Retatrutide (LY3437943)
Also known as: LY3437943 · Triple G · GGG Agonist
A first-in-class triple incretin receptor agonist (GLP-1/GIP/Glucagon) demonstrating up to 24% weight loss in clinical trials — the most effective anti-obesity compound tested to date.
Overview
Retatrutide is a first-in-class triple incretin receptor agonist that simultaneously targets GLP-1, GIP, and glucagon receptors. Developed by Eli Lilly, it represents the next evolution beyond dual agonists like tirzepatide. In Phase 2 clinical trials, retatrutide demonstrated unprecedented weight loss results — participants lost up to 24.2% of their body weight over 48 weeks at the highest dose, making it the most effective anti-obesity compound ever tested in clinical trials at the time of reporting. The triple mechanism provides complementary metabolic benefits: GLP-1 receptor activation reduces appetite and slows gastric emptying; GIP receptor activation enhances insulin secretion and may improve fat metabolism; and glucagon receptor activation increases energy expenditure, promotes hepatic fat oxidation, and reduces liver fat.
This glucagon component is what distinguishes retatrutide from tirzepatide and semaglutide, as it actively increases caloric burn rather than just reducing intake. Phase 2 data also showed significant reductions in liver fat (up to 86% reduction), improvements in glycemic control in type 2 diabetes patients, and favorable effects on cardiovascular risk markers. Retatrutide is currently in Phase 3 clinical trials for obesity, type 2 diabetes, and metabolic dysfunction-associated steatohepatitis (MASH/NASH). If approved, it could become the most potent pharmaceutical tool for metabolic health optimization available.
Mechanism of Action
Retatrutide is a single peptide molecule engineered to activate three distinct receptors: GLP-1R (glucagon-like peptide-1 receptor), GIPR (glucose-dependent insulinotropic polypeptide receptor), and GCGR (glucagon receptor). GLP-1R activation in the hypothalamus suppresses appetite, slows gastric emptying, and enhances glucose-dependent insulin secretion. GIPR activation complements insulin secretion and may improve adipose tissue function and fat metabolism. GCGR activation — the novel third mechanism — stimulates hepatic glycogenolysis and gluconeogenesis, increases energy expenditure through thermogenesis, promotes fatty acid oxidation in the liver, and reduces hepatic lipid accumulation. The synergy of these three pathways creates a comprehensive metabolic effect that addresses obesity, diabetes, and fatty liver disease simultaneously. The glucagon component is particularly significant because it shifts the body toward actively burning more calories rather than solely relying on appetite suppression.
Key Benefits
Potential Side Effects
Common Stacks
This peptide is commonly combined with the following compounds for synergistic effects:
Known Interactions
The following interactions have been documented for Retatrutide (LY3437943). Always consult a healthcare professional before combining compounds.
Contraindicated (2)
Retatrutide already includes GLP-1 agonism. Adding semaglutide creates dangerous receptor overlap with high risk of severe GI distress and hypoglycemia.
Both include GLP-1 and GIP agonism. Combining creates excessive receptor stimulation with severe GI side effects and hypoglycemia risk.
Scientific References
Quick Reference
Typical Dose
Phase 2 trial doses: 1mg, 4mg, 8mg, 12mg weekly (subcutaneous injection). Titration schedule used in trials: start at lower dose and increase every 4 weeks to minimize GI side effects. Currently investigational — not yet approved for clinical use.
Frequency
Once weekly subcutaneous injection
Route
Subcutaneous injection
Half-Life
~6 days (supports once-weekly dosing)
Cycle Length
Ongoing (chronic treatment in clinical trials)
FDA Status
Investigational — Phase 3 clinical trials ongoing (not yet FDA approved)
Need to calculate dosing?
Use our reconstitution calculator to determine exact syringe measurements.
Open CalculatorThis information is for educational purposes only. Consult a qualified healthcare professional before using any peptide. Dosing information reflects commonly reported protocols and may not be appropriate for everyone.
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