Overview

Retatrutide (LY3437943) is an investigational synthetic peptide agonist at three incretin/glucagon-family receptors: glucagon (GCGR), glucose-dependent insulinotropic polypeptide (GIPR), and glucagon-like peptide-1 (GLP-1R). Like tirzepatide, it carries a fatty-acid moiety that binds serum albumin and produces a plasma half-life of approximately six days, supporting once-weekly administration in reported research protocols.

The peptide has been characterised in the TRIUMPH phase-2 and phase-3 programmes, primarily in obesity and type 2 diabetes cohorts.

Mechanism (as reported in the literature)

  • Triple receptor coverage. Research suggests the addition of glucagon-receptor agonism to the GIP+GLP-1 dual profile increases energy expenditure alongside the appetite-suppression and insulinotropic effects of the incretin arms.
  • Glucagon-driven thermogenesis. Animal studies indicate glucagon-receptor agonism raises resting energy expenditure and hepatic fatty-acid oxidation.
  • GLP-1 and GIP components. As with tirzepatide, the incretin components are characterised as contributing to reduced food intake and improved postprandial glucose handling.

Research findings

  • Phase-2 obesity trial. A 48-week randomised trial in adults with obesity without diabetes reported dose-dependent mean body-weight changes of −8.7%, −17.1%, −22.8%, and −24.2% for the 1, 4, 8, and 12 mg weekly dose arms respectively, versus −2.1% for placebo (Jastreboff et al., 2023, N Engl J Med; PMID 37366315).
  • Phase-2 type 2 diabetes trial. A 36-week trial reported HbA1c reductions comparable to dulaglutide comparator arms at lower doses and greater reductions at higher doses (Rosenstock et al., 2023, The Lancet).
  • MASH/hepatic steatosis. A 48-week phase-2 imaging substudy reported reductions in liver fat content across dose arms (Sanyal et al., 2024).

Retatrutide remains investigational; the reference dosing ranges above are drawn from published trial protocols.

Common dosing (from published research protocols)

Reported titration schedules begin at 0.5 mg weekly with 2–4-week step-ups toward 4, 8, or 12 mg weekly. As with other incretin peptides, gastrointestinal adverse events were most commonly reported during titration.

Reconstitution

An 8 mg vial reconstituted with 2 mL of bacteriostatic water yields a 4,000 mcg/mL solution. Under those conditions:

  • 500 mcg = 0.125 mL = 12.5 units on a U-100 syringe
  • 2 mg (2,000 mcg) = 0.50 mL = 50 units
  • 4 mg (4,000 mcg) = 1.00 mL = 100 units

Storage

Handling and storage described for retatrutide follow the standard incretin pattern: lyophilised material refrigerated on arrival, freezer storage for long-term preservation, and reconstituted solution held at 2–8 °C for short-term use.

  • Tirzepatide — the reference dual GIP/GLP-1 comparator.
  • Semaglutide — the reference GLP-1 monoagonist.
  • AOD-9604 — a distinct metabolic peptide fragment.

References

  • Jastreboff, A. M., et al. (2023). “Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial.” New England Journal of Medicine, 389(6). PMID 37366315.
  • Rosenstock, J., et al. (2023). “Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes.” The Lancet, 402(10401). PMID 37364590.
  • Sanyal, A. J., et al. (2024). “Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease.” Nature Medicine, 30(7). PMID 38951635.
  • Coskun, T., et al. (2022). “LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist.” Cell Metabolism, 34(9). PMID 35973425.