Metabolic & GLP-1PeptideEvidence B4 cited

Retatrutide

Triple Hormone Receptor Agonist

aka LY3437943 · triple agonist · GGG agonist

A first-in-class triple receptor agonist researched for its exceptional weight reduction and metabolic effects.

Molecular wt

4731g/mol

Formula

C221H342N46O68

Half-life

5 days

clinical

Tmax

1 day

PubChem

171934787

Sequence

One-letter19 residues

Y-Aib-QGTFTSDYSI-(alphaMeLeu)-LDKK(acyl)AQ-Aib-AFIEYLLEGGPSSGAPPPS-NH2

Read this before quoting the sequence

39-residue triple GIP/GLP-1/glucagon receptor agonist (LY3437943). ChEMBL records the backbone as YA1QGTFTSDYSIL2LDKK4AQA1AFIEYLLEGGPSSGAPPPS3 where A1 = Aib (alpha-aminoisobutyric acid, positions 2 and 20), L2 = alpha-methyl-leucine (position 13), K4 = the acylated lysine (position 17, bearing a gamma-Glu / linker / C20 fatty diacid side chain) and S3 = C-terminal Ser-amide. The acylation position is independently corroborated by Li et al. 2024, which describes acylation 'via a linker connected to the lysine residues at position 17'.

Source ↗

Mechanism of action

Retatrutide works by activating three receptors: GLP-1, GIP, and glucagon. This activation enhances insulin secretion, reduces appetite, and increases energy expenditure. The combined effect leads to significant weight loss and improved metabolic health. It also influences glucose metabolism and lipid profiles.

What the evidence actually shows

Grade B

There are a few human trials, primarily in Phase III, showing significant weight loss and metabolic improvements. However, long-term safety and efficacy data are still needed. The trials indicate promising results but are limited in duration and participant diversity.

Regulatory status

Status

Investigational; not approved by FDA or EMA.

Clinical stage

Phase 3. ClinicalTrials.gov lists 14 Phase 3 studies (8 active-not-recruiting, 5 completed, 1 recruiting) alongside completed Phase 1 and Phase 2 work.

emerging

Retatrutide is currently under investigation and not yet approved by the MHRA. It is considered an emerging treatment for obesity and metabolic disorders.

Source ↗

Pharmacokinetics

Half-life

5 days

Tmax

1 day

Absorption

subcutaneous

Elimination

both

Washout

35 days

Titration

Dose escalation per protocol

Low-confidence pharmacokinetics

These figures are recorded as clinical rather than measured in a published PK study. Treat them as an order of magnitude. Anything downstream of them — accumulation, steady state, washout — inherits that uncertainty.

Dosing — what backs each figure

Retatrutide is an investigational GIP/GLP-1/glucagon triple agonist with no approval anywhere; published phase 2 human dosing is once-weekly subcutaneous with stepwise escalation from a 2 mg start to maintenance doses of 1-12 mg, given continuously for 36-48 weeks. Escalation pace, not just final dose, is what the trials manipulated to control gastrointestinal side effects.

ClinicalApproved labelling or a published human trial

Subcutaneous once weekly for 48 weeks at maintenance doses of 1 mg, 4 mg (initial dose 2 mg or 4 mg), 8 mg (initial dose 2 mg or 4 mg) or 12 mg (initial dose 2 mg); the lower 2 mg start partially mitigated gastrointestinal adverse events
adults with BMI >=30, or BMI 27-<30 with a weight-related condition (n=338) · subcutaneous
Jastreboff et al., N Engl J Med 2023;389(6):514-526, phase 2 (NCT04881760) ↗
Subcutaneous once weekly for 36 weeks at maintenance doses of 0.5 mg, 4 mg (start 2 mg or no escalation), 8 mg (start 2 mg or 4 mg) or 12 mg (start 2 mg)
adults aged 18-75 with type 2 diabetes, HbA1c 7.0-10.5%, BMI 25-50 (n=281) · subcutaneous
Rosenstock et al., Lancet 2023;402(10401):529-544, phase 2 (NCT04867785) ↗

Handling and storage

No compound-specific stability data exists

No compound-specific stability data from an approved label or peer-reviewed stability study was located. Only generic research-peptide handling guidance exists, which is not compound-specific and is therefore not recorded here. Retatrutide is investigational and has no approved label. General peptide handling still applies — reconstitute gently, keep it cold, keep it dark — but any specific figure you see quoted for this compound elsewhere is someone's assumption, not a measurement.

→ Reconstitution walkthrough → Reconstitution calculator

Safety

Commonly reported

·Nausea
·Diarrhea
·Vomiting

Rarely reported

·Pancreatitis
·"Thyroid tumors"

Contraindications

·Personal or family history of medullary thyroid carcinoma
·Multiple endocrine neoplasia syndrome type 2

Drug interactions

·Insulin: May enhance hypoglycemic effect due to increased insulin sensitivity

GI effects (nausea, diarrhoea); dose-dependent heart-rate rise reported

Reported combinations

Reported as synergistic

·Metformin: May enhance glucose-lowering effects

Reported as antagonistic

·Corticosteroids: May counteract weight loss effects

Combination claims in this dataset are largely unsourced and should be treated as folk knowledge until a citation appears beside them.

References (4)

Jastreboff AM, Kaplan LM, Frias JP, Wu Q, Du Y, Gurbuz S, Coskun T, Haupt A, Milicevic Z, Hartman ML (2023) Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. ↗
The New England Journal of MedicinePMID 37366315DOI
Phase 2 trial (NCT04881760) in 338 adults with obesity; subcutaneous retatrutide once weekly for 48 weeks produced least-squares mean weight change of -8.7% (1 mg), -17.1% (4 mg), -22.8% (8 mg) and -24.2% (12 mg) versus -2.1% for placebo. Gastrointestinal adverse events were dose-related.
Coskun T, Urva S, Roell WC, Qu H, et al. (2022) 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 MetabolismPMID 35985340DOI
Discovery and first-in-human paper; reports balanced GCGR/GLP-1R with greater GIPR activity in vitro, weight and glycaemic benefit in obese mice, and a Phase 1 single-ascending-dose pharmacokinetic profile supporting once-weekly dosing.
Li W, Zhou Q, Cong Z, Yuan Q, et al. (2024) Structural insights into the triple agonism at GLP-1R, GIPR and GCGR manifested by retatrutide. ↗
Cell DiscoveryPMID 39019866DOI
Cryo-EM structures of retatrutide bound to all three receptors; confirms the Aib and alpha-methyl-Leu substitutions and acylation via a linker at the lysine at position 17.
Giblin K, Kaplan LM, Somers VK, et al. (2026) Retatrutide for the treatment of obesity, obstructive sleep apnea and knee osteoarthritis: Rationale and design of the TRIUMPH registrational clinical trials. ↗
Diabetes, Obesity and MetabolismPMID 41090431DOI
Design paper for the Phase 3 TRIUMPH registrational programme, documenting that retatrutide has advanced to Phase 3.

Data provenance

Chemistry and citations on this page were checked against primary sources on 2026-08-14. Values that could not be verified were left blank rather than filled with a plausible guess.

Could not verify
casNumber, storage, reconstitution, regulatory.wada

Research use only

This profile is educational reference material. It is not medical advice, not a prescription, and not an endorsement of self-administration. Compounds discussed here are research chemicals and most are not approved for human therapeutic use.

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