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Metabolic

Retatrutide

5mg vial

Retatrutide (LY-3437943) is a novel single-molecule triple receptor agonist developed by Eli Lilly, currently in Phase 3 trials. Unlike semaglutide (GLP-1) or tirzepatide (GLP-1/GIP), retatrutide also activates the glucagon receptor - adding hepatic fat oxidation, thermogenesis and energy-expenditure mechanisms absent from prior-generation agents.

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Researched for

  • 24.2% mean body weight reduction at 12mg/week over 48 weeks (Phase 2, NEJM 2023)
  • approx. 32kg average weight loss reported in TRIUMPH-4 Phase 3 (Dec 2025)
  • HbA1c reduction of 1.7–2.0% in TRIUMPH-T2D (Mar 2026)
  • Significant hepatic fat fraction reduction - NASH indication under investigation
  • Improvements across triglycerides, LDL and blood pressure
  • Elevated basal metabolic rate via glucagon-receptor thermogenesis

Mechanism of action

Balanced agonism of GIP (incretin effect and adipocyte lipid metabolism), GLP-1 (satiety, insulin secretion, delayed gastric emptying) and glucagon (hepatic fat oxidation, thermogenesis, basal metabolic rate). The glucagon arm is uniquely responsible for elevated energy expenditure vs GLP-1/GIP duals.

Research protocol

Phase 2/3 escalation: 2mg weekly (weeks 1–4) → 4mg (weeks 5–8) → 8mg (weeks 9–12) → maintenance at 8mg or 12mg weekly based on tolerability. Subcutaneous (abdomen, thigh or upper arm). Not FDA-approved - research use only.

Half-life

approx. 144 hours (approx. 6 days), enabling once-weekly dosing.

Reconstitution

Reconstitute 5–10mg vials with 1–2mL bacteriostatic water for a 4–8mg/mL working concentration. Swirl gently - do not agitate vigorously.

Storage

Lyophilised: 2–8°C (stable 24–36 months); avoid freeze-thaw cycling. Reconstituted: 2–8°C, do not freeze, use within 28 days.

Research considerations
  • GI events (approx. 60% rate at therapeutic doses in Phase 2) - class effect amplified by glucagon component, dose-limiting at escalation.
  • Modest resting heart-rate elevation (+2–4 BPM) - a distinguishing safety signal vs pure GLP-1 agents.
  • No long-term human safety dataset yet; post-market signals remain open questions.