Retatrutide

Category: Triple Agonist (GLP-1/GIP/Glucagon)

Retatrutide (LY3437943) is a first-in-class triple agonist simultaneously activating GLP-1, GIP, and glucagon receptors — sometimes called a "triple G" or GGG agonist. Developed by Eli Lilly, it is currently in Phase 3 clinical trials. Phase 2 data (NEJM 2023) showed an unprecedented ~24% mean body weight reduction at 48 weeks at the highest dose (12mg), surpassing all approved agents. Its glucagon receptor agonism boosts energy expenditure and hepatic fat clearance, while GIP and GLP-1 activity drive appetite suppression and glucose control. It also shows early promise for NASH/metabolic liver disease and sleep apnea.

Half-Life: 144 hours

Common Dosage: 1mg

Benefits

  • Unprecedented weight loss — up to 24% body weight reduction (Phase 2, 48 weeks)
  • Superior to semaglutide and tirzepatide in head-to-head trial comparisons
  • Triple-receptor synergy: GLP-1 (appetite) + GIP (insulin sensitivity) + Glucagon (energy expenditure)
  • Significantly reduces liver fat — promising for NASH/MAFLD
  • Improves HbA1c and fasting glucose (type 2 diabetes)
  • Reduces triglycerides and improves lipid panel
  • Lowers systolic blood pressure
  • Improves sleep apnea outcomes (early data)
  • Potential reduction in cardiovascular risk (CVOT trial ongoing)
  • Once-weekly subcutaneous injection — convenient dosing
  • Rapid weight loss onset with continued loss trajectory to ~1 year
  • May improve kidney function markers in obese patients

Side Effects

  • Nausea (most common — ~60% at higher doses, typically transient)
  • Vomiting (dose-dependent, usually resolves within 4 weeks per dose level)
  • Diarrhea or loose stools
  • Decreased appetite (expected and therapeutic)
  • Constipation
  • Eructation (belching) — more than GLP-1s alone due to glucagon component
  • Increased heart rate (+2–4 bpm, from glucagon receptor activity)
  • Injection site reactions (mild)
  • Fatigue (usually transient during titration)
  • Headache
  • Dyspepsia / heartburn