Retatrutide

At a Glance

Molecular Properties

Overview

Compound Description

Retatrutide is a synthetic 39-amino-acid peptide rationally designed by Eli Lilly scientists to simultaneously engage three G-protein-coupled receptors central to metabolic homeostasis: the glucose-dependent insulinotropic polypeptide (GIP) receptor, the glucagon-like peptide-1 (GLP-1) receptor, and the glucagon receptor. The backbone is primarily built on a GIP receptor agonist scaffold, which was then systematically modified to introduce cross-reactivity at the GLP-1 and glucagon receptors. It represents the first triple-incretin agonist to advance to large-scale clinical investigation.

Mechanism of Action

Research-Identified Pathways

Key Research Findings

Published Study Highlights

• Phase 2 obesity trial reported that more than 90% of participants at the highest evaluated amount achieved 10% or greater weight reduction from baseline
• Systematic review and meta-analysis across 640 participants showed significant reductions in body weight, BMI, and waist circumference versus placebo
• Phase 2a liver study demonstrated liver fat reductions of up to 82.4% from baseline, with 86% of participants achieving normal liver fat levels
• Cryo-EM structural studies have revealed the molecular binding conformations at all three target receptors
• TRIUMPH registrational program is investigating the compound in obesity and related comorbidities including obstructive sleep apnea

Areas of Research Interest

Why Researchers Are Investigating This Compound

This compound has attracted significant research attention in the following areas. These represent active fields of scientific inquiry, not validated therapeutic claims. No medical benefits are stated or implied.

• Advanced metabolic research: as the first triple-receptor agonist to reach large-scale clinical investigation, it has become one of the most closely watched compounds in metabolic science
• Triple-receptor metabolic research: the first compound to engage all three incretin receptors, representing a new frontier in metabolic pathway research
• Liver fat and MASLD research: preclinical and clinical investigations into hepatic lipid metabolism have drawn significant attention from hepatology researchers
• Energy expenditure mechanisms: the glucagon receptor component, unique to this triple-agonist, is being studied for its role in thermogenesis and hepatic energy metabolism

Published Research

Peer-Reviewed References

1. Jastreboff AM, Kaplan LM, Frias JP, et al. "Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial." New England Journal of Medicine (2023). doi:10.1056/NEJMoa2301972
2. Alharbi SH "Effects of once-weekly subcutaneous retatrutide on weight and metabolic markers: A systematic review and meta-analysis of randomized controlled trials." Metabolism Open (2024). doi:10.1016/j.metop.2024.100321
3. Sanyal AJ, Kaplan LM, Frias JP, et al. "Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial." Nature Medicine (2024). doi:10.1038/s41591-024-03018-2
4. Wang X, Cheng L, Liu Y, et al. "Structural insights into the triple agonism at GLP-1R, GIPR and GCGR manifested by retatrutide." Cell Discovery (2024). doi:10.1038/s41421-024-00700-4