GLP-1 Agonists: Selection and Titration

GLP-1 receptor agonists mimic and enhance the incretin effect — the phenomenon whereby oral glucose stimulates 2-3 times more insulin secretion than equivalent intravenous glucose because intestinal L-cells release glucagon-like peptide-1 (GLP-1) in response to nutrient ingestion. Native GLP-1 has a half-life of only 2-3 minutes due to rapid degradation by dipeptidyl peptidase-4 (DPP-4); synthetic GLP-1 agonists are engineered for resistance to DPP-4 cleavage, extending half-lives from hours (exenatide BID) to days (semaglutide weekly). GLP-1 receptor activation on pancreatic beta cells enhances glucose-dependent insulin secretion via cAMP-PKA signaling — critically, this is glucose-dependent, meaning insulin release diminishes as blood glucose falls, conferring low hypoglycemia risk when used without sulfonylureas or insulin. Simultaneously, GLP-1 suppresses glucagon secretion from alpha cells (which is paradoxically elevated in T2DM), slows gastric emptying by 20-30% (contributing to postprandial glucose reduction and the primary GI side effects of nausea and vomiting), and acts on hypothalamic appetite centers (arcuate nucleus) to promote satiety and reduce caloric intake. Gradual dose titration over 4-8 weeks allows desensitization of the vagal afferent nausea pathway, which is why rapid escalation causes...