Retatrutide — pharmacology
Molecular targets, mechanism of action, pharmacokinetics and interactions as characterised in humans.
§2Pharmacology
§2.1Molecular targets
Table 2. Molecular targets recorded for Retatrutide, with the character of the interaction and the potency where the Institute holds it.
| Target | Interaction | Note |
|---|---|---|
| GIP receptor (GIPR) | Agonist | Balanced with GLP-1 arm |
| GLP-1 receptor (GLP1R) | Agonist | Approximately equipotent with GIPR in the reported profile |
| Glucagon receptor (GCGR) | Agonist | Lower relative potency; contributes energy expenditure and hepatic effects |
§2.2Mechanism of action
Retatrutide adds glucagon receptor agonism to the dual incretin mechanism. Glucagon receptor activation increases hepatic fatty-acid oxidation and resting energy expenditure and reduces hepatic steatosis, and in the reported phase 2 data appears to contribute weight loss beyond that attributable to appetite suppression alone. The counterpoise is glucagon-driven hepatic glucose output, which must be offset by the incretin arms; the reported profile is engineered so that net glycaemic effect remains favourable.[1,2]
§2.3Pharmacokinetics
- Terminal half-life
- ≈6 days
- Time to maximum concentration
- approximately 24–48 h
- Volume of distribution
- not published
- Plasma protein binding
- high (albumin-binding diacid)
- Clearance
- not published
- Bioavailability
- not published
Assumed proteolytic and beta-oxidative, consistent with the acylated-peptide class. Human mass-balance data have not been published.
§2.4Interactions
- Not characterised in dedicated interaction studies
References cited on this page
References are numbered in order of first citation in this document. Each superscript in the text links to its entry below.
- Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, Coskun T, Haupt A, Milicevic Z, Hartman ML. Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial. New England Journal of Medicine 2023;389(6):514–526. doi:10.1056/NEJMoa2301972 · PMID 37366315
- Rosenstock J, Frias J, Jastreboff AM, Du Y, Lou J, Gurbuz S, Thomas MK, Hartman ML, Haupt A, Milicevic Z, Coskun T. 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. The Lancet 2023;402(10401):529–544. doi:10.1016/S0140-6736(23)01053-X · PMID 37385280
Identifiers are reproduced only where the Institute holds them. Where a digital object identifier or PubMed identifier is not shown, the Institute has recorded the journal and year and has not constructed an identifier.