Mechanism-Based Pharmacotherapy of Obesity: From Pathophysiology to Precision and Next-Generation Therapeutics

Abstract

Obesity is a chronic, relapsing, and highly heterogeneous disease driven by genetic susceptibility, neuroendocrine and reward circuitry, gut–brain signalling, adipose-tissue dysfunction, inflammation, metabolic adaptation, and interacting environmental and behavioural influences. As these mechanisms have become better understood, the therapeutic landscape has expanded accordingly, and the rapid emergence of incretin-based and multi-pathway pharmacotherapies has pushed treatment expectations well beyond modest weight loss toward clinically meaningful improvement in obesity itself and its downstream complications. This review draws together obesity pathophysiology and its molecular therapeutic targets with established pharmacotherapies, emerging agents, drug-repurposing opportunities, precision treatment, and next-generation drug discovery to build a mechanism-based, clinically oriented synthesis. Current and investigational strategies are evaluated in terms of efficacy, safety, tolerability, durability, body composition, complication-specific benefit, and translational maturity, with particular attention to glucagon-like peptide-1 (GLP-1)–based therapies, dual and triple receptor agonists, amylin-containing combinations, oral and engineered long-acting agents, and strategies that extend beyond appetite suppression. Substantial progress notwithstanding, several questions remain unresolved, including long-term treatment persistence and maintenance, weight regain after treatment interruption, preservation of lean mass and physical function, accessibility, heterogeneity of treatment response, optimal sequencing and combination strategies, and complication-guided drug selection. Phenotype- and mechanism-informed prescribing, tissue-directed drug delivery, modulation of energy expenditure, and novel gut–brain pathways could address some of these limitations, although several of these approaches remain at an early stage of translational development. Progress will therefore hinge not simply on achieving greater weight reduction, but on translating mechanistic advances into treatments that deliver durable clinical benefit with acceptable safety, feasibility, and functional outcomes — pushing obesity pharmacotherapy toward a more precise, complication-informed, and longitudinal model of disease management tailored to each patient's biology and clinical needs.