Mazdutide¶
Tags: Mazdutide, GLP-1, Glucagon, Weight Loss, Obesity
Quick Summary
Mazdutide (IBI362/LY3305677) is a dual GLP-1 and glucagon receptor agonist showing up to ~20% weight loss and superior glycemic control in Phase 3 trials. Once-weekly dosing with fatty-acid conjugation; approved/under review in select markets.
Quick Facts¶
- Typical Dose: 3–9 mg weekly (once weekly)
- Route: Injectable — Abdomen, thigh, or upper arm (rotate sites)
- Cycle: 48–60+ weeks (typical duration)
- Storage: Lyophilized: -20°C long-term; Reconstituted: 2–8°C, use within 30 days
Overview¶
Mazdutide (IBI362 / LY3305677) is a dual GLP-1 and glucagon receptor agonist — a synthetic oxyntomodulin analog. It combines GLP-1–mediated appetite suppression with glucagon-driven increases in energy expenditure and thermogenesis. Phase 3 trials (GLORY-1, GLORY-2) demonstrated large weight reductions (up to ~20% at higher doses) and improved glycemic control versus comparators.
Key Benefits¶
- Substantial weight loss (up to ~20% reported in trials)
- Superior glycemic control vs semaglutide in head-to-head data
- Increased energy expenditure via glucagon receptor activation
- Improvements in cardiometabolic markers (BP, lipids, liver fat)
- Once-weekly dosing enabled by fatty-acid conjugation
Mechanism of action¶
Dual agonism at GLP-1 and glucagon receptors: GLP-1 promotes insulin release, reduces appetite and slows gastric emptying; glucagon activation increases energy expenditure and improves hepatic fat metabolism. The combination yields synergistic weight-loss effects while GLP-1 helps counteract glucagon's glycemic effects.
Molecular information¶
- Weight: 4,563.1 Da
- Length: 33 amino acids
- Type: Oxyntomodulin analog with fatty acid conjugation
Amino Acid Sequence:
33-amino acid linear synthetic peptide conjugated to C20 fatty diacid moiety through hydrophilic linker at Lys20
C20 fatty diacid conjugation via hydrophilic linker extends half-life for once-weekly dosing.
Research Indications¶
- Weight loss — GLORY trials showed substantial efficacy (including high-dose 9 mg results)
- Metabolic syndrome improvements (waist, BP, triglycerides, LDL, liver fat)
- Liver fat reduction (exploratory analyses suggest MASLD/MASH benefits)
- Type 2 diabetes — improved glycemic control in trials, including head-to-head comparisons
Research protocols¶
| Goal | Dose | Frequency | Route |
|---|---|---|---|
| Weight loss initiation (3 mg target) | 1.5 mg → 3 mg | Once weekly | SubQ injection |
| Weight loss progression (4.5 mg target) | 1.5 mg → 3 mg → 4.5 mg | Once weekly | SubQ injection |
| Weight loss optimization (6 mg target) | 2 mg → 4 mg → 6 mg | Once weekly | SubQ injection |
| Maximum weight loss (9 mg target) | 3 mg → 6 mg → 9 mg | Once weekly | SubQ injection |
| T2D management (mild–moderate) | 3–4.5 mg weekly | Once weekly | SubQ injection |
| T2D with obesity (intensive) | 6–9 mg weekly | Once weekly | SubQ injection |
Timing: Inject any time of day, with or without food. Choose a consistent day each week. If a dose is missed, take as soon as possible within 3 days, then resume regular schedule.
Interactions¶
Compatible / Complementary
- GLP-1 class agents — Metabolic synergy (but avoid dual therapy without medical oversight)
- Metformin — Compatible
Monitor
- Insulin — Monitor glucose closely; reduce insulin doses as needed
- Sulfonylureas — Monitor glucose closely; reduce doses as needed
- Other antidiabetic agents — Risk of hypoglycemia; coordinate with healthcare provider
Avoid
- GLP-1 receptor agonist dual therapy — Avoid without medical oversight
- Personal/family history of medullary thyroid carcinoma — Contraindicated (GLP-1 class warning)
- MEN2 syndrome — Contraindicated
- Pregnancy and breastfeeding — Not recommended
How to Reconstitute¶
- Remove vial from freezer/refrigerator and allow to reach room temperature (15–20 minutes).
- Clean vial top with an alcohol swab; allow to air dry completely.
- Calculate reconstitution volume based on desired concentration.
- Draw the calculated amount of bacteriostatic water (BAC) into a syringe; remove air bubbles.
- Insert needle at a 45° angle against the vial wall — not directly into the powder.
- Inject BAC slowly down the side of the vial (drop by drop) to prevent foaming.
- Remove needle and gently swirl vial in a circular motion — never shake vigorously.
- If cloudiness persists, allow solution to sit 2–3 minutes then swirl gently until clear.
- Final solution should be completely clear and colorless — discard if cloudy or containing particles.
- Label vial with reconstitution date and concentration.
- Store reconstituted solution at 2–8°C; use within 30 days.
Quality Indicators¶
Positive Signs
- White to off-white lyophilized powder, light and fluffy without clumps
- Clear, colorless reconstituted solution with no visible particles
- Intact vial seal with clear mg dosage, visible batch numbers, and expiration date
- Proper storage maintained (temperature control, protected from light, no freeze–thaw cycles)
- Source verification with purity testing and supplier reputation confirmed
Warning Signs
- Clumping, discoloration, or moisture in lyophilized powder — do not use
- Persistent cloudiness or visible particles in reconstituted solution — do not use
- Broken vial seal or missing batch information — avoid
- Improper storage history or temperature excursions — quality compromised
What to expect (timeline)¶
- Week 1–2: Appetite reduction, possible mild nausea
- Week 3–4: Early weight loss (1–2%), improved satiety
- Week 4–8: Dose escalation phase; GI symptoms typically improve; 3–5% weight loss
- Week 8–16: Steady weight loss (7–12%), energy-expenditure effects appear
- Week 16–32: Significant weight reduction (12–17%), metabolic markers improving
- Week 32–60: Peak effects (up to ~20% weight loss), sustained improvements in BP, lipids, glucose
Side effects & safety¶
- Start low and escalate every ~4 weeks to reduce GI side effects
- Common: GI symptoms (nausea, diarrhea, vomiting) — usually mild–moderate and transient
- Increased heart rate (observed 5–17 bpm in trials)
- Monitor for pancreatitis (severe abdominal pain radiating to back)
- Caution with personal/family history of medullary thyroid carcinoma or MEN2 (GLP-1 class warning)
- Monitor glucose closely when used with insulin or sulfonylureas; reduce doses as needed
- Not recommended in pregnancy or breastfeeding
References¶
GLORY-1 Phase 3 Trial - NEJM (2025)
- 610 Chinese adults with obesity/overweight | 48 weeks | 4 mg and 6 mg doses
First Phase 3 weight management trial showing clinically meaningful weight reductions with once-weekly mazdutide. Both doses achieved significant weight loss vs placebo with favorable safety profile.
View Study → https://pubmed.ncbi.nlm.nih.gov/40421736/
GLORY-2 Phase 3 Trial (2025)
- 462 Chinese adults with obesity (BMI ≥30) | 60 weeks | 9 mg dose
High-dose 9 mg mazdutide achieved 20.1% weight loss in non-diabetic participants vs 2.8% placebo. 48.7% achieved ≥20% weight reduction.
DREAMS-3 Phase 3 Trial - Head-to-Head vs Semaglutide (2025)
- 349 Chinese adults with T2D and obesity | 32 weeks | Mazdutide vs Semaglutide
Mazdutide showed superiority over semaglutide on primary endpoint: 48.0% vs 21.0% achieved HbA1c <7.0% AND ≥10% weight reduction (p<0.0001).