Chemistry:Retatrutide

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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]

Mechanism of action

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.[1]

Adverse effects

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.[4]

Clinical trials

Retatrutide has been studied in a phase 2 trial involving adults without diabetes but with obesity or preobesity (overweight).[5][6][4] 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]

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:

  • 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.[1]

Research

Preclinical studies suggest that retatrutide may influence obesity-associated cancer progression. In a study led by Marathe et al., retatrutide-induced weight loss reduced tumor engraftment, delayed tumor onset, and significantly attenuated tumor growth in pancreatic and lung cancer models, with greater tumor suppression than the GLP-1 receptor agonist semaglutide; antitumor effects persisted despite partial weight regain and were associated with durable systemic and tumor immune reprogramming.[16]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 "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. September 2022. doi:10.1016/j.cmet.2022.07.013. PMID 35985340. 
  2. ↑ "Efficacy and safety of incretin co-agonists: Transformative advances in cardiometabolic healthcare". World Journal of Cardiology 17 (8). August 2025. doi:10.4330/wjc.v17.i8.107991. PMID 40949933. 
  3. ↑ "Efficacy and safety of anti-obesity drugs in metabolic dysfunction-associated steatotic liver disease: An updated review". World Journal of Gastroenterology 31 (37). October 2025. doi:10.3748/wjg.v31.i37.111435. PMID 41025003. 
  4. ↑ 4.0 4.1 "Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial". The New England Journal of Medicine 389 (6): 514–526. August 2023. doi:10.1056/NEJMoa2301972. PMID 37366315. 
  5. ↑ "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.
  6. ↑ "Eli Lilly experimental obesity drug could beat rivals in total weight loss for patients". CNBC.com. 26 June 2023. https://www.cnbc.com/2023/06/26/eli-lilly-obesity-drug-helped-patients-lose-weight.html. 
  7. ↑ "A Study of Retatrutide (LY3437943) in Participants With Obesity and Cardiovascular Disease (TRIUMPH-3) - Lilly Clinical Trials" (in en-US). https://trials.lilly.com/en-US/trial/405675. 
  8. ↑ "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. August 2025. doi:10.1016/S2213-8587(25)00092-0. PMID 40609566. 
  9. ↑ "Compound: RETATRUTIDE (CHEMBL5095485)". https://www.ebi.ac.uk/explore/compound/CHEMBL5095485. 
  10. ↑ 10.0 10.1 "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. 2025. doi:10.1080/17512433.2025.2450254. PMID 39817343. 
  11. ↑ 11.0 11.1 "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. 2025. doi:10.1080/08998280.2025.2456441. PMID 40291085. 
  12. ↑ 12.0 12.1 "Retatrutide-A Game Changer in Obesity Pharmacotherapy". Biomolecules 15 (6): 796. May 2025. doi:10.3390/biom15060796. PMID 40563436. 
  13. ↑ 13.0 13.1 "Efficacy of Tirzepatide, Retatrutide, and Semaglutide for Weight Loss in Obese Individuals Without Diabetes". Academic Emergency Medicine 32 (11): 1255–1258. November 2025. doi:10.1111/acem.70088. PMID 40583149. 
  14. ↑ 14.0 14.1 "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. November 2025. doi:10.1002/oby.24360. PMID 40685589. 
  15. ↑ "Retatrutide". Compound Report Card. European Bioinformatics Institute, European Molecular Biology Laboratory. n.d.. https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL5095485/. 
  16. ↑ "Incretin triple agonist retatrutide (LY3437943) alleviates obesity-associated cancer progression". npj Metabolic Health and Disease 3 (1). 2025-03-14. doi:10.1038/s44324-025-00054-5. PMID 40094000. 

Further reading



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