Retatrutide
Also known as: LY3437943
A synthetic triple agonist activating GIP, GLP-1, and glucagon receptors simultaneously, studied for its multi-pathway effects on weight and metabolic regulation.
Molecular Data
- Class
- Triple hormone receptor agonist (GIP / GLP-1 / glucagon) — synthetic peptide
- Molecular Weight
- ~4,731 Da (fatty-acid-modified peptide)
- Molecular Formula
- C₂₂₁H₃₄₂N₄₆O₆₈
- Half-Life
- ~6 days (estimated; fatty-acid modification supports once-weekly dosing)
- Sequence / Structure
- 39-amino-acid synthetic peptide on a GIP backbone with non-coded residues (Aib-2, Aib-20, alpha-Me-Leu-13) and a C20 fatty diacid conjugate for albumin binding
Mechanism of Action
Retatrutide is a synthetic peptide engineered to activate three metabolic receptors simultaneously: the glucose-dependent insulinotropic polypeptide (GIP) receptor, the glucagon-like peptide-1 (GLP-1) receptor, and the glucagon receptor. This triple-agonist design distinguishes it from single- and dual-agonist incretin peptides and is the subject of active pharmacological research.
- GIP receptor agonism: Enhances glucose-dependent insulin secretion and has been investigated for effects on adipocyte metabolism and energy expenditure.
- GLP-1 receptor agonism: Potentiates insulin secretion, suppresses glucagon release, slows gastric emptying, and engages central satiety pathways — mechanisms shared with semaglutide and tirzepatide.
- Glucagon receptor agonism: The distinguishing feature of retatrutide's mechanism; glucagon receptor activation increases hepatic energy expenditure and promotes lipolysis, an effect absent from GIP/GLP-1-only agonists.
- Fatty acid modification: A conjugated C20 fatty diacid promotes albumin binding, extending plasma half-life and supporting once-weekly subcutaneous dosing.
The combined activation of lipolytic (glucagon) and insulinotropic (GIP/GLP-1) pathways is the basis for research interest in retatrutide's comparatively large effect sizes on body weight observed in early trials.
Research History
Retatrutide (LY3437943) was developed by Eli Lilly as an extension of incretin-based metabolic research following tirzepatide's dual GIP/GLP-1 mechanism. Coskun et al. (2018) described the design rationale for a balanced triple agonist adding glucagon receptor activity to the GIP/GLP-1 platform.
A Phase 2 dose-ranging trial (Jastreboff et al., 2023, New England Journal of Medicine) randomized adults with obesity to weekly subcutaneous retatrutide at 1, 4, 8, or 12 mg, or placebo, over 48 weeks, with gradual dose escalation for the higher-dose arms. The 12 mg dose produced mean weight reductions of 24.2%, with the 8 mg arm reaching 22.8% — among the largest effect sizes reported in incretin-based obesity research at the time of publication. The trial also reported substantial reductions in liver fat content among participants with elevated baseline levels.
As of the most recent published data, retatrutide has progressed into Phase 3 clinical development but has not received regulatory approval. It remains an investigational compound, and its long-term safety and efficacy profile continues to be studied in ongoing trials.
Notable Studies
Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial
2023Jastreboff AM, Kaplan LM, Frías JP, et al. · New England Journal of Medicine
Phase 2 dose-ranging trial (n=338) in adults with obesity; the 12 mg weekly dose produced 24.2% mean body weight reduction at 48 weeks, with dose-dependent reductions in HbA1c and liver fat.
Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial
2024Sanyal AJ, Bedossa P, Fraessdorf M, et al. · Nature Medicine
Phase 2a trial investigating retatrutide's effects on liver fat and fibrosis markers in participants with steatotic liver disease, building on hepatic findings from the primary obesity trial.
Rationale and Discovery of Retatrutide (LY3437943)
2018Coskun T, Urva S, Roell WC, et al. · Journal of Medicinal Chemistry
Describes the molecular design rationale for combining GIP, GLP-1, and glucagon receptor agonism in a single balanced synthetic peptide.
Research Protocols
The following protocols describe doses used in published research studies. They are not prescriptions or recommendations for human use.
Phase 2 obesity dose-ranging trial
- Dose
- 1 mg, 4 mg, 8 mg, or 12 mg (weekly subcutaneous)
- Route
- Subcutaneous injection
- Frequency
- Once weekly
- Duration
- 48 weeks, with dose escalation over the first 4–12 weeks for higher-dose arms
Doses used in the Jastreboff et al. 2023 NEJM Phase 2 trial; these are clinical research doses, not an approved or recommended regimen.