What is GLP-1 and why do so many drugs target it?

GLP-1 (glucagon-like peptide-1) is a 30-amino-acid peptide hormone secreted by L cells in the small intestine after nutrient ingestion. It engages a specific G-protein-coupled receptor (GLP-1R) on multiple tissues to produce three integrated physiological effects: glucose-dependent insulin secretion from pancreatic beta cells (potentiating the insulin response only when glucose is elevated), suppression of glucagon secretion from pancreatic alpha cells, and delayed gastric emptying combined with central appetite suppression via hypothalamic pathways.

The combination of these effects made GLP-1 an attractive drug target for type 2 diabetes: insulinotropic in the physiological context, glucagon-suppressing to reduce hepatic glucose output, and appetite-reducing to address the obesity component of type 2 diabetes. Native GLP-1's 2-minute half-life made direct therapeutic use impractical, but engineered long-acting analogues solved that. Semaglutide (approved for type 2 diabetes in 2017 and for obesity as Wegovy in 2021) uses fatty-acid conjugation to extend half-life to about 165 hours (weekly dosing). Tirzepatide (approved 2022 in diabetes as Mounjaro, in obesity as Zepbound) engages both GLP-1R and GIPR as a dual agonist, producing larger effects than pure GLP-1 agonism.

The clinical impact has been enormous — SURMOUNT-1 (tirzepatide) reported ~22.5% mean weight loss at 72 weeks; STEP-1 (semaglutide 2.4 mg) reported ~14.9% at 68 weeks. These are effect sizes that had not been achieved by any prior pharmacological approach to obesity.