Mazdutide

Mazdutide Molecular Structure & Chemical Properties

Mazdutide peptide represents a pioneering dual GLP-1 and glucagon receptor agonist that has advanced through clinical development to become the first GLP-1R/GCGR dual agonist approved for human use. Originally developed by and licensed to Innovent Biologics for development in China, this once-weekly injectable peptide gained approval from China’s NMPA in June 2025 for chronic weight management in adults with overweight or obesity. Structurally derived from the endogenous gut hormone oxyntomodulin, mazdutide incorporates strategic modifications including a C20 fatty acid chain conjugated through a hydrophilic linker, enabling once-weekly administration with an extended half-life of 7 to 44 days depending on dose. This synthetic 33-amino acid peptide demonstrates balanced agonist activity at both GLP-1 and glucagon receptors, distinguishing it from single-target GLP-1 agonists through enhanced metabolic effects including increased energy expenditure and improved hepatic fat metabolism.

Chemical Structure

2D molecular structure (Source: PubChem)

Technical Specifications

The peptide comprises a 33-amino acid sequence conjugated to a C20 fatty diacid moiety through a hydrophilic linker at lysine-20, designed to enhance metabolic stability and prolong systemic exposure. The structural modifications confer resistance to dipeptidyl peptidase-4 (DPP-4) degradation while maintaining balanced dual receptor activation.

Mazdutide Mechanism of Action

Mazdutide exerts its biological effects through balanced co-agonism of glucagon-like peptide-1 receptors (GLP-1R) and glucagon receptors (GCGR), mimicking the physiological activity of the endogenous gut hormone oxyntomodulin. This dual-receptor activation creates synergistic metabolic effects that extend beyond those achieved by single-target GLP-1 agonists. Research demonstrates potent binding affinity to both human GLP-1R (Ki: 28.6 nM) and GCGR (Ki: 17.7 nM), with similar binding profiles in mouse models, supporting translational relevance.

Primary Cellular Pathways

GLP-1 Receptor Activation – Glucose Control & Appetite Regulation

Mazdutide activates GLP-1 receptors in pancreatic beta-cells, intestinal tissue, and central nervous system regions involved in appetite regulation. This activation produces:

• Glucose-dependent insulin secretion from pancreatic islets (EC50: 5.2 nM in mouse islets)
• Suppression of glucagon release during hyperglycemia
• Delayed gastric emptying to promote satiety
• Reduction of appetite through central GLP-1R activation in hypothalamic nuclei
• Enhanced beta-cell survival and proliferation signals

Studies in db/db mice demonstrated improved glucose control and HbA1c reduction through these mechanisms, with effects maintained across multiple dosing regimens.

Glucagon Receptor Activation – Energy Expenditure & Hepatic Metabolism

Through GCGR activation, mazdutide enhances metabolic processes typically suppressed by GLP-1R-only agonists:

• Increased energy expenditure through thermogenic activation in brown and white adipose tissue
• Enhanced hepatic fatty acid oxidation via upregulation of genes including Ehhadh, Cyp4a14, and Hadha
• Activation of transcription factor ATF3, promoting lipid degradation pathways
• Improved hepatic insulin sensitivity
• Modulation of hepatic glucose production

Research comparing mazdutide to GLP1 monotherapy in mice revealed superior reductions in liver fat content, attributed to GCGR-mediated activation of oxidative phosphorylation and fatty acid degradation pathways.

Metabolic Signaling Integration

Mazdutide’s dual activation creates complementary metabolic effects:

• cAMP/PKA signaling pathway activation in target tissues
• PI3K-Akt pathway stimulation contributing to metabolic regulation
• Modulation of FGF21 and GDF15 expression, mediators of metabolic homeostasis
• Synergistic weight loss through combined reduction in caloric intake (GLP-1R) and increased energy expenditure (GCGR)

Neuroprotective Mechanisms

Emerging research in diabetic mouse models suggests additional CNS effects:

• Modulation of glutamate homeostasis through downregulation of vesicular glutamate transporter 2 (VGluT2)
• Upregulation of GABA-A receptor subunits, restoring excitatory-inhibitory balance
• Potential neuroprotection through indirect metabolic improvements
• Enhanced cognitive function in diabetes-associated cognitive dysfunction models

These effects appear mediated through both peripheral metabolic improvements and potential direct CNS actions, though blood-brain barrier penetration remains under investigation.

Mazdutide Research Applications & Key Findings

Obesity & Weight Management Research

Human Clinical Trials – Weight Reduction

Mazdutide peptide has been extensively studied in phase 1b, phase 2, and phase 3 clinical trials in Chinese adults with overweight or obesity:

• Phase 3 GLORY-1 trial (610 participants): At week 32, 4 mg and 6 mg doses achieved mean weight reductions of 10.09% and 12.55% respectively versus 0.45% for placebo
• Week 48 results: Weight loss reached 11.00% (4 mg) and 14.01% (6 mg) versus 0.30% placebo, with 49.5% of 6 mg participants achieving over 15% weight reduction
• Phase 2 studies: Dose-dependent weight loss up to 15.4% at 9 mg weekly dose over 24 weeks
• High-dose phase 1 trials: 16 mg weekly dosing demonstrated continued efficacy with acceptable tolerability in adults with obesity

Phase 3 results supported regulatory approval in China, marking mazdutide as the world’s first approved dual GCG/GLP-1 receptor agonist.

Cardiometabolic Improvements

Clinical investigations demonstrated comprehensive metabolic benefits beyond weight reduction:

• Waist circumference reduction of 8-12 cm from baseline across dose ranges
• Blood pressure improvements: Systolic blood pressure reductions of 5-8 mmHg
• Lipid profile optimization: Reductions in triglycerides, total cholesterol, and LDL-C
• Glycemic control: HbA1c reductions in participants with prediabetes or type 2 diabetes

Type 2 Diabetes Research

Glucose Control Studies

Multiple phase 3 trials have evaluated mazdutide in Chinese adults with type 2 diabetes:

• DREAMS-1 trial (731 participants with T2DM): Met primary endpoint of superior HbA1c reduction versus placebo
• Dual benefits: Simultaneous improvements in glucose control and body weight reduction
• Insulin sensitivity: Enhanced insulin sensitivity measures across treatment arms
• Comprehensive metabolic effects: Reductions in liver enzymes, serum uric acid, and improvements in blood pressure

Research comparing mazdutide to GLP-1R mono-agonist dulaglutide demonstrated superior HbA1c lowering and greater weight loss, attributed to the additive effects of GCGR activation.

Hepatic Metabolism Research

Liver Fat Reduction Studies

Investigations in both preclinical models and clinical trials examined hepatic effects:

• Phase 2 liver fat content analysis: Participants with baseline liver fat content over 10% experienced average relative reductions of 80.2% with 6 mg weekly dosing
• Mechanistic studies in mice: RNA-sequencing revealed mazdutide predominantly activated oxidative phosphorylation and fatty acid degradation pathways in liver tissue
• Biomarker improvements: Reductions in ALT, AST, and gamma-GT across clinical studies
• Metabolic pathway activation: Upregulation of lipid metabolism genes (Ehhadh, Cyp4a14, Hadha, Fgf21, Gdf15) compared to GLP-1R monotherapy

These findings support ongoing investigations in metabolic dysfunction-associated steatohepatitis (MASH) and metabolic-associated fatty liver disease (MAFLD).

Cardiovascular & Metabolic Comorbidities Research

Hyperuricemia Studies

Preclinical research in hyperuricemic rat models demonstrated:

• Uric acid reduction comparable to allopurinol, a standard anti-gout medication
• Potential mechanism: Increased urinary uric acid excretion
• Clinical relevance: Serum uric acid reductions observed across human clinical trials

Neuroprotection & Cognitive Function Research

Preclinical investigations in db/db diabetic mice revealed:

• Improved cognitive performance in behavioral testing compared to GLP-1R mono-agonist dulaglutide
• Neuronal structure preservation: Improvements in hippocampal neuron morphology
• Multi-omics analysis: Distinct molecular pathways involved in neuroprotection, energy metabolism, and synaptic plasticity
• Excitatory-inhibitory balance restoration: Modulation of glutamate (VGluT2) and GABA-A receptor systems

These findings suggest potential applications in diabetes-associated cognitive dysfunction, though human studies are needed.

Mazdutide Pharmacokinetics & Metabolism

Absorption & Distribution

Mazdutide exhibits pharmacokinetic properties designed to support once-weekly subcutaneous administration:

• Slow absorption kinetics: Peak plasma concentrations (Tmax) achieved at median 72 hours post-injection (range: 12-170 hours depending on dose)
• Dose-proportional exposure: Systemic exposure (AUC and Cmax) increases proportionally with dose escalation
• Subcutaneous bioavailability: Consistent absorption from subcutaneous injection sites
• Distribution characteristics: Moderate volume of distribution consistent with extravascular distribution

The fatty acid conjugation enables albumin binding and slow release from subcutaneous depot, contributing to prolonged systemic exposure.

Metabolism & Elimination

The metabolic fate of mazdutide reflects typical peptide degradation pathways modified by fatty acid conjugation:

• Extended plasma half-life: Terminal elimination half-life ranges from 174.8 to 1075.7 hours (7.3 to 44.8 days) depending on dose and individual variability
• Half-life at 16 mg dose: Approximately 8 days in phase 1 studies, supporting once-weekly dosing
• Proteolytic resistance: Structural modifications confer resistance to DPP-4 and other peptidases
• Likely degradation pathways: Proteolytic cleavage of peptide backbone followed by fatty acid metabolism

The exceptionally long half-life enables steady-state achievement within 4-6 weeks of weekly dosing and sustained pharmacological effects throughout the dosing interval.

Excretion Pathways

Limited published data on excretion indicates:

• Presumed renal elimination of peptide fragments after proteolytic degradation
• Hepatic metabolism contribution: Fatty acid moiety likely undergoes hepatic beta-oxidation
• No accumulation: No evidence of tissue accumulation in chronic dosing studies spanning 48 weeks
• Steady-state pharmacokinetics: Predictable accumulation to steady-state with weekly dosing

Pharmacokinetic modeling supports once-weekly administration without dose adjustment based on available data, though specific populations (severe renal or hepatic impairment) have not been extensively studied.

Mazdutide Research Protocols & Administration

Dosing in Published Research

Clinical investigations have employed dose-escalation strategies to optimize efficacy and tolerability:

• Phase 1b studies: Doses from 3 mg to 10 mg weekly with gradual escalation over 4-8 weeks
• Phase 2 studies: Final doses of 3 mg, 4.5 mg, and 6 mg weekly in obesity trials
• Phase 3 GLORY-1: Target doses of 4 mg and 6 mg weekly following escalation (starting 1 mg, escalated every 4 weeks)
• High-dose investigations: Up to 16 mg weekly in phase 1 trials in adults with obesity
• Type 2 diabetes studies: Similar dose ranges with gradual escalation protocols

Important: These doses are from human clinical trials conducted under strict medical supervision with extensive safety monitoring. The optimal therapeutic dose-escalation strategy involves starting at 1-2.5 mg weekly and gradually increasing over 8-16 weeks to minimize gastrointestinal adverse events. These are approved therapeutic protocols in China and investigational protocols elsewhere, and cannot be extrapolated to other contexts or populations without appropriate medical oversight and regulatory authorization. Individual response variability, concomitant medications, and patient-specific factors significantly influence both efficacy and safety profiles.

Administration Routes in Research

Mazdutide has been investigated exclusively via subcutaneous administration:

• Subcutaneous injection – Standard route across all clinical trials; administered once weekly
• Injection sites – Abdomen, thigh, or upper arm rotation recommended
• Delivery device – Prefilled autoinjector pen used in phase 3 trials
• Timing flexibility – Can be administered at any time of day, with or without meals

Study Populations

Clinical development has focused on specific populations:

• Chinese adults with obesity – Phase 2 and 3 studies (BMI ≥28 kg/m2 or BMI ≥24 kg/m2 with comorbidities)
• Chinese adults with type 2 diabetes – Multiple phase 3 trials ongoing and completed
• Global phase 2 studies – Ongoing trials in U.S. and other regions (primarily Western populations)
• Preclinical models – Extensive research in mouse models (db/db, diet-induced obesity, Gcgr-/-, Glp1r-/- mice) and rat models

Research Limitations & Regulatory Status

Critical Gaps in Current Evidence

Despite successful phase 3 trials and regulatory approval in China, significant evidence gaps remain:

Limited Population Diversity

Clinical trial data demonstrate important limitations:

• Geographic concentration: Phase 3 efficacy data predominantly from Chinese populations
• Generalizability questions: Efficacy and safety in diverse ethnic populations requires additional investigation
• Phase 2 U.S. studies: Currently ongoing but not yet published, limiting assessment of drug performance in Western populations
• Age range limitations: Pediatric and adolescent data limited, though studies in adolescent obesity are planned

Long-Term Safety Profile

Extended safety data remain incompletely characterized:

• Maximum trial duration: 48 weeks in published studies; effects beyond one year unstudied
• Cardiovascular outcomes: No dedicated cardiovascular outcomes trial (CVOT) data published
• Cancer surveillance: Long-term cancer incidence monitoring not yet available
• Chronic GCGR activation: Long-term effects of sustained glucagon receptor agonism in humans require further characterization

Mechanistic Understanding Gaps

Fundamental aspects of mazdutide’s mechanism require clarification:

• Blood-brain barrier penetration: Whether CNS effects are direct or peripherally mediated remains uncertain
• Tissue-specific receptor expression: How balanced agonism manifests in different tissue types incompletely understood
• Active metabolite contribution: Whether fatty acid cleavage products contribute to pharmacological effects unknown
• Individual response variability: Genetic or metabolic factors predicting response not characterized

Regulatory & Competitive Sport Status

Regulatory Approval Status

Mazdutide has achieved regulatory milestones in specific jurisdictions:

• China NMPA approval (June 2025): Approved for chronic weight management in adults with BMI ≥24 kg/m2 with comorbidities or BMI ≥28 kg/m2
• China NDA under review: Second indication for type 2 diabetes glycemic control
• United States: Phase 2 trials ongoing; not approved by FDA for any indication
• European Union: Not approved; clinical development status unclear
• Other jurisdictions: No regulatory approvals outside China as of September 2025

FDA Position (United States)

The FDA has issued guidance relevant to mazdutide and similar compounds:

• Not FDA-approved: Mazdutide has no approved indications in the United States
• Investigational status: Currently in phase 2 clinical trials for obesity
• Warning letters issued: FDA has issued warning letters to companies marketing unapproved GLP-1 compounds including mazdutide as “research chemicals”
• Compounding prohibition: Not eligible for compounding by 503A or 503B facilities
• Research use only: Only permitted for use in FDA-regulated clinical trials or legitimate laboratory research

The FDA’s December 2024 warning letters specifically named mazdutide among unapproved GLP-1/glucagon receptor agonists being illegally marketed for human use.

WADA Prohibition Status

Information not available: As of September 2025, mazdutide’s specific status on the World Anti-Doping Agency (WADA) Prohibited List has not been explicitly documented in available sources. However:

• General principle: Non-approved substances under development typically fall under WADA Section S0 (Non-Approved Substances)
• Similar compounds: Other GLP-1/incretin-based therapies are subject to WADA scrutiny
• Athlete guidance: Athletes subject to anti-doping testing should consult WADA and their sport’s governing body before using any GLP-1-based medication

Research Classification: Mazdutide is approved for clinical use in China under physician supervision. Outside China, it is available only for use in regulated clinical trials and legitimate laboratory research. It is not intended for unauthorized human consumption, veterinary applications, or use as a dietary supplement. All research must be conducted under appropriate ethical oversight and regulatory compliance with institutional review board approval where applicable.

Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China

Professor Linong Ji served as the leading principal investigator for the landmark GLORY-1 phase 3 trial that supported mazdutide’s regulatory approval in China. A prominent figure in Chinese endocrinology and diabetes research, Professor Ji has been instrumental in advancing clinical investigation of novel metabolic therapies including GLP-1-based treatments and dual-agonist approaches.

Professor Ji’s research contributions to mazdutide development include:

• Leadership of GLORY-1 trial: Principal investigator for the pivotal phase 3 study in 610 Chinese adults with overweight or obesity
• Type 2 diabetes investigations: Oversight of multiple phase 3 diabetes trials evaluating mazdutide’s glycemic and metabolic effects
• Cardiometabolic research: Extensive work characterizing comprehensive metabolic benefits including effects on blood pressure, lipids, and liver metabolism
• Clinical translation expertise: Bridging preclinical dual-agonist research to successful clinical application in Chinese populations

His leadership in mazdutide’s clinical development program has been crucial in establishing this first-in-class dual GCG/GLP-1 receptor agonist as a therapeutic option for weight management and metabolic disease.

Note on Development Partnership: Mazdutide was originally developed by and Company and licensed to Innovent Biologics for development and commercialization in China through an exclusive license agreement. The medicinal chemistry and preclinical development were led by researchers, while clinical development in China has been conducted by Innovent Biologics in collaboration with leading Chinese endocrinology centers.

Disclaimer: This spotlight is provided for educational purposes to acknowledge scientific contributions to mazdutide clinical research. Cenexa Labs has no affiliation with Professor Ji, Peking University People’s Hospital, Innovent Biologics, and Company, or any institutions involved in mazdutide research, and this information does not constitute an endorsement of any products or services.

References

1. Ji, L., Shi, M., Gao, W., Huang, D., Deng, H., Liu, L., Feng, P., et al. (2021). IBI362 (LY3305677), a weekly-dose GLP-1 and glucagon receptor dual agonist, in Chinese adults with overweight or obesity: A randomised, placebo-controlled, multiple ascending dose phase 1b study. EClinicalMedicine, 39, 101088. PubMed
   
2. Ji, L., Shi, M., Gao, W., Huang, D., Deng, H., Wu, L., Liu, L., et al. (2022). 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: A randomised, placebo-controlled, multiple-ascending-dose phase 1b trial. EClinicalMedicine, 54, 101691. PubMed
   
3. Chen, T., Sun, T., Bian, Y., Pei, Y., Feng, F., Chi, H., Li, Y., et al. (2022). The Design and Optimization of Monomeric Multitarget Peptides for the Treatment of Multifactorial Diseases. Journal of Medicinal Chemistry, 65(5), 3685-3705. PubMed
   
4. Shi, M., Gao, W., Ji, L., Sun, Y., Liu, Y., Liu, F., Chen, S., et al. (2023). A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity. Nature Communications, 14(1), 8500. PubMed
   
5. Ji, L., Jiang, H., Gao, W., Shi, M., Deng, H., Fan, Y., Liu, L., et al. (2025). Once-Weekly Mazdutide in Chinese Adults with Obesity or Overweight. New England Journal of Medicine, 393(9), 816-828. PubMed
   
6. Wu, Q., Wei, T., Cui, X., Yang, J., Wei, R., & Hong, T. (2025). The Dual Glucagon and Glucagon-Like Peptide 1 Receptor Agonist Mazdutide Outbalanced Glucagon-Like Peptide 1 Receptor Agonist GLP1 Monotherapy in Improving Mice Liver Fat Accumulation. Diabetes, 74(Supplement_1), 777-P. Abstract
   
7. Zhang, Y., Wang, L., Chen, X., Liu, J., Zhao, Y., Li, X., Wang, H., et al. (2025). Mazdutide, a dual agonist targeting GLP-1R and GCGR, mitigates diabetes-associated cognitive dysfunction: mechanistic insights from multi-omics analysis. eBioMedicine, 115, 105621. PubMed
   
8. Jiang, H., Zhang, Y., & Ren, Y.S. (2023). A Novel Glucagon-Like Peptide-1 (GLP-1R) and Glucagon (GCGR) Receptor Dual Agonist, Mazdutide (IBI362), Attenuates Hyperuricemia in Hyperuricemic Rats. Diabetes, 72(Supplement_1), 77-LB. Abstract
   
9. Bhattachar, S.N., Barve, A., Aziz, A., Chawla, D., Du, Y., Gupta, K., Knadler, M.P., et al. (2025). Mazdutide reduces body weight in adults with overweight or obesity: A high-dose Phase 1 trial. Diabetes, Obesity and Metabolism, 27(3), 1014-1024. Abstract
   
10. Company announcement: Innovent Biologics, Inc. (2024, February 7). Innovent’s First New Drug Application of Mazdutide for Chronic Weight Management has been Accepted by the NMPA of China. PRNewswire. [Company announcement; peer-reviewed publication not available]
11. Company announcement: Innovent Biologics, Inc. (2025, June 27). Innovent Announces Mazdutide, First Dual GCG/GLP-1 Receptor Agonist, Received Approval from China’s NMPA for Chronic Weight Management. PRNewswire. [Company announcement; peer-reviewed publication not available]
12. Jiang, H. (2025). Case Report: Efficacy and safety of dose-escalated Mazdutide, a GLP-1/GCGR dual agonist, in an adolescent with obesity, type 2 diabetes, and hyperuricemia. Frontiers in Endocrinology, 16. PubMed
    

All references open in new window. These citations are provided for educational and research purposes only. This information is not intended to diagnose, treat, cure, or prevent any disease. Mazdutide is approved for clinical use in China under medical supervision; outside China it is intended for use in regulated clinical trials and laboratory research only.