Pharmacogenomic determinants of long-term GLP-1 receptor agonist efficacy: Addressing the transition from acute weight loss to metabolic maintenance

Abstract. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have fundamentally revolutionized the pharmacological management of both obesity and type 2 diabetes mellitus, demonstrating unprecedented clinical efficacy in inducing acute weight loss and dramatically improving cardiometabolic profiles. However, the cessation of these therapies invariably precipitates a profound physiological rebound, characterized by rapid weight regain and the immediate reversal of established cardioprotective benefits. This exhaustive report investigates the precise pharmacogenomic, molecular, and metabolic determinants that govern the complex transition from acute weight loss to long-term, sustainable metabolic maintenance. Wide inter-individual variability in treatment response and susceptibility to the rebound effect are increasingly linked to intrinsic genetic polymorphisms within the GLP1R gene (such as rs10305420 and rs6923761) and interconnected downstream neuroendocrine pathways. Furthermore, transitioning clinical protocols from traditional peptide-based injectables to next-generation oral small-molecule GLP-1 RAs, particularly orforglipron, offers a transformative therapeutic strategy. Orforglipron utilizes non-canonical binding and -biased signaling to successfully mitigate receptor desensitization while ensuring robust efficacy and improved patient adherence. By systematically integrating rigorous pharmacogenomic screening with biomarker-guided therapy (utilizing markers such as GDF15 and FGF21), modern clinical paradigms can accurately optimize long-term maintenance, maximize the reduction of major adverse cardiovascular events (MACE), and establish highly cost-effective treatment algorithms when compared to traditional, invasive bariatric interventions.