Mazdutide (also known as IBI‑362 or LY3305677) is a once‑weekly dual agonist of the GLP‑1 and glucagon receptors modeled on oxyntomodulin. In phase 2 and 3 studies, mazdutide produced clinically meaningful weight loss alongside improvements in multiple metabolic markers; China granted its first approvals in 2025. This article explains how it works, what the data show, and how researchers can design high‑quality studies. (Nature)
Fast Answer / Executive Summary (40–60 words):
Mazdutide is a once‑weekly, oxyntomodulin‑based peptide that co‑activates GLP‑1 and glucagon receptors to reduce appetite and increase energy expenditure, driving clinically relevant weight loss and broader metabolic benefits in randomized trials. It received first marketing approvals in China in 2025 for chronic weight management and for glycemic control in adults with type 2 diabetes. (PubMed)
Entity Properties (for researchers)
| Property | Detail (educational) |
|---|---|
| Aliases / Synonyms | Mazdutide; IBI‑362; LY3305677 |
| Family / Pathway | Dual GLP‑1R / GCGR agonist (oxyntomodulin analog) |
| Sequence (AA) | Exact manufacturer sequence not publicly disclosed; mammalian oxyntomodulin–analog peptide with lipidation to prolong half‑life (albumin binding); reports note the use of non‑canonical residues typical of co‑agonists (e.g., Aib) and fatty‑acid acylation. (MDPI) |
| Molecular Weight (Da) | ~4476 g/mol (PubChem computed) |
| CAS | 2259884‑03‑0 |
| Typical Diluent(s) | Not standardized in public literature; follow supplier COA and study protocol (e.g., sterile buffered aqueous systems for in‑vivo/in‑vitro research). |
| Example Concentrations (educational) | Not specified in peer‑reviewed literature; determine by protocol (pilot tolerability/PK data first). |
| Storage (lyophilized / after reconstitution) | Per product COA; conditions vary by formulation. Avoid repeated freeze‑thaw cycles. |
| Notes | Once‑weekly dosing supported by lipidation and pharmacokinetics typical of long‑acting incretin analogs. (PubChem) |
Core Concepts & Key Entities
What is Mazdutide? Mazdutide is a dual GLP‑1/glucagon receptor agonist designed to combine GLP‑1–mediated appetite and glycemic effects with glucagon‑mediated increases in energy expenditure, a synergy observed with the natural gut hormone oxyntomodulin. This design aims to widen the therapeutic window beyond GLP‑1 alone. (Frontiers)
Why glucagon with GLP‑1? GLP‑1 slows gastric emptying, enhances insulin secretion, and reduces appetite; glucagon increases hepatic lipid oxidation and raises energy expenditure—effects shown in human studies with oxyntomodulin. The co‑agonist strategy seeks greater fat‑mass reduction without proportionally increasing GLP‑1‑related GI intolerance. (Nature)
How is Mazdutide built? Mazdutide is an oxyntomodulin‑analog peptide with fatty‑acid acylation to extend half‑life via albumin binding—similar to long‑acting incretins—enabling once‑weekly administration. Specific sequence and modification positions have not been fully disclosed publicly, but authoritative reviews describe this general architecture. (MDPI)
Key clinical outcomes (high‑level):
- Phase 2 RCT (24 weeks, 3–6 mg): Mazdutide produced dose‑dependent weight loss (LS mean −6.7%, −10.4%, −11.3% at 3, 4.5, 6 mg) versus +1.0% with placebo, with improvements in blood pressure, lipids, glycemic measures, ALT, and uric acid. (Nature)
- Phase 1b MAD (9–10 mg): With a step‑up regimen (e.g., 3→6→9 mg over 12 weeks), weight fell −11.7% at week 12 (9 mg); a 16‑week 10 mg cohort also showed significant loss.
- Phase 3 (NEJM, 32 weeks): 4 or 6 mg once weekly achieved clinically relevant weight reductions in Chinese adults with overweight/obesity. (Additional national approvals in China followed in 2025 for weight management and glycemic control.)
Safety signals to understand: Across trials, the most frequent adverse events were gastrointestinal (nausea, diarrhea, vomiting), generally mild to moderate; class‑typical increases in heart rate have been observed with GLP‑1/GCGR co‑agonists and reported with mazdutide (often transient; clinical significance under study). (Nature)
Evidence, Outcomes & What They Mean for Therapeutic Goals (educational)
Phase 2 randomized trial (Nature Communications, 2023). In a 24‑week, multi‑center RCT of Chinese adults with overweight or obesity, once‑weekly mazdutide produced dose‑dependent weight loss vs placebo: −6.7% (3 mg), −10.4% (4.5 mg), −11.3% (6 mg). Investigators also reported favorable shifts in glycemic variables (HbA1c, FPG, HOMA‑IR), blood pressure, lipids, and liver enzymes/uric acid. DEXA substudy data suggested proportionally greater fat mass than lean mass reduction. (Nature)
High‑dose explorations (eClinicalMedicine, 2022). A 9 mg 12‑week cohort using 3→6→9 mg titration achieved −11.7% mean weight change; a 10 mg 16‑week step‑up (2.5→5→7.5→10 mg) also showed significant loss. Adverse events were mostly mild/moderate GI or upper‑respiratory; no serious events were reported in these small cohorts.
Phase 3 (NEJM, 2025). Once‑weekly 4 mg or 6 mg for 32 weeks led to clinically meaningful weight reductions in adults with overweight/obesity (GLORY‑1 program). These data support the once‑weekly paradigm and informed China’s regulatory approvals for chronic weight management (June 2025) and type 2 diabetes glycemic control (September 2025).
Why outcomes may differ from GLP‑1 alone: Human and mechanistic data indicate glucagon co‑agonism can add energy‑expenditure benefits to GLP‑1’s appetite/glycemic effects—mirroring oxyntomodulin physiology, which increased total energy expenditure ~9% in a classic RCT. This helps explain robust fat‑mass reductions at relatively moderate GLP‑1 exposure. (Nature)
Information‑gain insight: A practical way to think about co‑agonists is the “Balance‑and‑Ramp” model:
- Balance the GLP‑1:GCGR activity ratio to suppress appetite without excessive hyperglycemic drive from glucagon.
- Ramp the dose deliberately to condition tolerability (GI) while tapping energy‑expenditure gains—mirroring the step‑ups used in trials (see below). (Frontiers)
Step‑by‑Step / How‑To (for research planning)
How should a researcher plan a mazdutide study? Define endpoints first (weight change, body composition, glycemia, BP/lipids, liver fat by MRI‑PDFF), then mirror trial‑proven titration where appropriate, and embed tolerability monitoring to protect data quality.
Step 1 — Specify the research question and endpoints
State the primary endpoint (e.g., % weight change at 12–24–32 weeks). Select secondary endpoints aligned to disease biology: fasting glucose/HbA1c, BP/lipids, ALT/AST, serum uric acid, and MRI‑PDFF if steatosis is of interest. These reflect the endpoints improved in RCTs. (Nature)
Step 2 — Choose study population and randomization
Match inclusion criteria to published trials (BMI thresholds, comorbidities), randomize against placebo or active comparator (e.g., semaglutide). Pre‑specify handling of anti‑drug antibodies (detected in a minority of subjects) and data imputation strategies. (Nature)
Step 3 — Model your dosing/titration on peer‑reviewed protocols
Examples drawn from trials:
- 3 mg arm: 1.5 mg weeks 1–4 → 3 mg weeks 5–24.
- 4.5 mg arm: 1.5 mg weeks 1–4 → 3 mg weeks 5–8 → 4.5 mg weeks 9–24.
- 6 mg arm: 2 mg weeks 1–4 → 4 mg weeks 5–8 → 6 mg weeks 9–24.
- 9 mg exploratory: 3→6→9 mg (12 weeks total).
- 10 mg exploratory: 2.5→5→7.5→10 mg (16 weeks total).
These step‑ups are educational exemplars derived from RCTs; align any new protocol to your IACUC/IRB and supplier documentation. (Nature)
Step 4 — Predefine AE surveillance and mitigation
Track GI symptoms (nausea, diarrhea, vomiting), heart rate, and injection‑site reactions at each visit. Build a dose‑pause/reduce rubric for moderate GI events and document cardiovascular signals given class effects on HR. (Nature)
Step 5 — Powering, statistics, and data integrity
Use historically observed placebo‑adjusted differences to power your primary endpoint (e.g., 8–12 percentage‑point placebo‑adjusted weight change over ~24 weeks in phase 2). Implement ANCOVA/MMRM as used in trials; prespecify sensitivity analyses and handling of COVID‑like disruptions if relevant. (Nature)
Step 6 — Resourcing: protocols & research material
For vial‑based protocol examples, see PeptideDosages.com’s educational pages for mazdutide 5 mg protocol and mazdutide 10 mg protocol (educational use only). For research‑grade material, PureLabPeptides provides 5 mg and 10 mg vials (for research use only).
Compliance note: This article is educational, not medical advice. Any in‑human use requires physician oversight and approved labeling; the purchase links are for research use only.
Comparison / Alternatives: Mazdutide vs Semaglutide vs Tirzepatide
Bottom line: Mazdutide adds energy‑expenditure via glucagon agonism (beyond appetite and glycemia), whereas semaglutide (GLP‑1) and tirzepatide (GLP‑1/GIP) rely primarily on intake reduction (and GIP‑dependent mechanisms). Clinical effect sizes depend on dose, duration, and population.
| Molecule | Mechanism | Dosing (typical) | Body‑weight change (trial & duration) | Notes |
|---|---|---|---|---|
| Mazdutide | Dual GLP‑1/GCGR (oxyntomodulin‑analog) | Once weekly | −11.3% (6 mg, 24 wk) vs +1.0% placebo (phase 2 RCT); phase 3 (32 wk) shows clinically relevant reductions at 4–6 mg | Improves BP, lipids, glycemic markers; GI AEs common; HR increase reported across class; ongoing liver‑fat investigations. (Nature) |
| Semaglutide (2.4 mg) | GLP‑1 RA | Once weekly | −14.9% (68 wk) vs −2.4% placebo (STEP‑1, NEJM) | Strong weight loss and CV benefits; GI AEs typical of GLP‑1s. |
| Tirzepatide (5–15 mg) | GLP‑1/GIP dual (“twincretin”) | Once weekly | Up to ~21% at 72 wk (SURMOUNT‑1, NEJM) | Higher mean weight loss at top dose; GI AEs; distinct GIP biology. |
Interpretation for outcomes: If maximal weight loss is the priority, tirzepatide currently holds the strongest mean reduction at 72 weeks; if a balanced metabolic profile with potential energy‑expenditure and hepatic benefits is the aim, mazdutide is a compelling co‑agonist to study further. Semaglutide remains a robust GLP‑1 benchmark.
Templates / Checklist / Example
Researcher’s Pre‑Study Checklist for Mazdutide (copy‑ready)
- Define a single primary endpoint (e.g., % weight change at week 24 or 32).
- Pre‑register analysis plan (ANCOVA/MMRM; handling of missing data).
- Stratify randomization (e.g., BMI bands, sex) to balance metabolic risk.
- Mirror published titration (e.g., 2→4→6 mg) and document pauses/reductions.
- Track GI AEs, vitals (including heart rate), and laboratory panels each visit.
- Add MRI‑PDFF if hepatic outcomes matter; standardize scanner & readers.
- Schedule DEXA or alternative body‑composition at baseline and outcome visit.
- Collect patient‑reported outcomes (e.g., IWQoL‑Lite), where relevant.
- Train staff on injection technique and blinded AE adjudication.
- Audit data entry weekly; run real‑time queries for outliers/missed visits. (Nature)
FAQs (NLP‑friendly, answer‑first)
What is mazdutide? Mazdutide is a once‑weekly dual GLP‑1/glucagon receptor agonist modeled on oxyntomodulin, designed to reduce appetite and increase energy expenditure; it has shown clinically meaningful weight loss and metabolic benefits in randomized trials. (Nature)
How does mazdutide work? Mazdutide co‑activates GLP‑1 and glucagon receptors, combining GLP‑1–driven appetite/glycemic effects with glucagon‑driven thermogenic/lipid‑oxidation effects seen with oxyntomodulin, thereby enhancing fat‑mass reduction. (PMC)
What results have clinical trials reported? Trials report dose‑dependent weight loss (e.g., −11.3% at 6 mg over 24 weeks vs +1% placebo) with favorable changes in BP, lipids, and glycemic indices; phase 3 (32 weeks) confirmed clinically relevant reductions at 4–6 mg. (Nature)
Is mazdutide approved anywhere? Yes—China approved mazdutide in 2025 for chronic weight management and glycemic control in adults with type 2 diabetes. Global development is ongoing.
How does mazdutide compare to semaglutide or tirzepatide? Semaglutide (GLP‑1) achieved −14.9% at 68 weeks; tirzepatide (GLP‑1/GIP) achieved ~20% at 72 weeks; mazdutide (GLP‑1/GCGR) showed double‑digit losses at 24–32 weeks with broader metabolic effects tied to glucagon biology. Mechanistic differences drive these profiles.
What adverse events are most common? GI events (nausea, diarrhea, vomiting) are most frequent and typically mild/moderate; small increases in heart rate are reported with GLP‑1/GCGR co‑agonists and observed with mazdutide, warranting monitoring. (Nature)
Next Steps
If you’re evaluating mazdutide in a research setting, ground your protocol in peer‑reviewed titration schedules, predefine hepatic and metabolic endpoints, and monitor GI and cardiovascular signals closely. For educational protocol examples, see PeptideDosages.com’s 5 mg and 10 mg pages. Research‑grade mazdutide is available via PureLabPeptides (5 mg, 10 mg). All products are for research use only.
Key takeaway: Mazdutide is a mechanistically distinct co‑agonist that pairs GLP‑1 appetite control with glucagon‑linked energy‑expenditure, yielding clinically meaningful weight loss and multi‑system metabolic benefits in trials. (Nature)