Retatrutide

Last updated

Retatrutide
Retatrutide.svg
Clinical data
Other namesLY-3437943
Identifiers
  • L-tyrosyl-2-methylalanyl-L-glutaminylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-tyrosyl-L-seryl-L-isoleucyl-2-methyl-L-leucyl-L-leucyl-L-α-aspartyl-L-lysyl-N6-(N-(19-carboxy-1-oxononadecyl)-L-γ-glutamyl-2-(2-(2-aminoethoxy)ethoxy)acetyl)-L-lysyl-L-alanyl-L-glutaminyl-2-methylalanyl-L-alanyl-L-phenylalanyl-L-isoleucyl-L-α-glutamyl-L-tyrosyl-L-leucyl-L-leucyl-L-α-glutamylglycylglycyl-L-prolyl-L-seryl-L-serylglycyl-L-alanyl-L-prolyl-L-prolyl-L-prolyl-L-serinamide
CAS Number
UNII
ChEMBL
Chemical and physical data
  • CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)C(C)(C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(=O)COCCOCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCCCCCC(=O)O)C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@](C)(CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)C(C)(C)NC(=O)[C@@H](N)Cc1ccc(O)cc1)[C@@H](C)O)[C@@H](C)O)[C@@H](C)CC)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)NCC(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(N)=O
  • InChI=1S/C221H342N46O68/c1-23-124(11)179(208(322)241-144(83-88-176(291)292)192(306)245-150(105-134-69-75-137(276)76-70-134)196(310)244-148(100-121(5)6)194(308)243-147(99-120(3)4)193(307)240-142(82-87-175(289)290)187(301)230-110-169(282)229-113-173(286)264-92-51-61-161(264)206(320)253-158(116-270)203(317)251-157(115-269)189(303)232-111-170(283)233-128(15)212(326)266-94-53-63-163(266)214(328)267-95-54-64-164(267)213(327)265-93-52-62-162(265)207(321)250-156(114-268)183(226)297)258-200(314)152(103-131-55-41-39-42-56-131)242-185(299)127(14)235-216(331)219(18,19)262-205(319)145(80-85-166(225)279)237-184(298)126(13)234-190(304)140(60-48-50-90-227-172(285)119-335-98-97-334-96-91-228-167(280)86-81-146(215(329)330)236-168(281)65-45-37-35-33-31-29-27-25-26-28-30-32-34-36-38-46-66-174(287)288)238-191(305)141(59-47-49-89-222)239-198(312)154(107-177(293)294)247-195(309)149(101-122(7)8)256-218(333)221(22,109-123(9)10)263-211(325)180(125(12)24-2)259-204(318)160(118-272)252-197(311)151(106-135-71-77-138(277)78-72-135)246-199(313)155(108-178(295)296)248-202(316)159(117-271)254-210(324)182(130(17)274)260-201(315)153(104-132-57-43-40-44-58-132)249-209(323)181(129(16)273)257-171(284)112-231-188(302)143(79-84-165(224)278)255-217(332)220(20,21)261-186(300)139(223)102-133-67-73-136(275)74-68-133/h39-44,55-58,67-78,120-130,139-164,179-182,268-277H,23-38,45-54,59-66,79-119,222-223H2,1-22H3,(H2,224,278)(H2,225,279)(H2,226,297)(H,227,285)(H,228,280)(H,229,282)(H,230,301)(H,231,302)(H,232,303)(H,233,283)(H,234,304)(H,235,331)(H,236,281)(H,237,298)(H,238,305)(H,239,312)(H,240,307)(H,241,322)(H,242,299)(H,243,308)(H,244,310)(H,245,306)(H,246,313)(H,247,309)(H,248,316)(H,249,323)(H,250,321)(H,251,317)(H,252,311)(H,253,320)(H,254,324)(H,255,332)(H,256,333)(H,257,284)(H,258,314)(H,259,318)(H,260,315)(H,261,300)(H,262,319)(H,263,325)(H,287,288)(H,289,290)(H,291,292)(H,293,294)(H,295,296)(H,329,330)/t124-,125-,126-,127-,128-,129+,130+,139-,140-,141-,142-,143-,144-,145-,146-,147-,148-,149-,150-,151-,152-,153-,154-,155-,156-,157-,158-,159-,160-,161-,162-,163-,164-,179-,180-,181-,182-,221-/m0/s1
  • Key:MLOLQJNKXBNWFW-JMUPIODPSA-N

Retatrutide (LY-3437943) 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]

Contents

Clinical trials

Retatrutide has been studied in a phase 2 trial involving adults without diabetes but with obesity or preobesity (overweight). [4] [5] [6] Retatrutide is also being evaluated in phase 3 clinical trials. [7] A substudy in adults with type 2 diabetes reported differences in total body fat mass between study groups at 36 weeks. [8]

Across clinical studies, the most commonly reported adverse events were gastrointestinal symptoms such as nausea, vomiting, and diarrhea. [6]

Preclinical and biochemical studies describe receptor activity at GLP-1, GIP, and glucagon receptors. [9] Reports on its development state that it was engineered for activity across these targets. [1]

Systematic reviews and meta-analyses of randomized controlled trials report that retatrutide produces substantial reductions in body weight in adults with obesity, with mean percentage weight loss typically between 15 and 24 percent over 48 to 72 weeks, depending on study protocols and populations. [10] [11] [12] [13] [14] Adverse events are most commonly gastrointestinal symptoms such as nausea and diarrhea, with relatively low rates of study discontinuation and infrequent serious adverse events reported during trials. [10] [11] [12] Safety assessments also indicate a low risk of hypoglycemia and no significant elevation in cardiovascular or hepatic adverse events in non-diabetic populations across published studies. [13] [14]

Chemistry

Retatrutide is a peptide with the following amino acid sequence [15]

YA¹QGTFTSDYSIL²LDKK⁴AQA¹AFIEYLLEGGPSSGAPPPS³

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

See also

References

  1. 1 2 Coskun T, Urva S, Roell WC, Qu H, Loghin C, Moyers JS, 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 (August 2025). "Efficacy and safety of incretin co-agonists: Transformative advances in cardiometabolic healthcare". World Journal of Cardiology. 17 (8) 107991. doi: 10.4330/wjc.v17.i8.107991 . PMC   12426997 . PMID   40949933.
  3. Concepción-Zavaleta MJ, Fuentes-Mendoza JM, Gonzáles-Yovera JG, Ruvalcaba-Barbosa GY, Cura-Rodríguez LD, González-Rodríguez JS, et al. (October 2025). "Efficacy and safety of anti-obesity drugs in metabolic dysfunction-associated steatotic liver disease: An updated review". World Journal of Gastroenterology. 31 (37) 111435. doi: 10.3748/wjg.v31.i37.111435 . PMC   12476660 . 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. Retrieved 3 July 2023.
  5. Constantino AK (26 June 2023). "Eli Lilly experimental obesity drug could beat rivals in total weight loss for patients". CNBC.com. Retrieved 3 July 2023.
  6. 1 2 Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, et al. (August 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. Free access subject to registration.
  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 T, Wu Q, Schloot NC, Haupt A, Milicevic Z, Khouli C, et al. (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. PMID   40609566.
  9. "Compound: RETATRUTIDE (CHEMBL5095485)". www.ebi.ac.uk. Retrieved 2025-11-24.
  10. 1 2 Tewari J, Qidwai KA, Tewari A, Kaur S, Tewari V, Maheshwari A (2025). "Efficacy and safety of triple hormone receptor agonist retatrutide for the management of obesity: a systematic review and meta-analysis". Expert Review of Clinical Pharmacology. 18 (1–2): 51–66. doi:10.1080/17512433.2025.2450254. PMID   39817343.
  11. 1 2 Abdrabou Abouelmagd A, Abdelrehim AM, Bashir MN, Abdelsalam F, Marey A, Tanas Y, et al. (2025). "Efficacy and safety of retatrutide, a novel GLP-1, GIP, and glucagon receptor agonist for obesity treatment: a systematic review and meta-analysis of randomized controlled trials". Proceedings. 38 (3): 291–303. doi:10.1080/08998280.2025.2456441. PMC   12026077 . PMID   40291085.
  12. 1 2 Katsi V, Koutsopoulos G, Fragoulis C, Dimitriadis K, Tsioufis K (May 2025). "Retatrutide-A Game Changer in Obesity Pharmacotherapy". Biomolecules. 15 (6): 796. doi: 10.3390/biom15060796 . PMC   12190491 . PMID   40563436.
  13. 1 2 Olowo-Oribi BA, Salway RJ (November 2025). "Efficacy of Tirzepatide, Retatrutide, and Semaglutide for Weight Loss in Obese Individuals Without Diabetes". Academic Emergency Medicine. 32 (11): 1255–1258. doi:10.1111/acem.70088. PMID   40583149.
  14. 1 2 Sinha B, Ghosal S (November 2025). "Efficacy and Safety of GLP-1 Receptor Agonists, Dual Agonists, and Retatrutide for Weight Loss in Adults With Overweight or Obesity: A Bayesian NMA". Obesity. 33 (11): 2046–2054. doi:10.1002/oby.24360. PMID   40685589.
  15. "Retatrutide". Compound Report Card. European Bioinformatics Institute, European Molecular Biology Laboratory. n.d. Retrieved August 5, 2024.