Progress in Anti-Obesity Drug Development: A Pharmacodynamics Perspective

Abstract

Background/Objectives: Obesity is a chronic, multifactorial condition driven by complex neuroendocrine and metabolic pathways that limit the long-term success of lifestyle interventions. Pharmacotherapy has advanced from early monoaminergic agents to incretin-based and multi-receptor agonists with substantially improved efficacy. This review aims to provide pharmacodynamics-focused synthesis of current and emerging anti-obesity medications, emphasizing mechanistic targets, receptor interactions, and translational implications. Methods: We conducted a narrative review integrating Phase I–III clinical trials, mechanistic pharmacology data (receptor affinity, potency, and signaling bias), and regulatory summaries for FDA-approved and selected emerging, investigational, repurposed, or regionally approved anti-obesity agents. Inclusion focused on clinical relevance, pharmacodynamic novelty, and weight-loss efficacy. Results: Approved anti-obesity medications act through diverse pathways, including the inhibition of fat absorption (orlistat), the modulation of central appetite circuits (phentermine/topiramate, naltrexone/bupropion), and incretin-based mechanisms (liraglutide, semaglutide, tirzepatide, and the oral GLP-1 receptor agonists semaglutide 25 mg and the nonpeptide orforglipron). GLP-1 receptor agonists achieve approximately 6–15% weight loss, while dual glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonists such as tirzepatide reach 15–20%. Emerging agents—including triple agonists (retatrutide), glucagon-based co-agonists, amylin analogs with Phase III efficacy data, earlier-stage growth differentiation factor 15 (GDF15) pathway agonists, and peripherally restricted cannabinoid-1 receptor inverse agonists—demonstrate enhanced metabolic effects and potential improvements in lean-mass preservation. Obesity-related alterations in pharmacokinetics and pharmacodynamics highlight the need for individualized dosing strategies. Conclusions: Clinical efficacy and tolerability cannot be inferred from receptor identity alone. They emerge from relative receptor potency and efficacy, exposure, tissue access, receptor trafficking, and mechanism-linked adverse effects. Dual and triple agonists can broaden efficacy, but receptor balance and standardized comparative pharmacology remain essential for rational development and individualized dosing.

The authors' abstract, as published at the source. Pharmaceutics, 2026 · DOI ↗