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.
MW ~4476 Da CAS 2259884-03-0 Dosing Once Weekly ✅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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01 Overview 02 Properties 03 Mechanism 04 Evidence 05 Titration 06 Comparison 📋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
- 🍽️ Appetite reduction — GLP-1 pathway
- 🔥 Energy expenditure↑ — glucagon pathway
- 📅 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 quality documentation; 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%):
3 mg −6.7% body weight 4.5 mg −10.4% body weight 6 mg −11.3% body weight✅ Additional Outcomes
- 🩸 Glycemic improvements — HbA1c, fasting glucose, HOMA-IR
- ❤️ Blood pressure reduction — systolic and diastolic
- 📉 Lipid improvements — favorable shifts in lipid panel
- 🫁 Liver enzymes — ALT reduction; liver fat under investigation
- ⚗️ Uric acid — reductions observed
- 📐 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 1–4: 1.5 mgWeeks 5–24: 3 mg
📊 4.5 mg Target
Weeks 1–4: 1.5 mgWeeks 5–8: 3 mg
Weeks 9–24: 4.5 mg
📊 6 mg Target
Weeks 1–4: 2 mgWeeks 5–8: 4 mg
Weeks 9–24: 6 mg
📊 9 mg Target (12 wk)
Step-up: 3 → 6 → 9 mgResult: −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
GLP-1 + Glucagon −11.3% 6 mg / 24 wkDual appetite + energy expenditure. Approved China 2025. GI AEs + HR increase to monitor.
Semaglutide
GLP-1 only −14.9% 2.4 mg / 68 wkStrong GLP-1 benchmark. FDA approved (Wegovy). Proven CV benefits. GI AEs typical.
Tirzepatide
GLP-1 + GIP ~21% 15 mg / 72 wkHighest 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
What is Mazdutide? A once-weekly dual GLP-1/glucagon receptor agonist modeled on oxyntomodulin, designed to reduce appetite and increase energy expenditure for weight loss and metabolic benefits. How does it differ from semaglutide? Semaglutide is GLP-1 only (appetite reduction). Mazdutide adds glucagon receptor activation, which increases energy expenditure — a distinct mechanism that may enhance fat-mass reduction. Is Mazdutide approved? Yes — China approved Mazdutide in 2025 for chronic weight management and glycemic control in T2D. Global development is ongoing; not yet FDA-approved in the US. What are the side effects? Most common are GI events (nausea, diarrhea, vomiting) — generally mild to moderate. Small increases in heart rate are a class effect of GLP-1/GCGR co-agonists. Anti-drug antibodies detected in a minority. How much weight loss? Phase 2: −11.3% at 6 mg over 24 weeks (vs +1% placebo). Phase 3 (32 weeks) confirmed clinically meaningful reductions at 4–6 mg. Higher doses (9–10 mg) showed up to −11.7% at 12 weeks. Why titrate the dose? Step-up titration improves GI tolerability. Starting at full dose causes more nausea/vomiting. Gradual escalation conditions the body while achieving target efficacy. ✅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.