Mazdutide and Orforglipron—New Evidence in Obesity and Diabetes

Abstract

Glucagon-like peptide 1 (GLP-1) receptor agonists and other incretin-based medications, especially the newer-generation long-acting medications, have transformed the treatment of type 2 diabetes, obesity, and related cardiometabolic disorders with broad-spectrum efficacy that is above and beyond robust weight reduction. Once-weekly subcutaneous semaglutide, a GLP-1 receptor agonist, is currently approved by the US Food and Drug Administration (FDA) for long-term weight management, type 2 diabetes, reduction of major adverse cardiovascular events (MACE) in patients with established cardiovascular disease with type 2 diabetes or those with overweight or obesity without diabetes, reduction of the progression of chronic kidney disease in patients with type 2 diabetes, and treatment of noncirrhotic metabolic dysfunction–associated steatohepatitis with moderate to advanced liver fibrosis. Daily oral formulations of semaglutide are also approved for type 2 diabetes to reduce the risk of MACE in patients with type 2 diabetes or overweight or obesity with established cardiovascular disease without diabetes and for weight reduction. Tirzepatide, a once-weekly subcutaneous dual agonist of GLP-1 and glucose-dependent insulinotropic polypeptide receptors, is approved for type 2 diabetes, for weight reduction in patients with overweight or obesity, and to treat moderate to severe obstructive sleep apnea in adults with obesity. Orforglipron, a once-daily oral nonpeptide GLP-1 receptor agonist, has been recently approved in the US for weight reduction in adults with overweight or obesity. Liraglutide, a once-daily subcutaneous GLP-1 receptor agonist, is also marketed for treatment of type 2 diabetes and overweight or obesity. Several new incretin-based medications and those combining these with medications with novel nonincretin mechanisms are in late stages of clinical development or under review by the FDA and regulatory agencies in other countries for treatment of obesity and ot