Three molecules dominate research on incretin-based peptides. They differ first and most clearly in which receptors they activate. This page compares them on pharmacology and public facts only. It is not a treatment comparison, and R3TA gives no advice on human use.
At a glance
Semaglutide | Tirzepatide | Retatrutide | |
|---|---|---|---|
Generation | Single agonist | Dual agonist | Triple agonist |
GLP-1 receptor | Yes | Yes | Yes |
GIP receptor | No | Yes | Yes |
Glucagon receptor | No | No | Yes |
Developer | Novo Nordisk | Eli Lilly | Eli Lilly |
Length | 31 amino acids | 39 amino acids | 39 amino acids |
Half-life extension | C18 fatty diacid | C20 fatty diacid | Fatty diacid side chain |
Regulatory status | Approved medicine | Approved medicine | Investigational |
Single agonist: GLP-1 receptor only
Semaglutide is an analogue of human GLP-1. A fatty-acid side chain binds it to albumin, and an amino-acid substitution protects it against DPP-4. It activates only the GLP-1 receptor.
Dual agonist: GIP and GLP-1 receptors
Tirzepatide is built on the GIP sequence and engineered to activate both the GIP and the GLP-1 receptor. Published pharmacology describes it as more potent at the GIP receptor than at the GLP-1 receptor, relative to the native hormones.
Triple agonist: GIP, GLP-1 and glucagon receptors
Retatrutide adds activity at the glucagon receptor. Lilly's preclinical publication (Coskun et al., Cell Metabolism, 2022) reported its relative potency at each human receptor, with the balance tuned towards GIP-receptor activity and lower relative potency at the GLP-1 and glucagon receptors than the native hormones.
Why the glucagon receptor matters in research
Glucagon-receptor activity is studied for its effects on liver metabolism and energy expenditure. Because glucagon also raises blood glucose, researchers study it together with incretin-receptor activity rather than alone — the core idea behind the triple-agonist design.
What this comparison does not show
Receptor targets do not tell you about efficacy or safety in any species; those come only from controlled studies. Treat any website that turns receptor charts into health promises with suspicion.
For the receptor biology itself, see the GIP, GLP-1 and glucagon receptor primer.