Product description
What is retatrutide?
Retatrutide (LY3437943) is an innovative research peptide representing a new generation of incretin compounds. It is a first-in-class triple hormone receptor agonist that simultaneously activates three key metabolic pathways: GIP (glucose-dependent insulinotropic peptide) receptor, GLP-1 (glucagon-like peptide 1) receptor and glucagon receptor.
This synthetic peptide consists of 39 amino acids and was designed based on the GIP peptide skeleton. Thanks to the conjugation with the C20 fatty acid moiety, retatrutide is characterized by an extended half-life of approximately 6 days, which is the subject of intensive research on the optimization of the pharmacokinetics of metabolic peptides.
Mechanism of action
Retatrutide is distinguished by a unique pharmacological profile combining three mechanisms of action:
GLP-1 receptor activation - a mechanism known from the action of semaglutide (Ozempic, Wegovy), associated with the regulation of glucose-dependent insulin secretion and modulation of satiety centers in the central nervous system.
GIP receptor activation – retatrutide has the strongest activity towards this receptor, which distinguishes it from other peptides of this class, including tirzepatide (Mounjaro). GIP interacts with GLP-1 in the regulation of glucose and lipid metabolism.
Glucagon receptor activation – the third, unique component of the mechanism. The liver, rich in glucagon receptors, is the direct target of action, which is the subject of research on hepatic lipid metabolism and energy expenditure.
Directions of scientific research
Retatrutide is currently the subject of intensive clinical trials conducted by Eli Lilly. Major research areas include:
Body weight and body composition research
Significant changes in participants' weight were observed in published Phase II studies. Body composition tests (DXA method) analyze the proportions of fat tissue reduction in relation to fat-free mass, which is an important parameter in assessing the quality of metabolic changes.
Glucose metabolism research
Studies are being conducted to assess the effect of retatrutide on glycemic parameters, including HbA1c levels, fasting glucose and insulin secretion. Comparative studies with dulaglutide provide data on the relative effectiveness of different classes of incretin agonists.
Liver tests (MASLD/MASH)
The effect of retatrutide on liver fat is of particular interest. A phase IIa MRI substudy analyzed changes in hepatic steatosis. Activation of the glucagon receptor, of which the liver is the primary site of expression, is a unique aspect of the mechanism of action studied in the context of metabolic liver diseases.
Cardiometabolic tests
The research program includes the assessment of the effect on the lipid profile (total cholesterol, LDL, triglycerides), blood pressure and waist circumference. The ongoing TRIUMPH-OUTCOMES trial is assessing long-term cardiovascular outcomes.
Nephrology tests
Post hoc analyzes of phase II studies showed changes in urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). The dedicated TRANSCEND-CKD study examines the mechanisms of action of retatrutide in people with chronic kidney disease.
Research on obesity complications
The TRIUMPH program includes research protocols for obstructive sleep apnea (AHI measurement) and knee osteoarthritis (WOMAC scale).
Scientific context
Retatrutide is part of the dynamically developing field of incretin peptides. It is an evolution from single GLP-1 agonists (such as semaglutide, used in Ozempic and Wegovy) and dual GIP/GLP-1 agonists (tirzepatide, known as Mounjaro and Zepbound). The addition of the third component - glucagon receptor agonism - opens up new research opportunities in the field of energy and hepatic metabolism.
Preclinical studies in animal models have demonstrated the ability of retatrutide to delay gastric emptying, reduce food intake and modulate energy expenditure. These observations provide a basis for further translational research.
Research safety profile
In published clinical trials, the most frequently reported adverse events were of a gastrointestinal nature (nausea, vomiting, diarrhea, constipation) and were comparable to the profile of other incretin agonists. The event rate was dose-related and highest during the dose escalation period.
Bibliography - latest scientific research
- Jastreboff AM, Kaplan LM, Frías JP, et al. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med2023;389:514-526. PubMed
- Rosenstock J, Frias J, Jastreboff AM, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomized, double-blind, placebo and active-controlled, parallel-group, phase 2 trial. Lancet 2023;402(10401):529-544. PubMed
- Sanyal AJ, Kaplan LM, Frias JP, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med 2024;30(7):2037-2048. PubMed
- Coskun T, Wu Q, Schloot NC, et al. Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, double-blind, parallel-group, placebo-controlled, randomized trial. Lancet Diabetes Endocrinol. 2025;13(8):674-684. PubMed
- Heerspink HJL, Lu Z, Du Y, et al. The Effect of Retatrutide on Kidney Parameters in Participants With Type 2 Diabetes Mellitus and/or Obesity. Kidney Int Rep 2025;10(6):1980-1992. PubMed
- Giblin K, Kaplan LM, Somers VK, et al. Retatrutide for the treatment of obesity, obstructive sleep apnea and knee osteoarthritis: Rationale and design of the TRIUMPH registrational clinical trials. Diabetes Obes Metab. 2026;28(1):83-93. PubMed
- Heerspink HJL, van Raalte DH, Bjornstad P, et al. Rationale, design and baseline characteristics of the TRANSCEND-CKD trial of retatrutide in patients with chronic kidney disease. Nephrol Dial Transplant. 2025;gfaf230. Oxford Academic
- Misra S, Narayan RK, Kaur M. Efficacy and safety of retatrutide for the treatment of obesity: a systematic review of clinical trials. J Basic Clin Physiol Pharmacol. 2025;36(4):263-274. PubMed
- Fathy WM, et al. 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. Proc (Bayl Univ Med Cent). 2025;38(2):205-212. PubMed
- Cuevas-Ramos D, Mehta R. Triple Agonism Based Therapies for Obesity. Curr Diab Rep 2025;25(1):47. PMC
