Retatrutide

About Retatrutide

Retatrutide (development code LY3437943) is a synthetic 39-amino-acid peptide developed by Eli Lilly that activates three receptors at once: the glucagon-like peptide-1 (GLP-1) receptor, the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon receptor. It belongs to the same family of incretin-based compounds as semaglutide (a GLP-1 agonist) and tirzepatide (a GLP-1/GIP dual agonist), and is the first of the so-called 'triple agonists' to reach late-stage clinical trials.

The peptide backbone is based on the GIP sequence, engineered so that a single molecule binds all three receptors with a balanced profile, and a C20 fatty-diacid side chain is attached to a lysine residue. That lipid tail binds albumin in circulation and is what gives the molecule a half-life long enough for once-weekly dosing in the clinical programme.

Retatrutide is one of the most closely watched compounds in metabolic research. A Phase 2 trial published in the New England Journal of Medicine in 2023 reported dose-dependent reductions in body weight over 48 weeks, and the Phase 3 TRIUMPH programme in obesity and type 2 diabetes reported its first primary completions in 2026. It is not approved by Health Canada, the FDA or any other regulator.

Mechanism

GLP-1 and GIP receptor activation are the incretin pathways that regulate insulin secretion, gastric emptying and appetite signalling; glucagon receptor activation raises energy expenditure and hepatic fat oxidation. In preclinical models the combination produced greater weight and liver-fat reduction than GLP-1 agonism alone, which is the rationale for the triple-agonist design.

Areas of research

1. Simultaneous activation of three incretin-related receptor pathways
2. Studied for effects on energy balance and body composition in clinical trial populations
3. Investigated in models of metabolic dysfunction and hepatic fat

References

1. Jastreboff AM et al. Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial. N Engl J Med. 2023;389(6):514-526. PubMed
2. Rosenstock J et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial. Lancet. 2023;402(10401):529-544. PubMed
3. 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. PubMed

Research use only. Information on this page is provided for educational and research purposes and summarises published literature, mostly from cell and animal studies; it is not a claim of efficacy or safety. Products are not intended for human or veterinary use, or for any diagnostic or therapeutic purpose.