What is Retatrutide?
Retatrutide (LY3437943) is a first-in-class 39-amino acid synthetic peptide developed by Eli Lilly and Company as a triple agonist targeting three key metabolic hormone receptors: the glucagon receptor (GCGR), the glucose-dependent insulinotropic polypeptide receptor (GIPR), and the glucagon-like peptide-1 receptor (GLP-1R). With a molecular weight of 4731.33 g/mol and CAS registry number 2381089-83-2, it represents the most advanced multi-receptor metabolic peptide in clinical development.
The peptide is built on a GIP backbone and incorporates three non-coded amino acid residues that optimize its pharmacological profile: aminoisobutyric acid (Aib) at positions 2 and 20, which confer DPP-4 resistance and contribute to GIP activity; and α-methyl-L-leucine (αMeL) at position 13, which contributes to both GIP and glucagon receptor activity. A C-20 fatty diacid moiety is conjugated at lysine-17 via a γ-glutamic acid and AEEA linker, enabling albumin binding for once-weekly pharmacokinetics.
In vitro binding studies demonstrate potent balanced activity: EC₅₀ values of 0.0643 nM (GIPR), 0.775 nM (GLP-1R), and 5.79 nM (GCGR) for human receptors. This triple receptor engagement enables a coordinated metabolic response — insulin secretion and appetite suppression (via GLP-1R and GIPR) combined with enhanced energy expenditure, fat oxidation, and hepatic lipid reduction (via GCGR). Retatrutide is available at AminoCore Research exclusively for laboratory and scientific investigation.
Mechanism of Action
Retatrutide's pharmacology is uniquely defined by its simultaneous activation of three metabolic hormone receptors, producing coordinated effects across multiple organ systems.
GLP-1 Receptor Activation
Through GLP-1R agonism, retatrutide stimulates glucose-dependent insulin secretion, suppresses glucagon in a glucose-dependent manner, delays gastric emptying, and activates central satiety pathways in the hypothalamus and brainstem. These effects reduce food intake, lower postprandial glucose, and promote weight loss through appetite regulation.
GIP Receptor Activation
GIPR activation enhances the insulinotropic response to meals and may influence adipose tissue biology. Preclinical evidence suggests GIP receptor signaling in adipocytes improves insulin sensitivity and lipid storage, while central GIP receptor activation may contribute to appetite regulation. The high GIPR potency (EC₅₀ 0.0643 nM) is a distinguishing feature of retatrutide.
Glucagon Receptor Activation — The Third Axis
The addition of glucagon receptor agonism distinguishes retatrutide from both single (GLP-1) and dual (GIP/GLP-1) receptor agonists. Glucagon receptor activation in the liver promotes glycogenolysis and gluconeogenesis acutely, but chronically stimulates hepatic fatty acid oxidation, ketogenesis, and energy expenditure. In adipose tissue, glucagon signaling promotes lipolysis and thermogenesis. In preclinical models, glucagon receptor activation has been shown to increase resting energy expenditure by 15-20%.
Coordinated Multi-Receptor Signaling
The balanced triple agonism creates a self-compensating metabolic system: GLP-1R and GIPR effects on insulin secretion counterbalance the hyperglycemic potential of glucagon receptor activation, while GCGR-driven increases in energy expenditure and fat oxidation amplify the weight loss achieved through appetite suppression. This coordinated approach may explain the unprecedented magnitude of weight loss observed in phase 2 clinical data.
Research & Clinical Studies
Phase 2 Trial: Body Weight and Obesity Research
Jastreboff et al. published the results of a pivotal phase 2, randomized, double-blind, placebo-controlled, dose-finding study of retatrutide in adults with obesity in the New England Journal of Medicine in 2023. The trial enrolled 338 adults without diabetes with BMI ≥30, or ≥27 with at least one weight-related comorbidity.
Participants were randomized to subcutaneous retatrutide at escalating dose levels (1 mg, 4 mg, 8 mg, or 12 mg once weekly) with different titration schedules, or placebo, for 48 weeks. The primary endpoint was percentage change in body weight from baseline to week 24.
The results demonstrated dose-dependent and unprecedented weight loss: at 48 weeks, mean body weight reductions were −8.7% (1 mg), −17.1% (4 mg), −22.8% (8 mg), and −24.2% (12 mg), compared to −2.1% with placebo. At the highest dose, 26% of participants achieved ≥30% body weight loss — a magnitude previously only achievable with bariatric surgery.
The weight loss trajectory had not plateaued at 48 weeks, suggesting that longer treatment duration might produce even greater reductions. Safety was consistent with the incretin class, with gastrointestinal events (nausea, diarrhea, vomiting) being the most common adverse effects, generally mild-to-moderate and diminishing over time.
[1] Jastreboff AM, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526. PubMed ↗
Phase 2 Trial: Glycemic Control in Type 2 Diabetes
Rosenstock et al. reported results of a phase 2 study evaluating retatrutide in adults with type 2 diabetes, published in the Lancet in 2023. The trial enrolled 281 adults with type 2 diabetes inadequately controlled with metformin alone, randomized to retatrutide (0.5 mg, 4 mg escalating to 8 mg, 4 mg escalating to 12 mg) or placebo for 36 weeks.
Retatrutide demonstrated potent and dose-dependent glycemic control: HbA1c reductions from baseline were −0.43% (0.5 mg), −1.39% (8 mg), and −1.46% (12 mg), compared to −0.01% with placebo. The proportion of participants achieving HbA1c <7.0% was 71% and 75% in the 8 mg and 12 mg groups, compared to 8% with placebo.
Concurrent weight loss was substantial: mean body weight reductions of −3.19% (0.5 mg), −7.92% (8 mg), and −10.37% (12 mg) at 36 weeks. Improvements in fasting glucose, fasting insulin, and HOMA-IR were observed across all active treatment groups.
The study also included a body composition substudy using dual-energy X-ray absorptiometry (DXA). Results showed that retatrutide predominantly reduced fat mass rather than lean mass, with a favorable fat-to-lean mass loss ratio. Total body fat mass reductions were significant, while lean body mass was relatively preserved — an important finding for metabolic health.
[2] Rosenstock J, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-comparator-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet. 2023;402(10401):529-544. PubMed ↗
Discovery and Preclinical Characterization
Coskun et al. published the discovery and preclinical characterization of retatrutide (LY3437943) in Cell Metabolism in 2022, detailing the rational design process and the in vitro and in vivo pharmacology that supported clinical development.
The research team systematically evaluated triple receptor agonist candidates using structure-activity relationship (SAR) studies, optimizing the peptide backbone for balanced activity across GCGR, GIPR, and GLP-1R. The final molecule demonstrated potent in vitro activity at all three human receptors, with EC₅₀ values of 5.79 nM (GCGR), 0.0643 nM (GIPR), and 0.775 nM (GLP-1R).
In diet-induced obese (DIO) mouse models, retatrutide produced significantly greater weight loss than matched doses of dual GIP/GLP-1 receptor agonists or selective GLP-1 receptor agonists. The additional glucagon receptor component contributed to increased energy expenditure, enhanced hepatic lipid oxidation, and reductions in liver fat content. Metabolomic profiling revealed that retatrutide produced distinct metabolite signature changes — including amino acid, lipid, and bile acid profiles — that differed from those produced by single or dual receptor agonists, indicating a unique metabolic mechanism.
The phase 1 clinical proof-of-concept study in 72 healthy participants confirmed pharmacokinetic suitability for once-weekly dosing and demonstrated dose-dependent reductions in body weight and improvements in metabolic parameters.
[3] Coskun T, et al. 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 Metab. 2022;34(9):1234-1247.e9. PubMed ↗
Research on Hepatic Lipid Metabolism
Emerging research has highlighted retatrutide's potential impact on hepatic lipid metabolism, an area of significant scientific interest given the global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD/NASH).
The glucagon receptor component of retatrutide is hypothesized to drive hepatic effects through multiple mechanisms: activation of hepatic fatty acid oxidation via upregulation of carnitine palmitoyltransferase 1 (CPT1), stimulation of ketogenesis, and reduction of de novo lipogenesis. In preclinical DIO mouse models, retatrutide produced greater reductions in liver triglyceride content compared to dual GIP/GLP-1 agonists, supporting the hypothesis that glucagon receptor activation provides additive hepatic benefit.
In the phase 2 clinical trial, post hoc analyses revealed significant reductions in alanine aminotransferase (ALT) levels — a biomarker of hepatic inflammation and steatosis — across retatrutide dose groups. These biochemical improvements, combined with the substantial weight loss and insulin sensitization, suggest favorable effects on hepatic fat content.
A dedicated phase 2 trial (NCT04881706) has been initiated to specifically evaluate retatrutide in patients with biopsy-confirmed MASH, with histological endpoints. Preclinical data suggest that the triple receptor mechanism may address multiple pathogenic pathways simultaneously: GLP-1R and GIPR activation reduce insulin resistance and nutrient influx, while GCGR activation directly enhances hepatic lipid disposal.
[4] Coskun T, et al. 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 Metab. 2022;34(9):1234-1247.e9. PubMed ↗
[5] Jastreboff AM, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526. PubMed ↗
Preclinical Research: Obesity-Associated Cancer Pathways
An emerging area of retatrutide research involves its potential influence on obesity-associated cancer progression. Marathe et al. published preclinical findings in NPJ Metabolic Health and Disease (2025) demonstrating that retatrutide-induced weight loss affected tumor biology in mouse models of pancreatic and lung cancer.
In diet-induced obese mice with implanted tumors, retatrutide treatment produced several notable observations: reduced tumor engraftment rates, delayed tumor onset, and significant attenuation of tumor growth compared to vehicle-treated controls. The study compared retatrutide to semaglutide (a selective GLP-1 receptor agonist) and found that retatrutide produced greater tumor suppression, suggesting that the triple receptor mechanism may provide additive anti-tumor effects beyond those achieved by weight loss alone.
Notably, the anti-tumor effects persisted even when mice experienced partial weight regain after treatment cessation, suggesting durable systemic and tumor microenvironment immune reprogramming. Immunological analyses revealed changes in tumor-infiltrating immune cell populations, including increased CD45+ immune cell infiltration, suggesting enhanced anti-tumor immune surveillance.
These findings are preliminary and preclinical, requiring validation in human studies. However, they raise important questions about the relationship between metabolic hormone signaling, body composition, and cancer biology — areas of active investigation in the obesity research community.
[6] Marathe CS, et al. Retatrutide-induced weight loss reduces tumor engraftment and attenuates tumor growth in pancreatic and lung cancer models. NPJ Metab Health Dis. 2025;3(1):10. PubMed ↗
Handling & Reconstitution Guidelines
Reconstitution Protocol
Retatrutide lyophilized powder should be reconstituted using sterile bacteriostatic water (BAC water) or sterile phosphate-buffered saline (PBS, pH 7.4). Allow the vial to reach room temperature (15-25°C) before opening. Inject the diluent slowly along the inner wall of the vial using a sterile syringe. Avoid directly streaming liquid onto the lyophilized cake. Gently swirl the vial until contents are fully dissolved. Do not vortex or shake vigorously. The resulting solution should be clear and free of visible particulates.
Recommended Diluent Volumes
For a 3 mg vial: 0.6 mL BAC water yields a 5 mg/mL concentration. For a 5 mg vial: 1.0 mL BAC water yields a 5 mg/mL concentration. For a 10 mg vial: 2.0 mL BAC water yields a 5 mg/mL concentration. Adjust volumes to achieve desired concentration for specific experimental protocols.
Post-Reconstitution Storage
Store reconstituted retatrutide at 2-8°C (refrigerated) and use within 28 days. For longer-term storage, prepare single-use aliquots in sterile low-bind polypropylene microcentrifuge tubes and store at -20°C. Avoid repeated freeze-thaw cycles as they may progressively compromise peptide activity.
Handling Precautions
Handle with appropriate PPE including nitrile gloves and safety glasses. Work under clean, aseptic conditions. The C-20 fatty diacid moiety increases the peptide's hydrophobicity and surface adsorption — use low-protein-binding labware (tubes, tips, filters) for quantitative experiments. Maintain reconstituted solutions near physiological pH (6.5-7.5) for optimal stability.
Storage & Stability Information
Lyophilized Form (Unreconstituted)
Store retatrutide lyophilized powder at -20°C in its original sealed container, protected from light and moisture. Under these conditions, the peptide maintains stability and purity for up to 24 months. Short-term storage at 2-8°C is acceptable for up to 60 days. Avoid exposure to temperatures exceeding 25°C for extended periods.
Reconstituted Solution
Store reconstituted retatrutide at 2-8°C and use within 28 days. For extended preservation, prepare aliquots in sterile low-bind microcentrifuge tubes and freeze at -20°C for up to 3 months. Minimize freeze-thaw cycles to maintain peptide integrity and biological potency.
Stability Considerations
Retatrutide's three non-coded amino acid residues (Aib2, αMeL13, Aib20) and C-20 fatty diacid conjugation provide enhanced metabolic stability compared to native incretin peptides. The Aib residues at positions 2 and 20 confer DPP-4 resistance, while the fatty diacid enables albumin binding that shields against renal filtration and proteolysis in circulation. Despite these stabilizing modifications, standard peptide handling best practices should be followed in the laboratory. Monitor reconstituted solutions for precipitation, turbidity, or color changes.
Shipping
Retatrutide is shipped as a lyophilized powder with cold packs to maintain integrity during transit. Upon receipt, inspect packaging for damage and immediately transfer to -20°C storage. A Certificate of Analysis (COA) is included with each shipment documenting purity and identity.
