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Retatrutide

Category: Peptides · Last updated

Retatrutide (Eli Lilly development code LY3437943) is a synthetic peptide engineered as a single-molecule agonist at three receptors simultaneously: glucagon-like peptide 1 receptor (GLP-1R), glucose-dependent insulinotropic polypeptide receptor (GIPR), and the glucagon receptor (GCGR). It is currently an investigational compound; no FDA approval has been granted as of the date of this article.

The substantive human data summarized below are the property of the original investigators and Eli Lilly. They are reproduced here as a citation, not as a claim of this product. Peppu Studio supplies retatrutide as a research-grade chemical reference compound for in-vitro use only.

Peppudex card: see the mechanism + evidence-grade summary at [Peppudex / Retatrutide](https://peppudex.com/peptides/retatrutide).

Overview

Retatrutide is part of Eli Lilly's incretin research pipeline alongside the dual GIP/GLP-1 agonist Tirzepatide. The peptide backbone is similar in length to tirzepatide (39 residues) but carries amino-acid substitutions and a fatty-acid linker that broaden receptor coverage to include the glucagon receptor in addition to the two incretin receptors.

The glucagon-receptor component is the key pharmacological differentiator vs tirzepatide: GCGR agonism increases hepatic glucose output and energy expenditure, theoretically partially offsetting the appetite-suppression-mediated weight loss with thermogenic activity.

Mechanism

Triple receptor engagement:

  • GLP-1R agonism. Glucose-dependent insulin secretion, glucagon suppression, delayed gastric emptying, central appetite suppression via brainstem/hypothalamic receptors.
  • GIPR agonism. Enhanced insulin secretion in the post-prandial window, modulation of adipocyte lipid handling, possible reduction in GLP-1-mediated nausea.
  • GCGR agonism. Hepatic glycogenolysis and gluconeogenesis (counter-regulatory to insulin), increased basal metabolic rate, possible direct lipolytic effects on white adipose.

The net glycemic effect is determined by the balance of GLP-1R/GIPR insulin-secretion drive against GCGR-driven hepatic glucose output. In published Phase 2 data, glycemic control improved despite glucagon-axis activation.

See: GLP-1_receptor, GIP_receptor, Glucagon_receptor.

Evidence

The pivotal Phase 2 data are published in The New England Journal of Medicine:

  • Jastreboff AM, Kaplan LM, Frías JP, et al. "Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial." N Engl J Med. 2023;389(6):514-526. PMID 37366315. (ClinicalTrials.gov NCT04881760.)

That paper reports the trial design, primary and secondary endpoints, and safety profile across the seven retatrutide dose arms (1 mg, 4 mg in two titration variants, 8 mg in two variants, 12 mg, and placebo). The full text is the authoritative reference; readers are directed to NEJM for the complete numerical results. All efficacy results in that paper are claims of the publishing investigators and Eli Lilly, not of Peppu Studio.

Phase 3 development is underway:

  • TRIUMPH (Phase 3 obesity program). Multiple companion trials. Status: enrolling/ongoing as of publication date.
  • TRIUMPH-1, -2, -3, -4, -5 registered at ClinicalTrials.gov under sponsor Eli Lilly.

Dosing literature

Phase 2 dose arms ranged from 1 mg to 12 mg weekly by subcutaneous injection, with stepwise titration to mitigate gastrointestinal adverse events. This wiki does not recommend any human dose. The compound is supplied as a research-grade chemical reference material for in-vitro use only.

Storage

Lyophilized: 2–8 °C, stable 12+ months. Reconstituted: 2–8 °C, use within 28 days. See Reconstitution.

Regulatory status

  • United States. Investigational compound. Not FDA-approved. Phase 3 (TRIUMPH program) in progress.
  • WADA. Not currently on the prohibited list as of the 2026 list publication.
  • Patent. Eli Lilly holds composition-of-matter patents covering the retatrutide molecule.

Side effects (per published Phase 2)

Adverse events reported in the Phase 2 trial were predominantly gastrointestinal (nausea, vomiting, diarrhea), dose-dependent and largely mild-to-moderate. Dose-dependent heart-rate increases were observed at 24 weeks. See the NEJM paper for the full safety table.

See also

References

Research framing only. Peppu Wiki documents the published research literature surrounding peptide compounds. Articles describe in-vitro and animal-model evidence, regulatory status, and community-reported protocols. Nothing on this site is medical advice, a recommendation for human use, or a substitute for consultation with a qualified clinician. All compounds discussed are research-use only. Citations should be verified at the source before relying on any quantitative claim.
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