From one-size-fits-all to phenotype-based pharmacotherapy: How far are we in obesity management?

Obesity is a global health crisis, projected to affect over one billion adults by 2030. Lifestyle modification strategies—diet, physical activity, and behavioral therapy—have achieved only modest and often unsustainable outcomes. Pharmacotherapy has therefore emerged as a cornerstone of modern obesity care. Glucagon-like peptide-1 (GLP-1) receptor agonists and dual incretin agents such as tirzepatide have demonstrated unprecedented efficacy, with weight reductions approaching surgical outcomes in some populations while improving glycemic and cardiometabolic parameters. These therapeutic advances align with recognition of the pathophysiological heterogeneity of obesity, often conceptualized through four phenotypes: “hungry brain” (impaired satiation), “hungry gut” (impaired satiety), “emotional hunger” (reward-driven eating), and “slow burn” (impaired metabolism). This framework offers a rationale for targeted interventions—GLP-1 receptor agonists for satiety-related phenotypes, naltrexone–bupropion for reward-driven eating, and dual incretin therapies for metabolic inefficiency. Beyond pharmacology, accumulating evidence indicates that surgical outcomes may also differ across patient subgroups, suggesting that phenotype-guided strategies could refine not only medical therapy but also surgical decision-making. However, these phenotypes remain heuristic, with overlapping traits, limited validation, and uncertain predictive value. Future research should refine phenotypic classification, identify reliable biomarkers, and conduct phenotype-stratified clinical trials to confirm matching of pharmacological and surgical interventions.