The evolution of obesity pharmacotherapy from sympathomimetics to incretin-based therapies

Obesity is a chronic metabolic disorder that has reached epidemic proportions globally and in South Africa, contributing to the increasing burden of cardiometabolic diseases. Although lifestyle modifications remain a fundamental approach, long-term weight loss is often limited, necessitating the use of pharmacotherapy. Historically, centrally acting sympathomimetics, such as phentermine, have been predominant in South African treatments, albeit with restrictions concerning their safety and duration. This review examines the evolution of obesity pharmacotherapy from traditional agents, including phentermine and orlistat, to contemporary incretin-based therapies. Particular emphasis is placed on glucagon-like peptide-1 receptor agonists and dual incretin agonists, such as semaglutide and tirzepatide, which have demonstrated unprecedented efficacy in clinical trials involving patients with obesity. Emerging multi-hormonal and non-injectable agents are also discussed. This article underscores the transition from short-term appetite suppression to sustained pharmacological management of obesity and its comorbidities.