Mazdutide

Beginner Protocol

Intermediate Protocol

Advanced Protocol

Reconstitution and handling notes

Stacking Notes

Additional Dosage Notes

Mazdutide (IBI-362 / LY-3305677), a once-weekly GLP-1/glucagon receptor dual agonist from Innovent Biologics, has been developed mainly in Chinese populations and has now completed Phase 3 trials and gained regulatory approval in China.

Early-phase work First-in-human and multiple-ascending-dose studies in Chinese healthy volunteers and adults with overweight/obesity established once-weekly pharmacokinetics, dose-dependent (largely gastrointestinal) tolerability, and early weight-loss signals. A Phase 1b study explored higher doses (9 mg and 10 mg), and Phase 2 dose-ranging defined the doses carried into Phase 3.

GLORY-1 (Phase 3, obesity) - the pivotal weight-management trial Ji L et al., N Engl J Med 2025;392:2215-2225 (NCT05607680) - https://pubmed.ncbi.nlm.nih.gov/40421736/

• Design: double-blind, placebo-controlled; 610 Chinese adults with BMI >=28, or BMI 24 to <28 plus at least one weight-related coexisting condition; randomized 1:1:1 to mazdutide 4 mg, 6 mg, or placebo for 48 weeks.
• Week 48 mean body-weight change: -11.00% (4 mg), -14.01% (6 mg), +0.30% (placebo).
• Weight loss >=5% at week 32: 73.9% (4 mg), 82.0% (6 mg), 10.5% (placebo).
• Weight loss >=15% at week 48: 35.7% (4 mg), 49.5% (6 mg), 2.0% (placebo).
• Beneficial effects across all prespecified cardiometabolic measures; adverse events were mostly mild-to-moderate gastrointestinal, and discontinuation for adverse events was low (1.5% at 4 mg, 0.5% at 6 mg, 1.0% placebo).

Phase 3 in type 2 diabetes (vs dulaglutide) Guo L et al., Nature 2025;652:181-188 - https://pubmed.ncbi.nlm.nih.gov/41407860/

• 731 Chinese adults with type 2 diabetes on background oral antidiabetic drugs, randomized 1:1:1 to mazdutide 4 mg, 6 mg, or dulaglutide 1.5 mg for 28 weeks.
• Both mazdutide doses were non-inferior AND superior to dulaglutide for HbA1c reduction (least-squares mean difference -0.24% at 4 mg, -0.30% at 6 mg) and produced significantly greater weight loss (difference -3.78% at 4 mg, -5.76% at 6 mg). Gastrointestinal adverse events were more frequent with mazdutide. These data supported the Chinese type 2 diabetes approval.

DREAMS-3 (Phase 3, head-to-head vs semaglutide, ongoing) Luo Y et al., Contemp Clin Trials 2025;160:108150 (design and baseline paper) - https://pubmed.ncbi.nlm.nih.gov/41260459/

• Randomized, open-label; 349 Chinese adults with type 2 diabetes and obesity (BMI >=28) assigned to mazdutide 6 mg or semaglutide 1 mg weekly for 32 weeks plus a 24-week extension; primary endpoint is the proportion reaching HbA1c <7.0% with >=10% weight loss at week 32. This is the first mazdutide-versus-semaglutide head-to-head; results were expected in early 2026.

Hepatic / metabolic effects Because glucagon-receptor activity drives hepatic fatty-acid oxidation, mazdutide trials have reported reductions in liver fat and improvements in liver enzymes and other cardiometabolic markers alongside weight loss. Dedicated MASLD/MAFLD read-outs are still maturing.

How it compares (indirect; no head-to-head vs Western drugs published)

• Semaglutide 2.4 mg: ~15% weight loss (STEP program).
• Tirzepatide (GLP-1/GIP): ~22% (SURMOUNT).
• Retatrutide (GLP-1/GIP/glucagon): ~24% at Phase 2.
• Mazdutide 6 mg: ~14% (GLORY-1), with added glucagon-driven energy expenditure and hepatic-fat benefits. Cross-trial comparisons are hypothesis-generating only, and mazdutide's efficacy has been characterized specifically in Chinese cohorts.

Regulatory status

• China NMPA: mazdutide injection (brand Xinermei) approved June 2025 for chronic weight management, and September 2025 for glycemic control in type 2 diabetes. A 9 mg dose is under NMPA review for moderate-to-severe obesity.
• US FDA / EU EMA: not approved; investigational. Innovent holds the Chinese rights (licensed from Eli Lilly in 2019); Lilly retains ex-China rights but has prioritized retatrutide for Western markets.

Research-use framing Material sold as 'mazdutide' outside licensed Chinese pharmacies is not the approved product and is not quality-assured for human use; the data above come from registered clinical trials, not from unregulated use.

Mazdutide's side-effect profile is dominated by gastrointestinal effects similar to GLP-1 agonists, with some dual-mechanism-specific considerations from the glucagon component.

Most Common Side Effects:

Gastrointestinal (dose-dependent):

• Nausea: 40-55% at 6-9 mg doses (vs 15-20% placebo)
• Vomiting: 15-25% at higher doses
• Diarrhea: 20-35%
• Constipation: 15-25%
• Decreased appetite: expected and desired (reaches problematic levels in 5-10%)
• Dyspepsia: moderate frequency
• Early satiety: expected effect
• Abdominal pain: 10-15%

Metabolic Effects:

• Fatigue: 10-20%, especially during rapid weight loss
• Headache: 15-25%
• Dizziness: especially in dehydrated individuals
• Hypoglycemia: uncommon in monotherapy, more common when combined with insulin/sulfonylureas
• Increased heart rate: modest increase typical (3-5 bpm)

Injection Site:

• Injection site reactions: mild, transient
• Induration or erythema at injection site

Glucagon-Specific Considerations:

Metabolic Effects: Unlike pure GLP-1 agonists, mazdutide's glucagon component produces:

• Modest heart rate increase: 3-5 bpm typical, generally not clinically significant
• Small transient blood pressure changes: typically transient
• Increased lipolysis: desired effect
• Hepatic effects: improved NAFLD, increased fatty acid oxidation

Glycemic Effects:

• Generally maintains glycemic control despite glucagon activity (balanced by GLP-1)
• In patients with poor beta-cell reserve, may need more careful monitoring
• Hypoglycemia rare in monotherapy

Metabolic Rate Effects:

• Increased resting energy expenditure (5-8%)
• May contribute to feeling warmer
• Generally well-tolerated

Rare Serious Adverse Events:

• Pancreatitis: theoretical risk with incretin-based therapies; careful monitoring
• Gallbladder disease: elevated during rapid weight loss
• Severe hypoglycemia: rare in monotherapy; more common with concurrent insulin/sulfonylureas
• Allergic reactions: uncommon; anaphylaxis rare
• Thyroid effects: theoretical concern with MTC (class effect)

Specific Concerns with Glucagon Agonism:

Hepatic Considerations: While glucagon activity is generally beneficial for hepatic fat, very high doses or prolonged use could theoretically cause:

• Hepatic stress in compromised liver
• Altered lipid profiles in some patients
• Need for monitoring in severe hepatic dysfunction

Cardiovascular: Glucagon can produce:

• Small increases in heart rate
• Modest transient blood pressure changes
• Generally well-tolerated at therapeutic doses
• Careful monitoring in cardiovascular disease patients

Thyroid:

• Similar concerns to other GLP-1 agonists
• MTC/MEN2 contraindicated
• Routine thyroid monitoring not required but vigilance

Specific Populations:

Pregnancy: Contraindicated; weight loss not indicated during pregnancy Elderly: Careful titration; monitor renal function Renal Impairment: Limited data in severe impairment; caution Hepatic Impairment: Interesting considerations given glucagon activity; caution in severe dysfunction Children/Adolescents: Not yet studied Diabetic Patients: Careful monitoring; adjust insulin/sulfonylureas

Red Flags Requiring Discontinuation:

• Severe persistent nausea/vomiting with dehydration
• Symptoms suggesting pancreatitis (severe abdominal pain radiating to back)
• Symptoms of gallbladder disease
• Severe hypoglycemia
• Psychiatric symptoms (mood changes)
• Severe injection site reactions
• Signs of thyroid abnormality (neck mass, dysphagia)
• Cardiovascular symptoms (new chest pain, severe palpitations)

Long-Term Safety: As a newer molecule with primarily Chinese clinical trial experience, mazdutide has less long-term safety data than established GLP-1 agonists. Ongoing post-marketing surveillance will be essential for:

• Cancer signals (particularly thyroid)
• Cardiovascular outcomes long-term
• Hepatic outcomes
• Psychiatric effects
• Weight regain profile
• Effects on lean body mass
• Chinese-specific considerations (if Western development occurs)

Comparison with Related Drugs:

Drug Interactions: Similar to other incretin-based therapies:

• Insulin: may need dose reduction
• Sulfonylureas: hypoglycemia risk
• Other weight-loss drugs: combination not well-studied
• Oral contraceptives: altered absorption possible
• Levothyroxine: timing consideration

Monitoring Strategy:

• Baseline: comprehensive evaluation including cardiac assessment
• Month 1: symptom review, GI tolerability
• Month 3: labs (glycemic, liver, lipid, renal), body composition
• Month 6: full reassessment including NAFLD if relevant
• Ongoing: quarterly symptoms, semi-annual labs

Management of Common Side Effects:

• GI symptoms usually improve with time
• Slow titration reduces nausea
• Adequate hydration important
• Small frequent meals
• Avoid high-fat meals initially
• Ondansetron for persistent nausea if physician-directed