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Retatrutide

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Retatrutide
Chemical structure of Retatrutide
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 is an experimental drug[1] for obesity developed by the American pharmaceutical company Eli Lilly and Company. It is a triple hormone receptor agonist on the GLP-1, GIP, and glucagon receptors.[2][3][4]

Adverse effects

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The safety profile of retatrutide is still under investigation. Reported side effects have been gastrointestinal symptoms, such as nausea, vomiting, diarrhea, constipation, and abdominal discomfort. An increase in side effects occurred with increased dosages. Less commonly reported side effects have included fatigue, headaches, and mild increases to heart rate. All drugs targeting GLP-1 receptors currently have the potential risk for pancreatitis, gallbladder disease, and gastrointestinal intolerance. These effects have not been linked to retatrutide in current trials. However, long-term outcomes of side effects are still being established.[5]

Mechanism of action

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GLP-1 receptors improve insulin sensitivity and increase satiety. Retatrutide has shown to increase insulin secretion. Furthermore, agonism of the glucagon receptor increases energy expenditure and promotes fat loss and metabolic activity. With current research, activation of these receptors has overall reduced caloric intake and increased energy expenditure, successfully leading to higher weight loss compared to alternative treatments.[2]

Chemistry

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Retatrutide is a peptide with the following amino acid sequence[6]

YA¹QGTFTSDYSIL²LDKK⁴AQA¹AFIEYLLEGGPSSGAPPPS³

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

  • A¹ – 2-aminoisobutyric acid (Aib).
  • L² – leucine modified with an α-methyl substituent (MeL, 2-methylleucine).
  • S³ – L-serinamide (L-serine with the carboxylic acid group replaced with a carboxamide).
  • K⁴ – 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).

Retatrutide is synthetically engineered and produced using solid-phase peptide synthesis (SPPS). This is when amino acids are added to a peptide chain and attached to solid resin forming a backbone. After the backbone is synthesized, the molecule is cleaved chemically, then purified. Lipidation modifications also occur, meaning a fatty-acid side chain is added to promote reversible binding to albumin. This modification allows for a longer drug half-life, raising compliance as it enables once-weekly dosing.[2]

History

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Clinical trials

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Retatrutide was initially studied in a phase II trial involving adults without diabetes who had obesity or overweight. Phase III trials are being conducted as part of the TRIUMPH clinical development program. In September 2026, results from two phase III trials were published. In the 80-week TRIUMPH-1 randomized trial of 2,339 adults with obesity without diabetes, mean body-weight reductions were 17.6%, 23.7%, and 25.0% with weekly retatrutide doses of 4 mg, 9 mg, and 12 mg, respectively, compared with 3.9% with placebo. The trial also reported reductions in knee-osteoarthritis pain and the severity of obstructive sleep apnea.[7] In TRIUMPH-2, retatrutide was studied in adults with obesity or overweight and type 2 diabetes, with the phase III trial reporting reductions in both body weight and glycated hemoglobin levels.[8]

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.[2]

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]

Society and culture

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Multiple black market sellers of the peptide emerged before approval of the Lilly drug, leading to multiple lawsuits with Lilly as the plaintiff.[1][15]

Research

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Retatrutide is under preliminary research for how it may influence obesity-associated cancer progression.[16]

See also

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References

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  1. 1 2 Robin Respaut (12 August 2026). "Lilly sues six companies over alleged illegal sales of experimental obesity drug retatrutide". Reuters. Retrieved 27 August 2026.
  2. 1 2 3 4 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ "Retatrutide". Compound Report Card. European Bioinformatics Institute, European Molecular Biology Laboratory. n.d. Retrieved August 5, 2024.
  7. ↑ Jastreboff AM, Kaplan LM, Davies MJ, Wilding JP, et al. (29 September 2026). "Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity". New England Journal of Medicine. doi:10.1056/NEJMoa2604169. PMID 42814954.
  8. ↑ Bellido V, le Roux CW, Ekinci EI, Bjornstad P, Frias JP, et al. (29 September 2026). "Retatrutide in adults with obesity and type 2 diabetes (TRIUMPH-2): a double-blind, parallel-group, randomised, placebo-controlled, phase 3 trial". The Lancet. doi:10.1016/S0140-6736(26)01861-1. PMID 42810372.
  9. ↑ "Compound: RETATRUTIDE (CHEMBL5095485)". www.ebi.ac.uk. Retrieved 2026-08-25.
  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. ↑ Berger E (August 31, 2026). "'Who knows what they're taking?': people risk the gray market for the newest weight-loss drug". The Guardian. Retrieved August 31, 2026.
  16. ↑ Marathe SJ, Grey EW, Bohm MS, Joseph SC, Ramesh AV, Cottam MA, et al. (2025-03-14). "Incretin triple agonist retatrutide (LY3437943) alleviates obesity-associated cancer progression". npj Metabolic Health and Disease. 3 (1) 10. doi:10.1038/s44324-025-00054-5. PMC 11908972. PMID 40094000.

Further reading

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