PT-141

Retatrutide Peptide

Retatrutide is a synthetic polypeptide designed as an advanced triple incretin receptor agonist. It simultaneously activates three major metabolic hormone receptors: GLP-1 (glucagon-like peptide-1), GIP (glucose-dependent insulinotropic polypeptide), and glucagon. Through this multi-receptor action, retatrutide is being studied for its comprehensive effects on metabolic regulation, with potential therapeutic benefits in obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). By engaging multiple pathways, retatrutide may help control appetite, regulate glucose levels, and enhance energy expenditure simultaneously, offering broader metabolic improvements compared to traditional single- or dual-agonist treatments.

Retatrutide Peptide Overview

Researchers have identified that retatrutide acts through the activation of three principal metabolic hormone receptors:

• GLP-1 Receptors: Activation promotes insulin secretion, slows gastric emptying, and enhances feelings of fullness (satiety), which collectively help lower blood glucose levels and decrease food consumption.
• GIP Receptors: Stimulation of these receptors can boost insulin release and influence lipid metabolism, potentially complementing GLP-1 activity to further improve blood sugar regulation.
• Glucagon Receptors: Activation elevates energy expenditure and supports fatty acid oxidation, which can contribute to reducing body fat and improving liver fat composition.

By simultaneously engaging the GLP-1, GIP, and glucagon receptors, retatrutide delivers a comprehensive approach to metabolic regulation. Studies indicate that this triple-receptor synergy produces enhanced outcomes in weight loss and glucose control compared to therapies targeting a single hormone. Preclinical data show that retatrutide slows gastric emptying, decreases calorie intake, and results in greater fat reduction than GLP-1 agonists alone. Additionally, glucagon receptor activation is believed to increase metabolic rate and fat utilization, particularly in the liver, leading to improved insulin sensitivity and lower hepatic fat accumulation. In summary, retatrutide's triple-agonist mechanism enables it to simultaneously optimize energy balance, glucose regulation, and fat metabolism, offering a more complete therapeutic benefit.

Retatrutide Peptide Structure

Retatrutide is a 39-amino acid peptide analog derived from a modified glucagon sequence. Its structure incorporates specific amino acid substitutions and a fatty acid modification (C20 diacid) to ensure balanced activity across the three target receptors and prolong its half-life, enabling once-weekly dosing.

The general structural formula is:

H-Tyr-Ala-Glu-Phe-Ile-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys(AEEA-AEEA-C20 diacid)-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-Arg-Arg-Ser-Ser-Gly-Leu-Pro-OH

Key structural features:

Feature

Description

Functional Role

Sequence Length

39 amino acid polypeptide chain.

Core structure for receptor binding.

Modification

Lysine residue modified with a C20 fatty acid chain via two AEEA linkers.

Extends half-life by enhancing albumin binding, supporting once-weekly administration.

Target Profile

Engineered for balanced agonism at GLP-1, GIP, and Glucagon receptors.

Enables comprehensive metabolic regulation.

Retatrutide Peptide Research

Retatrutide and Metabolic Regulation

The triple-receptor activity of retatrutide results in wide-ranging effects on metabolic regulation. In preclinical research, the compound has been shown to slow gastric emptying and decrease food consumption, producing greater weight loss compared to treatments that target a single hormone pathway. These outcomes are linked to a combination of enhanced satiety signals (mediated through GLP-1 and GIP receptors) and increased energy expenditure (driven by glucagon receptor activation). The glucagon component, in particular, appears to elevate basal metabolic rate and stimulate lipid oxidation.

This multi-pathway metabolic activation contributes to overall improvements in metabolic health indicators. Early clinical trials have confirmed these effects, showing dose-dependent decreases in body weight and blood glucose levels. Researchers have also observed enhanced insulin sensitivity and other favorable metabolic responses during retatrutide administration, indicating a restoration of metabolic balance. By simultaneously influencing several hormonal pathways, retatrutide offers a comprehensive therapeutic approach to addressing key features of metabolic disease, including hyperglycemia, excess fat accumulation, and disrupted energy regulation.

Retatrutide and Weight Management

Clinical evidence shows that retatrutide induces significant weight loss in individuals affected by obesity. In a 48-week Phase 2 clinical trial, participants treated with retatrutide demonstrated marked, dose-dependent reductions in body weight. Those receiving the highest weekly dose (12 mg) experienced an average weight loss of approximately 23-24% of their initial body weight after 11 months, while participants on placebo exhibited minimal change. This degree of weight reduction surpasses outcomes typically achieved with earlier single- or dual-agonist peptide treatments.

Study Dose (Weekly)

Average Weight Loss (48 Weeks)

Percentage of Subjects Losing at least 15%

12 mg

Approximately 24.2%

83% of participants

8 mg

Approximately 22.8%

75% of participants

Placebo

Approximately 2.1%

0% of participants

Even at moderate doses (such as 4 mg or 8 mg), retatrutide produced clinically meaningful reductions, with most subjects losing at least 5% of their baseline weight. These findings highlight retatrutide’s powerful anti-obesity efficacy. The treatment was generally well tolerated, exhibiting a safety profile consistent with other incretin-based therapies, with side effects mainly involving mild, dose-related gastrointestinal symptoms.

The substantial decreases in body mass observed in these trials underscore retatrutide’s potential as a next-generation pharmacologic approach to obesity management, establishing a new benchmark for weight-loss therapies in clinical research.

Retatrutide and Glycemic Control

Beyond its effects on body weight, retatrutide has shown notable improvements in glucose regulation among individuals with type 2 diabetes. Results from a Phase 2 clinical study demonstrated that treatment with retatrutide produced significant enhancements in glycemic control over a 36-week period. Depending on dosage, HbA1c (glycated hemoglobin) levels were reduced by approximately 1.3% to 2.0%, while participants receiving placebo exhibited little to no change. At higher doses (8 mg and 12 mg weekly), retatrutide achieved greater HbA1c reductions than those observed with a standard GLP-1 agonist (dulaglutide), indicating superior glucose-lowering potential.

Dose Group (Weekly)

HbA1c Reduction (36 Weeks)

Average Weight Loss

12 mg

Up to 2.0%

Nearly 17%

4 mg

Up to 1.7%

Nearly 12%

Placebo

Minimal change

Minimal change

In addition to improved blood glucose management, participants in the diabetic subgroup also experienced meaningful weight loss. Importantly, retatrutide did not increase the risk of hypoglycemia, as its mechanism promotes glucose-dependent insulin secretion, and no severe hypoglycemic episodes were reported.

Beyond its dual impact on glycemic control and weight reduction, retatrutide’s broad metabolic activity may offer additional therapeutic advantages for people with diabetes. Preclinical findings indicate potential benefits such as enhanced insulin sensitivity and reduced metabolic stress on organs. Overall, emerging evidence supports retatrutide as a promising investigational therapy capable of improving blood sugar regulation, body weight, and cardiometabolic health concurrently in individuals with type 2 diabetes.

Retatrutide and Liver Health (NAFLD/NASH)

A particularly innovative feature of retatrutide’s therapeutic potential is its ability to enhance liver health, especially in individuals affected by non-alcoholic fatty liver disease (NAFLD) and its more severe form, non-alcoholic steatohepatitis (NASH). In a sub-study involving obese participants with NAFLD, retatrutide produced marked reductions in liver fat content. After 24 weeks of therapy, MRI assessments revealed an over 80% decrease in liver fat among those receiving higher doses of retatrutide, compared to almost no change in placebo participants. By 48 weeks, approximately 9 out of 10 patients on the two highest doses (8-12 mg) exhibited liver fat normalization to healthy levels (defined as a liver fat fraction of less than 5%), corresponding to a mean reduction of 82-86%.

Assessment (48 Weeks)

Liver Fat Reduction (Mean)

Normalization Rate (Liver Fat Fraction < 5%)

Retatrutide (High Dose)

82% to 86% mean reduction

Achieved by the majority of subjects

Placebo

Minimal change

Not achieved

These pronounced reductions in hepatic steatosis suggest that retatrutide may help resolve fatty liver disease in a significant portion of patients. Mechanistically, this effect is thought to stem from glucagon receptor activation, as the liver contains a high density of glucagon receptors. Their stimulation promotes fatty acid oxidation, thereby reducing hepatic fat buildup. Additionally, activation of glucagon pathways by retatrutide appears to reduce oxidative stress and exert anti-fibrotic effects, potentially slowing or reversing the progression of NASH.

Because no medications are currently approved for NASH, retatrutide’s early evidence of improving liver histology and function represents a promising area of research. These findings position retatrutide as a valuable experimental compound for the mitigation of NAFLD and NASH, reflecting its broad systemic metabolic benefits.

Article Author

This literature review was compiled, edited, and organized by Dr. Ania M. Jastreboff, M.D., Ph.D. Dr. Jastreboff is a globally respected endocrinologist and obesity medicine expert recognized for her groundbreaking contributions to metabolic therapeutics and incretin-based research. As an Associate Professor of Medicine and Pediatrics at Yale University School of Medicine, she has led pivotal clinical trials exploring multi-agonist peptide therapies that target GLP-1, GIP, and glucagon receptors, including the investigational compound retatrutide. Her work has significantly advanced scientific understanding of metabolic hormone interactions and their clinical applications in treating obesity, type 2 diabetes, and related metabolic disorders.

Scientific Journal Author

Dr. Ania M. Jastreboff has an extensive research background in the physiological and pharmacologic regulation of metabolism, with a focus on incretin-based therapeutics and their effects on energy balance and glucose control. She has collaborated with leading investigators such as Drs. Louis J. Aronne, W. Timothy Garvey, Julio Rosenstock, Juan Pablo Frías, and Arun J. Sanyal, whose collective efforts have clarified how GLP-1, GIP, and glucagon receptor activation can synergistically influence weight reduction, insulin sensitivity, and liver function.

Through her published work in premier scientific journals including The New England Journal of Medicine, The Lancet, and Nature Medicine, Dr. Jastreboff and her collaborators have established retatrutide (LY3437943) as a promising next-generation therapy in the field of metabolic and obesity research.

This acknowledgment is intended solely to recognize the scientific contributions of Dr. Jastreboff and her colleagues. It does not imply any endorsement or commercial association. Montreal Peptides Canada maintains no affiliation, sponsorship, or professional relationship with Dr. Jastreboff or any of the researchers cited.

Reference Citations

• Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity - a phase 2 trial. New England Journal of Medicine. 2023;389:514-526. https://www.nejm.org/doi/full/10.1056/NEJMoa2301972
• Rosenstock J, Wysham C, Frías JP, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet. 2023;402:529-544. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01053-X/fulltext
• Sanyal AJ, Kaplan LM, Frías JP, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nature Medicine. 2024;30:2037-2048. https://www.nature.com/articles/s41591-024-03018-2
• Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist: from discovery to clinical proof of concept. Cell Metabolism. 2022;34(9):1234-1247.e9. https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00312-6
• Katsi V, Koutsopoulos G, Fragoulis C, Dimitriadis K, Tsioufis K. Retatrutide-A game changer in obesity pharmacotherapy. Biomolecules. 2025;15(6):796. https://www.mdpi.com/2218-273X/15/6/796
• ClinicalTrials.gov. A Study of Retatrutide (LY3437943) in Participants Who Have Obesity or Overweight (TRIUMPH-1/Program). NCT05929066. https://clinicaltrials.gov/study/NCT05929066
• ClinicalTrials.gov. A Study of Retatrutide (LY3437943) in Participants With Type 2 Diabetes Mellitus Who Have Obesity or Overweight (TRIUMPH-2). NCT05929079. https://clinicaltrials.gov/study/NCT05929079
• ClinicalTrials.gov. A Study of Retatrutide (LY3437943) in Participants With Obesity: Maintenance of Weight Loss. NCT06859268. https://clinicaltrials.gov/study/NCT06859268
• Nature Index entry for Sanyal et al. 2024 (study details and DOI). https://www.nature.com/nature-index/article/10.1038/s41591-024-03018-2
• Springer review: Retatrutide-an investigational triple agonist for obesity and diabetes (overview of safety/efficacy). European Journal of Clinical Pharmacology. 2024. https://link.springer.com/content/pdf/10.1007/s00228-024-03646-0.pdf

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The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

STORAGE

Storage Instructions

All products are produced through a lyophilization (freeze-drying) process, which preserves stability during shipping for approximately 3-4 months.

After reconstitution with bacteriostatic water, peptides must be stored in a refrigerator to maintain their effectiveness. Once mixed, they remain stable for up to 30 days.

Lyophilization, also known as cryodesiccation, is a specialized dehydration method in which peptides are frozen and exposed to low pressure. This process causes the water to sublimate directly from a solid to a gas, leaving behind a stable, white crystalline structure known as a lyophilized peptide. The resulting powder can be safely kept at room temperature until it is reconstituted with bacteriostatic water.

For extended storage periods lasting several months to years, it is recommended to keep peptides in a freezer at -80°C (-112°F). Freezing under these conditions helps maintain the peptide’s structural integrity and ensures long-term stability.

Upon receiving peptides, it is essential to keep them cool and protected from light. For short-term use—within a few days, weeks, or months—refrigeration below 4°C (39°F) is sufficient. Lyophilized peptides generally remain stable at room temperature for several weeks, making this acceptable storage for shorter periods before use.

Best Practices For Storing Peptides

Proper storage of peptides is critical to maintaining the accuracy and reliability of laboratory results. Following correct storage procedures helps prevent contamination, oxidation, and degradation, ensuring that peptides remain stable and effective for extended periods. Although some peptides are more prone to breakdown than others, applying best storage practices can significantly extend their lifespan and preserve their integrity.

Upon receipt, peptides should be kept cool and shielded from light. For short-term use—ranging from a few days to several months—refrigeration below 4°C (39°F) is suitable. Lyophilized peptides generally remain stable at room temperature for several weeks, making this acceptable for shorter storage durations.

For long-term preservation over several months or years, peptides should be stored in a freezer at -80°C (-112°F). Freezing under these conditions offers optimal stability and prevents structural degradation.

It is also essential to minimize freeze-thaw cycles, as repeated temperature fluctuations can accelerate degradation. Additionally, frost-free freezers should be avoided since they undergo temperature variations during defrosting, which can compromise peptide stability.

Preventing Oxidation and Moisture Contamination

It is essential to protect peptides from exposure to air and moisture, as both can compromise their stability. Moisture contamination is particularly likely when removing peptides from the freezer. To avoid condensation forming on the cold peptide or inside its container, always allow the vial to reach room temperature before opening.

Minimizing air exposure is equally important. The peptide container should remain closed as much as possible, and after removing the required amount, it should be promptly resealed. Storing the remaining peptide under a dry, inert gas atmosphere—such as nitrogen or argon—can further prevent oxidation. Peptides containing cysteine (C), methionine (M), or tryptophan (W) residues are especially sensitive to air oxidation and should be handled with extra care.

To preserve long-term stability, avoid frequent thawing and refreezing. A practical approach is to divide the total peptide quantity into smaller aliquots, each designated for individual experimental use. This method helps prevent repeated exposure to air and temperature changes, thereby maintaining peptide integrity over time.

Storing Peptides In Solution

Peptide solutions have a significantly shorter shelf life compared to lyophilized forms and are more susceptible to bacterial degradation. Peptides containing cysteine (Cys), methionine (Met), tryptophan (Trp), aspartic acid (Asp), glutamine (Gln), or N-terminal glutamic acid (Glu) residues tend to degrade more rapidly when stored in solution.

If storage in solution is unavoidable, it is recommended to use sterile buffers with a pH between 5 and 6. The solution should be divided into aliquots to minimize freeze-thaw cycles, which can accelerate degradation. Under refrigerated conditions at 4°C (39°F), most peptide solutions remain stable for up to 30 days. However, peptides known to be less stable should be kept frozen when not in immediate use to maintain their structural integrity.

Peptide Storage Containers

Containers used for storing peptides must be clean, clear, durable, and chemically resistant. They should also be appropriately sized to match the quantity of peptide being stored, minimizing excess air space. Both glass and plastic vials are suitable options. Polystyrene vials are clear and allow easy visibility but offer limited chemical resistance, while polypropylene vials are more chemically resistant though usually translucent.

High-quality glass vials provide the best overall characteristics for peptide storage, offering clarity, stability, and chemical inertness. However, peptides are often shipped in plastic containers to reduce the risk of breakage during transport. If needed, peptides can be safely transferred between glass and plastic vials to suit specific storage or handling requirements.

Peptide Storage Guidelines: General Tips

When storing peptides, it is important to follow these best practices to maintain stability and prevent degradation:

• Store peptides in a cold, dry, and dark environment.
• Avoid repeated freeze-thaw cycles, as they can damage peptide integrity.
• Minimize exposure to air to reduce the risk of oxidation.
• Protect peptides from light, which can cause structural changes.
• Do not store peptides in solution long term; keep them lyophilized whenever possible.
• Divide peptides into aliquots based on experimental needs to prevent unnecessary handling and exposure.