OVERVIEW

Retatrutide is a triple receptor agonist (GGG tri-agonist) that interacts with GLP-1, GIP, and glucagon receptors. While it shares similarities with traditional GLP-1 agonists, its additional activation of the glucagon receptor sets it apart. This unique feature boosts glucagon production, enhancing the breakdown of stored fats and glycogen, leading to an increase in basal metabolism and promoting fat loss.

By engaging GLP-1 and GIP receptors, Retatrutide also slows gastric emptying and helps regulate appetite, making it a promising candidate for obesity management and metabolic research. Ongoing studies continue to explore its full therapeutic potential.

RESEARCH

What is Retatrutide?

Retatrutide is a modified peptide that incorporates GCGR, GIPR, and GLP-1R agonist activities. Built upon the GIP peptide structure, it has undergone modifications to bind to albumin in the bloodstream, significantly extending its half-life. As a result, Retatrutide requires only once-weekly administration.

Mechanism of Action

Retatrutide activates three key metabolic receptors:

• GIPR (Gastric Inhibitory Polypeptide Receptor): Sends fullness signals from the gut to the brain, helping to control food intake.
• GLP-1R (Glucagon-like Peptide-1 Receptor): Slows gastric emptying, regulates blood sugar, and aids in metabolism management.
• GCGR (Glucagon Receptor): Increases glucagon levels, triggering fat and glycogen breakdown to enhance energy metabolism and weight loss.

Both human and animal studies have demonstrated that Retatrutide induces significant weight reduction, with some trials reporting up to 24% body weight loss over time.

Retatrutide and Energy Balance

Retatrutide aids weight management by increasing energy expenditure while reducing caloric intake:

• Boosted metabolism through glucagon receptor activation promotes greater fat breakdown.
• Appetite suppression occurs via central and peripheral mechanisms, reducing overall energy consumption.

Clinical Trials and Weight Loss Results

• Phase 2 human trials demonstrated up to 20 lbs of weight loss in just 12 weeks.
• A separate study found that waist circumference reductions ranged from 2.1 cm to 10.2 cm over 26 weeks.
• Research published in the New England Journal of Medicine showed dose-dependent weight loss, with some participants experiencing a 24% reduction in total body weight within 48 weeks.

Retatrutide and Blood Sugar Control

• Retatrutide has been shown to lower hemoglobin A1c (HbA1c) levels, an important indicator of long-term blood sugar control.
• Improved HbA1c levels contribute to a reduced risk of diabetes-related complications, including nerve damage, cardiovascular disease, kidney issues, and vision problems.

Retatrutide and Cardiovascular Health

• While no direct human studies have evaluated Retatrutide’s cardiovascular effects, research in monkeys suggests that it lowers blood pressure while increasing heart rate.
• Prior studies indicate that incretin receptor activation may support lower blood pressure, improved heart function, and better vascular flexibility.

STRUCTURE

• Molecular Formula: C₂₂₃H₃₄₃F₃N₄₆O₇₀
• Molecular Weight: 4731.33 g/mol
• CAS Registry Number: 2381089-83-2
• PubChem Identifier: 474492335
• Amino Acid Sequence: YA₁QGTFTSDYSIL₂LDKK₄AQA₁AFIEYLLEGGPSSGAPPPS

CITATIONS

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2. T. Coskun et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept., Mol. Metab., Oct. 2018
3. S. Urva et al. The novel GIP, GLP-1, and glucagon receptor agonist Retatrutide delays gastric emptying., Diabetes Obes. Metab., Sep. 2023
4. G. Winkler et al. A GLP-1 receptor agonist from glucose control to obesity treatment., Orv. Hetil., Oct. 2023
5. T. M. Frayling et al. A Common Allele in FGF21 Associated with Sugar Intake Is Associated with Body Shape, Lower Total Body-Fat Percentage, and Higher Blood Pressure., Cell Rep., Apr. 2018
6. T. Coskun et al. Fibroblast Growth Factor 21 Corrects Obesity in Mice., Endocrinology, Dec. 2008
7. J. P. Frias et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes., Lancet Lond. Engl., Nov. 2018
8. A. M. Jastreboff et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity – A Phase 2 Trial., N. Engl. J. Med., Aug. 2023
9. E. Harris Triple-Hormone Combination Retatrutide Induces 24% Body Weight Loss., JAMA, Jul. 2023
10. A. Ray Retatrutide: a triple incretin receptor agonist for obesity management., Expert Opin. Investig. Drugs, Nov. 2023
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12. A. Ceriello et al. Glucagon and heart in type 2 diabetes: new perspectives., Cardiovasc. Diabetol., 2016