≥98%HPLC Purity
COAIncluded
USAShipped
Retatrutide (LY3437943) Peptide
First-in-class triple hormone receptor agonist targeting GLP-1, GIP, and glucagon receptors simultaneously. 39-amino acid peptide with once-weekly pharmacokinetics. Phase 2 trials demonstrated up to 24.2% body weight reduction — the highest reported for any single anti-obesity compound.
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| SKU | AC-RETA |
|---|---|
| CAS Number | 2381089-83-2 |
| Molecular Formula | C221H342N46O68 |
| Molecular Weight | 4731.33 g/mol |
| Sequence | Tyr-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-αMeLeu-Leu-Asp-Lys-Lys(C20 diacid-γGlu-AEEA)-Ala-Gln-Aib-Ala-Phe-Ile-Glu-Tyr-Leu-Leu-Glu-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 |
| Purity | ≥98% |
| Physical Form | Lyophilized Powder |
| Storage | Store at -20°C |
What is Retatrutide?
Retatrutide (LY3437943) is a first-in-class 39-amino acid synthetic peptide developed by Eli Lilly as a triple agonist targeting three metabolic hormone receptors simultaneously: the glucagon-like peptide-1 receptor (GLP-1R), the glucose-dependent insulinotropic polypeptide receptor (GIPR), and the glucagon receptor (GCGR). With a molecular weight of 4,731.33 g/mol and CAS number 2381089-83-2, it represents the most advanced multi-receptor metabolic peptide in clinical development.
The peptide is constructed on a GIP backbone with three non-coded amino acid modifications: aminoisobutyric acid (Aib) at positions 2 and 20 for DPP-4 resistance, and α-methyl-L-leucine (αMeLeu) at position 13 contributing to both GIP and glucagon receptor activity. A C-20 fatty diacid moiety conjugated at Lys-17 via γ-glutamic acid and AEEA linker enables albumin binding, providing 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 coordinates insulin secretion and appetite suppression (GLP-1R/GIPR) with enhanced energy expenditure, fat oxidation, and hepatic lipid reduction (GCGR).
Mechanism of Action
GLP-1 Receptor Activation (EC₅₀ 0.775 nM): Retatrutide activates GLP-1R on pancreatic beta cells (glucose-dependent insulin secretion), hypothalamic neurons (appetite suppression via POMC/CART activation), and vagal afferents (gastric emptying delay). This is the same pathway activated by semaglutide and liraglutide.
GIP Receptor Activation (EC₅₀ 0.0643 nM): GIPR agonism enhances the incretin effect beyond GLP-1 alone, amplifying post-prandial insulin secretion and potentially improving beta-cell function. GIPR activation also modulates lipid metabolism in adipose tissue. This dual incretin approach mirrors tirzepatide's mechanism.
Glucagon Receptor Activation (EC₅₀ 5.79 nM): GCGR agonism is unique to retatrutide among approved/pipeline anti-obesity peptides. Glucagon receptor activation increases hepatic energy expenditure via glycogenolysis and gluconeogenesis, stimulates thermogenesis in brown adipose tissue, enhances hepatic fatty acid oxidation, and reduces liver fat content. This third receptor provides the additional metabolic boost that distinguishes retatrutide from dual agonists.
Fatty Acid Conjugation: The C-20 fatty diacid at Lys-17 enables non-covalent albumin binding (>99% protein-bound), extending the plasma half-life to approximately 6 days and enabling once-weekly administration in research protocols.
Research & Clinical Studies
Phase 2 Trial: Body Weight Reduction in Obesity (2023)
The pivotal Phase 2 trial published in the New England Journal of Medicine (Jastreboff et al., 2023) enrolled 338 adults with obesity (BMI ≥30) or overweight (BMI ≥27) with at least one weight-related comorbidity. Participants were randomized to retatrutide 1, 4, 8, or 12 mg (with dose escalation) or placebo for 48 weeks.
Key Results:
- 12 mg dose: -24.2% body weight reduction at 48 weeks (mean change from baseline)
- 8 mg dose: -22.8% reduction
- 4 mg dose: -17.5% reduction
- Placebo: -2.1% reduction
- 100% of participants in the 12 mg group achieved ≥5% weight loss
- 93% achieved ≥10% weight loss
- 63% achieved ≥20% weight loss
The -24.2% reduction at 48 weeks was the largest reported for any single anti-obesity compound at the time of publication, surpassing tirzepatide (-20.9% at 72 weeks in SURMOUNT-1) despite a shorter treatment duration.
[1] Jastreboff AM, Kaplan LM, Frías JP, 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 (2023)
A parallel Phase 2 trial (Rosenstock et al., 2023, The Lancet) evaluated retatrutide in 281 adults with type 2 diabetes and BMI ≥25. Participants received retatrutide 0.5-12 mg or placebo for 36 weeks.
Key Results:
- HbA1c reduction of -2.02% at 12 mg (from baseline ~8.3%)
- 71% of the 12 mg group achieved HbA1c <7.0%
- 54% achieved HbA1c <6.5%
- Body weight reduction of -16.9% at 12 mg at 36 weeks
- Improvements in fasting glucose, lipid profile, and liver enzymes
Retatrutide demonstrated glycemic control comparable to tirzepatide while achieving weight loss at a faster rate, attributed to the additional glucagon receptor-mediated energy expenditure.
[1] Rosenstock J, Frias J, Jastreboff AM, 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. Lancet. 2023;402(10401):529-544. PubMed ↗
Phase 2 Research: Hepatic Lipid Metabolism (MASLD)
A sub-study of the Phase 2 obesity trial evaluated liver fat content using MRI-proton density fat fraction (MRI-PDFF). Results demonstrated dramatic hepatic fat reduction with retatrutide, attributed primarily to glucagon receptor-mediated enhancement of hepatic fatty acid oxidation.
Key Results:
- Liver fat reduction of -82.4% at the 12 mg dose (relative change)
- 81.8% of participants with baseline MASLD (≥5% liver fat) achieved resolution to <5%
- Improvements in ALT and AST liver enzymes across all dose groups
- Effect magnitude exceeded that seen with tirzepatide or semaglutide in NAFLD studies
The robust hepatic fat reduction is considered a direct consequence of the glucagon receptor component, as glucagon physiologically promotes hepatic lipid oxidation and ketogenesis. This positions retatrutide as a potential breakthrough compound for MASLD/NASH research.
[1] Gastaldelli A, Cusi K, Fernández Landó L, et al. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI substudy). Lancet Diabetes Endocrinol. 2022;10(6):393-406. PubMed ↗
[2] Jastreboff AM et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial (supplementary data). N Engl J Med. 2023;389(6):514-526. PubMed ↗
Discovery and Preclinical Characterization
Retatrutide was developed through rational peptide engineering starting from the native GIP(1-42) sequence. Key modifications were systematically introduced to achieve balanced triple agonism while maintaining metabolic stability:
- Aib² and Aib²⁰: α-aminoisobutyric acid substitutions conferring resistance to DPP-4 cleavage (the enzyme that rapidly degrades native GIP and GLP-1), extending plasma half-life
- αMeLeu¹³: α-methyl-L-leucine substitution enabling simultaneous GIP and glucagon receptor engagement
- C-20 fatty diacid at Lys¹⁷: Albumin-binding moiety via γ-Glu-AEEA linker, achieving >99% protein binding and ~6-day half-life
In preclinical models (diet-induced obese mice), retatrutide produced greater weight loss, improved glucose tolerance, and reduced hepatic steatosis compared to equi-effective doses of semaglutide or tirzepatide analogs, supporting the additive benefit of glucagon receptor activation.
[1] Coskun T, Urva S, Roell WC, 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. PubMed ↗
Preclinical Research: Metabolic Syndrome and Cardiovascular Markers
Across Phase 2 trials, retatrutide demonstrated broad metabolic improvements beyond weight loss and glycemic control:
- Systolic blood pressure: -6 to -9 mmHg reduction (12 mg groups)
- Triglycerides: -30 to -40% reduction
- LDL cholesterol: -10 to -15% reduction
- Waist circumference: -14 to -18 cm reduction
- C-reactive protein (CRP): Significant reduction, suggesting anti-inflammatory effects
These cardiometabolic improvements, combined with the robust hepatic fat reduction, suggest retatrutide addresses multiple components of metabolic syndrome simultaneously — a consequence of engaging three complementary metabolic pathways rather than one or two.
Chemical & Physical Properties
Retatrutide (LY3437943) is a 39-amino acid peptide with the following verified specifications:
| Molecular Formula | C₂₂₁H₃₄₂N₄₆O₆₈ |
|---|---|
| Molecular Weight | 4,731.33 g/mol |
| CAS Number | 2381089-83-2 |
| Sequence Length | 39 amino acids |
| Non-coded Residues | Aib² (DPP-4 resistance), Aib²⁰, αMeLeu¹³ (GCGR/GIPR activity) |
| Conjugation | C-20 fatty diacid at Lys¹⁷ via γ-Glu-AEEA linker |
| Protein Binding | >99% (albumin-bound) |
| Plasma Half-life | ~6 days (enables once-weekly dosing) |
| EC₅₀ (GIPR) | 0.0643 nM |
| EC₅₀ (GLP-1R) | 0.775 nM |
| EC₅₀ (GCGR) | 5.79 nM |
| Physical Form | White to off-white lyophilized powder |
| Solubility | Soluble in bacteriostatic water, PBS, and dilute acetic acid |
| Purity | ≥98% by HPLC |
Handling & Reconstitution Guidelines
Reconstitution Protocol:
- Allow the sealed retatrutide vial and bacteriostatic water (BAC water) to equilibrate to room temperature (15-25°C) for 10-15 minutes.
- Swab both vial stoppers with a sterile alcohol prep pad and allow to air dry.
- Using a sterile insulin syringe, withdraw the desired volume of BAC water.
- Insert the needle through the retatrutide vial stopper at a slight angle, directing the stream of water down the inside wall of the vial — never inject directly onto the lyophilized cake.
- Allow the vial to sit undisturbed for 5-10 minutes. The peptide should dissolve completely without agitation.
- If any material remains undissolved, gently roll the vial between your palms. Never shake or vortex — mechanical stress can denature the peptide.
- The reconstituted solution should be clear and colorless. Discard if cloudy or discolored.
Recommended Reconstitution Volume: For a 10 mg vial, 1 mL of BAC water yields a 10 mg/mL concentration. Adjust proportionally for other vial sizes.
Important: Retatrutide is a 39-amino acid peptide with a fatty acid conjugation. It is more sensitive to agitation than smaller peptides. Always handle gently and protect from light.
Storage & Stability Information
Lyophilized (unreconstituted):
- Long-term storage: -20°C (recommended) — stable for up to 24 months
- Short-term storage: 2-8°C — stable for up to 6 months
- Room temperature: Stable for up to 30 days (for shipping/transit)
- Protect from light and moisture at all times
Reconstituted:
- Store at 2-8°C (refrigerator) immediately after reconstitution
- Use within 21 days of reconstitution when stored properly
- Do not freeze reconstituted solution — ice crystal formation can damage the peptide structure
- Avoid repeated freeze-thaw cycles
- Protect from light — store in original vial or wrap in foil
Stability Notes: The fatty acid conjugation on retatrutide provides inherent stability through albumin binding in solution, but the free peptide in BAC water is still susceptible to oxidation (Met residues) and deamidation (Asn/Gln residues). Refrigeration and light protection maximize reconstituted shelf life.
Frequently Asked Questions
What is Retatrutide and how does it work?
Retatrutide (LY3437943) is a first-in-class triple hormone receptor agonist that simultaneously activates GLP-1, GIP, and glucagon receptors. The GLP-1 and GIP receptor activation provides incretin-based appetite suppression and insulin secretion, while the unique glucagon receptor activation adds enhanced energy expenditure, fat oxidation, and hepatic lipid reduction — a mechanism absent from semaglutide (GLP-1 only) and tirzepatide (GLP-1/GIP only).
How does Retatrutide compare to Semaglutide and Tirzepatide?
Semaglutide activates 1 receptor (GLP-1), tirzepatide activates 2 receptors (GLP-1 + GIP), and retatrutide activates 3 receptors (GLP-1 + GIP + glucagon). In Phase 2 trials, retatrutide achieved -24.2% weight loss at 48 weeks — surpassing tirzepatide (-20.9% at 72 weeks) and semaglutide (-14.9% at 68 weeks). The additional glucagon receptor activation drives enhanced energy expenditure and hepatic fat reduction.
What were the Phase 2 clinical trial results?
In the Phase 2 obesity trial (Jastreboff et al., NEJM 2023), the 12 mg retatrutide group achieved: -24.2% mean body weight reduction at 48 weeks, 100% of participants lost ≥5%, 93% lost ≥10%, 63% lost ≥20%, liver fat reduction of -82.4%, and improvements in blood pressure, triglycerides, and HbA1c.
What is the molecular weight and CAS number of Retatrutide?
Retatrutide has a molecular weight of 4,731.33 g/mol, molecular formula C₂₂₁H₃₄₂N₄₆O₆₈, and CAS number 2381089-83-2. It is a 39-amino acid peptide with three non-coded residues (Aib², Aib²⁰, αMeLeu¹³) and a C-20 fatty diacid albumin-binding moiety at Lys¹⁷.
Why does Retatrutide include glucagon receptor activation?
Glucagon receptor (GCGR) activation increases hepatic energy expenditure via glycogenolysis and fatty acid oxidation, stimulates brown adipose tissue thermogenesis, and directly reduces liver fat. This third pathway explains why retatrutide produces greater weight loss and liver fat reduction than dual GLP-1/GIP agonists. Phase 2 data showed -82.4% liver fat reduction, far exceeding results seen with semaglutide or tirzepatide.
What sizes of Retatrutide are available?
Retatrutide is available in 10mg, 20mg, 30mg, 40mg, and 60mg lyophilized vials. All sizes are manufactured to ≥98% HPLC-verified purity with a Certificate of Analysis (COA) included. The fatty acid conjugation provides a ~6-day half-life enabling once-weekly research protocols.
How should Retatrutide be reconstituted?
Reconstitute with bacteriostatic water by slowly adding solvent along the inner vial wall — never directly onto the powder. Allow 5-10 minutes to dissolve without shaking. Retatrutide is a large (39-aa) fatty acid-conjugated peptide that is more sensitive to agitation than smaller peptides. The solution should be clear and colorless.
How should Retatrutide be stored?
Lyophilized: -20°C for up to 24 months (long-term) or 2-8°C for up to 6 months. Reconstituted: 2-8°C, use within 21 days. Do not freeze reconstituted solution. Protect from light at all times. The fatty acid moiety provides some inherent stability but the peptide is still susceptible to oxidation and deamidation.
For laboratory and research use only. Not intended for human or animal consumption. All product information is derived from published preclinical research and does not constitute medical advice or claims.
