Retatrutide

Research · Retatrutide

Overview

Retatrutide (LY3437943) is an investigational single-molecule agonist of three receptors: the GIP receptor, the GLP-1 receptor, and the glucagon receptor. First described by Eli Lilly researchers, the 39-residue sequence is derived from a GIP backbone and modified with a C-20 fatty diacid moiety that supports albumin binding and a half-life of approximately six days. It is in late-stage clinical development and is studied as a reference compound for triple incretin and glucagon receptor agonism.

Mechanism of action

In vitro receptor assays show that retatrutide is more potent than native GIP at the human GIP receptor, while its potency at the GLP-1 and glucagon receptors is lower than that of the respective native hormones. GLP-1 and GIP receptor activation stimulate glucose-dependent insulin secretion, slow gastric emptying, and engage central appetite circuits. Glucagon receptor activation in the liver is linked to increased energy expenditure, hepatic lipid oxidation, and amino acid turnover. The combined profile is proposed to couple reduced energy intake with increased energy expenditure.

Key research findings

1. 01

   Preclinical studies in rodent models characterized effects on energy expenditure, food intake, body weight, and glucose control, and phase 1 studies documented pharmacokinetics consistent with an extended half-life.

2. 02

   A phase 2 trial in participants with type 2 diabetes characterized dose-dependent changes in glycated hemoglobin and body weight against placebo and an active GLP-1 receptor agonist comparator.

3. 03

   Phase 2 investigations in participants without diabetes characterized body weight endpoints and, in a substudy, changes in hepatic fat content measured by imaging.

4. 04

   Phase 3 programs have characterized glycemic, body weight, and cardiometabolic biomarker endpoints, with gastrointestinal events reported as the most common adverse events.

Published references

• LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept

  Coskun T et al. — Cell Metab, 2022 · PMID: 35985340

• 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 conducted in the USA

  Rosenstock J et al. — Lancet, 2023 · PMID: 37385280

The information above is derived from published preclinical and clinical research. It is provided for educational purposes only and does not constitute medical advice, diagnosis, or treatment recommendations.