Retatrutide

Historical Background

Retatrutide (LY3437943) is a triple receptor agonist developed by Eli Lilly, simultaneously activating GLP-1, GIP, and glucagon (GCG) receptors. It builds on the dual GLP-1/GIP agonism of tirzepatide by adding glucagon receptor co-agonism — which drives energy expenditure (thermogenesis) in addition to appetite suppression and incretin effects. Phase 2 trial data (NEJM, 2023) showing up to 24.2% weight loss at 48 weeks made retatrutide the highest-efficacy weight loss compound published to date.

What It's Used For

• Triple incretin receptor co-agonism research (GLP-1R/GIPR/GCGR)
• Maximum metabolic and weight loss research
• Hepatic fat reduction and NASH/MASH models
• Thermogenesis and energy expenditure studies
• Dyslipidemia research (lipid-lowering via GCGR)
• Comparison with dual agonists (tirzepatide) for additive GCG contribution

Positive Effects

• GLP-1R agonism: appetite suppression, insulin secretion, cardiovascular protection
• GIPR agonism: enhanced weight loss (mechanism shared with tirzepatide)
• GCGR agonism: hepatic fat reduction, increased energy expenditure (thermogenesis), lipid lowering
• Phase 2: 24.2% mean weight loss at highest dose (12 mg) over 48 weeks — highest published for any single agent
• Marked reduction in liver fat (>80% relative reduction in hepatic steatosis)
• Significant triglyceride reduction (GCGR-mediated lipid effects)
• Improves all components of metabolic syndrome simultaneously

Potential Side Effects

• GI side effects: nausea, vomiting, diarrhea (class effect — dose-dependent)
• Tachycardia (GCGR-mediated, distinct from GLP-1/GIP class)
• Higher nausea rate than tirzepatide or semaglutide at high doses
• Requires careful dose escalation

Administration

Subcutaneous injection once weekly. Phase 2 escalation: 0.5 mg → 1 mg → 2 mg → 4 mg → 8 mg → 12 mg over 24 weeks. Reconstitute with bacteriostatic water; store at 2–8°C. For research use only.