This literature review examines how dietary fructose intake and fat mass and obesity-associated (FTO) gene polymorphisms may influence the efficacy of glucagon-like peptide-1 (GLP-1)- and glucose-dependent insulinotropic polypeptide (GIP)-based therapies in obesity and metabolic syndrome. The narrative review synthesizes evidence showing that incretin-based therapies, particularly GLP-1 receptor agonists and dual GLP-1/GIP agonists, produce substantial weight loss and metabolic improvement, but response varies considerably among individuals. A central theme is that high fructose consumption promotes hepatic steatosis, de novo lipogenesis, insulin resistance, oxidative stress, and systemic inflammation, thereby creating a metabolic environment that may contribute to variability in incretin responsiveness. In parallel, FTO risk alleles are associated with increased obesity susceptibility, altered appetite regulation, impaired leptin signaling, and greater vulnerability to metabolic dysfunction. The review proposes an integrated model in which FTO-mediated leptin resistance and fructose-induced hepatic and inflammatory stress converge to reduce the appetite-suppressive and metabolic benefits of GLP-1/GIP therapies. Furthermore, it discusses the clinical implications of this interaction, emphasizing dietary fructose reduction, combination pharmacotherapy, and precision medicine strategies such as FTO genotyping and individualized therapeutic selection. Overall, the evidence suggests that gene-diet interactions may meaningfully shape incretin treatment outcomes and that more personalized, multi-targeted approaches may improve weight-loss efficacy in patients with obesity and metabolic syndrome. However, direct clinical evidence linking FTO genotype and fructose intake to reduced GLP-1/GIP therapeutic efficacy remains limited.
