Medical Management of Obesity: A Comprehensive Review of Food and Drug Administration (FDA)-Approved and Investigational Therapies

The global rise in obesity has accelerated both clinical and pharmaceutical innovation in antiobesity pharmacotherapy. This narrative review synthesizes current evidence on Food and Drug Administration-approved medications and emerging investigational agents that are shaping clinical practice. We summarize mechanisms of action, pivotal efficacy data, safety profiles, indications, prescribing guidance, and key uncertainties. Approved long-term agents, orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide, semaglutide, and tirzepatide, differ in mechanism, weight-loss magnitude, and safety considerations. Semaglutide and tirzepatide have redefined expectations for pharmacological weight loss, while next-generation drugs, such as oral glucagon-like peptide 1 receptor agonists (e.g., orforglipron) and multireceptor agonists (e.g., retatrutide), show even greater efficacy in early studies. Common safety concerns include gastrointestinal effects, gallbladder events, pancreatitis risk, thyroid C-cell tumor warnings, teratogenicity, and cost barriers. Appropriate patient selection depends on body mass index, comorbidities, contraindications, and treatment goals, with close monitoring throughout therapy. Long-term data on cardiovascular outcomes and posttreatment weight durability are emerging. Future research should prioritize direct comparative trials, real-world effectiveness, long-term safety, and strategies to improve access and adherence. This review offers clinicians a concise, evidence-based guide for obesity pharmacotherapy and outlines key research priorities as the treatment landscape rapidly evolves.