Phenotypic and genomic frameworks for precision pharmacotherapy in obesity: a narrative review

Lopez Delgado D.S.; Reyes-Zermeño M.G.; Lemus E.D.S.; Acosta-Celis C.G.; Kantún-Marín M.A.; Gomez-Lujan M.; Fallaza-Moya K.G.; Muñoz-Chuquilín O.; Trujillo-Levano S.; Gutierrez-Chavez G.; Bonilla-Asalde C.; Rivera-Lozada O.; Barboza J.J. · Frontiers in Medicine (2026) · DOI: 10.3389/fmed.2026.1803474

Resumen

Background – Obesity is a chronic, heterogeneous disease with marked interindividual variability in response to anti-obesity medications. Although GLP-1 receptor agonists (GLP-1RAs) and dual incretin agonists produce substantial average weight loss in clinical trials, real-world effectiveness is limited by interindividual variability, gastrointestinal intolerance, incomplete dose escalation, cost and access barriers, poor long-term persistence, and weight plateau or regain in a subset of treated patients. Weight regain is particularly consistent after treatment discontinuation, reinforcing the chronic-care nature of obesity pharmacotherapy. Objective – To synthesize evidence on phenotypic and genomic determinants of variability in pharmacotherapy response and propose a pragmatic framework for precision pharmacotherapy in obesity. Methods – Narrative review integrating data from randomized trials, post-hoc subgroup analyses, observational cohorts, neurobehavioral studies, pharmacogenomic investigations, and polygenic risk score research addressing predictors of efficacy and tolerability. Results – Response heterogeneity reflects interactions among central satiety and reward circuitry, baseline metabolic and glycemic status, sex, baseline adiposity, treatment indication, previous GLP-1RA exposure, adherence, and tolerability. Early on-treatment weight change, usually assessed within 12–16 weeks and in some liraglutide studies as early as 1 month, is the most clinically actionable predictor of longer-term outcomes. Phenotype-guided approaches that classify dominant mechanisms such as impaired satiation, postprandial hunger, emotional or hedonic eating, and low energy expenditure offer a feasible bridge between pathophysiology and medication selection. Emerging genomic signals are promising but remain insufficiently replicated for routine clinical use. Conclusion – Precision pharmacotherapy in obesity is most viable today through phenotype-guided treatment, structured early-response monitoring, and proactive management of adherence and tolerability. Genomic tools may eventually refine treatment selection, but they remain investigational and require prospective, multi-ancestry validation. Copyright

Instituciones: Universidad Nacional de Trujillo; Universidad Científica del Sur; Universidad Continental; Universidad Nacional Federico Villarreal; Universidad Señor de Sipán