Scientific Reference
Retatrutide
Evidence profile: Human Phase 3 evidence
Retatrutide (development code LY3437943) is a synthetic peptide designed to stimulate three hormone receptors at once: those for GIP, GLP-1 and glucagon. GIP and GLP-1 are incretins, hormones the gut releases in response to food, while glucagon comes from the alpha cells of the pancreas, and all three receptors belong to one family. Earlier synthetic agonists of this family acted on one or two of the receptors; retatrutide's distinguishing feature is engaging 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
The three targets are class B G-protein-coupled receptors that signal mainly through Gs and cyclic AMP, and retatrutide is reported to activate each in cell-based assays. On pancreatic beta cells, GIP and GLP-1 receptors are tied to glucose-dependent insulin release, and both also occur in the brain and elsewhere. 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 alpha-aminoisobutyric acid, which in this class resists dipeptidyl peptidase-4, plus a fatty-acid side chain of the sort that binds serum albumin and lengthens time in circulation.
Molecular Information
- Type: Lipidated triple-agonist peptide
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