Retatrutide — 8mg

Retatrutide is a 39-amino acid synthetic peptide developed by Eli Lilly that functions as a balanced agonist at all three incretin and glucagon family receptors: GLP-1R, GIPR, and GCGR. This triple-agonist profile is its defining pharmacological feature. While GLP-1 receptor agonists like semaglutide address appetite suppression, and dual GLP-1/GIP agents like tirzepatide add insulin sensitization, retatrutide adds a third mechanism — glucagon receptor activation that directly stimulates hepatic lipolysis and increases energy expenditure. The result is a compound that simultaneously reduces caloric intake, improves insulin sensitivity, and accelerates fat oxidation.

The peptide is structured with a C20 fatty diacid modification at Lys²⁰, enabling once-weekly subcutaneous dosing through albumin binding. Phase 2 dose-escalation data showed mean weight loss of 24.2% at 48 weeks at the highest dose tested — substantially exceeding semaglutide's 14.9% and approaching tirzepatide's 22.5% in comparable timeframes. Phase 3 TRIUMPH-4 data extended this to 28.7% at 68 weeks, establishing a new clinical benchmark for pharmacological weight reduction.

Beyond obesity, the triple-receptor mechanism has opened research applications in metabolic comorbidities where no single-receptor approach has proven sufficient. Ongoing Phase 3 trials are evaluating retatrutide in knee osteoarthritis (where weight-independent anti-inflammatory effects have been observed), obstructive sleep apnea, and non-alcoholic steatohepatitis. Its glucagon receptor activity also makes it a subject of interest in hepatic fat research independent of body weight effects.