The Natural Hormone
GLP-1 is a 30-AA incretin hormone from intestinal L-cells. Four effects: (1) glucose-dependent insulin release, (2) glucagon suppression, (3) slowed gastric emptying, (4) appetite reduction via hypothalamic POMC/CART activation.
The problem: DPP-4 destroys native GLP-1 in 2 minutes.
The Engineering Solutions
Exenatide (2005): Gila monster venom peptide, naturally DPP-4 resistant. t½=2.4h. First GLP-1 drug ever.
Liraglutide (2010): C16 fatty acid for albumin binding. t½=13h. First long-acting. Daily injection.
Semaglutide (2017): Aib8 + C18 fatty diacid. t½=7 days. Weekly injection. Market leader.
Tirzepatide (2022): Dual GLP-1/GIP. C20 fatty diacid. 22.5% weight loss. Most effective single-agent obesity drug.
Retatrutide (Phase III): Triple GLP-1/GIP/Glucagon. 24.2% weight loss. Adds energy expenditure via glucagon.
Why They Cause Weight Loss
Primarily: reduced appetite from CNS GLP-1R activation (hypothalamic satiety neurons). Not a 'metabolism boost' — you eat fewer calories because hunger signals are dampened.
Weight returns when you stop: ~2/3 regained within 1 year (STEP extension). These drugs treat obesity as a chronic condition.
Deep encyclopedia entries on every GLP-1 drug: exenatide → liraglutide → semaglutide → tirzepatide → retatrutide → CagriSema