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The introduction of incretin-based obesity management medications has transformed the treatment landscape of obesity, enabling significant levels of weight loss. However, substantial interindividual variability in therapeutic response and the high prevalence of weight regain following treatment discontinuation remain major clinical challenges. These limitations highlight the need for strategies that extend beyond pharmacotherapy alone. This conceptual review synthesizes current evidence on glucagon-like peptide-1 (GLP-1) receptor agonists and dual or triple incretin-based therapies, emphasizing the biological factors that modulate treatment efficacy, including host genetics, gut microbiota composition, and metabolic phenotype. Emerging data suggests that genetic variants affecting incretin signaling pathways, as well as microbiome-driven modulation of hormone secretion and energy metabolism, may partially explain heterogeneity in clinical outcomes. Importantly, incretin-based therapies are frequently accompanied by reductions in lean body mass, nutritional inadequacies, and gastrointestinal adverse effects, which may compromise long-term metabolic health and treatment adherence. In this context, precision nutrition approaches integrating nutrigenomics, metabolomics, and microbiome profiling offer a complementary framework to personalize dietary strategies, preserve lean mass, mitigate adverse effects, and enhance weight-loss maintenance. By integrating pharmacotherapy with individualized nutritional and lifestyle interventions, obesity management may shift toward more sustainable, biologically informed treatment models that address the chronic and relapsing nature of obesity. • Incretin-based therapies are effective but present limitations for long-term obesity management • Precision nutrition may mitigate adverse effects and weight recovery during pharmacotherapy • Genetic, microbiota, body composition and lifestyle factors inform individualized interventions • Integrating nutrition and incretin therapies may improve weight-loss durability and adherence