Retatrutide (LY3437943): A Triple-Agonist Peptide in Metabolic Research

What is retatrutide?

Retatrutide (developmental code LY3437943) is a synthetic single-molecule peptide that acts as an agonist at three metabolic hormone receptors at once: the glucose-dependent insulinotropic polypeptide (GIP) receptor, the glucagon-like peptide-1 (GLP-1) receptor, and the glucagon (GCGR) receptor. It is an investigational compound and has not been approved by any medicines regulator.

A triple-receptor agonist

Combining GIP, GLP-1, and glucagon receptor activity in a single molecule is intended to pair the appetite- and glucose-related effects associated with incretin (GIP and GLP-1) signalling with the energy-expenditure effects associated with glucagon-receptor activity. In the discovery report, Coskun and colleagues characterised LY3437943 as having balanced glucagon and GLP-1 receptor activity with relatively greater GIP receptor activity, and described weight reduction in preclinical models driven by both reduced calorie intake and increased energy expenditure (Coskun et al., Cell Metabolism, 2022).

Early clinical research

The first-in-human study — a phase 1b, multiple-ascending-dose trial in people with type 2 diabetes — reported the initial safety, tolerability, and pharmacology of the compound (Urva et al., Lancet, 2022).

Phase 2 trials

In a 48-week phase 2 trial in adults with obesity, retatrutide was associated with a least-squares mean change in body weight of up to −24.2% at the highest dose (12 mg), compared with −2.1% for placebo (Jastreboff et al., New England Journal of Medicine, 2023). A separate phase 2 trial in adults with type 2 diabetes reported improvements in glycaemic control alongside body-weight reductions of up to roughly −16.9% at 24 weeks (Rosenstock et al., Lancet, 2023). Gastrointestinal effects were the most commonly reported adverse events, consistent with other incretin-based agents.

Research status

Retatrutide remains investigational and is progressing through later-stage clinical development. The findings summarised here describe results from published clinical trials of the drug candidate; they do not describe the product supplied here, which is intended solely for laboratory research.

Handling

• Supplied as a lyophilized powder; store at -20°C and protect from light.
• Allow vials to reach room temperature before opening to avoid condensation.
• Reconstitute with an appropriate solvent (commonly sterile or bacteriostatic water) for laboratory use; aliquot to avoid repeated freeze–thaw cycles.

References

• 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 Metabolism. 2022;34(9):1234–1247.
• Urva S, et al. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multiple-ascending-dose trial. Lancet. 2022;400(10366):1869–1881.
• Jastreboff AM, et al. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. New England Journal of Medicine. 2023;389(6):514–526. doi:10.1056/NEJMoa2301972.
• 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. doi:10.1016/S0140-6736(23)01053-X.

All products referenced are for laboratory research use only — not for human or veterinary use, diagnosis, or treatment. This content is informational and is not medical advice.