Retatrutide

A GIP/GLP-1/glucagon triple agonist developed by Lilly. Presented by Kenneth Custer at Session VII.

Why Add Glucagon?

Adding glucagon to the GIP/GLP-1 backbone is counterintuitive — glucagon drives hepatic glucose output. But glucagon also:

• Stimulates lipid oxidation in the liver
• Drives thermogenesis in adipose
• Adds incremental satiety signaling

Key Data — TRIUMPH-4

Phase 3 (obesity + osteoarthritis knee pain):

• 28.7% weight loss at 68 weeks at highest dose
• Compare: tirzepatide achieves ~21–22% — retatrutide adds 5–6 percentage points
• WOMAC pain subscale: ~75% reduction; significant proportion of patients pain-free at end of trial
• Additional Phase 3 in chronic lower back pain ongoing

Context

• “85% of patients on tirzepatide did not achieve a BMI of 25 or below. As proud as I am of this medicine — it is still not good enough.” — Custer
• Each generation of incretins outmodes the last by efficacy
• Part of the incretin evolution landscape