Mazdutide
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Dual GLP-1/glucagon receptor agonist; once-weekly injectable for obesity and type 2 diabetes (Innovent Biologics / Eli Lilly).
Quick Facts
| Property | Value |
|---|---|
| Also Known As | IBI362, LY3305677 |
| Category | Dual GLP-1/Glucagon Receptor Agonist (Metabolic) |
| Sequence | Modified peptide with GLP-1 and glucagon receptor agonist activities (proprietary; fatty acid-acylated for albumin binding and extended half-life) |
| Molecular Weight | ~4200 Da |
| Molecular Formula | Not publicly disclosed |
| PubChem CID | N/A (proprietary) |
| Administration | SubQ once weekly |
| Typical Dose Range | 3-10 mg once weekly (dose-escalation over 8-16 weeks) |
| Half-Life | ~6 days |
| Storage | Refrigerate 2-8C; do not freeze |
| FDA Status | Approved in China (June 2024) for chronic weight management; Phase 3 globally; not yet FDA-approved |
| WADA Status | Not listed (investigational outside China) |
Mechanism of Action
Mazdutide is a rationally designed acylated peptide that simultaneously activates two receptors: the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR). This dual agonism produces complementary metabolic effects that exceed those achievable by GLP-1R agonism alone, engaging fundamentally different metabolic pathways through each receptor.
GLP-1R agonism provides established incretin effects: glucose-dependent insulin secretion, glucagon suppression (from pancreatic alpha cells), delayed gastric emptying, and central appetite suppression through hypothalamic GLP-1R activation. These are the same mechanisms exploited by Semaglutide, Liraglutide, and other GLP-1 receptor agonists.
Glucagon receptor agonism adds a mechanistically distinct metabolic dimension:
- Hepatic lipid oxidation — Glucagon activates hepatic AMPK and PPARalpha signaling, promoting beta-oxidation of fatty acids. This directly addresses hepatic steatosis and is the key mechanism for potential MASH/NAFLD benefit.
- Increased energy expenditure — Glucagon increases resting energy expenditure through thermogenesis, particularly in brown adipose tissue and through futile cycling pathways. This adds caloric expenditure on top of the caloric reduction from GLP-1-mediated appetite suppression.
- Amino acid metabolism — Glucagon stimulates hepatic amino acid catabolism and ureagenesis, contributing to the overall increase in energy expenditure.
The critical design challenge was balancing the opposing glycemic effects: GLP-1R agonism lowers glucose while GCGR agonism raises it. Mazdutide was optimized for a GLP-1R:GCGR activity ratio that achieves robust weight loss and hepatic fat reduction without clinically significant hyperglycemia.
Mazdutide shares the same dual agonist mechanism as Survodutide (BI 456906, Boehringer Ingelheim). It is differentiated from Tirzepatide (GIP/GLP-1 dual agonist — different second receptor) and Retatrutide (GIP/GLP-1/glucagon triple agonist — adds GIP on top of the dual mechanism).
Key Research Areas
- Obesity / Weight Management — Phase 3 GLORY-1 trial demonstrated 14.0% body weight loss at 48 weeks with 6 mg dose in Chinese adults (PMID: 40421736, NEJM 2025)
- Type 2 Diabetes — Phase 2 data showed significant HbA1c reductions alongside weight loss; DREAMS-3 head-to-head trial vs. semaglutide underway (PMID: 37943529)
- MASH/NAFLD — Glucagon-mediated hepatic fat oxidation provides mechanistic rationale; clinical data anticipated
- High-Dose Efficacy — Phase 1b data with 9-10 mg showed up to 11.7% weight loss in just 12 weeks (PMID: 36247927)
Evidence Level Summary
| Evidence Type | Count | Notes |
|---|---|---|
| Human RCTs | 3 | Phase 1b, Phase 2, Phase 3 (GLORY-1) |
| Human observational | 0 | — |
| Animal in vivo | 0 | Preclinical data in regulatory filings |
| In vitro | 0 | — |
| Systematic reviews | 1 | Meta-analysis of RCTs (PMID: 38440786) |
Clinical Applications
- Weight Management — Primary indication; approved in China for chronic weight management
- Fat Loss — Significant body fat reduction demonstrated across trials
- Type 2 Diabetes — HbA1c reduction with weight loss; Phase 3 data pending
- Metabolic Syndrome — Improvements in waist circumference, blood pressure, lipids
- NAFLD — Mechanistic rationale from glucagon-mediated hepatic fat oxidation (data pending)
Protocols Using This Peptide
- Weight Loss Protocol — Potential addition as dual agonist option
- Metabolic Reset Protocol — Candidate for metabolic optimization
Ageless Peps Products
- APWS-Mazdutide-Vial — Mazdutide Vial, wholesale/clinical-label
Dosing Reference
Research Dosing Ranges (from literature)
| Route | Dose Range | Frequency | Duration | Source |
|---|---|---|---|---|
| SubQ | 3-6 mg | Once weekly | 24-48 weeks | PMID 40421736 (Phase 3) |
| SubQ | 9-10 mg | Once weekly | 12 weeks | PMID 36247927 (Phase 1b) |
Dose Escalation (Phase 3 protocol)
- Weeks 1-4: Starting dose (typically 1.5-3 mg)
- Weeks 5-8: Intermediate dose
- Weeks 9+: Target maintenance dose (4 mg or 6 mg)
- Escalation schedule designed to mitigate GI adverse events
Cycling
No cycling protocol established. Approved as chronic therapy in China. Weight regain expected upon discontinuation, consistent with GLP-1 class effects.
Contraindications & Safety
- Contraindications: Personal or family history of medullary thyroid carcinoma (MTC) or MEN2 (GLP-1 class labeling); known hypersensitivity
- Common side effects: Nausea, vomiting, diarrhea, decreased appetite, injection site reactions — consistent with GLP-1 class
- Drug interactions: Insulin and sulfonylureas (increased hypoglycemia risk); oral medications may have altered absorption due to delayed gastric emptying
- Pregnancy/nursing: Contraindicated (animal data insufficient; weight loss not appropriate during pregnancy)
- Special populations: Not studied in severe renal or hepatic impairment; caution in patients with gastroparesis; not studied in pediatric populations
Synergistic Combinations
- Not typically combined with other GLP-1 RAs — overlapping mechanism would increase GI side effects without proportional benefit
- Potential theoretical combination with 5-Amino-1MQ (different metabolic pathway — NNMT inhibition)
- Potential theoretical combination with MOTS-C (mitochondrial exercise mimetic — complementary energy expenditure mechanism)
Related Research
| PMID | Title | Year | Study Type |
|---|---|---|---|
| 36247927 | Mazdutide Phase 1b High-Dose Obesity Trial | 2023 | RCT |
| 38092790 | Phase 2 RCT in Chinese Overweight/Obese Adults | 2023 | RCT |
| 40421736 | Phase 3 GLORY-1: Once-Weekly Mazdutide (NEJM) | 2025 | RCT |
| 38440786 | Systematic Review & Meta-Analysis of Weight Loss RCTs | 2024 | Systematic Review |
References
- PMID 36247927 — Phase 1b high-dose (9-10 mg) safety and efficacy
- PMID 38092790 — Phase 2 dose-ranging (3, 4.5, 6 mg) at 24 weeks
- PMID 40421736 — Phase 3 GLORY-1 NEJM publication (4 mg, 6 mg at 48 weeks)
- PMID 38440786 — Systematic review and meta-analysis of mazdutide RCTs
- PMID 37943529 — Phase 2 T2D trial
- PMID 41028652 — Mazdutide: First Approval (Drugs review)
Related
FDA Disclaimer: The products and claims made about specific products have not been evaluated by the United States Food and Drug Administration and are not approved to diagnose, treat, cure, or prevent disease. Mazdutide is approved in China but is not FDA-approved in the United States.
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