Mazdutide: The First Approved Dual GLP-1/Glucagon Agonist for Metabolic Research

Mazdutide (development codes LY3305677, IBI362) represents a significant milestone in incretin-based therapeutics—the first dual agonist of the glucagon-like peptide-1 (GLP-1) receptor and glucagon receptor (GCGR) to receive regulatory approval. Developed through a partnership between Eli Lilly and Innovent Biologics, this long-acting oxyntomodulin analog received approval in China in June 2025 for chronic weight management, establishing proof-of-concept for the dual agonist approach. Mazdutide offers researchers a clinically validated tool for investigating how combined GLP-1 and glucagon receptor activation affects energy homeostasis, glucose metabolism, and metabolic disease.

The development of Mazdutide addresses a key question in metabolic pharmacology: can the benefits of GLP-1 receptor activation be enhanced by adding glucagon receptor agonism? While GLP-1 agonists like semaglutide have transformed obesity treatment, glucagon adds complementary metabolic effects including increased energy expenditure and hepatic fat oxidation. Mazdutide was designed to capture both pathways in a single molecule, creating a more comprehensive metabolic intervention.

Molecular Structure and Design

Mazdutide is a synthetic peptide analog based on oxyntomodulin (OXM), a naturally occurring gut hormone that is a cleavage product of preproglucagon. Oxyntomodulin naturally activates both GLP-1 and glucagon receptors, making it an ideal scaffold for dual agonist development. However, native oxyntomodulin has a short plasma half-life, limiting therapeutic utility.

The engineering of Mazdutide incorporates modifications to extend half-life and optimize receptor activity:

• Oxyntomodulin backbone: The peptide retains the core sequence that enables dual receptor recognition
• Long-acting formulation: Structural modifications and potential acylation extend plasma half-life to enable weekly dosing
• Balanced agonism: Tuned affinity for both GLP-1R and GCGR to achieve therapeutic efficacy while managing safety

The resulting molecule binds to human GLP-1 receptor and glucagon receptor with affinities that support robust activation of both targets. This balanced dual agonism distinguishes Mazdutide from selective GLP-1 agonists and provides the mechanistic basis for its enhanced metabolic effects.

Mechanism of Action: Dual Receptor Activation

The therapeutic effects of Mazdutide emerge from the complementary actions of GLP-1 and glucagon receptor signaling:

GLP-1 Receptor Effects: Activation of GLP-1 receptors in the hypothalamus and brainstem reduces appetite and food intake. In the periphery, GLP-1 enhances glucose-dependent insulin secretion, suppresses glucagon release (paradoxically, given the dual agonism), and delays gastric emptying. These effects are well-established from extensive experience with GLP-1 selective agonists.

Glucagon Receptor Effects: Glucagon receptor activation adds distinct metabolic benefits. In the liver, glucagon promotes fatty acid oxidation and ketogenesis, potentially enhancing hepatic fat metabolism. Glucagon also increases energy expenditure through thermogenic effects and may enhance satiety signaling through distinct neural pathways.

Integrated Metabolic Effects: The combination produces comprehensive metabolic improvements:

• Reduced energy intake: Through GLP-1-mediated appetite suppression
• Increased energy expenditure: Through glucagon-mediated thermogenesis
• Enhanced hepatic fat metabolism: Through glucagon receptor activation in the liver
• Improved glycemic control: Through GLP-1-mediated insulin enhancement and glucagon suppression

This dual mechanism creates a “push-pull” effect on energy balance that may exceed what either pathway achieves alone.

Clinical Research and Approval

Mazdutide has advanced through extensive clinical development, culminating in the first regulatory approval for a dual GLP-1/glucagon agonist:

GLORY-1 Phase 3 Trial: The pivotal trial in Chinese adults with overweight or obesity demonstrated significant weight loss efficacy. Participants achieved clinically meaningful reductions in body weight, with the 9 mg dose producing approximately 20% weight loss over 60 weeks. The trial also showed improvements in cardiometabolic risk factors and liver fat content.

Head-to-Head vs. Semaglutide: In direct comparison trials, Mazdutide demonstrated superiority to semaglutide on composite endpoints combining glycemic control and weight loss. This head-to-head victory against the established standard validates the dual agonist approach.

Type 2 Diabetes: Dedicated trials in patients with type 2 diabetes showed robust A1C reductions alongside weight loss, establishing efficacy across the metabolic disease spectrum.

MAFLD/MASH: The glucagon component’s hepatic effects make Mazdutide particularly interesting for metabolic dysfunction-associated fatty liver disease. Clinical trials show reductions in liver fat content, with potential implications for MASH treatment.

Regulatory Approval: In June 2025, Mazdutide received approval from China’s National Medical Products Administration (NMPA) for chronic weight management in adults with obesity or overweight with weight-related comorbidities. This marks the first approval worldwide for a dual GLP-1/glucagon receptor agonist.

Mazdutide vs. Other Incretin Agonists

Understanding Mazdutide’s position requires comparison with other metabolic peptides:

Semaglutide (Ozempic/Wegovy) is a selective GLP-1 receptor agonist that produces ~15% weight loss. It represents the first-generation standard against which newer agents are compared.

Tirzepatide (Mounjaro/Zepbound) is a dual GIP/GLP-1 agonist that achieves ~21% weight loss. It adds GIP receptor activation to the GLP-1 mechanism, demonstrating that multi-receptor approaches enhance efficacy.

Retatrutide is a triple GIP/GLP-1/glucagon agonist in development by Eli Lilly that achieves ~24% weight loss. It represents the logical extension of the multi-receptor strategy to three targets.

Mazdutide occupies a unique position as the first approved dual agonist specifically combining GLP-1 and glucagon (not GIP). Its ~20% weight loss efficacy positions it between semaglutide and tirzepatide, with the glucagon component potentially offering advantages for hepatic metabolism.

Survodutide is another GLP-1/glucagon dual agonist in development by Boehringer Ingelheim, representing competition in this mechanistic class.

Safety Profile and Tolerability

The safety profile of Mazdutide in clinical trials has been consistent with other incretin-based therapies. Gastrointestinal events—nausea, vomiting, diarrhea—are the most common adverse effects, occurring primarily during dose escalation. These effects are generally transient and manageable.

Importantly, Mazdutide has shown favorable discontinuation rates. The GLORY-1 trial reported only 0.5% discontinuation due to adverse events, compared to 4-7% for comparator agents. This suggests good tolerability that may support long-term adherence.

Theoretical concerns about glucagon receptor activation causing hyperglycemia have not materialized in clinical practice. The GLP-1 component’s insulinotropic and glucagonostatic effects appear to balance any hyperglycemic potential of glucagon agonism, resulting in net glycemic improvement.

Research Applications and Considerations

Laboratories working with Mazdutide have access to a clinically validated dual agonist for investigating metabolic pathways. Research applications include:

• Receptor pharmacology: Characterizing dual agonist signaling and potential bias between GLP-1R and GCGR
• Energy homeostasis: Separating the contributions of reduced intake versus increased expenditure
• Hepatic metabolism: Investigating glucagon-mediated effects on liver fat and glucose production
• Comparative studies: Head-to-head evaluation against selective GLP-1 agonists
• Combination approaches: Exploring interactions with other metabolic interventions

The once-weekly dosing profile simplifies research protocols. Standard reconstitution uses bacteriostatic water, with storage of lyophilized powder under refrigeration.

As a clinically approved agent in China, Mazdutide offers researchers a compound with established human efficacy data, reducing some of the uncertainty associated with purely investigational peptides.

Global Development Status

While Mazdutide is approved in China, it remains in clinical development for Western markets. Eli Lilly is conducting Phase 3 trials in the United States and other regions to support global registration. The GLORY clinical program includes multiple Phase 3 studies:

• GLORY-1: Weight management in Chinese adults (completed, published in NEJM)
• GLORY-2: Moderate-to-severe obesity in Chinese adults
• GLORY-3: Head-to-head versus semaglutide in MAFLD
• US/EU trials: Ongoing studies to support FDA and EMA submissions

The partnership between Eli Lilly and Innovent Biologics reflects a growing trend of global pharmaceutical development, with China serving as both a major market and a site for clinical research.

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References

• “Mazdutide: First Approval.” PubMed. https://pubmed.ncbi.nlm.nih.gov/41028652/
• “Mazdutide reduces body weight in adults with overweight or obesity: A high-dose Phase 1 trial.” Diabetes, Obesity and Metabolism, Wiley. https://dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.70040
• “Mazdutide, a dual agonist targeting GLP-1R and GCGR, mitigates diabetes-associated cognitive dysfunction.” NCBI PMC. https://pmc.ncbi.nlm.nih.gov/articles/PMC12205698/
• “Mazdutide versus Semaglutide for the treatment of type 2 diabetes.” PubMed. https://pubmed.ncbi.nlm.nih.gov/41260459/
• “Mazdutide.” Wikipedia. https://en.wikipedia.org/wiki/Mazdutide

Disclaimer: This product is sold for laboratory research purposes only. Mazdutide is not intended for human consumption, medical treatment, or diagnostic use outside of approved jurisdictions. It is approved in China but remains investigational in most other regions. This information is provided for educational purposes and does not constitute medical or scientific advice. Always consult relevant scientific literature and follow proper laboratory safety protocols.