GLP-1, "GLP-2" and "GLP-3": Semaglutide, Tirzepatide and Retatrutide Compared at the Molecular Level

Search for research peptides and you’ll see semaglutide sold as "GLP-1," tirzepatide as "GLP-2" and retatrutide as "GLP-3." They’re handy, but chemically misleading. This guide covers what each molecule is, what it binds, and how to tell them apart on a certificate of analysis.

What does "GLP-3" mean?

"GLP-3" is informal shorthand for retatrutide, one peptide that activates three receptors: GLP-1, GIP and glucagon. It is not the name of a hormone. The number counts targets, which is why the dual agonist tirzepatide gets called "GLP-2."

The biology doesn't support the naming. The proglucagon precursor is cut into glucagon, GLP-1, GLP-2, oxyntomodulin and glicentin. GLP-2 is a 33-amino-acid hormone made by intestinal L cells, and it acts on its own receptor, found mainly in the gut (Drucker & Yusta, 2014). Tirzepatide doesn't act on that receptor, and no "GLP-3" hormone exists.

When you order, record or cite these compounds, use the nonproprietary name or the developer code: semaglutide, tirzepatide (LY3298176) and retatrutide (LY3437943).

Which receptors does each compound activate?

Semaglutide activates the GLP-1 receptor only. Tirzepatide activates the GIP and GLP-1 receptors. Retatrutide activates the GIP, GLP-1 and glucagon receptors, all three members of the class B1 family of G-protein-coupled receptors (Li et al., 2024).

• Tirzepatide activated both GIP and GLP-1 receptor signaling in cell-based assays in Lilly's discovery paper (Coskun et al., 2018).
• Retatrutide, compared with each receptor's natural hormone, is about 8.9 times more potent at the GIP receptor, and about 0.4 and 0.3 times as potent at the GLP-1 and glucagon receptors (Coskun et al., 2022, as summarized by Li et al., 2024).
• Cryo-EM structures show retatrutide binding all three receptors as a single continuous helix, with its N-terminal segment reaching into the receptor core (Li et al., 2024).

How are the three molecules built?

All three are synthetic peptides of 31 to 39 amino acids that share two design features. Non-natural residues such as Aib (2-aminoisobutyric acid) near the N-terminus resist cleavage by the enzyme DPP-4. A fatty diacid on one lysine side chain, attached through a short linker, lets the peptide bind serum albumin, which stretches its half-life to days (Lau et al., 2015).

• Semaglutide: 31 residues on a GLP-1 backbone, with an Aib at position 2 and a C18 fatty diacid on a lysine.
• Tirzepatide: 39 residues built mainly on the GIP sequence, with two Aib residues and a C20 fatty diacid.
• Retatrutide: 39 residues, also GIP-based: Aib at positions 2 and 20, α-methyl-leucine at position 13, a C20 fatty diacid on lysine 17 and a C-terminal amide (ChEMBL).

How do you tell them apart on a COA?

Mass spectrometry, not HPLC. An HPLC trace shows how pure a sample is, not which peptide it is; mass spec confirms identity by matching the measured mass to the expected one (see our HPLC vs. mass spectrometry guide).

Peptides this size pick up several protons in electrospray mass spec, so a COA may list multiply charged ions instead of the intact mass:

These values come from average masses. A lab reporting monoisotopic mass will show an intact mass about 3 Da lower. Tirzepatide and retatrutide differ by about 82 Da, easy to resolve, so a swapped or mislabeled vial shows up immediately.

What's the regulatory status in 2026?

• Semaglutide is the active ingredient in the FDA-approved medicines Ozempic (2017), Rybelsus (2019) and Wegovy (2021).
• Tirzepatide is the active ingredient in Mounjaro (2022) and Zepbound (2023).
• Retatrutide is not approved anywhere. Lilly says its phase 3 data package supports a U.S. application in the first quarter of 2027 (Lilly Q2 2026 results). The FDA has said retatrutide can't lawfully be compounded or sold to consumers (Reuters, Aug 12, 2026).

How Zorva Lab documents these compounds

Every lot ships with a lot-specific certificate of analysis: HPLC purity plus a mass-spec identity check against the expected mass above. Current lots are in the COA Library, and How to Read a Certificate of Analysis walks through each field.

References

• Drucker DJ, Yusta B. Physiology and pharmacology of the enteroendocrine hormone glucagon-like peptide-2. Annu Rev Physiol. 2014;76:561–583. doi:10.1146/annurev-physiol-021113-170317
• Coskun T, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol Metab. 2018;18:3–14. doi:10.1016/j.molmet.2018.09.009
• Coskun T, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: from discovery to clinical proof of concept. Cell Metab. 2022;34(9):1234–1247. doi:10.1016/j.cmet.2022.07.013
• Li W, et al. Structural insights into the triple agonism at GLP-1R, GIPR and GCGR manifested by retatrutide. Cell Discov. 2024;10:77. doi:10.1038/s41421-024-00700-0
• Lau J, et al. Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J Med Chem. 2015;58(18):7370–7380. doi:10.1021/acs.jmedchem.5b00726
• EMBL-EBI ChEMBL. Retatrutide (CHEMBL5095485). ebi.ac.uk
• Eli Lilly and Company. Second-quarter 2026 financial results, Form 8-K exhibit, Aug 5, 2026. sec.gov
• Respaut R. Lilly sues six companies over alleged illegal sales of experimental obesity drug retatrutide. Reuters, Aug 12, 2026.