Mazdutide

Mazdutide is a synthetic peptide. It is an acylated, long-acting analog of the human hormone oxyntomodulin, designed as a dual agonist that acts on both the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR). It acts as a therapeutic agent for obesity and type 2 diabetes by reducing appetite and increasing energy expenditure.

Key Benefits

• May support significant weight loss by helping reduce appetite and calorie intake
• Commonly researched for improving blood sugar control and metabolic health
• May help support healthy fat loss while preserving lean body mass
• Research suggests potential benefits for cardiovascular and overall metabolic wellness support

FDA-Approved Uses

Mazdutide is under active clinical development in the US by Eli Lilly.

China NMPA approvals (Xinermei®)

Obesity / Weight Management (June 2025):

• World’s FIRST approved dual GLP-1/glucagon receptor agonist for obesity
• Indicated for adults with BMI ≥28 kg/m² or ≥24 kg/m² with weight-related comorbidity
• Type 2 Diabetes (September 2025):
• Approved as adjunct to diet and exercise for glycemic control in adults with T2DM

US FDA Development Timeline:

• Phase 1 (high-dose): Completed 2025 (doses up to 16 mg studied; Diabetes Obes Metab 2025)
• Phase 2 (US): Active enrollment (NCT06143956) — ongoing
• Phase 3: Expected 2026–2027
• NDA/BLA submission: Estimated 2027–2028
• FDA decision: Estimated 2028–2029
• [If granted Priority Review as first dual GLP-1/GCGR agonist: possible 2027]

Conditions being studied:

• Obesity / Overweight (primary US indication under development)
• Type 2 Diabetes
• Metabolic dysfunction-associated fatty liver disease (MAFLD/MASLD)
• Cardiovascular outcomes (planned)

Mechanism distinction vs. existing GLP-1 drugs:

• Semaglutide, liraglutide: GLP-1 receptor agonist only
• Tirzepatide: GLP-1 + GIP dual agonist
• Retatrutide: GLP-1 + GIP + glucagon triple agonist
• Mazdutide: GLP-1 + GLUCAGON dual agonist (different pairing from tirzepatide)

WADA status: Not on WADA Prohibited List

Trade Names in the USA and Manufacturers

China-approved brand:
– Xinermei® (mazdutide injection) — approved China NMPA June/September 2025
Manufacturers: Innovent Biologics (Suzhou) Co. Ltd. / Innovent Biologics, Inc.
Distributor in China: Eli Lilly and Company (partnership)

Developers:
– Originally developed by: Innovent Biologics (Suzhou) Co. Ltd. (China)
– Co-developed/licensed: Eli Lilly and Company (Indianapolis, IN, USA)
– Compound codes: IBI362 (Innovent) / LY3305677 (Eli Lilly)

US availability (as of May 2026):
– Phase 2 clinical trial (NCT06143956): Only legal supervised US access
– Importation of Xinermei® from China: Legally complex; not recommended without medical supervision
– Not available via US pharmacies, compounding, or telehealth for general use

Molecular identity:
– Long-acting GLP-1 and glucagon receptor (GCGR) dual agonist peptide
– Administered as once-weekly subcutaneous injection
– Fatty acid chain modification enables long half-life (~7 days) for weekly dosing
– Exact full sequence not publicly disclosed in available literature

Dosage

China-approved dosing (Xinermei®):
Once-weekly subcutaneous injection with dose escalation:

Obesity indication:
Weeks 1–4: 1 mg/week
Weeks 5–8: 2 mg/week
Weeks 9–12: 3 mg/week
Week 13+: 4–6 mg/week (maintenance; max studied: 6 mg for obesity)

Type 2 Diabetes indication:
Similar escalation schedule; doses per physician judgment

US Phase 1 trial doses (research only — NOT approved):
Up to 16 mg/week studied (Diabetes Obes Metab, 2025 publication)

US Phase 2 trial doses (NCT06143956 — investigational):
Multiple doses under evaluation; results pending

Route: Subcutaneous injection, abdomen, thigh, or upper arm
Frequency: Once weekly (consistent with semaglutide and tirzepatide dosing schedules)
No dose adjustment required for mild-to-moderate renal impairment (based on dual GLP-1/GCGR profile)

Pricing

China pricing (Xinermei® — where approved):
Estimated: ~$200–$400/month (based on NMPA pricing and market reports)
[Exact China retail price varies by province and insurance coverage]

US cost to patients:
– Phase 2 trial (NCT06143956): Free to enrolled participants
– No other legal US access pathway as of May 2026

Projected US commercial pricing (post-FDA approval — speculative):
Expected to be comparable to tirzepatide (Zepbound/Mounjaro) given Eli Lilly’s existing GLP-1 pricing structure
Likely: $1,000–$1,400/month list price (estimated; not confirmed)
With insurance + savings programs: Potentially as low as $25–$99/month for eligible commercially insured patients

Tips

• Monitor Eli Lilly’s Phase 3 trial initiation (expected 2026–2027) and NDA submission (estimated 2027–2028). FDA priority review designation as the first dual GLP-1/GCGR agonist could accelerate the timeline to 2027.
• Mazdutide’s key differentiator from tirzepatide is the glucagon receptor component (vs. tirzepatide’s GIP component). Glucagon receptor activation increases energy expenditure and thermogenesis ; a different additional mechanism from GIP’s insulin-sensitizing effects.
• Patients in China with access to Xinermei® have the only current legitimate pharmaceutical access. Importation for personal use in the US is legally complex and not generally recommended.
• For US patients: The only supervised, legitimate US access is via clinical trial enrollment. Search ClinicalTrials.gov for ‘mazdutide’ or ‘LY3305677’ or ‘NCT06143956’.
• Side effect profile is consistent with the GLP-1 drug class (nausea, vomiting, GI effects) ; similar management strategies apply (slow dose escalation, eating habits, antiemetics if needed).

Side Effects

From Phase 1, Phase 2, and Phase 3 GLORY-1 clinical trial data:

Consistent with GLP-1 drug class profile:
– Nausea: Most commonly reported; dose-dependent; typically improves with dose escalation period
– Vomiting: Less common than nausea; also dose-dependent
– Mild gastrointestinal discomfort / abdominal pain
– Constipation or diarrhea
– Decreased appetite (therapeutically desired effect; sometimes excessive)

General tolerability assessment:
– Phase 2 (Nature Communications, 2023): ‘Well tolerated over 24 weeks; no serious safety signals’
– Phase 1 high-dose trial (Diabetes Obes Metab, 2025): Up to 16 mg/week studied; ‘generally consistent with other GLP-1–based drugs’
– GLORY-1 Phase 3: 4 mg and 6 mg doses for 32 weeks in Chinese adults — adverse events consistent with GLP-1 class; no unexpected safety signals published

Glucocagon component-specific considerations:
– Glucagon receptor activation raises blood glucose (opposing GLP-1’s insulin-stimulating effect) — net effect in clinical trials is favorable glycemic control, but transient hyperglycemia is possible in some patients
– No hypoglycemia excess vs. GLP-1 monotherapy (glucose-dependent mechanisms)

⚠️ Long-term safety data (beyond 32–68 weeks) not yet available — Phase 3 trials ongoing

Contraindications

No formal FDA contraindications (no approved US label).
Based on Phase 2/3 trial exclusion criteria and GLP-1 class pharmacology:

– Personal or family history of medullary thyroid carcinoma (MTC): Expected class contraindication (GLP-1R activation → thyroid C-cell concern; shared with semaglutide, tirzepatide)
– Multiple endocrine neoplasia syndrome type 2 (MEN 2): Expected contraindication
– History of pancreatitis: Excluded from clinical trials
– Severe renal or hepatic impairment: Not fully characterized; excluded from key trials
– Pregnancy: Expected contraindication (GLP-1 class effect)
– Type 1 diabetes: Not studied; expected exclusion
– Hypersensitivity to mazdutide or components

⚠️ Final contraindications to be established in FDA-approved prescribing information if/when approved.

Pharmacology

Mazdutide (IBI362 / LY3305677) is a synthetic, long-acting peptide dual agonist of two receptors: the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR). It was developed by Innovent Biologics (China) in collaboration with Eli Lilly and Company.

Key pharmacological distinction:
– GLP-1R + GIP receptor (tirzepatide, retatrutide): This pairing leverages insulin secretion enhancement (GIP) + appetite suppression (GLP-1)
– GLP-1R + GCGR (mazdutide): This pairing leverages energy expenditure increase (glucagon) + appetite suppression (GLP-1) — a different complementary mechanism

Half-life enabling once-weekly dosing:
Engineered with fatty acid chain modification enabling albumin binding and extended half-life of approximately 7 days — same strategy as semaglutide (Ozempic/Wegovy).

FDA status: No approved drug; Phase 2 active in US; Phase 3 expected 2026–2027.

Approvals outside US:
– China NMPA: Obesity (June 2025) and T2DM (September 2025) under brand Xinermei®
– World’s FIRST approved dual GLP-1/glucagon receptor agonist for obesity

Mechanism of action

GLP-1 Receptor Activation (shared mechanism with semaglutide):
→ Glucose-dependent insulin secretion from pancreatic beta cells
→ Glucagon suppression from alpha cells
→ Slowed gastric emptying
→ Hypothalamic appetite suppression (reduced caloric intake)
→ Weight loss primarily via reduced food intake

Glucocagon Receptor (GCGR) Activation (unique addition vs. semaglutide):
→ Increases hepatic glucose output (acutely; balanced by GLP-1’s insulin effect)
→ Increases energy expenditure via thermogenesis (brown adipose tissue activation)
→ Promotes lipolysis in fat tissue (direct fat-burning effect)
→ Reduces liver fat (hepatic lipid metabolism improvement — basis for MAFLD indication)
Net metabolic effect: Greater energy expenditure + fat oxidation on top of GLP-1’s appetite suppression → enhanced weight loss vs. GLP-1 alone

Dual agonism balance:
The opposing glucose effects (GLP-1 lowers, GCGR raises) are carefully balanced in the designed molecule to produce favorable glycemic control overall, while the weight-loss effects are additive (both pathways reduce body weight through different mechanisms).

Result Claims from Different Companies

Innovent Biologics / Eli Lilly (based on published clinical trial data):

Phase 2 (Nature Communications, 2023 — Chinese adults):
– Doses: 3 mg, 4.5 mg, 6 mg vs. placebo; 24 weeks
– Body weight reductions: Statistically significant at all doses vs. placebo
– Well-tolerated; no serious safety signals
– Primary endpoint (% body weight change at week 24) met

Phase 1 high-dose trial (Diabetes Obes Metab, Aug 2025 — Eli Lilly-led, US-based):
– Doses up to 16 mg/week tested
– Statistically significant weight reductions vs. placebo
– Safety profile consistent with GLP-1 drug class
– Published by Melissa K. Thomas et al. (Eli Lilly)

Phase 3 GLORY-1 (NEJM publication):
– 4 mg or 6 mg once-weekly for 32 weeks in Chinese adults with overweight/obesity
– ‘Clinically relevant reductions in body weight’ vs. placebo
– NMPA approval for obesity based on this and supporting data

⚠️ US Phase 3 data pending. All efficacy data from Chinese populations. Cross-population generalizability to Western populations requires confirmation in ongoing/planned US Phase 3 trials. FDA will require US or global trial data for NDA approval.

Disclaimer

This content about “Mazdutide (IBI362 / LY3305677) Dual GLP-1 / Glucagon Receptor Agonist” is for informational and educational purposes only, is not medical advice, does not replace consultation with a licensed healthcare professional, and affiliate links may result in compensation at no additional cost to you.