GLP-1 Receptor Agonists

GLP-1 is an incretin hormone secreted by intestinal L-cells after meals. It binds GLP-1 receptors on pancreatic beta cells to amplify glucose-stimulated insulin secretion while suppressing alpha-cell glucagon output. In the brain, GLP-1 receptor activation in the hypothalamus and brainstem reduces appetite and food intake. Native GLP-1 has a half-life of only 2-3 minutes due to rapid DPP-4 enzyme degradation — therapeutic analogues use acylation (semaglutide), Fc fusion (dulaglutide), or exendin-4 scaffolds (exenatide) to extend duration from hours to weeks.

Semaglutide — the most widely studied GLP-1 agonist with once-weekly dosing. FDA-approved for type 2 diabetes (Ozempic) and chronic weight management (Wegovy). Achieved 15-17% body weight reduction in STEP trials. Tirzepatide — a dual GLP-1/GIP receptor agonist achieving up to 22.5% weight loss in SURMOUNT trials, the largest reductions seen with any anti-obesity medication. Retatrutide — a novel triple agonist (GLP-1/GIP/glucagon) that showed up to 24% weight loss at 48 weeks in phase 2 trials. Liraglutide — an earlier once-daily GLP-1 agonist (Victoza/Saxenda). Survodutide — a dual GLP-1/glucagon agonist showing promise for MASH (metabolic-associated steatohepatitis).

GLP-1 agonists have the strongest evidence base of any peptide class, with dozens of large-scale phase III RCTs, FDA approvals, and real-world outcomes data spanning over a decade. The STEP, SURMOUNT, and SELECT (cardiovascular outcomes) trials represent landmark evidence. Emerging research explores applications in MASH/NAFLD, Alzheimer's disease, addiction, and kidney disease. The cardiovascular benefits of semaglutide (20% MACE reduction in SELECT) have expanded the clinical rationale beyond glycemic control and weight management.

Common side effects include nausea, vomiting, diarrhea, and constipation — typically dose-dependent and transient. GLP-1 agonists carry a black box warning for thyroid C-cell tumors based on rodent studies (not confirmed in humans). Pancreatitis, gallbladder disease (due to rapid weight loss), and gastroparesis are monitored adverse events. Titration protocols starting at low doses and escalating over weeks significantly reduce GI side effects.