Retatrutide

Overview

Retatrutide is a novel triple-agonist peptide targeting GLP-1, GIP, and glucagon receptors simultaneously. It is in Phase 3 clinical trials for obesity and type 2 diabetes and has demonstrated the highest weight loss of any anti-obesity medication tested to date.

Mechanism of Action

Retatrutide simultaneously activates three receptors: GLP-1R (appetite suppression, insulin secretion), GIPR (insulin sensitivity, fat metabolism), and glucagon receptor (energy expenditure, hepatic fat reduction). The glucagon receptor component is unique and promotes thermogenesis and fatty acid oxidation beyond what dual agonists achieve.

Research Summary

The Phase 2 trial demonstrated up to 24.2% body weight loss at 48 weeks at the highest dose (12 mg), exceeding results of both semaglutide and tirzepatide. Significant reductions in hepatic steatosis (fatty liver) were also observed. Phase 3 trials are ongoing with results expected in 2025–2026. Eli Lilly is the developer.

Dosing Information

Reported Side Effects

• Nausea and vomiting
• Diarrhea
• Decreased appetite
• Constipation
• Injection site reactions
• Increased heart rate

Research References

• Retatrutide, a GIP, GLP-1, and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-comparator-controlled, parallel-group, phase 2 trial (2023)
• Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease (2023)
• GLP-1/GIP/glucagon receptor triagonism for the treatment of obesity: challenges and opportunities (2023)