Triple GLP-1 / GIP / Glucagon Receptor Agonist

Retatrutide

Also Known As: LY3437943, LY-3437943

Retatrutide (LY3437943) is a synthetic 39-amino-acid lipidated peptide that simultaneously activates the GLP-1, GIP and glucagon receptors. The triple-agonist architecture combines appetite-suppressing and insulinotropic incretin effects with glucagon-mediated increases in basal energy expenditure. It is currently in Phase 3 clinical development by Eli Lilly under the TRIUMPH program.

Identity & Chemistry

Amino acid sequence diagram of retatrutide (LY3437943), a 39-residue lipidated peptide showing the C20 fatty diacid conjugate at lysine 17.
Image credit: Benff, via Wikimedia Commons · CC BY-SA 4.0
Amino Acid Sequence
Y-Aib-Q-G-T-F-T-S-D-Y-S-I-(αMeLeu)-L-D-K-K(γGlu-AEEA-C20-diacid)-A-Q-Aib-A-F-I-E-Y-L-L-E-G-G-P-S-S-G-A-P-P-P-S-NH₂
Molecular Formula
C₂₂₁H₃₄₂N₄₆O₆₈
Molecular Weight
4731.41 Da
CAS Number
2381089-83-2
PubChem CID
171390338
IUPAC Name
L-tyrosyl-2-methylalanyl-L-glutaminylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-tyrosyl-L-seryl-L-isoleucyl-2-methyl-L-leucyl-L-leucyl-L-α-aspartyl-L-lysyl-N⁶-(N-(19-carboxy-1-oxononadecyl)-L-γ-glutamyl-2-(2-(2-aminoethoxy)ethoxy)acetyl)-L-lysyl-L-alanyl-L-glutaminyl-2-methylalanyl-L-alanyl-L-phenylalanyl-L-isoleucyl-L-α-glutamyl-L-tyrosyl-L-leucyl-L-leucyl-L-α-glutamylglycylglycyl-L-prolyl-L-seryl-L-serylglycyl-L-alanyl-L-prolyl-L-prolyl-L-prolyl-L-serinamide
Solubility
Soluble in sterile or bacteriostatic water and 0.9% NaCl for reconstitution. The lipophilic C20 side chain may require brief pre-wetting with a small volume of DMSO followed by aqueous dilution. Quantitative solubility values are not publicly disclosed by the originator.
Storage
Lyophilized peptide: −20 °C for short-term storage (1–3 months), −80 °C for long-term storage. Reconstituted solution: 2–8 °C, do not freeze, protect from light.

Mechanism of Action

Retatrutide is a synthetic peptide that simultaneously engages three metabolic G-protein-coupled receptors — GLP-1, GIP and glucagon. The combined activation pairs incretin-driven appetite and glycemic control with glucagon-driven energy expenditure.

Retatrutide is engineered to engage three metabolic GPCRs simultaneously, with reported in vitro potency biased toward GIPR while maintaining balanced GLP-1R and GCGR activity. GLP-1R and GIPR co-activation drive glucose-dependent insulin secretion and reduce caloric intake via central pathways and slowed gastric emptying. GCGR agonism is intended to raise basal energy expenditure and promote hepatic fatty-acid oxidation, theoretically amplifying weight loss beyond what GLP-1/GIP dual agonists achieve. The molecule incorporates 2-aminoisobutyric acid at positions 2 and 20 to block dipeptidyl peptidase-4 cleavage, and a C20 fatty diacid linked through a γ-Glu-AEEA spacer at lysine 17 enables reversible albumin binding, supporting a half-life compatible with once-weekly subcutaneous dosing. Cryo-EM studies have resolved retatrutide bound to all three receptors.

Molecular Targets

  • Glucagon-like peptide-1 receptor (GLP-1R)
  • Glucose-dependent insulinotropic polypeptide receptor (GIPR)
  • Glucagon receptor (GCGR)

Signaling Pathways

  • Gαs-coupled cAMP/PKA signaling at all three receptors
  • GLP-1R activation: glucose-dependent insulin secretion, delayed gastric emptying, central appetite suppression
  • GIPR activation: insulin secretion, modulation of adipocyte lipid handling
  • GCGR activation: hepatic glucose output (offset by incretin-driven insulin), increased basal energy expenditure, lipolysis, hepatic fatty-acid oxidation
  • Aib substitutions at positions 2 and 20 confer DPP-4 resistance; C20 diacid lipidation enables albumin binding and once-weekly dosing

Research Applications

Retatrutide is being evaluated in a comprehensive clinical program across multiple indications, with published Phase 2 data in obesity, type 2 diabetes and MASLD/MASH, and the first positive Phase 3 readout from the TRIUMPH program.

Obesity / weight management (adults without T2D)

Phase II

Studies report a least-squares mean body-weight change of −24.2% at 48 weeks at the 12 mg dose vs −2.1% on placebo (n=338).

— Jastreboff et al., NEJM 2023;389(6):514–526

Type 2 diabetes mellitus

Phase II

At 36 weeks, the 12 mg dose was associated with HbA1c reductions of approximately −2.0 percentage points and body-weight reductions of approximately −16.9% from baseline (n=281).

— Rosenstock et al., Lancet 2023;402(10401):529–544

MASLD / MASH (metabolic dysfunction-associated steatotic liver disease)

Phase II

Studies report relative liver-fat reductions at 24 weeks of −81.4% (8 mg) and −82.4% (12 mg) vs +0.3% placebo; 86% of participants on the 12 mg dose achieved liver fat <5%.

— Sanyal et al., Nat Med 2024;30(7):2037–2048

Obesity with knee osteoarthritis (TRIUMPH-4)

Phase III

At 68 weeks, participants on retatrutide 12 mg lost on average 28.7% of body weight; WOMAC pain scores fell by up to 4.5 points (~75.8%). A new dysesthesia signal was reported in 20.9% on 12 mg vs 0.7% on placebo.

— Eli Lilly press release, October 2025

Body composition in type 2 diabetes

Phase II

Studies report dose-dependent reductions in total fat mass and visceral adipose tissue, with greater absolute fat-mass than lean-mass loss; lean-to-fat-loss ratios consistent with lifestyle-induced weight loss.

— Coskun et al., Lancet Diabetes Endocrinol 2025;13(8):674–684

Preclinical pharmacology

preclinical

Studies report that LY3437943 produced sustained body-weight reduction and improved glycemic control in obese mouse models, attributed to GCGR-mediated increases in energy expenditure combined with incretin-driven hypophagia.

— Coskun et al., Cell Metab 2022;34(9):1234–1247

Clinical Status

Regulatory Status
Investigational. Not approved by the FDA, EMA, MHRA or other major regulatory authorities as of May 2026.
Highest Trial Phase
Phase 3 (TRIUMPH program; first positive Phase 3 readout reported October 2025)
Sponsor
Eli Lilly and Company

Key Clinical Trials

  • Phase 2 trial in adults with obesity (Jastreboff et al. 2023)
    Phase 2
    NCT04881760
  • Phase 2 trial in adults with type 2 diabetes (Rosenstock et al. 2023)
    Phase 2
    NCT04867785
  • TRIUMPH-1: Phase 3 in obesity/overweight without T2D
    Phase 3
    NCT05929066
  • TRIUMPH-2: Phase 3 in obesity/overweight with T2D
    Phase 3
    NCT05929079
  • TRIUMPH-3: Phase 3 in obesity and cardiovascular disease
    Phase 3
    NCT05882045
  • TRIUMPH-4: Phase 3 in obesity/overweight with knee osteoarthritis
    Phase 3
    NCT05931367

Safety Profile

Observed in research settings

Across Phase 2 and the first Phase 3 readouts, the safety profile is broadly consistent with the GLP-1 receptor agonist class — dominated by dose-dependent gastrointestinal adverse events that are mostly mild to moderate — with additional class-specific signals related to glucagon receptor activation and a recently reported dysesthesia signal at 12 mg in TRIUMPH-4.

Adverse Events Reported in Studies

  • Nausea (dose-dependent; reported in roughly one-third or more of higher-dose participants)
  • Diarrhea
  • Vomiting
  • Constipation
  • Decreased appetite
  • Injection-site reactions

Serious Adverse Events

  • Transient increases in heart rate (peaking around week 24, declining thereafter)
  • Transient changes in glycemic variability markers and modest blood-pressure changes reported in some subgroups
  • Dysesthesia (abnormal cutaneous sensation) reported in 20.9% on 12 mg vs 0.7% placebo in TRIUMPH-4 — described as a new safety signal under further evaluation
  • No severe hypoglycemia and no treatment-related deaths reported in published Phase 2 datasets

References

  1. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med 2023;389(6):514–526. 2023 .

    DOI: 10.1056/NEJMoa2301972 PMID: 37366315 View Source

  2. Rosenstock J, Frias J, Jastreboff AM, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet 2023;402(10401):529–544. 2023 .

    DOI: 10.1016/S0140-6736(23)01053-X PMID: 37385280 View Source

  3. Sanyal AJ, Kaplan LM, Frias JP, 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. 2024 .

    DOI: 10.1038/s41591-024-03018-2 PMID: 38858523 View Source

  4. Coskun T, Urva S, Roell WC, et al. 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 Metab 2022;34(9):1234–1247.e9. 2022 .

    DOI: 10.1016/j.cmet.2022.07.013 PMID: 35985340 View Source

  5. Urva S, Coskun T, Loh MT, et al. 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. Lancet 2022;400(10366):1869–1881. 2022 .

    DOI: 10.1016/S0140-6736(22)02033-5 PMID: 36354040 View Source

  6. Coskun T, Sloop KW, Loghin C, et al. Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2025;13(8):674–684. 2025 .

    DOI: 10.1016/S2213-8587(25)00092-0 PMID: 40609566 View Source

  7. Eli Lilly and Company 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, October 2025. 2025 .

    View Source

Frequently Asked Questions

What is retatrutide?
Retatrutide (development code LY3437943) is an investigational, once-weekly subcutaneous peptide developed by Eli Lilly that simultaneously activates the GLP-1, GIP and glucagon receptors. It is being studied for obesity, type 2 diabetes and related metabolic conditions and is currently in Phase 3 clinical evaluation.
How does retatrutide differ from tirzepatide?
Tirzepatide is a dual GLP-1/GIP receptor agonist, whereas retatrutide adds a third activity at the glucagon receptor, hypothesized to increase basal energy expenditure on top of incretin-driven appetite reduction. Cross-trial comparisons (no head-to-head trial published) suggest greater mean weight loss with retatrutide at higher doses, though gastrointestinal adverse events also appear more frequent at top doses.
Is retatrutide approved?
No. As of May 2026, retatrutide is not approved by the FDA, EMA, MHRA or any other major regulator and remains an investigational compound limited to clinical trials and laboratory research.
What is the molecular structure of retatrutide?
Retatrutide is a synthetic 39-amino-acid peptide with molecular formula C₂₂₁H₃₄₂N₄₆O₆₈ and a molecular weight of approximately 4731 Da; CAS number 2381089-83-2. It contains two 2-aminoisobutyric acid residues for DPP-4 resistance and a C20 fatty-diacid side chain at lysine 17 that enables albumin binding and once-weekly dosing.
What weight loss has been observed in retatrutide trials?
In the Phase 2 obesity trial, mean body-weight reduction at 48 weeks was 24.2% at 12 mg vs 2.1% placebo. In the TRIUMPH-4 Phase 3 trial in obesity with knee osteoarthritis, mean weight loss reached 28.7% at 68 weeks on the 12 mg dose.
What are the main side effects reported in retatrutide trials?
The most commonly reported adverse events are gastrointestinal — nausea, diarrhea, vomiting and constipation — most often mild to moderate and dose-dependent. Transient increases in heart rate have also been reported, and the TRIUMPH-4 readout disclosed a dysesthesia signal at the 12 mg dose that is under further evaluation.

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