Retatrutide: Safety Profile & Research Summary
17 PubMed CitationsExpert ReviewedGMP CertifiedLast Reviewed: February 2026
Preclinical & Clinical Research Summary
Key Preclinical (Animal) Studies
| Study | Model | Key Findings | Ref |
|---|---|---|---|
| Coskun et al. (2022) Cell Metabolism | DIO C57/Bl6 mice; 10 nmol/kg daily SC | 36.9% body weight loss (vs. 21.2% tirzepatide); 86.8% fat mass reduction; improved blood glucose, insulin, ALT, liver triglycerides; engages all three receptors in vivo | [4] |
| Urva et al. (2023) Diabetes Obes. Metab. | C57/Bl6 obese mice; 10 nmol/kg SC | Dose-dependent gastric emptying delay; chronic treatment attenuated GI slowing (tachyphylaxis); superior weight/food intake reduction vs. semaglutide alone | [17] |
| Ma et al. (2025) Endocrine | Diabetic db/db mice; 10 nmol/kg daily SC, 10 weeks | Superior efficacy over liraglutide and tirzepatide in reducing ALT, AST, cholesterol, triglycerides, LDL; mitigated inflammatory and fibrotic processes in diabetic kidney | [15] |
| Marathe et al. (2025) NPJ Metab. Health Dis. | Pancreatic and lung cancer models in obese mice | Reduced tumor engraftment; delayed tumor onset; greater tumor suppression than semaglutide; durable antitumor effects despite partial weight regain | [14] |
Key Clinical (Human) Studies
| Study | Population / Design | Key Results | Ref |
|---|---|---|---|
| Urva et al. (2022) Lancet (Phase 1b) | T2D patients; MAD, 0.5–12 mg SC weekly; RCT | Dose-dependent HbA1c and weight reductions; t1/2 ~6 days confirmed; GI AEs dose-related; well-tolerated overall | [8] |
| Jastreboff et al. (2023) NEJM (Phase 2) | Adults with obesity (no T2D); 1, 4, 8, 12 mg SC weekly; 48 wks; RCT | -24.2% mean weight loss (12 mg); dose-dependent; not plateaued at 48 wks; GI AEs most common | [1] |
| Rosenstock et al. (2023) Lancet (Phase 2) | Adults with T2D; 0.5–12 mg SC weekly; 36 wks; RCT | HbA1c -2.02% (12 mg); significant weight loss; improved insulin sensitivity; well-tolerated | [2] |
| Sanyal et al. (2024) Nature Med. (Phase 2a) | MASLD substudy; MRI-PDFF assessed liver fat; 48 wks | >85% achieved liver fat normalization (<5%) at 8–12 mg doses; up to 86% relative liver fat reduction | [3] |
| TRIUMPH-4 (Phase 3, 2025) Eli Lilly Press Release | Obesity + knee OA; 9 & 12 mg SC weekly; 68 wks | Up to 28.7% mean weight loss; WOMAC pain scores improved by up to 75.8%; first successful Phase 3 trial | [5] |
Safety Profile Summary
| Category | Detail | Incidence / Notes |
|---|---|---|
| Common GI AEs | Nausea, diarrhea, vomiting, constipation, decreased appetite | Nausea up to 63% at highest doses; dose-dependent; most common during titration[12][13] |
| Skin Hyperesthesia | Increased skin sensitivity, dysesthesia, "skin pain" | Up to 7% (vs. 1% placebo) in Phase 2[10] |
| Heart Rate | Dose-dependent increase, peaking at 24 weeks before declining | Mild to moderate arrhythmias reported[10] |
| Serious AEs | Acute pancreatitis (single cases); gallbladder disease; hypotension | SAE rate similar to placebo (~4–5%)[12] |
| Hepatic Safety | No hepatotoxicity signals; transient ALT/AST elevations resolved | Monitored in all trials[12] |
Dosage Summary
| Setting | Dose | Route / Schedule | Notes |
|---|---|---|---|
| In Vitro (EC50) | 0.0643 nM (GIPR), 0.775 nM (GLP-1R), 5.79 nM (GCGR) | Cell culture | Biased toward GIP potency[4] |
| Animal (Mice) | 10 nmol/kg daily | SC injection | Standard efficacy dosing; t1/2 21 h in mice[4] |
| Phase 1 (SAD) | 0.1–6 mg (single dose) | SC injection | Safety/PK assessment[8] |
| Phase 2 (Maintenance) | 1, 4, 8, 12 mg | SC once weekly; titrated from 2 or 4 mg | Titration by 2–4 mg every 4 weeks[1][2] |
| Phase 3 (TRIUMPH) | Target doses: 9 mg and 12 mg | SC once weekly; initiated at 2 mg | Ongoing registrational trials[5] |
Pharmacokinetic Profile
| Parameter | Value | Notes |
|---|---|---|
| Half-life (Human) | ~6 days | Supports once-weekly dosing[8] |
| Half-life (Mouse) | ~21 hours | Single 47 μg/kg dose[4] |
| Tmax | 12–72 hours | Post-SC dose in humans |
| Metabolism | Hepatic proteolysis; fatty acid β-oxidation | No CYP450 interaction |
| Clearance (Mouse) | 11.22 mL/h/kg | CD-1 mice |
&x26A0;️ Important Disclaimer
This product is sold strictly for in-vitro research and laboratory use only. It is not approved by the FDA for human consumption, medical use, diagnostic use, or veterinary use. Bodily introduction of any kind into humans or animals is strictly forbidden by law. All products are supplied as research chemicals only. The information provided here is compiled from peer-reviewed scientific literature and is intended solely for educational and informational purposes.
About This Research Profile
This research profile was compiled from peer-reviewed sources including publications in the New England Journal of Medicine, The Lancet, Nature Medicine, Cell Metabolism, and other high-impact journals. All citations reference publicly available scientific literature. The profile is regularly reviewed and updated to reflect the latest research findings. Last reviewed: February 2026.
References
- Jastreboff AM, Kaplan LM, Frias JP, Wu Q, Du Y, Gurbuz S, Coskun T, Haupt A, Milicevic Z, Hartman ML. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. New England Journal of Medicine, 389(6), 514-526, 2023.
- Rosenstock J, Frias J, Jastreboff AM, Du Y, Lou J, Gurbuz S, Thomas MK, Hartman ML, Haupt A, Milicevic Z, Coskun T. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet, 402(10401), 529-544, 2023.
- Sanyal AJ, Kaplan LM, Frias JP, Brouwers B, Wu Q, Thomas MK, Harris C, Schloot NC, Du Y, Mather KJ, Haupt A, Hartman ML. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nature Medicine, 30(7), 2037-2048, 2024.
- Coskun T, Urva S, Roell WC, Qu H, Loghin C, Moyers JS, O'Farrell LS, Briere DA, Sloop KW, Thomas MK, Pirro V, Wainscott DB, Willard FS, Abernathy M, Morford L, Du Y, Benson C, Gimeno RE, Haupt A, Milicevic Z. 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, 2022.
- Giblin K, Kaplan LM, Somers VK, Le Roux CW, Hunter DJ, Wu Q, Lalonde A, Ahmad N, Bethel MA. Retatrutide for the treatment of obesity, obstructive sleep apnea and knee osteoarthritis: Rationale and design of the TRIUMPH registrational clinical trials. Diabetes, Obesity and Metabolism, 28(1), 83-93, 2026.
- Coskun T, Wu Q, Schloot NC, Haupt A, Milicevic Z, Khouli C, Harris C. 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, 2025.
- Heerspink HJL, Lu Z, Du Y, Duffin KL, Coskun T, Haupt A, Hartman ML. The Effect of Retatrutide on Kidney Parameters in Participants With Type 2 Diabetes Mellitus and/or Obesity. Kidney International Reports, 10(6), 1980-1992, 2025.
- Urva S, Coskun T, Loh MT, Du Y, Thomas MK, Gurbuz S, Haupt A, Benson CT, Hernandez-Illas M, D'Alessio DA, Milicevic Z. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial. Lancet, 400(10366), 1869-1881, 2022.
- Heerspink HJL, van Raalte DH, Bjornstad P, Bunck MC, Wu P, Tunali I, Milicevic Z, Koeneman L. Rationale, design and baseline characteristics of the TRANSCEND-CKD trial of retatrutide in patients with chronic kidney disease. Nephrology Dialysis Transplantation, gfaf230, 2025.
- Katsi V, Koutsopoulos G, Fragoulis C, Dimitriadis K, Tsioufis K. Retatrutide - A Game Changer in Obesity Pharmacotherapy. Biomolecules, 15(6), 796, 2025.
- Abdul-Rahman T, Roy P, Ahmed FK, Mueller-Gomez JL, Sarkar S, Garg N, Femi-Lawal VO, Wireko AA, Thaalibi HI, Hashmi MU, Dzebu AS, Banimusa SB, Sood A. The power of three: Retatrutide's role in modern obesity and diabetes therapy. European Journal of Pharmacology, 985, 177095, 2024.
- Maharshi V, Singh S, Manjhi PK, Singh SK, Kumar A, Kumar R. Navigating retatrutide safety: comprehensive insights from systematic review and meta-analysis. Journal of Public Health and Development, 24(1), 318-338, 2026.
- Abouelmagd AA, Abdelrehim AM, Bashir MN, Abdelsalam F, Marey A, Tanas Y, Abuklish DM, Belal MM. 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 (Baylor University Medical Center), 38(3), 291-303, 2025.
- Marathe SJ, Grey EW, Bohm MS, Joseph SC, Ramesh AV, Cottam MA, et al. Incretin triple agonist retatrutide (LY3437943) alleviates obesity-associated cancer progression. NPJ Metabolic Health and Disease, 3(1), 10, 2025.
- Ma J, Hu X, Zhang W, Tao M, Wang M, Lu W. Comparison of the effects of Liraglutide, Tirzepatide, and Retatrutide on diabetic kidney disease in db/db mice. Endocrine, 87(1), 159-169, 2025.
- Tewari J, Qidwai KA, Tewari A, Kaur S, Tewari V, Maheshwari A. 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.
- Urva S, O'Farrell L, Du Y, Loh MT, Hemmingway A, Qu H, Alsina-Fernandez J, Haupt A, Milicevic Z, Coskun T. The novel GIP, GLP-1 and glucagon receptor agonist retatrutide delays gastric emptying. Diabetes, Obesity and Metabolism, 25(11), 2784-2788, 2023.
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