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Tuesday, July 14, 2026

Explainers

GLP-1, GIP, Glucagon, Amylin: The Gut-Hormone Alphabet

GLP-1, GIP, glucagon, and amylin power the new obesity drugs. A clear guide to what each hormone does and what dual, triple, and unimolecular agonists mean.

By Peptide News Network

A fluorescence microscopy image of cells glowing in magenta, blue, and green against a black background.
A fluorescence microscopy image of cells glowing in magenta, blue, and green against a black background.

The obesity drugs differ mostly in how many signals they pull at once. Learn four hormones and the whole class snaps into focus.

The names blur together — semaglutide, tirzepatide, retatrutide, CagriSema, amycretin — and the mechanisms hide behind jargon like “dual” and “triple agonist.” Underneath, it is simpler than it looks. Nearly every one of these drugs works by mimicking one or more of four gut and pancreatic hormones. Understand GLP-1, GIP, glucagon, and amylin, and the entire landscape becomes legible.

The four hormones

GLP-1 (glucagon-like peptide-1) is the workhorse. Released by the gut after eating, it curbs appetite, slows stomach emptying, and prompts the pancreas to release insulin. Semaglutide — Ozempic, Wegovy — mimics it. This is the single-receptor foundation the whole field is built on.

GIP (glucose-dependent insulinotropic polypeptide) is the second incretin hormone. On its own, its role is subtler, but paired with GLP-1, it amplifies the effect. Tirzepatide — Mounjaro, Zepbound — hits both GLP-1 and GIP, which is why it is called a dual agonist and why it tends to outperform semaglutide on weight.

Glucagon is the surprising one. Normally, it raises blood sugar — the opposite of what a diabetes drug wants. But at the right dose, glucagon also increases energy expenditure and helps the liver burn fat. Add it to the other two, and you get retatrutide, a triple agonist, source of the field-leading weight loss near 28% and of its rougher side effects.

Amylin is released by the pancreas alongside insulin and deepens the sense of fullness through its own brain circuits. Cagrilintide is an amylin analog; pair it with semaglutide, and you get CagriSema.

Decoding the labels

Once you know the hormones, the terminology is easy. A dual agonist hits two receptors (tirzepatide: GLP-1 + GIP). A triple agonist hits three (retatrutide: GLP-1 + GIP + glucagon). More targets can mean more weight loss — the numbers climb roughly with the count — but the relationship is not free.

A newer wrinkle is unimolecular. CagriSema combines two separate molecules (semaglutide and cagrilintide) in one injection. Amycretin, by contrast, is a single peptide engineered to hit two receptors — GLP-1 and amylin — at once: one molecule, two jobs. The unimolecular approach promises simpler manufacturing and dosing if the biology cooperates.

Why more isn’t automatically better

Here is the trade-off that shapes the whole field. Each added pathway tends to bring more gastrointestinal side effects — nausea, vomiting — and higher dropout. Retatrutide’s glucagon arm buys extra fat-burning and a bigger number, at the cost of tougher tolerability. The art is not simply stacking receptors; it is finding the combination that delivers deep, durable weight loss people can actually tolerate for years.

That is why amylin, long overlooked, is suddenly central. Combining GLP-1 with amylin — as CagriSema and amycretin do — may hit a sweet spot of strong effect and manageable side effects, rather than chasing raw magnitude with a third or fourth receptor.

The bottom line

Every headline drug in this space is a recipe of these four ingredients. Semaglutide is GLP-1 alone. Tirzepatide adds GIP. Retatrutide adds glucagon on top. CagriSema and amycretin bring amylin into the mix. The differences in weight loss, side effects, and dosing all trace back to which hormones a drug imitates and how.

The frontier question is no longer “how many receptors?” It is “which combination gives the best result a patient can live with?” Keep the four hormones in mind, and the next wave of drug news will read like variations on a theme you already understand.

Frequently asked questions

What’s the difference between a dual and a triple agonist? A dual agonist activates two hormone receptors; a triple agonist activates three. Tirzepatide is dual (GLP-1 + GIP). Retatrutide is triple (GLP-1 + GIP + glucagon). More targets can mean more weight loss, often with more side effects.

Is amylin the same as GLP-1? No. Both are hormones that reduce appetite, but they act through different brain circuits. That is why combining them — as CagriSema and amycretin do — can deepen the effect beyond what GLP-1 achieves alone.

Which drug causes the most weight loss? In trials to date, the triple agonist retatrutide has posted the highest figures, around 28% at its top dose, though it has not been tested head-to-head against its rivals and carries a heavier side-effect burden.

Sources

  1. Drucker, D.J. — reviews on incretin hormones (GLP-1, GIP) and metabolic disease, Cell Metabolism.
  2. Jastreboff, A.M., et al. — retatrutide triple-agonist mechanism, New England Journal of Medicine, 2023.
  3. Garvey, W.T., et al. — cagrilintide–semaglutide (amylin + GLP-1), New England Journal of Medicine, 2025.
  4. Eli Lilly and Novo Nordisk — prescribing information for tirzepatide and semaglutide products.