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MetabolicTier 2 β€” Good human studies

Retatrutide

LY3437943 Β· Triple Agonist

First-in-class triple GIP/GLP-1/glucagon receptor agonist (Eli Lilly) in Phase 3 trials. Demonstrated ~24.2% mean weight reduction at 48 weeks in Phase 2 β€” the highest of any anti-obesity agent studied to date. Glucagon component adds thermogenic energy expenditure on top of GLP-1/GIP appetite suppression.

πŸ’‰ SC injection🧊 Refrigerate at 2–8Β°C; protect from light; do not freeze. Reconstituted: use within 28 days.

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Mechanism of Action

Triple receptor co-agonism: (1) GLP-1R β€” slows gastric emptying, reduces appetite via hypothalamic signalling, improves insulin secretion; (2) GIPR β€” enhances GLP-1-mediated satiety, improves beta-cell function; (3) GcgR β€” activates hepatic glucose production, increases thermogenesis via brown adipose tissue, accelerates lipolysis. The glucagon arm is responsible for the superior weight loss versus tirzepatide.

Clinical Applications

  • βœ“Severe or treatment-refractory obesity (BMI β‰₯30, or β‰₯27 with comorbidities)
  • βœ“Obesity with non-alcoholic steatohepatitis / MASLD β€” glucagon arm improves hepatic steatosis
  • βœ“Type 2 diabetes with obesity β€” triple agonism improves glycaemic control beyond semaglutide
  • βœ“Metabolic syndrome with dyslipidaemia β€” significant LDL and triglyceride reduction in trials
  • βœ“Post-bariatric weight regain where GLP-1 monotherapy is insufficient
  • βœ“Investigational: cardiovascular risk reduction (SURMOUNT-like outcomes trials ongoing)

Dosing Protocol

Recommended Dosing

SC injection (abdomen, thigh, or upper arm). Phase 2/3 titration schedule: 0.5 mg/week Γ— 4 weeks β†’ 1 mg Γ— 4 weeks β†’ 2 mg Γ— 4 weeks β†’ 4 mg Γ— 4 weeks β†’ 8 mg Γ— 4 weeks β†’ 12 mg maintenance. Slow titration is mandatory to minimise GI side effects. Target dose in trials: 4–12 mg/week. Off-label compounded versions in circulation β€” quality and concentration vary widely; use only with compounding pharmacy COA.

Safety & Contraindications

Possible Side Effects

  • ⚠Nausea (most common, dose-dependent β€” typically resolves within 2–4 weeks of each dose increase)
  • ⚠Vomiting and diarrhoea (less frequent than nausea; dehydration risk at higher doses)
  • ⚠Tachycardia and elevated heart rate β€” glucagon component; monitor resting HR, especially first 8 weeks
  • ⚠Decreased appetite (desired effect; ensure adequate protein and micronutrient intake during rapid weight loss)
  • ⚠Injection site reactions (erythema, nodules β€” rotate injection sites)
  • ⚠Constipation in some patients (slower gut motility)
  • ⚠Not fully characterised at higher doses β€” pharmacovigilance data still accumulating

Contraindications

  • βœ•Personal or family history of medullary thyroid carcinoma (MTC) or MEN2 β€” class contraindication
  • βœ•Active pancreatitis or history of recurrent pancreatitis
  • βœ•Significant cardiovascular disease with resting tachycardia (HR >100 bpm) β€” glucagon component risk
  • βœ•Pregnancy and breastfeeding
  • βœ•Severe hepatic impairment (glucagon metabolism affected)
  • βœ•Type 1 diabetes β€” risk of unopposed glucagon stimulation worsening ketosis

Combinations & Synergies

πŸ”— Generally use as monotherapy β€” triple agonism is already broad; adding further metabolic agents rarely warranted
πŸ”— BPC-157 (adjunct)may help manage GI side effects during titration β€” cytoprotective effect on GI mucosa
πŸ”— Thymosin Alpha-1 (adjunct)immune support during rapid weight loss when immune function may be transiently suppressed
πŸ”— Magnesium + B-compleximportant micronutrient support given reduced food intake and GI effects
πŸ”— Avoid concurrent GLP-1 agonists (semaglutide, tirzepatide) β€” receptor overlap, additive adverse effects without proportional benefit
#metabolic#GLP-1#GIP#glucagon#obesity#triple-agonist#weight-loss#MASLD#phase-3#investigational
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