Overview

Status

  • In late-stage (Phase 3) clinical trials by Eli Lilly

How it Works

  • Triple agonist — targets GLP-1, GIP, and glucagon receptors simultaneously.

  • The glucagon activation increases energy expenditure, potentially amplifying fat-burning beyond appetite reduction.

Effects (in trials):

  • Most potent of all three — early studies show up to 24%+ average weight loss after about 48 weeks.

  • Still being tested for long-term safety and side effects before FDA approval.

Background

Retatrutide is an experimental drug for obesity developed by the American pharmaceutical company Eli Lilly and Company. It is a triple glucagon hormone receptor agonist (GLP-1, GIP, and GCGR receptors).[1][2][3] It has been shown to achieve a more than 17.5% mean weight reduction in adults without diabetes but with obesity or preobesity (overweight) during a phase 2 trial.[4][5][6] In the trial, the participants who received the highest dose (12 mg) showed a mean weight reduction of 24.2% after 48 weeks.[6] Retatrutide is currently in phase 3 clinical trials, one of many GLP-1 receptor agonists in development.[7] In a 2025 fat-mass substudy of adults with type 2 diabetes, Retatrutide achieved statistically significantly greater total body fat mass reduction at 36 weeks than both placebo and dulaglutide.[8]

Chemistry

Retatrutide is a peptide with the following amino acid sequence[9]

YA¹QGTFTSDYSIL²LDKK⁴AQA¹AFIEYLLEGGPSSGAPPPS³

where letters with superscripted numbers refer to the following chemical modifications:

  1. "A¹" refers to 2-aminoisobutyric acid (Aib).

  2. "L²" refers to leucine modified with an α-methyl substituent (MeL, 2-methylleucine).

  3. "S³" refers to L-serinamide (L-serine with the carboxylic acid group replaced with a carboxamide).

  4. "K⁴" refers to L-lysine with the amino group at position 6 modified with a side chain; specifically, (AEEA)-(γ-Glu)-(C20 diacid) (where AEEA is 2-[2-(2-aminoethoxy)ethoxy]acetic acid, commonly used as a spacer group in synthetic peptides).

REFERENCES

1. Coskun T, Urva S, Roell WC, et al. (September 2022). "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. 34 (9): 1234–1247.e9. doi:10.1016/j.cmet.2022.07.013. PMID 35985340. S2CID 251675508.

2. Bhat S, Fernandez CJ, Lakshmi V, Pappachan JM. Efficacy and safety of incretin co-agonists: Transformative advances in cardiometabolic healthcare. World J Cardiol. 2025 Aug 26;17(8):107991. doi:10.4330/wjc.v17.i8.107991 PMID 40949933.

3. Concepción-Zavaleta MJ, Fuentes-Mendoza JM, Gonzáles-Yovera JG, Ruvalcaba-Barbosa GY, Cura-Rodríguez LD, González-Rodríguez JS, Concepción-Urteaga LA, Pérez-Reyes AI, Quiroz-Aldave JE, Paz-Ibarra J. Efficacy and safety of anti-obesity drugs in metabolic dysfunction-associated steatotic liver disease: An updated review. World J Gastroenterol. 2025 Oct 7;31(37):111435. doi:10.3748/wjg.v31.i37.111435 PMID 41025003.

4.  "Lilly's phase 2 retatrutide results published in The New England Journal of Medicine show the investigational molecule achieved up to 17.5% mean weight reduction at 24 weeks in adults with obesity and overweight". investor.lilly.com (Press release). Eli Lilly. 26 June 2023. 

5. Constantino, Annika Kim (26 June 2023). "Eli Lilly experimental obesity drug could beat rivals in total weight loss for patients". CNBC.com. 

6. Jastreboff AM, Kaplan LM, Frías JP, et al. (June 2023). "Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial". The New England Journal of Medicine. 389 (6): 514–526. doi:10.1056/NEJMoa2301972. PMID 37366315. S2CID 259260926. 

7.  "A Study of Retatrutide (LY3437943) in Participants With Obesity and Cardiovascular Disease (TRIUMPH-3) - Lilly Clinical Trials". Lilly Trials. Retrieved 2025-08-24.

8. Coskun, Tamer; Wu, Qiwei; Schloot, Nanette C.; Haupt, Axel; Milicevic, Zvonko; Khouli, Courtney; Harris, Charles (August 2025). "Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, double-blind, parallel-group, placebo-controlled, randomised trial". The Lancet. Diabetes & Endocrinology. 13 (8): 674–684. doi:10.1016/S2213-8587(25)00092-0. ISSN 2213-8595. PMID 40609566.

9.  "Compound Report Card". ebi.ac.uk. European Bioinformatics Institute, European Molecular Biology Laboratory.