The incretin peptide classes: GLP-1, GIP, glucagon, and amylin

The metabolic peptides in the news — semaglutide, tirzepatide, retatrutide, cagrilintide — are best understood as a family defined by which receptors each one engages, from single-receptor agonists to triple agonists.

The metabolic peptides that dominate research headlines are easiest to understand not one at a time but as a family, grouped by which hormone receptors each engages. The relevant receptors are GLP-1, GIP, glucagon, and amylin. A molecule may act on one of them (a mono-agonist), two (a dual agonist), or three (a triple agonist), and the breadth of receptor coverage is the main axis along which the class is organised. This article is an educational overview of the landscape; the individual reference pages linked at the end carry the per-compound detail.

The incretin effect

Incretins are gut hormones released after eating that amplify the body's insulin response. The two principal incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Native incretins are broken down within minutes, so the pharmaceutical strategy has been to engineer analogues that resist degradation and persist long enough for once-daily or once-weekly schedules. Glucagon and amylin are not incretins themselves but are pancreatic hormones whose receptors have become co-agonist targets in the same research programmes.

GLP-1 receptor agonists (single target)

The first generation engages the GLP-1 receptor alone. Semaglutide and liraglutide are the most studied examples, the difference between them being pharmacokinetic: liraglutide is dosed once daily, semaglutide once weekly, owing to structural modifications that extend its circulation. In clinical trials these agents reduced body weight and improved glycaemic markers; the trial endpoints, not any individual outcome, are what the literature reports.

Dual GLP-1 / GIP agonists

Tirzepatide engages both the GLP-1 and GIP receptors in a single molecule. The rationale is that combining the two incretin pathways produces a larger effect on glycaemic control and body weight in trials than engaging GLP-1 alone, and the head-to-head trial data is the basis for that comparison. Tirzepatide is dosed once weekly.

Triple GLP-1 / GIP / glucagon agonists

Retatrutide adds the glucagon receptor to the GLP-1 and GIP pair, making it a triple agonist. The glucagon-receptor component is thought to contribute additional energy-expenditure effects on top of the incretin actions. Retatrutide remains investigational; its published early-phase trials reported the largest body-weight reductions of the class to date, but it is not approved and the later-phase record is still being established.

Amylin and co-agonist approaches

Amylin is a separate pancreatic hormone, and its receptor is the target of cagrilintide, a long-acting amylin analogue. Cagrilintide has been studied both on its own and co-formulated with semaglutide (the combination informally called 'CagriSema'), pairing an amylin agonist with a GLP-1 agonist. Amycretin takes a different route to the same idea — a single molecule that is both a GLP-1 and an amylin agonist. Both amylin approaches are investigational.

Reading the class this way clarifies why the compounds are constantly compared: they sit on a spectrum of receptor coverage, and most head-to-head questions ('retatrutide vs tirzepatide', for example) are really questions about whether adding another receptor target changed the trial outcomes. Approval status varies sharply across the family — some agents are FDA-approved for specific indications while others remain purely investigational — so the regulatory note on each reference page matters as much as the mechanism.