Mazdutide

Mazdutide (IBI362, also known as LY3305677) is a once-weekly subcutaneous GLP-1/glucagon dual receptor agonist co-developed by Innovent Biologics and Eli Lilly. Based on the oxyntomodulin backbone, mazdutide is designed to activate both the GLP-1 receptor and the glucagon receptor simultaneously, combining GLP-1-mediated appetite suppression and glycemic control with glucagon-mediated increases in energy expenditure and hepatic lipid mobilization.

Overview

Mazdutide is derived from oxyntomodulin, a naturally occurring 37-amino acid peptide hormone produced by intestinal L-cells alongside GLP-1 and released postprandially. Native oxyntomodulin activates both GLP-1 and glucagon receptors but has a half-life of only a few minutes, making it unsuitable for therapeutic use. Mazdutide is an engineered analog with chemical modifications — including fatty acid acylation for albumin binding — that extend its half-life to approximately one week, enabling once-weekly subcutaneous dosing.

The dual receptor agonism of mazdutide creates a fundamentally different metabolic profile compared to selective GLP-1R agonists like semaglutide. While the GLP-1R component drives appetite suppression, insulin secretion, and delayed gastric emptying (as with semaglutide), the glucagon receptor component stimulates hepatic glycogenolysis, gluconeogenesis (in a controlled manner), lipolysis, thermogenesis, and fatty acid oxidation. The net effect is enhanced weight loss through both reduced energy intake (GLP-1R) and increased energy expenditure (GCGR), with particularly notable effects on liver fat reduction.

Mazdutide is being primarily developed in China through Innovent Biologics' GLORY clinical trial program, with Phase 3 trials ongoing in both obesity and type 2 diabetes. It has received Breakthrough Therapy Designation from the Chinese National Medical Products Administration (NMPA) for obesity.

Mechanism of Action

Mazdutide exerts its therapeutic effects through coordinated activation of two metabolically important receptor systems:

GLP-1 Receptor Agonism: Mazdutide potently activates GLP-1 receptors on pancreatic beta cells, hypothalamic and brainstem neurons, and vagal afferents. This drives glucose-dependent insulin secretion, appetite suppression, delayed gastric emptying, and reduced food intake — the same mechanisms responsible for the metabolic benefits of semaglutide and other GLP-1R agonists.

Glucagon Receptor Agonism: Unlike pure GLP-1R agonists, mazdutide simultaneously activates hepatic glucagon receptors. Glucagon receptor signaling stimulates hepatic lipid oxidation, increases energy expenditure through thermogenesis, promotes amino acid catabolism, and drives lipolysis in adipose tissue. This component is particularly important for reducing hepatic steatosis and increasing total energy expenditure beyond what GLP-1R agonism alone achieves.

Synergistic Weight Loss Mechanism: The dual agonism creates a metabolic environment where energy intake is reduced (via GLP-1R-mediated anorexia) while energy expenditure is simultaneously increased (via GCGR-mediated thermogenesis). This bidirectional approach to energy balance may produce greater net weight loss than either receptor agonist alone.

Hepatic Fat Mobilization: Glucagon receptor activation in hepatocytes promotes fatty acid beta-oxidation, reduces de novo lipogenesis, and stimulates ketogenesis. Combined with GLP-1R-mediated improvements in insulin sensitivity and reduced lipotoxicity, mazdutide has shown substantial reductions in liver fat content, making it a strong candidate for MASH/NAFLD treatment.

Glycemic Regulation: Despite the glucagon component's hyperglycemic potential, the concurrent GLP-1R agonism provides glucose-dependent insulin secretion and glucagon suppression that counterbalances the glucose-raising effects. In clinical trials, mazdutide has consistently reduced HbA1c in patients with type 2 diabetes, demonstrating that the GLP-1R component predominates in glycemic control.

Reconstitution Calculator

Research

Safety Profile

In Phase 2 and Phase 3 trials, mazdutide's adverse event profile is predominantly gastrointestinal and consistent with GLP-1R agonist pharmacology. Nausea occurred in 23-39% of participants, diarrhea in 12-19%, vomiting in 10-17%, and decreased appetite in 8-13%. Most GI events were mild to moderate and occurred during dose titration. Discontinuation rates due to adverse events were 5-9% across dose groups. Mild dose-dependent increases in heart rate (2-5 bpm) were observed. Notably, despite concerns that glucagon receptor activation could raise blood glucose, mazdutide consistently reduced HbA1c in diabetic populations and did not cause hyperglycemia in non-diabetic participants, indicating the GLP-1R component effectively counterbalances glucagon-driven glucose elevation. No pancreatitis signals were detected. Transient, mild elevations in liver transaminases (ALT/AST) were observed in some participants, potentially related to rapid hepatic fat mobilization rather than hepatotoxicity.

Pharmacokinetic Profile

Ongoing & Future Research

• Global Phase 3 program: Expansion beyond China to global markets anticipated, potentially through Eli Lilly's development infrastructure.
• MASH/NASH: Dedicated Phase 2/3 trials for metabolic-associated steatohepatitis are anticipated based on the strong liver fat reduction data. The glucagon component's effect on hepatic fat oxidation makes mazdutide particularly suited for this indication.
• Cardiovascular outcomes: A dedicated CVOT will be needed for a cardiovascular risk reduction indication. Dual agonism may provide cardiovascular benefits through both weight loss and glucagon-mediated improvements in lipid metabolism.
• Combination with insulin: Studies in advanced T2D with insulin co-administration are expected.
• Higher-dose exploration: Whether doses above 9 mg could safely increase efficacy is under evaluation.
• Head-to-head comparisons: Comparator trials against semaglutide or tirzepatide would help position mazdutide relative to established GLP-1R agonists.