New Horizons for Incretin-Based Therapeutics.

Glucagon-like peptide-1 (GLP-1)-based therapies marked a major breakthrough in obesity pharmacotherapy, while subsequent advancements targeting multiple entero-pancreatic hormones now deliver weight loss previously achievable only with bariatric surgery, alongside improvements in obesity-related complications. Despite this progress, significant challenges persist, including reduced efficacy in diabetic populations, gastrointestinal adverse effects, and high costs that drive a real-world adherence gap. Consequently, next-generation therapies, including receptor polyagonists, oral formulations, and small-molecule incretin mimetics with optimized pharmacokinetic profiles, are being developed to enhance efficacy, tolerability, and accessibility while maintaining safety. However, weight regain after treatment cessation remains a critical hurdle. Growing evidence underscores the importance of sustained lifestyle interventions and muscle mass preservation to facilitate weight stabilization. Concurrently, research is heavily focused on identifying the biological drivers of weight regain, such as altered neuroregulation, metabolic adaptation, and adipose tissue remodeling. This review examines the current landscape, limitations, and emerging strategies of obesity pharmacotherapy.