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The Peptide Effect
Comprehensive Guide

Retatrutide: The Complete Guide to the Triple-Agonist Peptide

A comprehensive guide to retatrutide (LY3437943), Eli Lilly's investigational triple-agonist peptide targeting GIP, GLP-1, and glucagon receptors. Covers mechanism, clinical trial results, dosing, side effects, cost, and availability.

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Medical Disclaimer

This article is for educational and informational purposes only. It is not medical advice. Always consult a licensed healthcare provider before making decisions about peptide therapies. Retatrutide is not approved by the FDA for any medical use. Information on this page may include early or preclinical research and should not be treated as treatment guidance.

Key Takeaways

  • •Retatrutide is a first-in-class triple-agonist targeting GIP, GLP-1, and glucagon receptors simultaneously
  • •Phase 2 trials showed up to 24.2% body weight loss at 48 weeks — the highest ever reported for an anti-obesity drug
  • •Currently in phase 3 clinical trials (TRIUMPH program); not yet FDA approved
  • •Expected to cost $1,000-$1,300 per month based on comparable drug pricing if approved
  • •Only available through clinical trial enrollment; not commercially sold or legally available online

Overview

Retatrutide (LY3437943) is a first-in-class triple-hormone receptor agonist developed by Eli Lilly that targets GIP, GLP-1, and glucagon receptors simultaneously. In phase 2 clinical trials, retatrutide produced up to 24.2% body weight loss at 48 weeks — the highest weight reduction ever reported for an anti-obesity drug. Currently in the phase 3 TRIUMPH trial program, retatrutide represents a potentially significant advance in the treatment of obesity and metabolic disease.

What Is Retatrutide?

Retatrutide, also known by its research designation LY3437943, is an investigational injectable peptide developed by Eli Lilly and Company. It belongs to a new class of drugs called triple-hormone receptor agonists, meaning it simultaneously activates three distinct metabolic receptors: GIP (glucose-dependent insulinotropic polypeptide), GLP-1 (glucagon-like peptide-1), and glucagon. This triple-agonist approach distinguishes retatrutide from existing therapies like semaglutide (single GLP-1 agonist) and tirzepatide (dual GIP/GLP-1 agonist). Retatrutide is currently being evaluated in the phase 3 TRIUMPH clinical trial program for the treatment of obesity and type 2 diabetes, with results expected to inform potential FDA submission.

How Retatrutide Works

Retatrutide's mechanism of action involves three complementary pathways that may address obesity from multiple angles. The GLP-1 receptor agonism reduces appetite and slows gastric emptying, leading to decreased caloric intake. The GIP receptor agonism appears to enhance insulin sensitivity and influence fat metabolism, potentially improving how the body stores and processes energy. The glucagon receptor agonism — the component that makes retatrutide unique — may increase hepatic energy expenditure, promote fat oxidation, and stimulate thermogenesis.

  • GLP-1 activation: Reduces appetite, promotes satiety, and slows gastric emptying
  • GIP activation: May improve insulin sensitivity and modulate fat metabolism
  • Glucagon activation: Potentially increases energy expenditure, fat oxidation, and thermogenesis
  • Combined effect: Attacks obesity through both reduced caloric intake AND increased energy output

Clinical Trial Results

The phase 2 trial of retatrutide for obesity, published in the New England Journal of Medicine in 2023 by Jastreboff et al., enrolled 338 adults with obesity or overweight with at least one comorbidity. At 48 weeks, participants receiving the 12 mg maintenance dose achieved a mean weight loss of 24.2% of body weight, while those on the 8 mg dose lost 22.8% and the 4 mg dose group lost 17.5%. More than 90% of participants in the 12 mg group lost at least 10% of their body weight, and approximately 75% lost at least 20%. These results represent the highest weight loss ever reported in a phase 2 anti-obesity drug trial.

  • 12 mg dose: 24.2% mean body weight loss at 48 weeks
  • 8 mg dose: 22.8% mean body weight loss at 48 weeks
  • 4 mg dose: 17.5% mean body weight loss at 48 weeks
  • >90% of 12 mg participants lost at least 10% of body weight
  • Approximately 75% of 12 mg participants lost at least 20% of body weight

Dosing and Administration

In clinical trials, retatrutide is administered as a once-weekly subcutaneous injection. Dosing follows a gradual escalation schedule to minimize gastrointestinal side effects, starting at 0.5 mg per week and titrating upward over several weeks. Three maintenance dose tiers were evaluated in phase 2: 4 mg, 8 mg, and 12 mg per week. The phase 3 TRIUMPH program will help determine the optimal dose or doses that balance efficacy with tolerability for potential commercial use.

  • Route: Subcutaneous injection
  • Frequency: Once weekly
  • Starting dose: 0.5 mg with gradual titration upward
  • Maintenance dose tiers studied: 4 mg, 8 mg, and 12 mg per week
  • Phase 3 trials will confirm the recommended commercial dose(s)

Side Effects Profile

The most commonly reported side effects in phase 2 trials were gastrointestinal in nature, consistent with the GLP-1 class of drugs. Nausea was reported in 16-34% of participants depending on dose, diarrhea in 16-22%, and vomiting in 9-19%. These effects were generally mild to moderate in severity, occurred most frequently during the dose-escalation period, and tended to diminish over time. A mild increase in heart rate was observed in some participants, which may be related to the glucagon receptor component.

  • Nausea: 16-34% of participants (dose-dependent)
  • Diarrhea: 16-22% of participants
  • Vomiting: 9-19% of participants
  • Decreased appetite (often considered a therapeutic effect)
  • Mild heart rate increase observed in some participants
  • Potential hepatic effects being monitored in phase 3 trials
  • Most GI side effects were mild to moderate and occurred during dose titration

Retatrutide vs Other Weight Loss Drugs

While cross-trial comparisons have inherent limitations due to differences in study populations and designs, retatrutide's phase 2 results suggest it may produce greater weight loss than currently available options. Semaglutide (Wegovy), a single GLP-1 agonist, produced approximately 15% weight loss in its pivotal STEP trials. Tirzepatide (Zepbound), a dual GIP/GLP-1 agonist, achieved approximately 22% weight loss in its phase 3 SURMOUNT trials. Survodutide, a dual GLP-1/glucagon agonist in development by Boehringer Ingelheim, has shown approximately 19% weight loss in phase 2 data.

  • Retatrutide (triple GIP/GLP-1/glucagon): Up to 24.2% weight loss (phase 2)
  • Tirzepatide (dual GIP/GLP-1): ~22% weight loss (phase 3)
  • Survodutide (dual GLP-1/glucagon): ~19% weight loss (phase 2)
  • Semaglutide (single GLP-1): ~15% weight loss (phase 3)
  • Note: Cross-trial comparisons should be interpreted with caution

Cost and Availability

Retatrutide is not yet commercially available and can currently only be accessed through enrollment in clinical trials. Eli Lilly has not announced pricing, but based on the list price of tirzepatide (Mounjaro/Zepbound at approximately $1,000-$1,060 per month), analysts estimate retatrutide could be priced in the range of $1,000-$1,300 per month if approved. Insurance coverage and formulary placement will significantly affect out-of-pocket costs. FDA approval could potentially come in 2026-2027, assuming positive phase 3 results, though this timeline is speculative.

  • Not currently available for commercial purchase
  • Accessible only through clinical trial enrollment at this time
  • Estimated pricing: $1,000-$1,300 per month based on comparable drug pricing
  • Phase 3 TRIUMPH program ongoing; results expected to inform FDA submission
  • Potential FDA approval timeline: 2026-2027 (speculative)

Who May Be a Candidate

Based on the inclusion criteria used in retatrutide clinical trials and the FDA's general framework for anti-obesity medications, potential candidates for retatrutide — if approved — would likely include adults with a BMI of 30 or greater (obesity), or a BMI of 27 or greater with at least one weight-related comorbidity such as type 2 diabetes, hypertension, or dyslipidemia. Retatrutide is also being evaluated specifically for type 2 diabetes management. It is important to emphasize that retatrutide is currently only available through clinical trial participation and is not approved for any indication.

  • Adults with BMI >= 30 (obesity) based on typical anti-obesity drug criteria
  • Adults with BMI >= 27 with at least one weight-related comorbidity
  • Individuals with type 2 diabetes (being evaluated in dedicated trials)
  • Currently only available through clinical trial enrollment
  • Not suitable for individuals seeking over-the-counter or gray-market access

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References

  1. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial (2023) — PubMed
  2. 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) — PubMed
  3. GIP/GLP-1/Glucagon Receptor Co-agonism for the Treatment of Obesity and Type 2 Diabetes (2023) — PubMed
  4. Retatrutide Phase 2 Trial Results: Efficacy on Liver Fat Reduction in Participants with MASLD (2024) — PubMed

Frequently Asked Questions

When will retatrutide be approved?
Retatrutide is currently in phase 3 clinical trials as part of Eli Lilly's TRIUMPH program. Based on typical drug development timelines, FDA approval could potentially come in late 2026 or 2027, assuming the phase 3 results are positive and the regulatory review proceeds on schedule. However, this timeline is speculative and subject to change based on trial outcomes and regulatory decisions. Official announcements from Eli Lilly and the FDA are the most reliable sources for approval timeline updates.
Is retatrutide better than Ozempic?
Retatrutide and Ozempic (semaglutide) work through different mechanisms. Retatrutide is a triple-agonist targeting GIP, GLP-1, and glucagon receptors, while Ozempic targets only the GLP-1 receptor. In clinical trials, retatrutide produced greater weight loss (up to 24.2% in phase 2) compared to semaglutide (approximately 15% in phase 3). However, cross-trial comparisons have significant limitations, as study populations, designs, and endpoints may differ. Head-to-head data would be needed to draw definitive conclusions about relative efficacy.
Can I buy retatrutide online?
Retatrutide is not legally available for purchase. It is an investigational drug that has not been approved by the FDA or any other regulatory agency, and it can only be obtained through enrollment in authorized clinical trials. Products sold online claiming to be retatrutide are unverified, potentially counterfeit, and may pose serious health risks. Research chemical suppliers are not regulated for human use. Anyone interested in retatrutide should consult their healthcare provider and consider clinical trial enrollment through clinicaltrials.gov.
What is the TRIUMPH trial?
TRIUMPH is the name of Eli Lilly's phase 3 clinical trial program for retatrutide. It encompasses multiple large-scale, randomized, controlled trials evaluating retatrutide for the treatment of obesity and type 2 diabetes in diverse patient populations. The program is designed to confirm the efficacy and safety findings from the phase 2 trials and to establish the optimal dosing regimen for commercial use. Successful results from the TRIUMPH program would support an FDA submission for marketing approval.
Does retatrutide work for type 2 diabetes?
Phase 2 trial data published by Rosenstock et al. in The Lancet (2023) showed that retatrutide significantly improved glycemic control in participants with type 2 diabetes. Participants achieved meaningful reductions in HbA1c levels alongside weight loss. The phase 3 TRIUMPH program includes trials specifically focused on type 2 diabetes as a primary indication. If approved, retatrutide may be indicated for both obesity and type 2 diabetes management, though final indications will depend on the results of these ongoing trials.

Last updated: 2026-02-14