Four generations of one idea
Glucagon-like peptide-1 (GLP-1) is a gut hormone released after a meal. It stimulates glucose-dependent insulin release, suppresses glucagon, slows gastric emptying and signals satiety in the brain. Native GLP-1 has a half-life of a couple of minutes, so the whole field is a series of engineering solutions to that problem: protect the peptide from the enzyme DPP-4 and attach a fatty-acid chain so it binds albumin and circulates for about a week.
Once weekly single-receptor agonists worked, the next question was whether adding a second or third receptor did more. Tirzepatide added GIP; retatrutide added GIP and glucagon; cagrilintide is not an incretin at all but an amylin analogue designed to be paired with semaglutide. That is the family below.
Side by side
| Compound | Receptors | Developer · code | Status | Headline trial result |
|---|---|---|---|---|
| Semaglutide | GLP-1 | Novo Nordisk · NN9535 | Approved (US 2017 type 2 diabetes, 2021 chronic weight management) | STEP 1, 2.4 mg weekly: −14.9% body weight at 68 weeks vs −2.4% placebo (Wilding et al., NEJM 2021) |
| Tirzepatide | GIP + GLP-1 | Eli Lilly · LY3298176 | Approved (US 2022 type 2 diabetes, 2023 chronic weight management) | SURMOUNT-1, 15 mg weekly: −20.9% at 72 weeks vs −3.1% placebo (Jastreboff et al., NEJM 2022) |
| Retatrutide | GLP-1 + GIP + glucagon | Eli Lilly · LY3437943 | Investigational; phase 3 TRIUMPH programme ongoing | Phase 2, 12 mg weekly: −24.2% at 48 weeks vs −2.1% placebo (Jastreboff et al., NEJM 2023) |
| Cagrilintide | Amylin and calcitonin receptors | Novo Nordisk · NN9838 (AM833) | Investigational; in phase 3 as CagriSema (with semaglutide 2.4 mg), REDEFINE programme | Phase 2, 4.5 mg weekly monotherapy: −10.8% at 26 weeks (Lau et al., Lancet 2021); REDEFINE 1 topline −22.7% at 68 weeks for the combination (2024) |
Trial figures are as reported in the cited publications and company disclosures, in the populations those trials enrolled. They are quoted here as published research context, not as claims about any product sold on this site.
What the extra receptors are for
GIP
Glucose-dependent insulinotropic polypeptide is the other incretin. On its own it is a weak agent, and for years it was assumed to be redundant. Tirzepatide's result, larger than semaglutide's in a head-to-head diabetes trial (SURPASS-2, Frías et al., NEJM 2021), is the evidence that GIP receptor activity adds something when combined with GLP-1, most plausibly through effects on adipose tissue and on nausea tolerance.
Glucagon
Glucagon raises hepatic glucose output, which is the opposite of what a diabetes drug wants. It also raises energy expenditure. Retatrutide's design bet is that with GLP-1 and GIP holding glucose down, a measured amount of glucagon receptor activity nets out as additional weight and liver-fat reduction. The phase 2 data (Jastreboff 2023; Rosenstock et al., Lancet 2023 in type 2 diabetes) are consistent with that, and phase 3 is the test.
Amylin
Amylin is co-secreted with insulin and acts on satiety and gastric emptying through a different receptor family. Cagrilintide is a long-acting amylin analogue built to be given alongside semaglutide, on the reasoning that two independent satiety pathways add rather than overlap.
Molecular notes
- All four are acylated peptides: a C18 or C20 fatty diacid on a lysine side chain gives albumin binding and the once-weekly profile.
- Semaglutide carries an α-aminoisobutyric acid (Aib) at position 8 to block DPP-4 cleavage. Tirzepatide and retatrutide use the same trick at position 2 of their own sequences.
- Retatrutide, formula C221H342N46O68, molecular weight about 4731 g/mol. Tirzepatide, C225H348N48O68, about 4814 g/mol. Both are supplied as lyophilised powder.
In our catalog
We stock retatrutide in 10mg and 20mg vials and tirzepatide in 10mg and 20mg vials, for laboratory research use only. We do not currently carry semaglutide or cagrilintide. Each product page lists the compound's specifications, storage conditions and the references cited above with PubMed links.