Mazdutide

What is Mazdutide?#

Mazdutide (IBI362, also known as LY3305677 or OXM-3) is a dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist developed jointly by Innovent Biologics and Eli Lilly. It represents a next-generation approach to metabolic disease therapy, combining the appetite-suppressing and insulin-secretagogue effects of GLP-1 receptor agonism with the energy expenditure-enhancing and lipid-lowering effects of glucagon receptor activation. Mazdutide is a synthetic analog of the endogenous gut hormone oxyntomodulin (OXM), which naturally activates both GLP-1 and glucagon receptors.

The peptide consists of 33 amino acids with a non-natural amino acid (2-aminoisobutyric acid, Aib) at position 2 to confer resistance to dipeptidyl peptidase-4 (DPP-4) degradation. A C20 fatty diacid is conjugated through a hydrophilic linker at lysine-20, enabling strong albumin binding in plasma and extending the half-life sufficiently for once-weekly subcutaneous dosing.

In June 2025, mazdutide injection was approved for marketing in China for weight management in adults with obesity or overweight with at least one weight-related comorbidity, making it the first dual GLP-1/glucagon receptor agonist to receive regulatory approval in any market.

Mechanism of Action#

Dual Receptor Agonism#

Mazdutide's therapeutic effects arise from simultaneous activation of two distinct G-protein coupled receptors:

GLP-1 Receptor Agonism: Activation of the GLP-1 receptor in pancreatic beta cells stimulates glucose-dependent insulin secretion, providing glycemic control without the risk of hypoglycemia in normoglycemic individuals. GLP-1 receptor signaling in the hypothalamus and brainstem reduces appetite and food intake through central satiety pathways. Additionally, GLP-1 receptor activation slows gastric emptying, contributing to post-prandial glucose control and enhanced satiety.

Glucagon Receptor Agonism: Activation of the glucagon receptor in hepatocytes increases hepatic glucose production, lipolysis, and energy expenditure through thermogenesis. This glucagon component differentiates mazdutide from pure GLP-1 receptor agonists like semaglutide. The enhanced energy expenditure via glucagon receptor activation may contribute to greater fat mass reduction, particularly visceral adipose tissue, and improved lipid profiles.

The synergy between these two receptor pathways produces metabolic effects that may exceed those achievable with GLP-1 receptor agonism alone: the GLP-1 component reduces food intake and improves glycemic control, while the glucagon component enhances energy expenditure and hepatic fat metabolism.

Receptor Binding Affinity#

In vitro binding studies have characterized mazdutide's receptor pharmacology:

• Glucagon receptor (GCGR) binding: Ki = 17.7 nM (human) and 15.9 nM (mouse)
• GLP-1 receptor (GLP-1R) binding: Ki = 28.6 nM (human) and 25.1 nM (mouse)
• Insulin secretion stimulation from mouse islets: EC50 = 5.2 nM

The balanced affinity for both receptors is designed to achieve complementary metabolic effects while maintaining the glucose-lowering safety profile of GLP-1 agonism to offset the hyperglycemic potential of glucagon receptor activation.

Clinical Evidence#

Phase III Obesity Trials (GLORY Program)#

The GLORY-2 study was a Phase III, randomized, double-blind, placebo-controlled trial evaluating mazdutide in Chinese adults with obesity or overweight plus at least one weight-related comorbidity. Participants received 4 mg, 6 mg, or 9 mg of mazdutide or placebo subcutaneously once weekly.

Weight Loss Results:

• At week 48, mean body weight reduction was 10.09% (4 mg), 12.55% (6 mg), and 0.45% (placebo)
• At week 60, the 9 mg group achieved a mean weight reduction of 18.55% vs 3.02% with placebo
• The highest dose (9 mg) achieved up to 20.1% weight loss in the study
• The proportion achieving at least 5% weight loss was 73.9% (4 mg), 82.0% (6 mg), and 10.5% (placebo)

Phase II/III Type 2 Diabetes Trials#

In patients with type 2 diabetes, mazdutide demonstrated significant glycemic improvements:

• HbA1c reduction: -1.57% (4 mg) and -2.15% (6 mg) vs -0.14% (placebo) at week 24
• Fasting plasma glucose reductions accompanied the HbA1c improvements
• Weight loss was maintained in the diabetes population alongside glycemic control

Head-to-Head Comparison (DREAMS-3)#

The DREAMS-3 trial is a Phase III, randomized, open-label study directly comparing mazdutide with semaglutide in Chinese adults with type 2 diabetes and obesity. Preliminary results suggest mazdutide demonstrates superior glycemic control and weight loss compared to semaglutide, potentially due to the additive metabolic effects of glucagon receptor activation.

Pharmacokinetics#

Mazdutide's pharmacokinetic profile supports once-weekly subcutaneous dosing. The C20 fatty diacid conjugation at lysine-20 enables extensive albumin binding (>99% protein bound), which both protects the peptide from enzymatic degradation and extends its circulating half-life. The elimination half-life is approximately 4-6 days, allowing steady-state plasma concentrations to be achieved within 4-5 weeks of weekly dosing.

The Aib substitution at position 2 confers resistance to DPP-4 cleavage, which is the primary degradation pathway for endogenous GLP-1 and glucagon. This combination of DPP-4 resistance and albumin binding results in a pharmacokinetic profile suitable for convenient once-weekly administration.

Comparison with Other Metabolic Peptides#

Mazdutide belongs to a rapidly evolving class of incretin-based therapies. Key comparisons include:

• Semaglutide (Ozempic/Wegovy): Pure GLP-1 receptor agonist; mazdutide adds glucagon receptor activation for enhanced energy expenditure
• Tirzepatide (Mounjaro/Zepbound): Dual GLP-1/GIP receptor agonist; different dual mechanism (GIP vs glucagon co-agonism)
• Survodutide: Another GLP-1/glucagon dual agonist (developed by Boehringer Ingelheim); similar mechanism but different molecular design
• Retatrutide: Triple agonist (GLP-1/GIP/glucagon); broader receptor profile

Evidence Gaps and Limitations#

• Long-term efficacy and safety data beyond 60 weeks is limited
• Phase III data is primarily from Chinese populations; global generalizability needs confirmation
• Head-to-head comparison data with tirzepatide is not yet available
• Cardiovascular outcomes trial data (MACE endpoints) is pending
• Effects on non-alcoholic fatty liver disease (NAFLD/MASH) are under investigation but not yet established
• Long-term effects on lean body mass and bone density require further study
• Regulatory submissions outside of China are ongoing but approval timeline uncertain

Key Research Findings#

Safety and efficacy of a GLP-1 and glucagon receptor dual agonist mazdutide (IBI362) 9 mg and 10 mg in Chinese adults with overweight or obesity, published in eClinicalMedicine (The Lancet) (Ji L et al., 2022; PMID: 36247927):

• The study showed mean body weight reduction of 11.7% at 12 weeks
• The study showed weight change of 1.8%

Efficacy and Safety of Mazdutide in Chinese Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial, published in Diabetes Care (Ji L et al., 2024; PMID: 37943529):

• The study showed HbA1c reduction of 1.57% and -2.15% vs -0.14% placebo

Once-Weekly Mazdutide in Chinese Adults with Obesity or Overweight, published in New England Journal of Medicine (Ji L et al., 2025; PMID: 40421736):

• The study showed 4 mg group of 10.09% weight loss at week 48
• The study showed 6 mg group of 12.55% weight loss at week 48
• Pivotal Phase III trial in Chinese adults showing mazdutide achieved up to 20.1% body weight reduction. Published in NEJM, supporting Chinese regulatory approval.

Related Reading#

• Mazdutide research studies and evidence
• Mazdutide dosing protocols
• Mazdutide side effects profile
• Cotadutide (MEDI0382) research guide
• Retatrutide research guide