What Is Retatrutide? The Triple Agonist Explained

Retatrutide (LY3437943) is a synthetic 39-amino-acid peptide developed by Eli Lilly and Company that activates three class B G protein-coupled receptors at once: the GLP-1 receptor, the GIP receptor and the glucagon receptor. It is built on a GIP-derived backbone, carries three non-coded amino acids and a fatty diacid side chain for albumin binding, and is investigational: as of September 2026 it is not approved in any country.

That combination of targets is why the compound is often called a "triple agonist" or "triple G" molecule. This profile covers where retatrutide came from, what is known about its structure and receptor pharmacology from published papers, what human trials registered on ClinicalTrials.gov have measured, and how the lyophilized peptide is handled as an in-vitro reagent. It does not cover use in people or animals. In the Anhydrolabs catalog, retatrutide is listed as GLP-3 RT.

Retatrutide at a glance

The formula and weight above are the values KEGG DRUG gives for the free peptide. Salt forms differ: a supplier's acetate or trifluoroacetate salt will have a higher formula weight than the free peptide, which matters when you convert a weighed mass into a molar concentration.

Where retatrutide came from

Retatrutide belongs to a line of work on single peptides that engage more than one receptor of the glucagon family. The three hormones involved (GLP-1, GIP and glucagon) share an N-terminal architecture: an unstructured first few residues that reach into the receptor's transmembrane core, followed by a long helix that rests against the receptor's extracellular domain. Because the sequences are related, a single designed peptide can be tuned to activate two or three of the receptors.

Lilly's first molecule of this kind to reach approval was tirzepatide, a GIP and GLP-1 receptor agonist. Retatrutide extends the approach to the glucagon receptor. The discovery paper by Coskun and colleagues, published in Cell Metabolism in 2022, describes LY3437943 as a triple agonist with balanced activity at the glucagon and GLP-1 receptors and greater activity at the GIP receptor. The same paper reports characterization in cell lines expressing each receptor and in diet-induced obese mice, followed by a Phase 1 single ascending study in people.

The two compounds are close relatives. Both are 39 residues long, both start with tyrosine followed by Aib, and both end in the same eleven residues, GGPSSGAPPPS, a C-terminal segment also found in exenatide. Of the 39 positions, 30 are identical. The side-by-side is covered in tirzepatide vs retatrutide.

Structure: sequence, non-coded residues and the lipid chain

The one-letter sequence listed by KEGG DRUG is:

Y X Q G T F T S D Y S I L L D K K A Q X A F I E Y L L E G G P S S G A P P P S

In that listing, X marks a non-coded residue. The published structural work adds detail:

• Position 2, Aib (α-aminoisobutyric acid). Native GIP and GLP-1 are cut after residue 2 by dipeptidyl peptidase-4 (DPP-4). An Aib at position 2 blocks that cleavage. The same substitution appears in tirzepatide and, at the equivalent position, in semaglutide.
• Position 13, α-methyl-L-leucine. Cryo-EM analysis identifies αMeL13 making hydrophobic contacts with the receptor's transmembrane helix 1. KEGG writes this residue as L because it is a leucine derivative.
• Position 17, lysine carrying a fatty diacid. The ε-amine of Lys17 is acylated with a fatty diacid through a linker. The diacid binds serum albumin, which slows renal clearance and protects the peptide from proteolysis. This is the same half-life strategy used by semaglutide and tirzepatide, although each attaches the chain at a different lysine.
• Position 20, a second non-coded residue, shown as X in the KEGG sequence.

The lipid chain is what separates retatrutide from the native hormones in a practical sense. The Phase 1b trial in adults with type 2 diabetes reported a retatrutide half-life of approximately 6 days, a figure that depends on albumin binding rather than on the peptide backbone alone.

Receptor pharmacology

Retatrutide acts at three receptors, each a class B (secretin family) GPCR that signals mainly through Gs and cyclic AMP:

The relative potencies are those summarized by Li and colleagues in Cell Discovery (2024), citing the discovery work. In plain terms, retatrutide is more potent than native GIP at the GIP receptor and somewhat less potent than the native hormones at the GLP-1 and glucagon receptors. Such values depend on the assay (cell line, receptor expression level, and whether albumin is present), so figures from different labs should not be compared directly.

What cryo-EM shows

The Cell Discovery study solved three structures of retatrutide bound to each receptor in complex with the Gs protein, using single-particle cryo-electron microscopy. The overall resolutions were:

• Retatrutide with GLP-1R and Gs: 2.68 Å
• Retatrutide with GIPR and Gs: 3.26 Å
• Retatrutide with GCGR and Gs: 2.84 Å

The authors describe a shared binding mode. The N-terminal Tyr1 forms salt bridges and aromatic contacts deep in the transmembrane pocket, Phe22 packs against a conserved tryptophan in the extracellular domain, and Asp15 hydrogen-bonds with a residue of the receptor's extracellular domain. Alanine mutations at two conserved glutamate and aspartate positions reduced retatrutide-induced cAMP signaling at all three receptors, by different amounts at each. The structures also show receptor-specific contacts, for example a salt bridge from Lys17 to GLP-1R that is absent in GIPR because GIPR carries an arginine at that position.

For researchers building assays, these structures are a starting point for mutational studies, for comparing retatrutide with dual agonists, and for docking work on new multi-receptor peptides.

Research context

Published work on retatrutide falls into three groups:

1. In-vitro pharmacology. cAMP accumulation and binding assays in cell lines expressing recombinant human GIPR, GLP-1R or GCGR. These are the assays in-vitro users most often reproduce.
2. Animal models. The discovery paper used diet-induced obese mice. It attributes part of the observed pharmacology to glucagon-receptor-mediated changes in energy expenditure, in addition to GIP and GLP-1 receptor effects on food intake.
3. Human trials. Lilly has run Phase 1, Phase 2 and Phase 3 programs. We list what these trials studied, not their outcomes.

Trials registered on ClinicalTrials.gov

The Phase 2 trial, published in the New England Journal of Medicine in 2023, measured percentage change in body weight at 24 and 48 weeks as its primary and secondary end points, along with safety. The TRIUMPH program adds trials in knee osteoarthritis pain and chronic low back pain, and a separate Phase 3 trial with long-term cardiovascular and kidney end points. None of this makes retatrutide an approved product; it remains investigational until a regulator acts on an application.

Retatrutide and cagrilintide as a combined reagent

The catalog also lists a GLP-3 RT / Cagrilintide blend, which combines retatrutide with cagrilintide, a long-acting amylin analog developed by Novo Nordisk. The two act on unrelated receptor families. Retatrutide targets the glucagon-family receptors above, while cagrilintide targets amylin receptors, which are the calcitonin receptor paired with a receptor activity-modifying protein (RAMP). A combined vial is useful for assay work that needs both ligands at a fixed molar ratio. For an assay that needs each ligand titrated independently, two single-compound vials are the better choice.

Laboratory handling

Retatrutide is a large, lipidated, amphipathic peptide. These notes are general practice for in-vitro stock solutions. The certificate of analysis for the lot you receive takes precedence.

• Storage of the powder. Keep the sealed vial at −20 °C or colder, dry and protected from light. Let the vial reach room temperature before opening so moisture does not condense on the cold powder. Our storage and handling page covers this in more detail.
• Reconstitution. Lipidated incretin analogs usually dissolve best in a slightly basic aqueous buffer, because the fatty diacid and the acidic residues carry negative charge above neutral pH. Add solvent down the vial wall, swirl rather than vortex, and allow time for full dissolution. Our guide to reconstituting lyophilized peptides walks through the arithmetic for a target concentration in mg/mL.
• Adsorption. Acylated peptides stick to some plastics and glass at low concentrations. Low-binding tubes and a carrier protein in assay buffer (often 0.1% BSA, where the assay tolerates it) reduce losses. Remember that albumin also binds the lipid chain and lowers apparent potency in cell assays. Report whether albumin was present.
• Aliquoting. Split stock solutions into single-use aliquots and store them frozen. Avoid repeated freezing and thawing.
• Identity and purity. Reversed-phase HPLC purity and a mass spectrum matching the expected molecular weight are the two checks that matter. Our explainer on peptide purity shows how the area of the principal peak becomes a percentage purity figure.

Anhydrolabs supplies retatrutide as a lyophilized powder in vacuum-sealed vials, and also as 10-vial kits. Each lot ships with its own certificate of analysis. Background on the freeze-drying process is in lyophilized peptides. All material is for laboratory research only, as set out on our research use page.

What is still unknown

Several points about retatrutide remain open in the published record. The open papers we reviewed describe the side chain only as a fatty diacid on a linker, without stating its carbon chain length. How balanced triple agonism compares with dual agonism over long exposure is the question the Phase 3 program is designed to address. The contribution of glucagon-receptor signaling in each tissue is still being worked out in animal models. Researchers comparing multi-receptor ligands should state the receptor species, cell background and albumin conditions of every assay, since these change the apparent balance between receptors more than small differences in sequence do.