Incretin Dominance and Emerging Mechanisms in Obesity Pharmacotherapy: Insights from 275 Registered Clinical Trials...

Obesity remains a critical global health challenge, with rising prevalence and a substantial cardiometabolic and psychosocial burden. Recent therapeutic advances, particularly in incretin-based strategies, underscore the need for a comprehensive characterization of the evolving pharmacological landscape. We conducted a systematic review of clinical trials registered on ClinicalTrials.gov between October 2019 and October 2024, focusing on pharmacological interventions for obesity from early exploratory stages to Phase 3. A total of 275 eligible trials were identified and analyzed. Incretin pathway modulators predominated (69.8%), especially GLP-1 receptor agonists and dual or triple agonists targeting GLP-1, GIP, and glucagon receptors. Most trials were in Phase 2 (40.7%) or Phase 3 (31.3%), indicating a maturing pipeline, while early-stage innovation remained limited (3.3% of trials). Drug repurposing was common (22.2%), notably involving semaglutide and liraglutide, originally approved for type 2 diabetes. Industry-sponsored trials constituted the majority (75.3%), with limited academic (22.2%) and governmental (2.5%) participation. Geographically, trials were concentrated in the United States, China, and Denmark, with relatively few international multicenter studies. While the obesity drug pipeline is expanding rapidly, it remains heavily centered on incretin-based therapies. This dominance, despite strong clinical efficacy, raises concerns regarding long-term safety, accessibility, and mechanistic diversity. Greater investment in early-phase innovation and alternative pharmacological targets will be essential to diversify treatment options and address the unmet need for equitable and sustainable obesity management.