Retatrutide 10mg

Compound Name: Retatrutide

Synonyms: LY3437943, 2381089-83-2, EX-A7826E, GTPL13769

CAS Number: 2381089-83-2

Molecular Formula: C₂₂₁H₃₄₂N₄₆O₆₈

Molecular Weight: ~4992.6 Da

Molar Mass: 4731 g/mol

Structure: Synthetic 39-amino acid peptide

Peptide Sequence: Tyr-{Aib}-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-{α-Me-Leu}-Leu-Asp-Lys-{diacid-C20-gamma-Glu-(AEEA)-Lys}-Ala-Gln-{Aib}-Ala-Phe-Ile-Glu-Tyr-Leu-Leu-Glu-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2

Source: PubChem

Mechanism of Action: Retatrutide functions as a potent triple agonist at the GLP-1, GIP, and glucagon receptors. By simultaneously activating these receptors, it lowers blood glucose, enhances insulin secretion and sensitivity, reduces appetite, and increases energy expenditure, resulting in pronounced weight loss and improved metabolic health^1,3.

Biological Activity: Full agonist at human GLP-1, GIP, and glucagon receptors; shows robust anti-obesity, anti-diabetic, and cardiometabolic effects in preclinical and clinical studies, including significant reductions in body weight, glycemic markers, blood pressure, and lipids^1,3,5.

Storage: −20°C or below, protect from moisture and light

Drug Categories: Amino Acids, Peptides, and Proteins; Lipids

Additional Notes:

• Administered via once-weekly subcutaneous injection in clinical trials.
• Engineered for DPP-IV resistance and long half-life via fatty acid conjugation^1,3,5.
• Has demonstrated up to 24% weight reduction over 48 weeks and significant improvements in metabolic risk factors^1,3.
• Currently under investigation for obesity, type 2 diabetes, and metabolic liver diseases.

Summary Table:

Disclaimer: For Research Use Only. Not intended for human or veterinary use. This compound is supplied solely for laboratory and R&D purposes.

Detailed Product Description

Retatrutide is a novel investigational medication classified as a triple hormone receptor agonist. Specifically, it acts as a single peptide that simultaneously activates three receptors involved in metabolic regulation: the glucose-dependent insulinotropic polypeptide receptor (GIPR), the glucagon-like peptide-1 receptor (GLP-1R), and the glucagon receptor (GCGR). The compound consists of 39 amino acids and is structurally engineered for enhanced stability and once-weekly subcutaneous injection due to its extended half-life of approximately six days.

Retatrutide is under clinical development as a treatment for obesity, type 2 diabetes, and related metabolic conditions such as metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as non-alcoholic fatty liver disease).

Research Highlights

Retatrutide’s combined triple agonist action leads to several clinically important effects:

• Induces Substantial Weight Loss: Clinical trials consistently demonstrate robust, dose-dependent reductions in body weight. Up to 24.2% body weight reduction after 48 weeks has been observed with higher doses in people with obesity; these effects are greater than those reported for currently approved single or dual agonists^1,3.
• Improves Glycemic Control: In persons with type 2 diabetes, retatrutide lowers HbA1c and fasting glucose levels, with efficacy sometimes exceeding established glucose-lowering medications^1,2.
• Reduces Liver Fat: In individuals with MASLD, retatrutide leads to profound reductions (over 80% at high doses) in liver fat and often normalization of hepatic fat content—changes strongly linked to improved metabolic health¹.
• Improves Metabolic and Cardiovascular Biomarkers: Treatment results in lower blood pressure, improved insulin sensitivity, reduced triglycerides and non-HDL cholesterol, and favorable changes in adiponectin and leptin, all contributing to cardiovascular and metabolic benefits^1,4.

Mechanism of Action

Retatrutide exerts its unique therapeutic profile through simultaneous activation of three gut hormone receptors, each contributing distinct and synergistic effects:

1. GLP-1 Receptor (GLP-1R) Agonism

• Stimulates glucose-dependent insulin secretion: Enhances pancreatic beta-cell insulin release, thus lowering blood glucose^1,3,4.
• Suppresses appetite (central action): Reduces hunger signals in the brain, leading to decreased food intake and weight loss^1,2.
• Slows gastric emptying: Contributes to satiety and reduces post-meal glucose spikes^1,5.
• Receptor binding affinity (EC₅₀, Human) = 5.79 nM

2. GIP Receptor (GIPR) Agonism

• Further increases insulin secretion: Complementing the effects of GLP-1, GIPR activation improves pancreatic insulin response⁴.
• May improve insulin sensitivity: Some studies show GIP agonism modulates lipid metabolism and energy homeostasis^1,3.
• Supports maintenance of lean mass during weight loss¹.
• Receptor binding affinity (EC₅₀, Human) = 0.0643 nM

3. Glucagon Receptor (GCGR) Agonism

• Increases energy expenditure: Glucagon activation raises metabolic rate, which is thought to amplify fat loss. This is distinct from the appetite-suppressing effect of GLP-1 and GIP.
• Promotes breakdown of liver fat (hepatic steatosis): GCGR activity boosts fatty acid oxidation in the liver, explaining marked reductions in hepatic fat seen in trials^1,2.
• Enhances amino acid metabolism: Aids regulation of gluconeogenic and branched-chain amino acids, which are linked to metabolic health².
• Receptor binding affinity (EC₅₀, Human) = 0.775 nM

Synergy of Triple Agonism

The simultaneous action on these three receptors achieves effects not observed with single- or dual-receptor agonists:

• Greater weight reduction, driven by combined appetite suppression (GLP-1, GIP) and increased energy expenditure (glucagon)¹.
• Dramatic reduction of liver fat through synchronized effects on appetite, metabolism, and lipid oxidation¹.
• Improved glucose regulation by boosting insulin secretion, reducing glucagon spikes, and enhancing insulin sensitivity¹.

Pharmacokinetic Profile:

• Route of Administration: Subcutaneous (SC)
• Dosing Frequency: Once weekly
• Half-Life: ~6 days (due to albumin binding and DPP-IV resistance)
• Formulation: Lipidated for enhanced stability and extended systemic exposure

Formulation & Handling

• Reconstitute in sterile water or PBS (pH ~7.4) for in vivo/in vitro use
• Store at –20°C in aliquots to prevent freeze-thaw degradation
• Shelf-stable for 12 months under recommended storage condition

Clinical Trial Activity

References

¹Sanyal, A. J. et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat. Med. 30, 2037–2048 (2024). https://doi.org/10.1038/s41591-024-03018-2

²Coskun, T. et al. 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, 529–544 (2023). https://doi.org/10.1016/S0140-6736(23)01053-X

³Urva, S. et al. The novel GIP, GLP-1 and glucagon receptor agonist retatrutide delays gastric emptying. Diabetes Obes. Metab. 25, 2784–2788 (2023). https://doi.org/10.1111/dom.15167

⁴Kaur, M. & Misra, S. A review of an investigational drug retatrutide, a novel triple agonist agent for the treatment of obesity. Eur. J. Clin. Pharmacol. 80, 669–676 (2024). https://doi.org/10.1007/s00228-024-03646-0

⁵Jastreboff, A. M. et al. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N. Engl. J. Med. 389, 514–523 (2023). https://doi.org/10.1056/NEJMoa2301972