Review details pharmacodynamics of novel anti-obesity drugs, including GLP-1/GIP agonists and oral semaglutide

Obesity is a chronic, multifactorial metabolic condition characterized by excessive fat accumulation, significantly increasing global morbidity and mortality through associations with cardiovascular disease, type 2 diabetes mellitus (T2DM), and certain cancers. Despite lifestyle interventions, long-term weight loss remains challenging due to complex neuroendocrine mechanisms that tightly regulate energy homeostasis. Pharmacotherapy has thus become a critical adjunct for individuals with a BMI ≥ 30 kg/m2 or ≥27 kg/m2 with comorbidities, targeting these intricate pathways to reduce appetite, enhance satiety, or inhibit nutrient absorption.

This comprehensive review synthesized recent literature on anti-obesity medications (AOMs), focusing on their pharmacodynamic profiles, mechanisms of action, and clinical efficacy. The authors systematically analyzed data from preclinical studies and clinical trials concerning FDA-approved drugs such as orlistat, phentermine-topiramate, naltrexone-bupropion, liraglutide, semaglutide, and tirzepatide, alongside emerging agents like oral semaglutide 25 mg and orforglipron. The methodology involved a pharmacodynamics perspective to evaluate how these agents interact with central and peripheral neuroendocrine pathways to regulate appetite, satiety, and energy expenditure, thereby addressing the complex pathophysiology of obesity.

The review highlighted the diverse pharmacodynamic mechanisms of AOMs, ranging from direct nutrient absorption inhibition by orlistat to complex neuroendocrine modulation by incretin-based therapies. It detailed how GLP-1R agonists like liraglutide and semaglutide enhance satiety and reduce appetite, leading to significant weight loss. Dual GLP-1R/GIPR agonists, exemplified by tirzepatide, were noted for their superior efficacy, with clinical trials demonstrating body weight reductions potentially exceeding 20%. The recent approval of oral semaglutide 25 mg in December 2025 was identified as a significant advancement, offering a non-injectable option for chronic weight management. Furthermore, the review introduced orforglipron (Foundayo), a novel non-peptide GLP-1R agonist approved in April 2026, emphasizing its potential for improved patient adherence due to its oral bioavailability and distinct pharmacokinetic profile.

The review underscored that effective AOMs primarily target the intricate neuroendocrine systems that tightly regulate energy homeostasis, overcoming the body's defense mechanisms against weight loss. It also discussed combination therapies and the evolving landscape of drug development, moving towards agents with multi-receptor agonism or novel mechanisms to achieve greater efficacy and tolerability in obesity management.