What Is Retatrutide?

Research Overview

Retatrutide (LY3437943) is a first-in-class incretin-based triple hormone receptor agonist developed by Eli Lilly and Company to address the limitations of current obesity and type 2 diabetes therapeutics by simultaneously engaging three distinct metabolic pathways. The molecule was first described by Coskun et al. in a 2022 publication in Cell Metabolism, detailing its discovery, mechanism, and proof of concept from preclinical models through Phase 1 human data.[4]

Structurally, retatrutide is a 39-amino acid synthetic peptide engineered from a GIP peptide backbone. It incorporates three non-coded amino acid residues — two α-aminoisobutyric acid (Aib) residues at positions 2 and 20, and one α-methyl-L-leucine residue at position 13 — to enhance metabolic stability and receptor binding. A C20 fatty diacid moiety is conjugated at lysine-17 via an AEEA-γGlu linker, promoting albumin binding and extending the plasma half-life to approximately 6 days, enabling convenient once-weekly subcutaneous administration.[4][8]

The foundational therapeutic rationale for retatrutide rests on the hypothesis that simultaneously activating receptors for GLP-1, GIP, and glucagon can produce superior metabolic outcomes compared to mono- or dual-receptor agonists. GLP-1 receptor agonism suppresses appetite and stimulates insulin secretion; GIP receptor agonism enhances the insulinotropic response and supports lipid metabolism; and critically, glucagon receptor agonism increases energy expenditure and drives lipolysis and hepatic fatty acid oxidation — a mechanism absent from existing dual agonists like tirzepatide.[1][10][11]

Clinical trials have demonstrated remarkable efficacy. The pivotal Phase 2 trial by Jastreboff et al. (2023) in the New England Journal of Medicine reported dose-dependent weight loss in adults with obesity, reaching up to 24.2% mean body weight reduction at 48 weeks with the 12 mg dose — and weight loss had not plateaued at study conclusion.[1] A parallel Phase 2 trial by Rosenstock et al. (2023) in The Lancet demonstrated HbA1c reductions of up to -2.02% in participants with type 2 diabetes.[2] Phase 3 results from the TRIUMPH program have since confirmed these findings, with data showing up to 28.7% mean weight loss at 68 weeks and significant relief from obesity-related comorbidities including knee osteoarthritis.[5]

Beyond obesity and diabetes, retatrutide is under investigation for metabolic dysfunction-associated steatotic liver disease (MASLD), where a Phase 2a substudy by Sanyal et al. (2024) published in Nature Medicine demonstrated that the 8 mg and 12 mg doses normalized liver fat (<5%) in over 85% of participants, with relative reductions of up to 86% from baseline.[3] Additional ongoing Phase 3 trials are evaluating the drug for cardiovascular outcomes (TRIUMPH-OUTCOMES), chronic kidney disease (TRANSCEND-CKD), obstructive sleep apnea, and knee osteoarthritis.[5][7][9] Preclinical research has also revealed intriguing potential in obesity-associated cancer progression, with Marathe et al. (2025) demonstrating that retatrutide reduced tumor engraftment and delayed tumor onset, outperforming semaglutide in tumor suppression.[14]