The retatrutide stack is a two-compound research protocol that pairs two of the most powerful weight-loss peptides in late-stage development. The plain-English version: retatrutide does the heavy lifting on appetite, blood sugar, and energy use. It adds a separate fullness signal that retatrutide does not hit on its own.

In the Phase 3 REDEFINE-1 trial, adding to semaglutide pushed average weight loss from 14.9% to 20.4%. The reta + cag stack swaps semaglutide for retatrutide – which already hits three receptors – aiming to layer amylin satiety on top of broader metabolic effects.

What Each Compound Does

Retatrutide (LY3437943) is a triple agonist: GLP-1 (cuts appetite, slows the stomach), GIP (improves insulin signaling), and glucagon (raises energy use and fat burning). In Phase 3 TRIUMPH-4, retatrutide at 12 mg produced 28.7% body weight loss at 68 weeks vs 2.1% for placebo.

Why People Pair Them

Retatrutide is powerful, but it does not activate amylin receptors:

Two separate fullness channels. GLP-1 (reta) tells your gut to slow down. Amylin (cag) tells your hindbrain you are full. Different brain regions, different pathways.
Stacked digestion slowdown. Both compounds slow gastric emptying. Food stays in the stomach longer, which extends fullness after meals.
Four receptor pathways covered. GLP-1 (appetite) + GIP (insulin) + glucagon (energy burn) + amylin (fullness). No other current peptide stack covers this many pathways.
CagriSema rationale extended. REDEFINE-1 showed that adding amylin to a GLP-1 backbone improves results. This stack tests the same logic with a triple-agonist backbone.