Mazdutide
Once-weekly dual GLP-1/glucagon receptor agonist modeled on oxyntomodulin, designed to reduce appetite and increase energy expenditure for clinically meaningful weight loss.
Approved in China (2025) for chronic weight management and glycemic control in adults with type 2 diabetes. This is one of the first regulatory approvals for a dual GLP-1/glucagon receptor agonist worldwide.
⚡ Executive Summary
Mazdutide (IBI-362, LY3305677) is an oxyntomodulin-based peptide that co-activates GLP-1 and glucagon receptors. This dual mechanism combines GLP-1–driven appetite/glycemic effects with glucagon-driven energy expenditure. Phase 2/3 trials showed −11.3% weight loss at 6 mg (24 weeks) plus improvements in BP, lipids, and glycemic markers. China approved it in 2025 for obesity and T2D.
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Overview
💊 What is Mazdutide?
Mazdutide is a dual GLP-1/glucagon receptor agonist designed to combine the benefits of both pathways in a single molecule.
It’s modeled on oxyntomodulin, a natural gut hormone that activates both receptors and increases energy expenditure.
🎯 Key Features
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Appetite reduction — GLP-1 pathway
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Energy expenditure↑ — glucagon pathway
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Once weekly — lipidated for long half-life
Why both receptors? GLP-1 slows gastric emptying and reduces appetite; glucagon increases hepatic lipid oxidation and raises energy expenditure. Together, they produce greater fat-mass reduction than GLP-1 alone.
Entity Properties
| Aliases | Mazdutide, IBI-362, LY3305677 |
|---|---|
| Family | Dual GLP-1R / GCGR agonist (oxyntomodulin analog) |
| Structure | Oxyntomodulin-analog peptide with lipidation (fatty-acid acylation for albumin binding) |
| Molecular Weight | ~4476 Da |
| CAS Number | 2259884-03-0 |
| PubChem CID | 167312357 |
| Dosing | Once weekly (subcutaneous injection) |
| Clinical Doses | 3 mg, 4 mg, 4.5 mg, 6 mg, 9 mg, 10 mg (trial-dependent) |
| Regulatory Status | Approved in China (2025) for weight management and T2D |
| Storage | Per product COA; avoid repeated freeze-thaw cycles |
Mechanism of Action
🧠 How does Mazdutide work?
Mazdutide co-activates GLP-1 and glucagon receptors, mimicking the effects of oxyntomodulin. This dual mechanism targets both energy intake (via appetite suppression) and energy expenditure (via thermogenesis).
The “Balance-and-Ramp” model explains the strategy: balance the GLP-1:GCGR ratio to suppress appetite without excessive hyperglycemia, then ramp dose to maximize energy-expenditure gains.
🍽️ GLP-1 Effects
Slows gastric emptying, enhances insulin secretion, reduces appetite via central satiety signals
🔥 Glucagon Effects
Increases hepatic lipid oxidation, raises energy expenditure ~9%, promotes fat mobilization
📅 Long-Acting
Fatty-acid acylation enables albumin binding → extended half-life → once-weekly dosing
Oxyntomodulin basis: Natural oxyntomodulin increased total energy expenditure ~9% in a classic RCT. Mazdutide replicates this physiology with modifications for once-weekly stability.
Clinical Evidence
📈 Phase 2 RCT Results (24 weeks)
In Chinese adults with overweight/obesity, mazdutide produced dose-dependent weight loss vs placebo (+1.0%):
✅ Additional Outcomes
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Glycemic improvements — HbA1c, fasting glucose, HOMA-IR
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Blood pressure reduction — systolic and diastolic
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Lipid improvements — favorable shifts in lipid panel
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Liver enzymes — ALT reduction; liver fat under investigation
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Uric acid — reductions observed
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Body composition — DEXA showed proportionally greater fat vs lean mass loss
Safety signals: Most common AEs are GI (nausea, diarrhea, vomiting) — generally mild to moderate. Small increases in heart rate reported with GLP-1/GCGR co-agonists. Monitor accordingly.
Titration Schedules
Clinical trials used step-up titration to improve GI tolerability while achieving target doses. Below are examples from published protocols (educational only):
📊 3 mg Target
Weeks 5–24: 3 mg
📊 4.5 mg Target
Weeks 5–8: 3 mg
Weeks 9–24: 4.5 mg
📊 6 mg Target
Weeks 5–8: 4 mg
Weeks 9–24: 6 mg
📊 9 mg Target (12 wk)
Result: −11.7% at week 12
Titration purpose: Gradual dose escalation conditions GI tolerability while tapping into full energy-expenditure benefits. Align any protocol to your institutional guidelines.
Comparison
How does Mazdutide compare to other GLP-1-based therapies? Each has a distinct receptor profile driving different efficacy and tolerability patterns.
Mazdutide
Dual appetite + energy expenditure. Approved China 2025. GI AEs + HR increase to monitor.
Semaglutide
Strong GLP-1 benchmark. FDA approved (Wegovy). Proven CV benefits. GI AEs typical.
Tirzepatide
Highest mean weight loss. FDA approved (Zepbound). Distinct GIP biology. GI AEs common.
Key distinction: Mazdutide’s glucagon component adds energy-expenditure benefits (thermogenesis, lipid oxidation) not present in GLP-1-only or GLP-1/GIP agents. This may explain robust fat-mass reductions at relatively moderate GLP-1 exposure.
FAQ
Bottom line: Mazdutide is a mechanistically distinct co-agonist that pairs GLP-1 appetite control with glucagon-linked energy expenditure, yielding clinically meaningful weight loss (−11.3% at 6 mg / 24 wk) plus improvements in BP, lipids, glycemic markers, and liver enzymes. First approved in China 2025 — a significant milestone for dual GLP-1/glucagon therapy.