RETATRUTIDE
The Triple-Threat Weight Loss Peptide | Triple GLP-1/GIP/Glucagon Agonist - Weight Loss & Diabetes
What is Retatrutide?
Retatrutide (LY3437943) is a novel triple hormone receptor agonist targeting GLP-1, GIP, and glucagon receptors. Phase III TRIUMPH-4 trial (Dec 2025) achieved 28.7% weight loss (71.2 lbs) at 68 weeks with 12mg dose - the highest recorded for any obesity medication.
The Triple-Threat Weight Loss Peptide Retatrutide is a powerful new medication that mimics three different hormones to control hunger and how your body processes fat. It acts like a "triple switch" that tells your brain you’re full, helps your pancreas manage blood sugar, and signals your body to burn stored fat more aggressively.
Key Benefits
Triple hormone receptor activation provides superior weight loss (24.2%), improved glycemic control, and enhanced cardiovascular benefits compared to single or dual agonists.
Maximum Weight Loss: Currently shows the highest weight loss potential of any peptide in its class.
Appetite Suppression: Shuts down food cravings and "food noise" effectively.
Blood Sugar Control: Helps the body maintain stable, healthy glucose levels.
Fat Burning: Specifically targets visceral fat (the dangerous fat around organs).
Liver Health: May help reduce fat buildup in the liver.
Cardiovascular Support: Can lead to improvements in blood pressure and cholesterol.
Quick Start Guide
Typical Dose
Start 0.5mg weekly (clinical practice) or 1mg weekly (trial protocol),
Titrate every 4 weeks to target 8-12mg
How Often
Once weekly
Where to Inject
Subcutaneous: abdomen, thigh, or upper arm
Injection Timing
Any time of day, maintain same day each week for consistency
Effects Timeline
24-48 hours: appetite suppression; 4-8 weeks: significant weight loss; 24+ weeks: maximum benefits
Storage
Refrigerate at 2-8°C
Cycle Length
Continuous therapy - effects reverse upon discontinuation if habits have not changed
Break Between
No cycling required - designed for continuous use
Research Indications
🟢 Weight Loss - Most Effective
Superior Weight Reduction
Clinical trials demonstrate 17.5% at 24 weeks and 24.2% at 48 weeks - highest recorded for any obesity medication in development
Sustained Weight Management
Continuous weight loss throughout trials with no plateau reached at 48 weeks, suggesting greater long-term potential than current therapies
Triple Mechanism Obesity Treatment
Addresses obesity through appetite suppression, increased energy expenditure, and improved metabolic efficiency via three hormone pathways
🔵 Diabetes - Effective
Superior Glycemic Control
HbA1c reductions up to 2.16% with 82% of participants achieving target levels below 6.5% - exceeding dual agonist performance
Glucose-Dependent Regulation
Glucose-dependent insulin secretion and glucagon suppression provide balanced glycemic control with minimal hypoglycemia risk
Insulin Sensitivity Enhancement
Marked improvements in insulin sensitivity with potential for significant reduction in exogenous insulin requirements
⚪️ Cardiovascular - Moderate
Comprehensive Lipid Improvement
Non-HDL cholesterol reductions up to 26.9%, triglyceride reductions up to 40.6%, and ApoB reductions up to 24.2%
Blood Pressure Optimization
Consistent decreases in both systolic and diastolic blood pressure across clinical trials, supporting cardiovascular risk reduction
Hepatic Fat Reduction
Up to 82% reduction in liver fat with normalization in 90% of participants, addressing MASLD and reducing cardiovascular risk
What to expect
Week 1-2: Initial appetite suppression and mild GI effects as body adapts to triple hormone activation
Week 2-4: Noticeable reduction in food cravings and portion sizes, early weight loss (2-5%)
Week 4-8: Significant appetite control and steady weight loss (5-10%), improved glucose control if diabetic
Week 8-16: Substantial weight reduction (10-18%) with enhanced energy expenditure and metabolic improvements
Week 16-24: Major weight loss milestone (15-22%) with cardiovascular benefits and liver fat reduction
Week 24-48: Maximum clinical efficacy (20-24.2%) with comprehensive metabolic improvements and sustained benefits
Side Effects & Safety
Side Effects | When to Stop |
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Mechanism of Action & Molecular Information
Activates GLP-1 for appetite suppression, GIP for insulin sensitivity, and glucagon for increased energy expenditure and hepatic fat oxidation
Weight | Length | Type |
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4,731.33 Da | 39 amino acids | Triple GLP-1/GIP/glucagon agonist |
Amino Acid Sequence: | ||
His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser | ||
References
Research Studies | Citations |
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Phase III TRIUMPH-4 Trial - Eli Lilly (Dec 2025)
First successful Phase III trial in 445 adults with obesity and knee osteoarthritis. 12mg dose achieved 28.7% weight loss (71.2 lbs from 248.5 lb baseline) with 75.8% pain reduction. Discontinuation rates 12-18% due to GI effects; new dysesthesia signal in 8.8-20.9% of participants. | Eli Lilly and Company (2025). Lilly's triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful Phase 3 trial (TRIUMPH-4). Press Release. |
MASLD Substudy - Nature Medicine (2024)
Metabolic dysfunction-associated steatotic liver disease study showing dramatic liver fat reductions with normalization in over 90% of participants at highest doses. | Jastreboff, A.M., Aronne, L.J., Ahmad, N.N., et al. (2023). Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. New England Journal of Medicine, 389(6), 514-526.
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TRIUMPH-Outcomes Cardiovascular Study (2024-2029)
Major cardiovascular outcomes trial assessing effects on MACE and kidney outcomes in participants with obesity and established cardiovascular or kidney disease. | Rosenstock, J., Frias, J., Jastreboff, A.M., et al. (2023). Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, phase 2 trial conducted in the USA. The Lancet, 402(10401), 529-544.
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Phase II Obesity Trial - NEJM (2023)
Landmark randomized controlled trial in 338 participants with obesity showing dose-dependent weight loss with 12mg achieving 24.2% reduction - the highest weight loss recorded for any obesity medication in clinical trials at the time. | Sanyal, A.J., Cusi, K., Hartman, M.L., et al. (2024). Efficacy and safety of retatrutide for treatment of people with obesity and metabolic dysfunction-associated steatotic liver disease: a randomised, double-blind, placebo-controlled, phase 2 trial. Nature Medicine, 30(7), 2037-2048.
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Phase II Type 2 Diabetes Study - Lancet (2023)
Trial in 281 participants with type 2 diabetes demonstrating significant glycemic control improvements with HbA1c reductions up to 2.16% and concurrent substantial weight loss. | Li, W., Xu, Y., Wang, M., et al. (2024). Structural insights into triple agonism at GLP-1R, GIPR and GCGR by retatrutide. Cell Discovery, 10(1), 77.
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TRIUMPH-1 Phase III Trial (2023-2026)
Pivotal Phase III trial in participants with obesity without diabetes or osteoarthritis, evaluating maintenance dose (4mg) in addition to 9mg and 12mg. Results expected 2026. | Coskun, T., Sloop, K.W., Loghin, C., et al. (2022). LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metabolism, 36(7), 1461-1474.e9.
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Phase I Pharmacokinetics - Cell Metabolism (2022)
First-in-human study establishing safety profile, dose-proportional pharmacokinetics, and the extended half-life enabling once-weekly administration. | Urva, S., Coskun, T., Loh, M.T., et al. (2023). LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial. The Lancet, 400(10366), 1869-1881.
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Urva, S., Coskun, T., Benson, C., et al. (2023). LY3437943 triple receptor agonist demonstrates superior efficacy compared to incretin therapies. Diabetes, Obesity and Metabolism, 25(10), 2784-2794.
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Ahmad, N.N., Pons-Belda, O.D., Foltz, M., et al. (2024). Pharmacokinetics and pharmacodynamics of retatrutide (LY3437943), a novel triple glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptor agonist. Clinical Pharmacokinetics, 63(2), 189-202.
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