Retatrutide: Scientific Profile
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Retatrutide (LY3437943; CAS 2381089-83-2): a synthetic 39-amino-acid peptide, a triple agonist of GIPR/GLP-1R/GCGR. Research reagent.
Retatrutide (English name Retatrutide; development code LY3437943; CAS 2381089-83-2) is a long-acting synthetic peptide belonging to the class of TRIPLE incretin/glucagon agonists. It is a 39-amino-acid peptide chain structurally derived from the GIP backbone, modified with a fatty acid that gives it reversible binding to serum albumin and, with it, a prolonged half-life compatible with weekly dosing schedules in research models. Retatrutide was developed by Eli Lilly and is one of the molecules that has expanded interest in multi-receptor metabolic pharmacology.
Its distinctive feature compared with dual agonists is that it simultaneously activates THREE class B G protein-coupled receptors: the GIP receptor (GIPR), the glucagon-like peptide-1 receptor (GLP-1R), and the glucagon receptor (GCGR). The design of this type of unimolecular tri-agonist seeks to bring together in a single sequence the recognition determinants of the three systems, with a relative potency balanced among them.
The proposed mechanism of action combines the three pathways in a coordinated manner. Through the GLP-1R arm, classic incretin signaling is reproduced (potentiation of glucose-dependent insulin secretion, slowing of gastric emptying, and modulation of satiety). Through the GIPR arm, complementary effects on lipid metabolism and insulin sensitivity are added. Through the GCGR arm, activation of the glucagon receptor is associated in animal models with increased energy expenditure and effects on hepatic lipid metabolism, including the mobilization of liver fat. The working hypothesis is that balanced co-activation of the three receptors produces an integrated metabolic effect superior to that of dual agonists.
In research, Retatrutide is used as a reference tool for studying combined incretin and glucagon signaling, glucose homeostasis, energy expenditure, and hepatic lipid metabolism in cell and animal models, as well as a comparator against dual and selective agonists.
Retatrutide is supplied as a lyophilized powder for reconstitution. Frozen storage of the lyophilized vial, protection from light and reconstitution with bacteriostatic water or the sterile diluent indicated in the protocol are recommended, avoiding vigorous agitation. This product is offered exclusively as a research reagent (research use only): it is not intended for the diagnosis, prevention or treatment of any disease, nor for human or veterinary consumption.
Mechanism of action
Retatrutide binds with comparable affinity and potent activation to three secretin-family G protein-coupled receptors: GLP-1R, GIPR and GCGR. Signaling via GLP-1R in pancreatic β cells increases cAMP and glucose-dependent insulin secretion; GIPR activation in adipocytes modulates insulin sensitivity and lipid uptake; and GCGR activation in hepatocytes and white/brown adipocytes induces transient hepatic gluconeogenesis, lipolysis, β-oxidation and thermogenesis via UCP1. The net balance on plasma glucose remains favorable because the GLP-1 component antagonizes glucagon-induced hyperglycemia. In the central nervous system, retatrutide activates POMC neurons of the arcuate nucleus and inhibits NPY/AgRP, producing sustained anorexia. In vivo studies in primates demonstrate an 8-12% increase in basal energy expenditure. Retatrutide activates GIPR with the greatest potency of the three receptors (EC50 0.064 nM), followed by GLP-1R (EC50 0.775 nM) and GCGR with the lowest potency (EC50 5.79 nM) — Coskun et al., Cell Metabolism 2022, PMID 35985340. Plasma half-life: 6 days in humans. Elimination by proteolytic catabolism. No CYP450 metabolism, which minimizes pharmacological interactions.
Mechanism summary
Triple agonist of the GIPR, GLP-1R, and GCGR (glucagon) receptors. A 39-amino-acid peptide with a lipophilic albumin-binding side chain and a half-life of ~6 days, used as a reagent for in vitro and preclinical metabolic research.
Clinical Studies (3)
- Retatrutide in MASLD – Phase 2 study (Sanyal AJ, Kaplan LM, Frias JP, et al. · Nature Medicine · 2024) — Post-hoc analysis of patients with MASLD in the phase 2 obesity trial, evaluating change in hepatic fat by MRI-PDFF. PMID 38858523.
- Retatrutide for obesity – Phase 2 trial (Jastreboff AM, Kaplan LM, Frías JP, et al. · New England Journal of Medicine · 2023) — 48-week phase 2 study in 338 adults with obesity, evaluating retatrutide 1/4/8/12 mg weekly vs placebo. PMID 37366315.
- Retatrutide in T2DM – Phase 2 trial (Rosenstock J, Frías J, Jastreboff AM, et al. · The Lancet · 2023) — 36-week phase 2 study in 281 patients with T2DM evaluating retatrutide vs dulaglutide 1.5 mg and placebo. PMID 37385280.
Warnings
Retatrutide is a research-use-only (RUO) compound; the following warnings and handling considerations apply to its laboratory use:
- Agent in clinical research – without regulatory approval
- Dose-dependent increase in heart rate (monitor)
- Possible transient elevation of transaminases
- Theoretical risk of thyroid tumors (class)
- Possible hypoglycemia with insulin/sulfonylureas
- Delayed gastric emptying affects oral absorption
- Acute pancreatitis as a class event
- Personal/family history of medullary thyroid carcinoma
- Multiple endocrine neoplasia type 2 (MEN2)
- Known hypersensitivity to the compound
- Active acute pancreatitis
- Severe hepatic insufficiency
Technical data
- CAS
- 2381089-83-2
- Molecular formula
- C221H342N46O68
- Molecular weight
- 4731.3 Da
- Compound type
- peptide
- Storage
- -20 °C liofilizado; 2-8 °C reconstituido
- Shelf life (lyophilized)
- 24 months at 2-8°C
- Shelf life (reconstituted)
- 14-21 days at 2-8°C with bacteriostatic preservative
- Light-sensitive
- Sí
Available for research
Retatrutide is available as a research reagent (RUO) with HPLC-verified purity and COA per batch:
Frequently asked questions about Retatrutide
What is Retatrutide?
Retatrutide (LY3437943; CAS 2381089-83-2): a synthetic 39-amino-acid peptide, a triple agonist of GIPR/GLP-1R/GCGR. Research reagent.
What is the mechanism of action of Retatrutide?
Triple agonist of the GIPR, GLP-1R, and GCGR (glucagon) receptors. A 39-amino-acid peptide with a lipophilic albumin-binding side chain and a half-life of ~6 days, used as a reagent for in vitro and preclinical metabolic research.
What is Retatrutide researched for?
In preclinical research, Retatrutide is studied mainly in: weight reduction in research; models of glycemic homeostasis; studies of basal energy expenditure. Material exclusively for scientific research.
What are the chemical properties of Retatrutide?
Molecular formula C221H342N46O68; molecular weight 4731.3 Da; CAS number 2381089-83-2.
How is Retatrutide stored?
Condiciones de conservación: -20 °C liofilizado; 2-8 °C reconstituido; estabilidad liofilizado: 24 meses a 2-8°C; una vez reconstituido: 14-21 días a 2-8°C con conservante bacteriostático; protéjase de la luz.
What routes of administration are studied for Retatrutide?
In the research models the following are described: Subcutaneous. Use is exclusively for scientific research.