Vitals Knowledge Vault

Mazdutide

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Mazdutide (IBI-362 / LY3305677)

Developer: Innovent Bio (China); Eli Lilly (ex-China rights, code LY3305677)
Class: Dual GLP-1 receptor agonist + glucagon receptor (GCGR) agonist — same mechanistic class as Survodutide (BI 456906)
Route: Once-weekly subcutaneous injection
Regulatory status: NMPA-approved in China for chronic weight management (mid-2025) and T2D (late 2025); no FDA, EMA, or other ex-China approval found

Mazdutide and Survodutide are both dual GLP-1/GCGR agonists. They differ in sponsor, trial population, phase 3 maturity, and regulatory status. Do not treat them as interchangeable or conflate their evidence bases.

TL;DR

Mazdutide is a dual GLP-1/GCGR agonist with the strongest evidence from GLORY-1, a phase 3 RCT in Chinese adults with obesity (n=610). At 48 weeks, mazdutide 6 mg produced −14.01% weight loss versus +0.30% placebo. It is NMPA-approved in China but has no FDA or EMA approval; non-Chinese phase 3 obesity outcomes are not available. GI adverse events dominate the safety profile. Direct head-to-head comparisons versus semaglutide 2.4 mg, Tirzepatide, Retatrutide, or Orforglipron have not been completed.

Why it matters for Vitals

  • Body composition: weight-loss magnitude is meaningful and in the range of injectable GLP-1 monotherapy benchmarks; lean mass impact is not well characterized (no published DXA data).
  • Glycemic monitoring: T2D populations show HbA1c reduction; CGM translation is defensible in diabetes contexts but not in obesity-only users.
  • Wearable interpretation: RHR/HRV/activity signals are expected class-level pharmacologic effects but are not mazdutide-specific; automated coaching rules do not exist.
  • Coaching boundary: treat as an NMPA-approved medication topic in China-facing contexts; treat as investigational in all other jurisdictions; human signoff required for any dosing, stack, or adverse-event interpretation.

Key facts

ParameterValue
Half-life~8 days at 16 mg (U.S. phase 1); supports once-weekly SC
Tmax~72 h (slow absorption)
Dose range studied3 mg, 4 mg, 4.5 mg, 6 mg, 9 mg, 10 mg, 16 mg
Phase 3 anchorGLORY-1 (NCT05607680); Chinese adults with obesity/overweight
Weight loss, GLORY-1 6 mg / 48 wk−14.01% vs +0.30% placebo
Weight loss, GLORY-1 4 mg / 48 wk−11.00% vs +0.30% placebo
T2D evidencePhase 2/3 vs placebo and vs dulaglutide (DREAMS-2); HbA1c + weight reductions confirmed
SafetyGI-dominant; mostly mild-to-moderate; low discontinuation due to AEs in GLORY-1
CV outcomesNo dedicated MACE/CVOT found
Regulatory (ex-China)None found; no FDA NDA/BLA, EMA EPAR, or MAA identified

Mechanism summary

Mazdutide is a unimolecular peptide dual agonist modeled on oxyntomodulin-like pharmacology.

GLP-1R agonism produces:

  • Appetite suppression via hindbrain/hypothalamus
  • Delayed gastric emptying → prolonged satiety
  • Glucose-dependent insulin secretion

GCGR agonism produces:

  • Hepatic glycogenolysis and gluconeogenesis stimulation
  • Lipolysis and hepatic lipid oxidation
  • Increased resting energy expenditure (thermogenesis) — biologically plausible; human mazdutide-specific REE measurement is a Gap

Mechanistic boundary: human studies confirm weight and glycemic effects but do not isolate the incremental GCGR contribution to weight loss. GCGR energy-expenditure claims are biologically plausible and class-supported; mazdutide-specific thermogenesis in humans is not directly established.

What the current evidence suggests

Strongest evidence (Confirmed)

  • GLORY-1 phase 3: −10.09% (4 mg) and −12.55% (6 mg) at week 32; −11.00% (4 mg) and −14.01% (6 mg) at week 48, vs placebo (PMID 40421736)
  • Phase 2 obesity: dose-related −6.7%, −10.4%, −11.3% at 3/4.5/6 mg vs −1.0% placebo at 24 weeks (PMID 38092790)
  • T2D: HbA1c and weight reduction vs placebo and vs dulaglutide (PMID 37943529, 41407859, 41407860)

Supported evidence

  • High-dose 9–16 mg phase 1b: large short-term weight loss; sample sizes small; early-phase only (PMID 36247927, 40832785)
  • Dual GLP-1/GCGR mechanism is biologically plausible for combined appetite suppression + energy-expenditure effect

Key gaps

  • No completed direct obesity head-to-head vs semaglutide 2.4 mg, Tirzepatide, Retatrutide, survodutide, or Orforglipron
  • DREAMS-3 compares mazdutide 6 mg vs semaglutide 1 mg in T2D+obesity — outcomes not yet found (baseline only; PMID 41260459)
  • GLORY-2 9 mg phase 3 obesity outcomes not yet published
  • Non-Chinese phase 3 obesity data not found
  • Lean mass / DXA body composition data not found
  • Dedicated MACE/CVOT not found
  • Active metabolite profile not established
  • BBB / tissue distribution not established

Risks and uncertainty

  • GI adverse events are the primary tolerability barrier; mostly mild-to-moderate in GLORY-1
  • Lipase elevations reported in small phase 1b T2D trial; no investigator-suspected pancreatitis; cardiac ischemia events judged unrelated (PMID 35750681)
  • Long-term CV safety is the largest open gap — no MACE/CVOT data available
  • Jurisdiction gap: all completed phase 3 obesity trials are in Chinese adults; non-Chinese efficacy and tolerability are unknown
  • Regulatory gap: no FDA, EMA, or other ex-China approval, label, or NDA/BLA/EPAR found
  • Lean mass: no DXA data published; assume uncertain impact; apply standard GLP-1 Muscle Preservation precautions
  • GCGR energy-expenditure: not directly measured in mazdutide human trials
DrugMechanismApprox. weight lossKey distinction
Semaglutide 2.4 mgGLP-1 mono~15%Established CV evidence; FDA approved
TirzepatideGLP-1 + GIP dual~21%GIP adds lipid buffering; FDA approved
RetatrutideGLP-1 + GIP + Glucagon triple~28.7%GCGR prevents plateau; phase 3
OrforglipronGLP-1 mono, oral non-peptide~9–11%Oral; no fasting; GI tolerability limits
SurvodutideGLP-1 + Glucagon dual (BI 456906)~15% (phase 2)Phase 3 SYNCHRONIZE; MASH signal
MazdutideGLP-1 + Glucagon dual~14% (phase 3)China-approved only; Chinese adults; no head-to-head data

Indirect comparisons differ by population, duration, estimand, background, and dose. Do not use this table to claim superiority or equivalence.

Vitals monitoring protocol

mazdutide_monitoring_policy:
  evidence_status: investigational (ex-China); approved (China only)
  human_signoff_required: true
  direct_metrics:
    - body_weight
    - waist_or_bmi
    - glycemic_labs_when_diabetes_context_exists
    - gi_symptoms
    - appetite_or_decreased_appetite_self_report
  proxy_metrics:
    - resting_heart_rate
    - hrv
    - activity
    - cgm_metrics_in_diabetes_context_only
  speculative_metrics:
    - wearable_energy_expenditure
    - sleep_recovery_rules
    - automated_adherence_detection
  disallowed_claims:
    - fda_approved_without_label_source
    - best_in_class_without_head_to_head_data
    - validated_wearable_coaching_rules
    - non_chinese_efficacy_without_trial_data

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