Common Dosage
Clinical trials ongoing (typically titrated weekly)
Category
Weight Loss
- Significant weight reduction
- Improved lipid profile
- Liver fat reduction
Retatrutide is a triple hormone receptor agonist developed by Eli Lilly as the next step beyond tirzepatide in the obesity pharmacotherapy pipeline. It adds glucagon receptor agonism to the GLP-1 and GIP dual action, creating a truly unprecedented hormonal profile for metabolic intervention. Phase 2 clinical trial results published in 2023 in The New England Journal of Medicine demonstrated weight loss outcomes exceeding any previously observed medication — generating substantial attention across endocrinology and obesity medicine.
By simultaneously activating GLP-1, GIP, and glucagon receptors, retatrutide orchestrates a multi-pronged metabolic response. GLP-1 reduces appetite and slows gastric emptying. GIP enhances insulin response and modulates adipocyte function. Glucagon receptor activation directly stimulates energy expenditure in the liver and peripheral tissues — essentially turning up the metabolic rate. This third component is considered the key differentiator from tirzepatide.
- Obesity management — Phase 2 trials showed up to 24.2% weight reduction
- Non-alcoholic fatty liver disease (NAFLD) with documented hepatic fat reduction
- Type 2 diabetes glycemic management
- Cardiovascular metabolic risk factor reduction
- Dyslipidemia improvement
- Exploring potential for NASH reversal
Phase 2 Trial (NEJM 2023)
The Phase 2 trial demonstrated an average body weight reduction of 24.2% at the highest dose (12mg) over 48 weeks — surpassing the best outcomes from tirzepatide or semaglutide trials. Approximately 83% of participants achieved ≥5% weight loss at the top dose. Phase 3 trials (TRIUMPH program) were initiated based on these results.
Liver Fat Reduction
MRI-based liver fat quantification in trial participants showed dramatic hepatic steatosis reduction alongside body weight loss, consistent with effects expected from combined GLP-1, GIP, and glucagon action on hepatic lipid metabolism.
- Still in Phase 3 clinical trials as of 2025 — not FDA-approved for any indication
- Nausea and GI side effects are expected to be at least as common as semaglutide/tirzepatide
- Glucagon receptor agonism raises potential concerns about glycogen depletion and muscle catabolism at high doses
- Elevated heart rate — a common GLP-1 class effect — may be more pronounced with triple agonism
- Research peptide versions are entirely uncharacterized for dose accuracy or purity
- Long-term cardiovascular and renal effects under investigation
- Nausea
- Vomiting
- Increased heart rate