Multi-targeted GLP-1: Retatrutide

The latest compounded weight loss peptide, Retatrutide, is the most powerful yet. Acting on three different receptor pathways, this powerful peptide is the first of its class. While it is still undergoing clinical studies, preliminary data shows reason to be optimistic that this peptide may become a leading therapy option in obesity and metabolic medicine.

Glucagon-Like-Peptide-1 (GLP-1) agonist peptides were developed in 2005 and paved the way for new interventions to help treat insulin resistance and Type 2 Diabetes. The common medications included in the class include semaglutide, dulaglutide, and liraglutide. In addition to improving insulin sensitivity with out the side effects of dropping blood sugar levels, these peptides showed promise by improving cardiovascular health, decreasing heart failure, improving kidney function and reducing overall cardiovascular related deaths. GLP-1 receptors have been found in many tissues in the body including the brain, heart, lungs, kidneys, immune cells and the pancreas.

Glucose-Dependent Insulinotropin Polypeptide (GIP) was discovered in 1969 and shown to increase after a meal is eaten. It has several actions in the body including reducing appetite, enabling insulin release and working hand in hand with GLP-1. It seems to stimulate fat burning inside cells and to inhibit fat production. The well known peptide Tirzepetide (Mounjaro) offers this dual action by combining both GLP-1 and GIP action in a single injection.

Glucagon is a hormone that is found primarily in pancreatic cells and to a lesser extent in the small intestine. Discovered in 1921, this molecule was soon associated with type 2 diabetes and opened up a whole new way of studing medications and blood sugar. When blood sugar levels drop, glucagon stimulates the release of blood glucose from storage in tissues. Part of this process includes breaking down fat to release glucose. It also slows the GI tract.

To date, Retatrutide is the only triple acting peptide that works on all three of these receptors. Clinical outcomes indicate significant improvement in blood sugar regulation, metabolic health, insulin sensitivity and weight loss. Research is ongoing to determine the long-term effects of this peptide.

Retatrutide is not FDA approved yet beyond being used in clinical trials. As with all the GLP-1 agonist medications, people should avoid Retatrutide if they have Type 1 Diabetes or a personal or family history of medullary thyroid carcinoma (MTC), Multiple Endocrine Neoplasia syndrome type 2 (MEN 2), or a known hypersensitivity to semaglutide or any of its components.

It is highly recommended to speak with a knowledgeable healthcare provider prior to starting on a weight loss program which includes peptide therapy. Peptide therapy is indicated to promote weight loss as part of a complete lifestyle plan to include nutritional guidance, lifestyle guidance and stress management. Lab testing before and during treatment is essential. Not everyone who starts on peptides tolerates them well nor does everyone lose weight.

References

Ussher J.R., Drucker D.J. Glucagon-like Peptide 1 Receptor Agonists: Cardiovascular Benefits and Mechanisms of Action. Nat. Rev. Cardiol. 2023;20:463–474. doi: 10.1038/s41569-023-00849-3.

Katsi V, Koutsopoulos G, Fragoulis C, Dimitriadis K, Tsioufis K. Retatrutide-A Game Changer in Obesity Pharmacotherapy. Biomolecules. 2025 May 30;15(6):796. doi: 10.3390/biom15060796. PMID: 40563436; PMCID: PMC12190491.

Drucker D.J. The Biology of Incretin Hormones. Cell Metab. 2006;3:153–165. doi: 10.1016/j.cmet.2006.01.004.

Alsalim W, Lindgren O, Ahrén B. Glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 secretion in humans: Characteristics and regulation. J Diabetes Investig. 2023 Mar;14(3):354-361. doi: 10.1111/jdi.13962. Epub 2022 Dec 20. PMID: 36539382; PMCID: PMC9951578.