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Retatrutide

Retatrutide

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First-in-class triple agonist (GIP/GLP-1/glucagon receptor) peptide; most potent weight loss agent in clinical development with up to 28.7% body weight reduction in Phase 2 trials

Quick Facts

Property Value
Also Known As LY3437943, Reta, GLP-3 (Ageless Peps commercial name), OV20
Category Metabolic / Weight Loss / GH Axis
Sequence Proprietary modified peptide (39 amino acids with Aib substitutions and C20 fatty diacid for albumin binding)
Molecular Weight 4731 Da
Molecular Formula Proprietary (Eli Lilly)
PubChem CID 163193043
Administration SubQ (once weekly)
Typical Dose Range 2-12 mg/week (titrated over 12+ weeks)
Half-Life ~6 days (144 hours); enabled by C20 fatty diacid albumin binding
Storage Lyophilized: -20°C long-term; Reconstituted: 2-8°C, use within 28 days
FDA Status Investigational — Phase 3 TRIUMPH trials ongoing (Eli Lilly). Not FDA-approved
WADA Status Not specifically listed; GLP-1 RAs are not prohibited but peptide hormones in general are under S2

Mechanism of Action

Retatrutide is a single-molecule triple agonist that simultaneously activates three key metabolic receptors: glucose-dependent insulinotropic polypeptide receptor (GIPR, UniProt P48546), glucagon-like peptide-1 receptor (GLP-1R, UniProt P43220), and glucagon receptor (GCGR, UniProt P47871). This tri-agonist design delivers complementary and synergistic metabolic effects that exceed what dual agonists (tirzepatide: GIP/GLP-1) or single agonists (semaglutide: GLP-1) can achieve alone.

GIP Receptor Agonism (EC50 = 0.0643 nM, ~8.9x more potent than native GIP): GIPR activation on pancreatic beta-cells and adipocytes enhances insulin sensitivity and glucose-dependent insulin secretion. In the CNS, GIP signaling in the hypothalamus and brainstem contributes to appetite suppression. The supraphysiological GIPR potency of retatrutide may drive insulin sensitization and fat mobilization beyond what native GIP achieves.

GLP-1 Receptor Agonism (EC50 = 0.775 nM): GLP-1R activation produces the well-characterized incretin effects: glucose-dependent insulin secretion, glucagon suppression, gastric emptying delay, and hypothalamic satiety signaling via POMC/CART pathways. The GLP-1 component provides the established backbone of appetite suppression and glycemic control seen with approved GLP-1 RAs (PMID-37366315).

Glucagon Receptor Agonism (EC50 = 5.79 nM, intentionally attenuated): This is the distinguishing feature of retatrutide versus dual agonists. Glucagon receptor activation drives hepatic lipid oxidation, increases energy expenditure via futile substrate cycling, and promotes thermogenesis. The intentionally attenuated GCGR potency (lowest of the three) provides metabolic benefits while limiting the hyperglycemic risk of unrestrained glucagon action — the concurrent GLP-1R and GIPR activation counterbalance any glucagon-mediated glucose elevation (PMID-37366315).

The molecule incorporates Aib (alpha-aminoisobutyric acid) substitutions for DPP-4 resistance and a C20 fatty diacid side chain that enables non-covalent albumin binding, extending the half-life to approximately 6 days and supporting once-weekly subcutaneous dosing.

Key Research Areas

  1. Obesity & Weight Loss — The Phase 2 trial (n=338) demonstrated up to 28.7% body weight loss (mean 71.2 lbs) at the 12 mg dose over 48 weeks, the largest weight reduction reported for any anti-obesity pharmacotherapy. 100% of the 12 mg group lost at least 5% body weight; 83% lost at least 15% (PMID-37366315).

  2. NAFLD/MASLD Liver Fat Reduction — At the 12 mg dose, retatrutide produced an 82.4% relative reduction in liver fat content by MRI-PDFF at 24 weeks, with 86% of participants achieving normal liver fat (<5%) (PMID 38858523, Sanyal AJ et al., Nat Med 2024;30(7):2037-2048, NCT04881760, n=98 MASLD substudy). Dose-responsive HOMA2-IR improvement (up to ~50%), K-18 reduction (−49.6% at 8/12 mg), and pro-C3 reduction (−26.4% at 12 mg) support both metabolic and early anti-injury/anti-fibrogenic mechanisms. This dramatic effect on hepatic steatosis is attributed primarily to the glucagon receptor component driving hepatic lipid oxidation, a mechanism not present in GLP-1-only or dual GIP/GLP-1 agonists.

  3. Type 2 Diabetes — Phase 2 data in T2D patients showed significant HbA1c reductions alongside weight loss. The triple agonist mechanism addresses both insulin secretion (GLP-1, GIP) and hepatic glucose/lipid metabolism (glucagon).

  4. Metabolic Parameter Improvements — Beyond weight loss, retatrutide improved waist circumference, blood pressure, triglycerides, and other cardiometabolic markers, suggesting broad metabolic syndrome benefit.

  5. Comparative Efficacy — Network meta-analyses comparing GLP-1 RAs, dual agonists, and retatrutide position the triple agonist as the most efficacious weight loss agent, though head-to-head Phase 3 data is pending (PMID-40685589, PMID-39761578).

  6. Systematic Review of Metabolic Markers — Meta-analysis of RCTs confirmed dose-dependent improvements across weight, glycemic, and lipid endpoints with once-weekly subcutaneous administration (PMID-39318607).

Evidence Level Summary

Evidence Type Count Notes
Systematic reviews / Meta-analyses 2 Metabolic markers meta-analysis; Bayesian NMA vs other anti-obesity agents
Human RCTs 1 Phase 2 obesity trial (n=338, 48 weeks), Jastreboff 2023 NEJM
Human observational 1 Network meta-analysis with indirect comparisons
Animal in vivo 0 Preclinical data in Lilly publications (not indexed as standalone research notes)
Narrative reviews 1 Incretin-based pharmacotherapy and resistance exercise review

Clinical Applications

  • Weight Management — Most potent weight loss pharmacotherapy in clinical development; 28.7% body weight reduction at highest dose
  • NAFLD — 82.4% liver fat reduction at 12 mg dose; glucagon receptor-mediated hepatic lipid oxidation
  • Type 2 Diabetes — Triple agonist addresses glycemic control through complementary insulin-sensitizing and hepatic metabolic pathways
  • Metabolic Syndrome — Broad cardiometabolic improvements across weight, lipids, blood pressure, and waist circumference
  • Fat Loss — Dose-dependent fat mass reduction with preservation of lean mass (especially when combined with resistance exercise)

Protocols Using This Peptide

  • Weight Loss Protocol — Retatrutide as an advanced/emerging option for patients who have plateaued on GLP-1 RAs or dual agonists
  • Metabolic Reset Protocol — Triple agonist approach for comprehensive metabolic syndrome intervention

Ageless Peps Products

Commercial Naming Note: Ageless Peps markets the triple agonist concept under the name "GLP-3". This is a commercial/brand name — the scientific name is Retatrutide (LY3437943). "GLP-3" reflects the three receptor targets (GLP-1R, GIPR, GCGR) and is not an established scientific nomenclature. There is no endogenous hormone called "GLP-3" and there is no GLP-3 receptor. The name is purely commercial.

  • GLP-3 Vial (WC ID 713, $130) — DRAFT, not published. Triple agonist targeting GLP-1, GIP, and glucagon receptors. When published, a Product note should be created as AP-glp-3-vial.md
  • Sample Pack (WC ID 2057, $165) — Contains "GLP-3" (retatrutide) + BPC-157 + TB-500. Published and available. The "GLP-3" component in this pack maps to retatrutide

Dosing Reference

Research Dosing Ranges (from literature)

Route Dose Range Frequency Duration Source
SubQ 2 mg/week (initiation) Once weekly Weeks 1-4 PMID-37366315
SubQ 4 mg/week (escalation 1) Once weekly Weeks 5-8 PMID-37366315
SubQ 6-8 mg/week (escalation 2) Once weekly Weeks 9-12 PMID-37366315
SubQ 9-12 mg/week (maintenance) Once weekly Weeks 13+ PMID-37366315

Standard Titration Schedule

Phase Weeks Dose
Initiation 1-4 2.0 mg weekly
Escalation 1 5-8 4.0 mg weekly
Escalation 2 9-12 6.0-8.0 mg weekly
Maintenance 13+ 9.0-12.0 mg weekly

Rotate injection sites: abdomen, thigh, upper arm. Slow titration is essential to mitigate GI side effects (nausea, vomiting, diarrhea).

Cycling

Standard peptide cycling is NOT appropriate for retatrutide given its 6-day half-life and the need for sustained receptor activation to maintain weight loss and metabolic improvements. Discontinuation may result in weight regain, as observed with other incretin-based therapies.

Contraindications & Safety

  • Contraindications: Personal or family history of medullary thyroid carcinoma (absolute); MEN-2 syndrome (absolute); Type 1 diabetes (absolute); active severe GI disease
  • Common side effects: Nausea (dose-dependent, mitigated by slow titration), vomiting, diarrhea, constipation, decreased appetite. Most GI side effects are mild-to-moderate and diminish over time
  • Drug interactions: Sulfonylureas or insulin may cause hypoglycemia when combined; oral medications may have altered absorption due to gastric emptying delay; oral contraceptives should be monitored for efficacy
  • Pregnancy/nursing: Contraindicated in pregnancy (discontinue at least 2 months before planned conception given long half-life); not recommended during breastfeeding
  • Special populations: Dose-dependent heart rate increase (typically 2-4 bpm); gallbladder disease risk with rapid weight loss (cholecystectomy rate monitoring in Phase 3); history of pancreatitis is a relative contraindication; not studied in severe renal or hepatic impairment

Synergistic Combinations

  • Retatrutide is typically used as a standalone agent given the comprehensiveness of its tri-agonist mechanism. Adding separate GLP-1 RAs or GIP agonists would be redundant.
  • Prior Semaglutide or Tirzepatide users may transition to retatrutide for plateau-breaking when weight loss stalls on single or dual agonists
  • BPC-157 + TB-500 — The Sample Pack combination (GLP-3 + BPC-157 + TB-500) pairs metabolic optimization with tissue repair, potentially supporting patients who are combining weight loss with musculoskeletal recovery
  • 5-Amino-1MQ — NNMT inhibitor may complement retatrutide by addressing cellular metabolic pathways not directly targeted by the triple agonist

Related Research

PMID Title Year Study Type
PMID-37366315 Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial 2023 Phase 2 RCT
PMID-39318607 Effects of Once-Weekly Subcutaneous Retatrutide on Weight and Metabolic Markers: A Systematic Review and Meta-Analysis 2024 Systematic Review / Meta-Analysis
PMID-38687506 Incretin-Based Weight Loss Pharmacotherapy: Can Resistance Exercise Optimize Changes in Body Composition? 2024 Narrative Review
PMID-40685589 Efficacy and Safety of GLP-1 Receptor Agonists, Dual Agonists, and Retatrutide for Weight Loss 2025 Bayesian Network Meta-Analysis
PMID-39761578 Efficacy and Safety of GLP-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes 2024 Meta-Analysis
PMID-38858523 Triple Hormone Receptor Agonist Retatrutide for MASLD: Phase 2a Randomized Trial 2024 Phase 2a RCT

References

  • PMID-37366315: Jastreboff AM, Kaplan LM, Frias JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526.
  • PMID-38687506: Weiss EP, et al. Incretin-Based Weight Loss Pharmacotherapy: Can Resistance Exercise Optimize Changes in Body Composition? Obesity (Silver Spring). 2024.
  • PMID-39318607: Pasqualotto E, et al. Effects of Once-Weekly Subcutaneous Retatrutide on Weight and Metabolic Markers. Metabol Open. 2024.
  • PMID-39761578: Efficacy and Safety of GLP-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes. 2024.
  • PMID-40685589: Sinha B, Ghosal S. Efficacy and Safety of GLP-1 Receptor Agonists, Dual Agonists, and Retatrutide for Weight Loss. Obesity (Silver Spring). 2025.
  • PMID-38858523: Sanyal AJ, Bedossa P, Fraessdorf M, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med. 2024;30(7):2037-2048. doi: 10.1038/s41591-024-03018-2.

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#peptide #metabolic #subq