What is Mazdutide?
Mazdutide (development codes IBI362 / LY3305677 / OXM3) is a long-acting dual agonist of the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR). It was originally discovered at Eli Lilly and licensed to Innovent Biologics for development and commercialization in Greater China. Mazdutide is the first GLP-1/glucagon dual agonist approved anywhere in the world.
Approval timeline in China:
- June 27, 2025 — NMPA approval for chronic weight management in adults
- September 19, 2025 — NMPA approval for type 2 diabetes glycemic control
Eli Lilly retains rights outside Greater China but has not yet pursued separate approvals; orforglipron and retatrutide are Lilly's primary obesity-pipeline focus globally.
Structure
Mazdutide is a modified oxyntomodulin (OXM) analogue — engineered from the natural human OXM peptide, which itself is an endogenous gut peptide that intrinsically activates both GLP-1R and GCGR. The molecule incorporates:
- A 39-amino-acid OXM-derived peptide backbone
- A C20 fatty acid (γ-Glu-fatty acid) acylation at a specific lysine residue for non-covalent albumin binding (extending half-life to once-weekly dosing)
- Selected residue substitutions to fine-tune the GLP-1R:GCGR potency ratio
This positions mazdutide alongside the broader oxyntomodulin-derived dual-agonist class that includes survodutide and pemvidutide.
Mechanism of Action
Native oxyntomodulin signals through both receptors:
- GLP-1R activation → glucose-dependent insulin secretion, suppressed glucagon, slowed gastric emptying, central appetite suppression (the same axis as semaglutide, tirzepatide, and other GLP-1 agonists)
- GCGR activation → increased hepatic energy expenditure, increased lipolysis in adipose tissue, increased thermogenesis, hepatic gluconeogenesis (offset by GLP-1 in the dual agonist)
The therapeutic hypothesis: GLP-1 agonism alone produces weight loss largely through reduced food intake; adding glucagon agonism adds an energy-expenditure component that further drives weight loss while improving liver fat (via lipolysis and reduced hepatic steatosis) — provided the GLP-1 component prevents the hyperglycemia that pure glucagon agonism would otherwise cause.
Clinical Evidence
GLORY-1 Phase 3 (NEJM 2025) — obesity:
- Chinese adults with overweight or obesity, randomized to mazdutide 4 mg, 6 mg, or placebo for 48 weeks
- Mean weight loss: 11.0% (4 mg), 14.0% (6 mg), 0.3% (placebo)
- ≥5% weight loss: 81-86% mazdutide vs 23% placebo
- Liver fat content reduced by 70-80%
- ALT and AST normalization
DREAMS-2 Phase 3 (Lancet D&E 2025) — type 2 diabetes:
- Chinese adults with T2D, mazdutide vs dulaglutide
- HbA1c reduction superior to dulaglutide 1.5 mg
- Body weight reduction substantially greater
- Lipid profile improvements
Approval History
- June 27, 2025 — NMPA China approval for chronic weight management
- September 19, 2025 — NMPA China approval for T2D glycemic control
- No FDA or EMA approval filings as of mid-2026; Lilly's Greater-China-only license terms shape the global development trajectory
Place in Therapy
In China, mazdutide is positioned as a once-weekly subcutaneous injection for adults with:
- Obesity or overweight with at least one comorbidity — chronic weight management
- Type 2 diabetes inadequately controlled by oral agents — glycemic control with weight benefit
It is the first dual-mechanism obesity peptide approved anywhere, ahead of survodutide (Boehringer, US/EU pipeline) and the GLP-1/GIP/glucagon triple agonist retatrutide (Lilly, US/EU Phase 3).
Safety Profile
The adverse event profile is similar to the GLP-1 class — nausea, vomiting, diarrhea — with the additional consideration that glucagon agonism can transiently elevate fasting glucose during dose titration. In clinical trials this was offset by GLP-1-mediated insulin secretion at maintenance doses. Heart rate elevation (modest) and a small ALT/AST decrease (favorable) have been observed.
Distinction from Other Dual/Triple Agonists
| Drug | GLP-1 | GIP | Glucagon | Status |
|---|---|---|---|---|
| Semaglutide | yes | — | — | FDA approved |
| Tirzepatide | yes | yes (agonist) | — | FDA approved |
| MariTide | yes | yes (antagonist) | — | Phase 3 |
| Survodutide | yes | — | yes | Phase 3 |
| Mazdutide | yes | — | yes | NMPA approved (China) |
| Pemvidutide | yes | — | yes | Phase 3 (MASH) |
| Retatrutide | yes | yes | yes | Phase 3 |
The dual GLP-1/glucagon class (mazdutide, survodutide, pemvidutide) and the triple agonist (retatrutide) represent the two main directions of next-generation incretin-based therapy beyond semaglutide and tirzepatide.