Mazdutide

Overview

Mazdutide, known during early development as LY3305677 and in Chinese regulatory filings as IBI362, is an investigational long-acting dual agonist of the glucagon-like peptide-1 (GLP-1) and glucagon receptors. It was originally discovered by Eli Lilly and later licensed to Innovent Biologics for development in Greater China. Mazdutide has progressed through Phase 2 and Phase 3 trials primarily in obesity and type 2 diabetes.

Mazdutide is based on the scaffold of oxyntomodulin, an endogenous post-translational peptide derived from the preproglucagon gene that naturally activates both GLP-1 and glucagon receptors. By balancing agonism at both receptors, dual agonists aim to combine the appetite-suppressing and glucose-lowering effects of GLP-1 pathway activation with the energy-expenditure-increasing effects of glucagon receptor signaling.

This places mazdutide in the same class as investigational molecules like cotadutide and survodutide, and distinguishes it from triple-agonist peptides such as retatrutide (which adds GIP activity).

Structure / Chemistry

• Class: Dual GLP-1 / glucagon receptor peptide agonist
• Scaffold: Oxyntomodulin-based 39-amino-acid peptide
• Modifications: Fatty acid side chain conjugation (C20 diacid via spacer) enabling albumin binding
• Intended dosing: Once-weekly subcutaneous injection
• Molecular weight: approximately 4.7 kDa

Fatty-acid-mediated albumin binding is the same strategy used in liraglutide and semaglutide to extend half-life. Mazdutide's amino acid sequence is engineered to balance relative potency at GLP-1 and glucagon receptors while limiting GIP activity and stabilizing against dipeptidyl peptidase-4 (DPP-4) cleavage.

Mechanism of Action

Mazdutide produces metabolic effects through simultaneous agonism of two receptors:

• GLP-1 receptor activation in pancreatic beta cells (glucose-dependent insulin secretion), hypothalamic appetite centers (reduced food intake), and gastric smooth muscle (slowed gastric emptying)
• Glucagon receptor activation in liver (increased hepatic energy expenditure, lipolysis, fatty acid oxidation) and adipose tissue

The net clinical effect is a combination of appetite suppression, improved glycemic control, and increased energy expenditure. Compared with GLP-1 monoagonists, dual agonists such as mazdutide aim to produce greater weight loss through the additional thermogenic contribution of glucagon signaling, while maintaining glycemic safety through GLP-1-driven insulin release.

Research Summary

Regulatory approval has been pursued in China for obesity and diabetes indications.

Pharmacokinetics

Albumin binding via the C20 diacid fatty acid chain extends mazdutide's plasma half-life to approximately 6–8 days, supporting once-weekly subcutaneous administration. Steady-state concentrations are achieved after roughly 4–5 weeks of consistent weekly dosing.

Absorption from subcutaneous tissue is slow and extensive, with peak plasma concentrations occurring 24–72 hours after injection. Elimination occurs via peptide-typical proteolytic catabolism rather than CYP-mediated metabolism, minimizing drug–drug interactions of that type.

Common Discussion Topics

• Comparison with tirzepatide (GLP-1/GIP) and retatrutide (GLP-1/GIP/glucagon)
• Balance between glucagon-driven lipolysis and potential hyperglycemic risk
• Phase 3 efficacy in East Asian populations and global extrapolation
• Role in non-alcoholic steatohepatitis (MASH) research
• Cardiovascular and renal outcome study pipeline

Related Compounds

• Liraglutide — GLP-1 monoagonist with similar fatty-acid acylation strategy
• Cagrilintide — amylin analog studied in combination with semaglutide
• Glucagon — endogenous ligand of the second receptor
• Exenatide — earlier-generation GLP-1 agonist
• Dulaglutide — Fc-fusion GLP-1 monoagonist

Educational information only. Mazdutide is an investigational medicine not broadly approved outside certain jurisdictions. This article does not constitute medical or dosing advice.