Retatrutide (LY3437943) is a revolutionary next-generation synthetic peptide and the first triagonist that acts simultaneously on three hormone receptors: GLP-1 (glucagon-like peptide-1), GIP (glucose-dependent insulinotropic polypeptide), and glucagon. Developed by Eli Lilly, it is currently in Phase 3 clinical trials and potentially represents the most significant advance in the treatment of obesity.
Main Benefits:
• Massive and unprecedented weight loss (up to 24% of body weight in 48 weeks)
• Extremely potent appetite suppression
• Increased energy expenditure and metabolism
• Improved glucose homeostasis and glycemic control
• Reduction of HbA1c in type 2 diabetics
• Increased lipolysis and fatty acid oxidation
• Reduction of hepatic steatosis (fatty liver)
• Improved blood pressure and waist circumference
• Improvement in lipid profile (triglycerides, HDL)
• Potential cardiovascular benefits
• Delayed gastric emptying
Typical Dosages (Clinical Trials):
- Initial Dose: 2-2.5 mg per week (subcutaneous)
- Gradual Scaling: Increase every 4 weeks
- Studied Doses: 4 mg, 8 mg, 12 mg per week
Maximum Tested Dose: 12 mg per week
- Administration: Weekly subcutaneous injection
- Study Duration: 48 weeks (Phase 2 trials)
Half-life: Approximately 6 days (allows for weekly dosing)
Retatrutide works through a unique and synergistic triple-action mechanism:
GLP-1 Agonism : Reduces appetite, slows digestion, suppresses calorie intake, increases post-meal satiety.
GIP Agonism : Improves fat metabolism, increases lipolysis in adipocytes (8.9x more potent than native GIP), reduces postprandial glucose, improves insulin sensitivity.
Glucagon Agonism : Increases energy expenditure, stimulates fatty acid oxidation by the liver, promotes hepatic gluconeogenesis (glucose production), reduces gastrointestinal motility.
Comparative Potency vs. Native Hormones:
• GLP-1: 0.4x (less potent than natural GLP-1)
• Glucagon: 0.3x (less potent than natural glucagon)
• GIP: 8.9x (MUCH more potent than natural GIP)
Extraordinary Clinical Results:
Phase 2 trial (338 adults, obesity without diabetes, 48 weeks)
• 4 mg: Average weight loss not specified
• 8 mg: Average weight loss of 23% of body weight.
• 12 mg: Average weight loss of 24% of body weight.
• 100% of participants in the highest doses lost ≥5% of their weight.
• Significant improvements in waist circumference, blood pressure, and glucose.
Systematic Meta-analysis
• Average overall difference: -14.33% weight reduction vs. placebo
• Consistent dose-dependent effect
• Efficacy comparable to or superior to other anti-obesity drugs
Comparison vs. Competitors
• Retatrutide 12 mg (48 weeks): 24% weight loss
• Tirzepatide 15 mg (52 weeks): 22.5-25% weight loss
• Semaglutide 2.4 mg (68 weeks): ~15% weight loss
Retatrutide achieves similar results in LESS time**
Advantages Over Other Peptides:
• Triple action vs. dual action (tirzepatide) or single action (semaglutide)
• Greater weight loss in a shorter period
• More comprehensive mechanism of metabolic regulation
• Potential for superior outcomes in type 2 diabetes
Side Effects: Mostly gastrointestinal, mild to moderate, dose-dependent.
• Nausea, vomiting, diarrhea, constipation (more common during escalation)
• Increased heart rate (dose-dependent, peak at 24 weeks)
• Altered skin sensations (mild to moderate, did not lead to discontinuation)
• Discontinuation rate: 4-10% (similar to other GLP-1 agonists)
• Rare serious side effects
Potential Therapeutic Applications:
• Obesity and chronic weight management (primary indication)
• Type 2 diabetes and glycemic control
• Non-alcoholic fatty liver disease (NAFLD)
• Metabolic syndrome
• Cardiovascular risk factors
Important Considerations:
• Dose-proportional pharmacokinetics
• Requires gradual escalation to minimize GI effects.
• Initial doses of 4 mg were associated with more adverse effects than initial doses of 2 mg.
• The scheduling scheme can be refined for Phase 3
Important Note: Retatrutide is CURRENTLY UNDER DEVELOPMENT and is NOT FDA approved. It is only available in clinical trials. It is not commercially available. The FDA warns against unregulated acquisition due to risks of contamination, incorrect dosage, and defective devices.