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Retatrutide

Also known as: LY-3437943

Research Only

Molecular Formula

C221 H342 N46 O68

Molecular Weight

4,731.34 Da

Half-Life

~6 days (human circulation)

Sequence

Y-{Aib}-QGTFTSDYSI-{α-Me-L}-LDKK((AEEA)-γ-Glu-C20 diacid)AQ-{Aib}-AFIEYLLEGGPSSGAPPPS-NH2

Clinical Applications & Evidence

Mechanism of Action

Retatrutide exhibits triple agonism across GLP-1R, GIPR, and GCGR. GLP-1 and GIP receptor activation enhances glucose-dependent insulin secretion, suppresses glucagon in hyperglycemia, and signals central satiety. Concomitant glucagon-receptor activation increases lipid mobilization and resting energy expenditure in preclinical models. The exact extent to which human weight loss is driven by appetite suppression versus increased energy expenditure remains under investigation.

Investigated Uses

  • Obesity & overweight (Investigational Phase 3 — TRIUMPH-1 reported mean weight change up to −28.3% at 80 weeks at 12 mg under efficacy estimand)
  • Knee osteoarthritis with obesity (Investigational Phase 3 — TRIUMPH-4 reported up to −28.7% weight loss and WOMAC pain reduction at 68 weeks)
  • Type 2 Diabetes Mellitus (Investigational Phase 3 — TRANSCEND-T2D-1 & TRIUMPH-2 reported HbA1c reductions up to 2.0% and weight loss up to −20.8%)
  • Metabolic dysfunction-associated steatotic liver disease / MASLD (Investigational Phase 2a — MRI substudy demonstrated >80% relative liver fat reduction)
  • Obstructive sleep apnea (Investigational Phase 3 nested cohorts)
Early Clinical / Animal Models

Regulatory & Safety Status

FDA Status

Research Only

WADA / Athletic Status

Prohibited at All Times (WADA S4.4.1)

Known Side Effects

Gastrointestinal events (nausea, diarrhea, vomiting, constipation, decreased appetite)Dysesthesia / cutaneous hyperesthesia (reported in 5.1%–12.5% in TRIUMPH-1 and up to 20.9% at 12 mg in TRIUMPH-4)Dose-dependent trial discontinuation due to adverse events (4.1% at 4 mg up to 11.3% at 12 mg in TRIUMPH-1)Transient pulse rate elevation and mild blood pressure changes

Contraindications

  • WADA-tested athletes (Prohibited at all times under S0 Non-Approved Substances)
  • Personal or family history of medullary thyroid carcinoma or MEN2 (Provisional class-related exclusion)
  • History of severe pancreatitis or active gallbladder disease (Provisional class-related precaution)
  • Pregnancy and lactation (Unstudied safety profile)

Drug Interactions

  • Insulin and insulin secretagogues / sulfonylureas (Anticipated class-related risk of hypoglycemia)
  • Concomitant oral medications requiring rapid gastrointestinal absorption (Delayed gastric emptying)

Citations & Clinical Trials

PubMed Triple-Hormone-Receptor Agonist Retatrutide for Obesity — Phase 2 Trial (NEJM 2023) PubMed Discovery and Characterization of LY3437943: A Novel GIP/GLP-1/Glucagon Triple Agonist (2022) Nature Medicine Retatrutide in MASLD: Phase 2a MRI Substudy Results (Nature Medicine 2024) Eli Lilly Investor Relations Lilly Phase 3 TRIUMPH-1 & TRIUMPH-4 Topline Disclosures (2026) FDA FDA Drug Alert: Concerns with Unapproved GLP-1/GIP Products for Weight Loss World Anti-Doping Agency WADA 2026 Prohibited List — S0 Non-Approved Substances Guidance