Weight ManagementEmerging ResearchResearch Only

Retatrutide

Also known as: LY3437943, Reta

Retatrutide is a novel investigational peptide developed by Eli Lilly that simultaneously activates three receptors: glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors. This triple-agonist mechanism represents the next evolution beyond dual-agonist drugs like tirzepatide. In Phase 2 clinical trials published in the New England Journal of Medicine, retatrutide produced unprecedented weight loss of approximately 24% of body weight at 48 weeks at the highest dose — surpassing results seen with any approved anti-obesity medication. The glucagon receptor component adds a thermogenic effect that increases energy expenditure, potentially offering advantages over drugs that primarily suppress appetite. Retatrutide is currently in Phase 3 trials and is not yet FDA-approved or commercially available.

Research Score8/10

Extensive clinical evidence

Safety Score7/10

Generally safe with some considerations

How It Works

Retatrutide is a triple agonist that activates GIP, GLP-1, and glucagon receptors simultaneously. GLP-1 and GIP reduce appetite and improve insulin secretion, while glucagon receptor activation increases hepatic energy expenditure, promotes lipolysis, and reduces liver fat.

Key Benefits

  • Highest weight loss efficacy observed in clinical trials to date
  • Triple-receptor mechanism for comprehensive metabolic effects
  • Glucagon component increases energy expenditure and thermogenesis
  • Significant improvements in glycemic control
  • Reduction in liver fat (potential MASLD/NASH benefit)
  • Improvements in blood pressure and lipid profiles
  • Once-weekly administration

Who May Benefit

  • Individuals with severe obesity seeking maximum weight loss potential
  • Patients who have plateaued on GLP-1 or dual-agonist therapy
  • People with metabolic-associated fatty liver disease (MASLD)
  • Those with obesity and type 2 diabetes requiring aggressive intervention

Dosage & Administration

Typical Dosage
Once weekly with dose titration; investigational dosing up to 12 mg
Cycle Length
Ongoing under medical supervision; dose titration over 24+ weeks in trials
Administration Routes
subcutaneous

Expected Timeline

Phase 2 data: appetite suppression within the first weeks. Significant weight loss by 12 weeks. Up to 24% average weight loss at 48 weeks. Not yet commercially available.

Safety Information

Possible Side Effects

NauseaDiarrheaVomitingConstipationDecreased appetiteDyspepsiaInjection site reactionsIncreased heart rate

Contraindications

Personal or family history of medullary thyroid carcinomaMultiple endocrine neoplasia syndrome type 2 (MEN 2)History of severe pancreatitisPregnancy or breastfeedingNot yet FDA-approved — available only through clinical trialsSevere gastrointestinal disease
Dr. Patrick Taylor, MD

Dr. Taylor's 2 Cents

“Retatrutide is the most exciting peptide on the horizon for metabolic medicine. The triple-agonist mechanism — adding glucagon to the GIP/GLP-1 combination — produces weight loss numbers we've never seen: 24% in Phase 2 trials. The glucagon component is the key differentiator, as it increases your body's energy expenditure rather than just suppressing appetite. I'm closely watching the Phase 3 results. Important caveat: retatrutide is NOT yet FDA-approved and is only available through clinical trials. When it does become available, I expect it will become a cornerstone of metabolic protocols.”

Discuss with Dr. Taylor →

Frequently Asked Questions

What is Retatrutide?
Retatrutide is an investigational triple-receptor agonist that activates GIP, GLP-1, and glucagon receptors simultaneously — making it the first triple-agonist obesity drug in late-stage development.
How does it differ from Tirzepatide?
Tirzepatide is a dual GIP/GLP-1 agonist. Retatrutide adds a third mechanism — glucagon receptor activation — which increases energy expenditure and may produce greater weight loss and liver fat reduction.
How much weight loss has been seen in trials?
Phase 2 trials showed up to 24.2% body weight loss at 48 weeks at the highest dose, the most of any anti-obesity drug studied to date.
Is Retatrutide available now?
No. Retatrutide is currently in Phase 3 clinical trials and is not yet FDA-approved or commercially available. It is expected to potentially reach the market in 2026-2027.
What are the side effects?
Similar to other incretin-based therapies: nausea, diarrhea, vomiting, and constipation, especially during dose escalation. The glucagon component may also increase heart rate slightly.
Could Retatrutide help with fatty liver?
Early data is very promising — Phase 2 trials showed up to 90% of participants with fatty liver achieved normalization of liver fat content.

Published Research

1

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

Rosenstock J, Frias JP, Rodbard HW, et al. · The Lancet (2023)

Key Finding: Retatrutide at the highest dose achieved HbA1c reductions of up to 2.02% and body weight reductions of up to 16.9% at 36 weeks in patients with type 2 diabetes, outperforming dulaglutide.

PubMed →DOI →
2

Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial

Jastreboff AM, Kaplan LM, Frías JP, et al. · New England Journal of Medicine (2023)

Key Finding: Retatrutide produced dose-dependent weight reductions up to 24.2% at 48 weeks in adults with obesity, with 100% of participants in the highest-dose group achieving at least 5% weight loss.

PubMed →DOI →
3

Retatrutide Phase 2 Trial in MASLD: Liver Fat and Metabolic Improvements

Sanyal AJ, Kaplan LM, Frias JP, et al. · New England Journal of Medicine (2024)

Key Finding: Retatrutide achieved normalization of liver fat (<5%) in up to 90% of participants with MASLD at 48 weeks, demonstrating potential as a treatment for metabolic liver disease.

PubMed →DOI →

Protocols Featuring Retatrutide

GLP-1 Weight Management Protocol
Evidence-based metabolic support

Related Peptides

Tirzepatide
Weight Management
Semaglutide
Weight Management

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Medical Disclaimer: This information is for educational purposes only and is not medical advice. Consult a healthcare provider before starting any peptide protocol.