GLP-1 Receptor

The glucagon-like peptide 1 receptor — a Class B GPCR that is the primary target of the incretin therapeutic revolution. Central to Session VII.

The Incretin Arc

The pharmacological progression traces through progressive constraint-removal:

1. Foundational GLP-1 biology (Habener, Holst, Drucker)
2. Exenatide (2005) — from Gila monster venom, twice daily
3. Weekly formulations → oral formulations
4. The pivot: nausea/appetite suppression recognized as the primary indication (not just diabetes side effect)

Drugs Acting on GLP-1R

Drug	Mechanism	Developer
Semaglutide	GLP-1 mono-agonist	Novo Nordisk
Tirzepatide	Dual GIP/GLP-1 agonist	Lilly
Orforglipron	Oral small-molecule GLP-1R agonist	Lilly
Maritide	GIPR antagonist + GLP-1 agonist peptides (heterodimerization)	Amgen
Retatrutide	GIP/GLP-1/glucagon triple agonist	Lilly

See also: tirzepatide, orforglipron, maritide, retatrutide, eli-lilly, amgen

Beyond Cardiometabolic

GLP-1R signaling is being reconceived as general-purpose neuromodulation: Lilly has Phase 3 trials in substance use disorder, MDD, schizophrenia, bipolar, alcohol/tobacco/opioid use disorder, plus asthma, IBS, IBD, psoriasis.

Cross-References

• Obesity — primary indication
• Maritide — the “geometry as pharmacology” approach