter, and most of the field’s headlines decode themselves.
The incretins: GLP-1 and GIP
When you eat, the gut releases hormones that tell the pancreas food is coming. Two of them, GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide), are called incretins, and together they explain why a meal eaten by mouth triggers far more insulin than the same glucose given by vein.
GLP-1 is the one the first generation of drugs copied. Per StatPearls, it stimulates insulin secretion when blood glucose is high, suppresses glucagon (the hormone that raises blood sugar), slows the stomach’s emptying so meals are absorbed more gradually, and acts on the hypothalamus to increase satiety. Semaglutide is a long-acting GLP-1 mimic. GIP, the second incretin, also boosts meal-triggered insulin; tirzepatide activates both GLP-1 and GIP receptors, which is why it is often called a “dual” or “twincretin” agonist.
Glucagon: the counterweight, turned tool
Glucagon normally does the opposite of insulin, telling the liver to release stored glucose. That sounds like the wrong thing to add to a diabetes drug, but at the right balance glucagon also raises energy expenditure. Retatrutide’s “triple-G” design adds a glucagon-receptor action on top of GLP-1 and GIP, and researchers believe that third target is part of why its trial weight-loss numbers ran so high.
Amylin: the field’s next favorite
Amylin is released from the same pancreatic cells as insulin and works through a separate pathway, curbing appetite and slowing gastric emptying. It is the field’s most-watched second target after GLP-1. Novo Nordisk is pursuing it two ways at once: amycretin (zenagamtide) fuses GLP-1 and amylin activity into a single molecule, while CagriSema pairs an amylin analog with semaglutide as two drugs in one injection.
Why keep combining them
The pattern across every recent readout is the same. Take GLP-1 as the foundation, then add a second or third hormone to reach further. Each addition targets a different lever (insulin, glucagon suppression, energy expenditure, satiety), and the bet is that hitting several at once does more than any one alone. That is the throughline connecting drugs that otherwise look unrelated, and it is why “how many receptors, and which ones?” is usually the first question worth asking about any new candidate.
This is background, not medical advice. Peptide News Network reports on the science; decisions about any medication belong with a licensed clinician.