Mazdutide
Weight LossPreclinicalAlso known as: LY3305677
Mazdutide (also known as IBI362, Lilly compound LY3305677) is a dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist originally discovered by Eli Lilly and exclusively licensed to Innovent Biologics in 2019 for development and commercialization in Mainland China, Hong Kong, Macau, and Taiwan. Structurally it is a 39-amino-acid synthetic peptide based on the oxyntomodulin scaffold — the natural L-cell gut hormone that shares its first 29 residues with glucagon and has intrinsic dual GLP-1/glucagon activity — with strategic modifications including lipid conjugation (similar to semaglutide and liraglutide) for extended half-life, enabling once-weekly subcutaneous administration.
Overview
At A Glance
Mazdutide engages two distinct receptor systems through a single peptide molecule, each contributing to metabolic effects.…
Mechanism of Action
Mazdutide engages two distinct receptor systems through a single peptide molecule, each contributing to metabolic effects.
GLP-1 Receptor Agonism: Similar to semaglutide and liraglutide. GLP-1 binds to GLP-1 receptor (GLP1R), a Gαs-coupled G-protein-coupled receptor that activates adenylyl cyclase and increases intracellular cAMP. GLP-1 receptor expression is widespread:
- Pancreatic beta cells: stimulates glucose-dependent insulin secretion
- Pancreatic alpha cells: suppresses glucagon secretion
- Brainstem and hypothalamus: appetite suppression, satiety signaling
- Gastrointestinal tract: slows gastric emptying
- Cardiovascular system: various effects
Glucagon Receptor Agonism: The critical addition in mazdutide. Glucagon binds to glucagon receptor (GCGR), also Gαs-coupled. Glucagon receptor activity:
- Liver: stimulates glycogenolysis and gluconeogenesis (raises blood glucose), but also fatty acid oxidation (burns fat)
- Adipose tissue: promotes lipolysis
- Skeletal muscle: minimal direct effect
- Brain: effects on appetite and energy expenditure
- Heart: modest inotropic effects
The Synergy Principle: The apparent paradox of adding glucagon activity (which raises blood glucose) to a diabetes/obesity drug is resolved by the counterbalancing GLP-1 activity. In clinical practice:
- GLP-1 activity stimulates insulin and suppresses glucagon response, mitigating glucagon's glucose-raising effect
- Glucagon activity increases energy expenditure (+5-8% from baseline)
- Glucagon activity promotes hepatic lipid oxidation (reducing hepatic steatosis)
- Combined: similar glycemic control to GLP-1 alone + greater weight loss + improved NAFLD
Energy Expenditure Effect: One of mazdutide's distinguishing features is measurable increase in resting energy expenditure (REE). Studies have shown 5-8% increases in REE in mazdutide-treated patients vs placebo. This translates to roughly 100-200 additional kcal burned per day at rest — a meaningful contribution to weight loss over time. This contrasts with pure GLP-1 agonists (semaglutide, liraglutide) which primarily act via appetite suppression without significant metabolic rate changes.
Hepatic Effects: Glucagon agonism promotes:
- Beta-oxidation of fatty acids in the liver
- Reduced triglyceride synthesis
- Reduced hepatic steatosis (NAFLD improvement)
- Favorable hepatic lipid profile
Mazdutide shows significant improvement in NAFLD markers in trials, often exceeding what's seen with pure GLP-1 agonists at comparable weight loss levels.
Lipid Profile: Glucagon activity favorably affects:
- LDL cholesterol reduction
- Triglyceride reduction
- Hepatic fat reduction
- Lipolysis promotion in adipose tissue
Pharmacokinetic Profile:
- Half-life: ~140-170 hours (5-7 days) — once-weekly dosing
- Bioavailability: ~78% subcutaneous
- Tmax after SC injection: 48-72 hours
- Distribution: albumin-bound (similar to semaglutide, cagrilintide)
- Metabolism: enzymatic proteolysis
- Elimination: primarily catabolism; minor renal excretion
- Steady state: achieved after 5-6 weekly doses
Dose-Response: Phase 2 established dose-response for weight loss:
- 3 mg weekly: modest weight loss
- 4.5 mg weekly: moderate weight loss (~8-10%)
- 6 mg weekly: strong weight loss (~12-14%)
- 9 mg weekly: maximum studied (~15%)
Higher doses produced more weight loss but also more GI side effects, with a practical ceiling around 9 mg balancing efficacy and tolerability.
Receptor Selectivity: Mazdutide has balanced GLP-1/glucagon activity, with roughly equal affinity and efficacy at both receptors at therapeutic concentrations. This contrasts with retatrutide, which has graduated activity across GLP-1/GIP/glucagon, and with pure GLP-1 agonists that have no glucagon activity.
Cardiac Effects: Unlike some glucagon-based therapies historically, mazdutide at therapeutic doses does not produce clinically significant increases in heart rate or adverse cardiac effects. This is attributed to careful design of the GLP-1/glucagon activity ratio.
Comparison with Monotherapies:
| Drug | GLP-1 | GIP | Glucagon | Weight Loss (Ph 3) |
|---|---|---|---|---|
| Semaglutide | Yes | No | No | ~15% |
| Tirzepatide | Yes | Yes | No | ~22% |
| Retatrutide | Yes | Yes | Yes | ~24% (Ph 2) |
| Mazdutide | Yes | No | Yes | ~15% (Ph 3, Chinese) |
Overview
Mazdutide (also known as IBI362, Lilly compound LY3305677) is a dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist originally discovered by Eli Lilly and exclusively licensed to Innovent Biologics in 2019 for development and commercialization in Mainland China, Hong Kong, Macau, and Taiwan. Structurally it is a 39-amino-acid synthetic peptide based on the oxyntomodulin scaffold — the natural L-cell gut hormone that shares its first 29 residues with glucagon and has intrinsic dual GLP-1/glucagon activity — with strategic modifications including lipid conjugation (similar to semaglutide and liraglutide) for extended half-life, enabling once-weekly subcutaneous administration. Mazdutide represents a different mechanistic philosophy from tirzepatide and semaglutide: while those drugs use GLP-1 signaling (sometimes with GIP in tirzepatide's case), mazdutide adds glucagon receptor agonism, which increases resting energy expenditure and promotes hepatic lipid utilization — in essence, combining appetite suppression (GLP-1) with increased metabolic rate and fat burning (glucagon).
The rationale for dual GLP-1/glucagon agonism goes back to the 1970s observation that oxyntomodulin administered to humans reduced food intake and body weight more than GLP-1 alone. Pure glucagon agonism has historically been avoided in diabetes drug development because glucagon raises blood glucose; however, GLP-1 signaling simultaneously stimulates insulin secretion and suppresses glucagon release, creating a counterbalancing effect when the two are combined in a single molecule. The net result in humans is that dual GLP-1/glucagon agonists like mazdutide produce weight loss comparable to semaglutide while also improving hepatic steatosis, raising energy expenditure ~5-8% above baseline, and delivering glycemic control at least as good as GLP-1 monotherapy. A related and more advanced triple agonist, Retatrutide, adds GIP activity and has shown even more dramatic weight loss in Phase 2 (~24% at 48 weeks) but is developed by Eli Lilly directly rather than licensed regionally.
Mazdutide's Phase 3 development in China has been rapid. The DREAMS-1 (obesity) and DREAMS-2 (type 2 diabetes + obesity) trials enrolled Chinese patients and delivered strong results. In DREAMS-1, 9 mg weekly mazdutide produced mean weight loss of ~15% at 48 weeks in adults with obesity (BMI ≥28 kg/m² per Chinese classification) — closely comparable to semaglutide's Western trial results. In GLORY-1, a Phase 3 trial of 6 mg mazdutide in overweight/obese adults, weight reduction was 14.4% at 48 weeks versus 0.3% placebo (Ji et al., 2024). NMPA (China's FDA equivalent) approval in China is expected in 2025-2026, positioning mazdutide as the first major incretin-class drug developed specifically for the Chinese population and potentially the first dual GLP-1/glucagon agonist to reach market globally (ahead of Eli Lilly's retatrutide triple agonist). Whether mazdutide will be developed or licensed for Western markets remains an open commercial question — Lilly retained rights outside the Innovent territories but has prioritized retatrutide.
Cross-references include Semaglutide (GLP-1 monoagonist competitor), Tirzepatide (GLP-1/GIP dual agonist competitor), Retatrutide (Lilly's GLP-1/GIP/glucagon triple agonist), Cagrilintide (amylin analog in CagriSema combination), and Orforglipron (oral non-peptide GLP-1 agonist).
Chemical Information
IUPAC Name
Not yet available
CAS Number
2498263-63-9
Molecular Formula
C232H358N60O79S
Molecular Mass
5045.0 g/mol
Dosing & Protocols
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Interactions
Interaction Matrix
Contraindications
Absolute Contraindications:
- Personal or family history of medullary thyroid carcinoma (MTC)
- Multiple endocrine neoplasia type 2 (MEN2)
- Known hypersensitivity to mazdutide or any component
- Pregnancy (weight loss contraindicated)
- Active eating disorders (anorexia nervosa, severe bulimia)
- Severe untreated psychiatric conditions
- Type 1 diabetes (unlike some dual agonists, not indicated for T1D)
- Known glucagonoma (functional pancreatic tumor)
Relative Contraindications (Require Careful Evaluation):
- History of pancreatitis: high caution
- Severe gastroparesis: may worsen
- Gallbladder disease: increased risk during rapid weight loss
- Inflammatory bowel disease: caution with GI effects
- Severe renal impairment (eGFR <30): limited data
- Severe hepatic impairment: limited data (interesting given glucagon mechanism)
- Significant cardiovascular disease: careful monitoring needed
- Age >75: careful titration
- Children/adolescents: not yet studied
- Recent myocardial infarction: delay initiation
- Uncontrolled hyperthyroidism: stabilize first
- Pheochromocytoma: contraindicated
Drug Interactions:
Medications Requiring Adjustment:
- Insulin: 20-40% dose reduction typical
- Sulfonylureas: consider discontinuation
- Glucagon emergency kits: still effective
- Beta-blockers: may mask heart rate changes
- Thyroid replacement: monitor and adjust
- Levothyroxine: absorption may change; separate by 30 min+
- Oral contraceptives: absorption may change; barrier backup
- Warfarin: monitor INR
Medications to Use with Caution:
- Other GLP-1 agonists: redundant, increased AE
- Other glucagon agonists: redundant
- Opioids: constipation compounding
- Sedatives: dizziness compounding
- Lithium: altered clearance possible
Medications Compatible:
- Most antihypertensives
- Statins
- Metformin (often beneficial)
- SSRIs (monitor mood)
- Most thyroid medications (with monitoring)
- Most HRT
Medical Conditions Requiring Caution:
Gastrointestinal:
- Gastroparesis: worsening risk
- IBD: caution
- Peptic ulcer disease: monitor
- History of bowel obstruction: contraindicated
Pancreatic:
- History of pancreatitis: high caution
- Pancreatic insufficiency: monitor
- Pancreatic cancer risk: theoretical
Thyroid:
- MTC (personal or family): contraindicated
- MEN2: contraindicated
- Benign nodules: monitor
- Autoimmune thyroiditis: manage separately
- Hyperthyroidism: stabilize first
Gallbladder:
- Gallstones: increased risk with rapid weight loss
- Previous cholecystectomy: no additional contraindication
- Active symptoms: manage before starting
Cardiovascular:
- Recent MI: delay start
- Unstable angina: contraindicated initially
- Severe heart failure: careful monitoring
- Atrial fibrillation: monitor heart rate changes
- Severe hypertension: stabilize first
Renal:
- Mild-moderate: no major concerns
- Severe (eGFR <30): limited data, caution
- Dialysis: not well-studied
Hepatic:
- NAFLD: typically improves with treatment
- Severe cirrhosis: limited data, caution
- Alcoholic liver disease: manage separately
- Acute hepatitis: delay
Psychiatric:
- Depression: monitor closely
- Anxiety: monitor
- Suicidal ideation history: careful monitoring
- Eating disorders: contraindicated if active
Pregnancy/Reproductive:
- Pregnancy: absolute contraindication
- Breastfeeding: not well-studied, likely avoid
- Effective contraception during treatment
- Pre-conception: discontinue 4-6 weeks before
Endocrine:
- Pheochromocytoma: contraindicated
- Glucagonoma: contraindicated
- Insulinoma: complex, requires endocrinology
- Other functional tumors: evaluate
When to Stop Immediately:
- Anaphylactoid/severe hypersensitivity
- Severe persistent pancreatitis symptoms
- Suspected medullary thyroid cancer
- Severe gallbladder disease
- Severe hypoglycemia (recurrent despite adjustments)
- Severe psychiatric emergency
- Pregnancy (discovery or planning)
- Unexplained severe weight loss
- New cardiac symptoms (severe palpitations, chest pain)
- New thyroid symptoms
- Severe or worsening hepatic dysfunction
When to Consult Physician:
- Severe or persistent GI symptoms
- Suspected pancreatitis
- New thyroid symptoms
- Gallbladder symptoms
- Significant mood changes
- Severe fatigue
- Unexpected lab results
- Pregnancy plans
- New medical conditions
- Cardiac concerns (rate, rhythm, BP)
Pre-Treatment Assessment:
- Complete medical history
- Medication reconciliation
- Baseline labs (complete metabolic panel, lipids, HbA1c, TSH, liver enzymes)
- Mental health screening
- Physical exam
- ECG recommended (given glucagon component)
- Baseline heart rate and BP
- Pregnancy test if applicable
- Patient education
Monitoring Schedule:
- Baseline: complete evaluation
- Week 1-4: close monitoring during titration
- Month 1: clinical visit
- Month 3: labs + clinical assessment
- Month 6: labs + body composition + NAFLD markers
- Month 12: annual complete evaluation
- Ongoing: symptom tracking, quality of life
Integration with Medical Care: Mazdutide benefits from medical oversight:
- Primary care with obesity expertise
- Endocrinology for diabetes co-management
- Hepatology for significant NAFLD
- Cardiology for cardiovascular concerns
- Nutrition counseling
- Mental health support
Given the dual mechanism and newer clinical profile, physician involvement is particularly important for mazdutide. Chinese prescribing environment typically includes these resources. Western prescribing would require adaptation.
Regional Considerations:
- China: approved pathway, specialist networks
- Other Asia: variable availability
- Western: limited access, emphasizes clinical trial or careful research use
- Quality assurance: critical in grey-market scenarios
Long-term Considerations:
- Annual complete reassessment
- Updated medical history
- Medication reconciliation
- Risk factor review
- Goal assessment
- Quality of life
- Contribution to post-marketing data
Research Disclaimer
This interaction data is compiled from published research and community reports. It may not be exhaustive. Always consult a healthcare professional before combining compounds.
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Related Articles
All PostsResearch Score
39 PubMed studies
Quality Indicators
Data Completeness
88%Research Credibility
Quick Facts
Molecular Weight
5045.0 g/mol
CAS Number
2498263-63-9
Trial Phase
Preclinical
Research Disclaimer
This information is for educational and research purposes only. Not intended as medical advice. Consult a healthcare professional before use.
Frequently Asked Questions
What is mazdutide and how is it different from semaglutide?
Mazdutide (IBI362/LY3305677) is a dual GLP-1 and glucagon receptor agonist originally developed by Eli Lilly and licensed to Innovent Biologics for China. Unlike Semaglutide which targets only GLP-1 receptors (causing appetite suppression and slowed gastric emptying), mazdutide adds glucagon receptor activity, which increases resting energy expenditure by 5-8% and promotes hepatic fat oxidation. In practice, this means mazdutide achieves similar weight loss to semaglutide (~15% at 48 weeks) but with the addition of increased metabolic rate and significant improvement in non-alcoholic fatty liver disease (NAFLD). It's based on the oxyntomodulin scaffold — a natural gut hormone that has dual GLP-1/glucagon activity — with lipid acylation for extended half-life enabling once-weekly dosing.
How effective is mazdutide for weight loss?
Mazdutide has shown strong weight loss in Chinese clinical trials. The Phase 3 GLORY-1 trial showed 14.4% mean weight loss at 48 weeks with 6 mg weekly dosing in overweight/obese Chinese adults without diabetes (Ji et al., 2024). The DREAMS-1 trial with 9 mg weekly showed approximately 15% weight loss in similar populations. These results are comparable to Semaglutide (~15%) but come with additional benefits of improved hepatic fat reduction and increased resting energy expenditure. Mazdutide's weight loss is less than Tirzepatide (~22%) or Retatrutide (~24% Phase 2) but may offer complementary metabolic benefits.
Why add glucagon to a weight loss drug? Doesn't glucagon raise blood sugar?
This is the clever mechanistic insight behind dual GLP-1/glucagon agonists. While pure glucagon does raise blood glucose, when combined with GLP-1 (which stimulates insulin and suppresses glucagon response), the net effect is balanced. What glucagon adds is: increased resting energy expenditure (~5-8% above baseline), increased lipolysis in adipose tissue, and critically, increased fatty acid oxidation in the liver — significantly improving NAFLD. The natural hormone oxyntomodulin shows this dual activity, and humans treated with it show more weight loss than GLP-1 alone. In clinical trials, mazdutide maintains good glycemic control while adding these metabolic benefits that pure GLP-1 agonists lack.
Is mazdutide available in the US or Europe?
As of April 2026, mazdutide is not yet approved in the US or Europe. Innovent Biologics has the exclusive license for China (including Hong Kong, Macau, Taiwan), and Eli Lilly retained rights for ex-China markets but has prioritized developing retatrutide (the triple agonist GLP-1/GIP/glucagon) for Western markets. Whether Lilly will develop mazdutide for Western markets, license it to another company, or focus exclusively on retatrutide remains unclear. Currently, Western patients can access mazdutide only through: (1) clinical trials if enrolled, (2) travel to China for prescription, (3) licensed compounding pharmacies (limited availability), or (4) research peptide sources (not recommended due to quality concerns). NMPA approval in China is expected in 2025-2026.
How does mazdutide compare to retatrutide?
Both are multi-receptor agonists but with different activity profiles. Retatrutide is a triple agonist activating GLP-1, GIP, and glucagon receptors; mazdutide is a dual agonist activating only GLP-1 and glucagon. Retatrutide shows greater weight loss in clinical trials (~24% Phase 2 at 48 weeks) versus mazdutide's ~15% Phase 3 at 48 weeks. However, mazdutide may be closer to market globally through Innovent's Chinese development, while retatrutide Phase 3 is still ongoing. Mazdutide has been extensively studied in Chinese populations; retatrutide in Western populations. Side effect profiles are similar overall (GI dominant), with retatrutide showing somewhat greater nausea due to triple mechanism. For patients, the practical difference may come down to availability and individual tolerance rather than mechanism choice.
Can I get mazdutide for NAFLD specifically?
Mazdutide shows impressive effects on NAFLD markers, making it a promising option for patients with non-alcoholic fatty liver disease and concurrent obesity. Studies have shown 20-40% reduction in liver fat content (measured by MRI-PDFF) with improvements in ALT, AST, and inflammatory markers exceeding what's expected from weight loss alone. The glucagon receptor activity directly stimulates hepatic fatty acid oxidation. Current availability limits access: mazdutide is primarily available in China through Innovent. Other NAFLD-specific agents are in development (resmetirom/thyroid receptor agonist was FDA-approved for MASH in 2024). For severe NAFLD, consultation with hepatology for the most appropriate pharmacotherapy is recommended, along with comprehensive lifestyle intervention.
What are the main side effects of mazdutide?
Mazdutide's side effect profile is similar to other GLP-1-based therapies with some glucagon-specific considerations. Most common: nausea (40-55% at full dose), vomiting (15-25%), diarrhea (20-35%), decreased appetite (nearly universal), constipation, headache, fatigue, and modest heart rate increase (3-5 bpm from glucagon component). Rare but serious: pancreatitis (theoretical), gallbladder disease (elevated during rapid weight loss), severe hypoglycemia (with concurrent insulin/sulfonylureas), and (like all GLP-1 agonists) potential thyroid MTC risk based on rodent studies. Chinese clinical experience suggests overall tolerability is acceptable with gradual dose titration. Long-term safety data is less mature than for established GLP-1 agonists given the newer development.
Does mazdutide have any cardiovascular concerns due to the glucagon component?
Pure glucagon can cause tachycardia and blood pressure changes, which is a legitimate concern for dual GLP-1/glucagon agonists. However, mazdutide's clinical trials have shown only modest cardiovascular effects: heart rate increase of 3-5 bpm typical (similar to other incretin-based therapies), no significant changes in blood pressure (typically improves with weight loss), and no cardiovascular safety signals in Phase 2-3 Chinese trials. The careful balancing of GLP-1 to glucagon activity in mazdutide's molecular design mitigates most concerning glucagon effects. That said, patients with cardiovascular disease should receive careful baseline assessment, and cardiovascular outcomes trials are ongoing. For patients with recent myocardial infarction or unstable coronary disease, mazdutide should be avoided or delayed.
Can mazdutide be combined with tirzepatide or cagrilintide?
There is no clinical trial data supporting combinations with Tirzepatide or Cagrilintide, and they are not recommended outside of clinical trials. Combining mazdutide (GLP-1/glucagon) with tirzepatide (GLP-1/GIP) would create redundancy in GLP-1 activity while adding GIP — potentially a form of triple agonism but with unpredictable effects. Adding cagrilintide (amylin) would create quadruple-mechanism therapy — dramatically increasing AE risk without known benefit. The logical evolution if triple or quadruple activity is desired would be through single-molecule multi-receptor agonists like retatrutide, which is Lilly's strategy. For now, mazdutide is typically used as monotherapy or with lifestyle interventions, not combined with other weight-loss peptides.
Will mazdutide need to be taken forever for weight loss to be maintained?
Clinical experience with all effective weight-loss medications (semaglutide, liraglutide, tirzepatide) suggests that discontinuation typically results in significant weight regain — 50-60% of lost weight within 1-2 years. Mazdutide-specific discontinuation data is still emerging, but similar patterns are expected given the underlying biology. The practical implication is that mazdutide (like other weight-loss drugs) is emerging as a chronic treatment rather than a finite course, similar to medications for hypertension or hyperlipidemia. Options for long-term include: continuation at full dose, reduced maintenance doses, switching to alternative agents (semaglutide, etc.), or graduated discontinuation with intensive lifestyle support. The decision to continue, reduce, or discontinue should be individualized based on weight loss achieved, side effect profile, cost, and patient preference — always with plan to minimize regain.
Research Tools
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