Scientific Reference
Retatrutide (LY3437943)
Evidence profile: Human Phase 3 evidence
Retatrutide is a synthetic peptide designed to activate three hormone receptors: those for GIP, GLP-1 and glucagon. GIP and GLP-1 are incretins, hormones released from the gut in response to food, and glucagon is secreted by the alpha cells of the pancreas; the receptors for all three belong to the same receptor family. Earlier synthetic agonists in this family acted at one or two of these receptors, and retatrutide's distinguishing feature is that it engages all three. Its pharmacology has been described in cell assays and animal studies, and it has been examined in human clinical trials in metabolic disease.
Mechanism of Action
All three targets are class B G-protein-coupled receptors that signal mainly through Gs and cyclic AMP, and retatrutide has been reported to activate each of them in cell-based assays. GIP and GLP-1 receptors on pancreatic beta cells are coupled to glucose-dependent insulin release, and both are also expressed in the brain and other tissues. Glucagon receptors, concentrated in the liver, mediate glycogen breakdown and glucose production there and influence fatty-acid oxidation. The peptide is reported to include non-natural residues such as α-aminoisobutyric acid, used in this class to resist cleavage by dipeptidyl peptidase-4, and a fatty-acid side chain of the kind used to bind serum albumin and lengthen time in circulation.
Molecular Information
- Type: Lipidated peptide
- Length: 39 amino acids
- Molecular weight: 4731 g/mol
- Molecular formula: C221H342N46O68
Pharmacokinetics
The pharmacokinetics of LY3437943 were dose proportional and its half-life was approximately 6 days. Across dose levels, the maximum observed drug concentration (Cmax) occurred between ~1 and 3 days postdose, while the mean terminal half-life was ~5 to 7 days, thus supporting a QW dosing regimen.
Published Research
Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial
Jastreboff AM et al. · The New England journal of medicine · 2023 · Clinical
PMID 37366315 — View on PubMedEfficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial
Bajaj HS et al. · Lancet (London, England) · 2026 · Clinical
PMID 42250575 — View on PubMedRetatrutide, 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
Rosenstock J et al. · Lancet (London, England) · 2023 · Clinical
PMID 37385280 — View on PubMedLY3437943, 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
Urva S et al. · Lancet (London, England) · 2022 · Clinical
PMID 36354040 — View on PubMedEfficacy and safety of triple hormone receptor agonist retatrutide for the management of obesity: a systematic review and meta-analysis
Tewari J et al. · Expert review of clinical pharmacology · 2025 · Review
PMID 39817343 — View on PubMedEfficacy and safety of retatrutide for the treatment of obesity: a systematic review of clinical trials
Misra S et al. · Journal of basic and clinical physiology and pharmacology · 2025 · Review
PMID 40728138 — View on PubMed