GLP-1 Receptor Agonists beyond Glycemic Control: Physiology and Pharmacological Evidence

Glucagon-like peptide-1 receptor agonists were initially developed for the treatment of type 2 diabetes mellitus because they enhance glucose-dependent insulin secretion, suppress glucagon release, delay gastric emptying, and reduce appetite. In recent years, their use has expanded beyond glycemic control. Clinical studies have reported effects on body weight, cardiovascular outcomes, chronic kidney disease, and metabolic liver disease. Semaglutide reduced major adverse cardiovascular events in patients with overweight or obesity and established cardiovascular disease without diabetes in the SELECT trial. In the FLOW trial, semaglutide reduced clinically important kidney outcomes in patients with type 2 diabetes and chronic kidney disease. Tirzepatide, a dual GIP and GLP-1 receptor agonist, produced substantial body-weight reduction in adults with obesity or overweight without diabetes. GLP-1-based therapies have also been evaluated in metabolic dysfunction-associated steatohepatitis and inflammatory conditions. However, many observed benefits may be related to weight reduction, improved insulin sensitivity, lower blood pressure, and reduced metabolic stress. Therefore, direct receptor-mediated effects should be interpreted carefully. This mini review summarizes the physiological basis and current pharmacological evidence for GLP-1 receptor agonists beyond glucose lowering.