Retatrutide

Retatrutide (LY3437943) is a novel investigational peptide developed by Eli Lilly and Company. It represents the next evolution in incretin-based therapies, being the first triple agonist to target all three key metabolic hormone receptors: GLP-1 (glucagon-like peptide-1), GIP (glucose-dependent insulinotropic polypeptide), and glucagon receptors simultaneously.

While semaglutide (Ozempic/Wegovy) targets only GLP-1 and tirzepatide (Mounjaro/Zepbound) targets GLP-1 and GIP, retatrutide adds glucagon receptor activation to the mix. This third mechanism is believed to be responsible for the unprecedented weight loss results seen in clinical trials, as glucagon activation increases energy expenditure and promotes fat breakdown (lipolysis).

Retatrutide gained significant attention following the publication of its Phase 2 trial results in The New England Journal of Medicine in 2023, which showed weight loss of up to 24.2% at the highest dose — surpassing results from any previously tested anti-obesity medication. The drug has since generated enormous public interest, with coverage from major outlets including The New York Times and extensive discussion from science communicators like Andrew Huberman.

Retatrutide's triple agonist mechanism addresses weight loss through three complementary pathways:

GLP-1 receptor activation: Like semaglutide, retatrutide activates GLP-1 receptors in the brain and gut, reducing appetite, slowing gastric emptying, and improving blood sugar regulation. This is the same mechanism behind the weight loss effects of Ozempic and Wegovy.

GIP receptor activation: Similar to tirzepatide, retatrutide activates GIP receptors, which enhances insulin sensitivity, may improve fat metabolism, and works synergistically with GLP-1 signaling to amplify appetite suppression and metabolic improvements.

Glucagon receptor activation: This is retatrutide's unique differentiator. Glucagon receptor activation increases energy expenditure (thermogenesis), promotes hepatic fat oxidation (fat burning in the liver), and stimulates lipolysis (breakdown of stored fat). This mechanism addresses the "energy out" side of the equation, whereas GLP-1 and GIP primarily address "energy in" through appetite suppression.

The combination of reduced caloric intake (via appetite suppression) and increased energy expenditure (via glucagon activation) creates what researchers describe as a "dual-pronged" approach to weight loss that exceeds what either mechanism can achieve alone.

Phase 2 Trial (2023): Published in The New England Journal of Medicine, the Phase 2 trial enrolled 338 adults with obesity. Key results at 48 weeks:

• 12 mg dose: -24.2% mean body weight loss (compared to -2.1% placebo)
• 8 mg dose: -22.8% mean body weight loss
• 4 mg dose: -17.5% mean body weight loss
• Nearly 100% of participants in the 12 mg group lost at least 5% body weight
• 63% of participants in the 12 mg group lost at least 20% body weight

For context, these results exceed those of tirzepatide (~22.5% at 72 weeks) and semaglutide (~15% at 68 weeks) at their respective highest doses in their pivotal trials.

Phase 3 Trials (Ongoing): Eli Lilly has initiated multiple Phase 3 trials (the TRIUMPH program) to confirm efficacy and safety in larger populations. These trials are expected to support a potential FDA submission. Results are anticipated in 2026-2027.

Additional indications: Retatrutide is also being studied for non-alcoholic steatohepatitis (NASH/MASH), Type 2 diabetes, and sleep apnea, reflecting the broad metabolic benefits of triple receptor activation.

Clinical trial dosing: In Phase 2 trials, retatrutide was administered once weekly via subcutaneous injection, with gradual dose escalation:

• Starting dose: 2 mg weekly for the first 4 weeks
• Escalation: Dose increased every 4 weeks
• Target maintenance doses studied: 4 mg, 8 mg, and 12 mg weekly

The gradual escalation protocol is designed to minimize gastrointestinal side effects as the body adjusts to the medication.

Important note: Retatrutide is an investigational drug that has not been approved by the FDA. It is not commercially available through legitimate pharmaceutical channels. Any retatrutide currently available is from research chemical suppliers and is not regulated for purity or safety. The dosing information above is from clinical trials and is provided for educational purposes only.

Phase 2 trial data revealed the following side effect profile:

Common side effects (>10% of participants):

• Nausea (ranging from 13-26% depending on dose)
• Diarrhea (15-22%)
• Vomiting (6-14%)
• Constipation (6-12%)
• Decreased appetite (this is partly the therapeutic effect)

Most side effects were: mild to moderate in severity, most common during dose escalation periods, and generally improved over time as the body adapted.

Serious adverse events: No major safety signals were identified in Phase 2 data. However, larger Phase 3 trials will provide a more complete safety picture.

Theoretical concerns (shared with GLP-1 class): Pancreatitis risk, gallbladder issues, potential thyroid concerns (C-cell tumors observed in rodent studies with GLP-1 agonists), and loss of lean muscle mass alongside fat loss are all areas being monitored in ongoing trials.