Clinical management of weight regain and cardiometabolic consequences after discontinuation of GLP-1 receptor agonists

Abstract

Background Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual incretin therapies produce substantial weight loss and cardiometabolic improvement, yet treatment discontinuation is common and associated with adverse metabolic consequences. Aims This review aims to synthesize current mechanistic and clinical evidence on metabolic trajectories following GLP-1RA discontinuation, identify predictors of relapse, and propose a multidisciplinary framework for post-treatment management. Materials and Methods We conducted a narrative review of evidence from randomized withdrawal trials (including STEP-1 extension, STEP-4, and SURMOUNT-4), systematic reviews, meta-analyses, and large real-world observational cohorts encompassing over 289,000 patients. Results Discontinuation is associated with substantial weight regain (60%-90% within one year) and parallel reversal of cardiometabolic benefits. Modelling studies suggest that glycaemic, blood pressure, and lipid parameters return to baseline within approximately 12 months, while HbA1c normalizes within 12-18 months. Early discontinuation (< 1 year) is associated with increased risks of coronary artery disease and heart failure compared with continued therapy. Discussion Weight recurrence reflects biological adaptations to weight loss, including reactivation of orexigenic pathways and adaptive thermogenesis. In the absence of validated tapering strategies, structured multidisciplinary transition approaches combining pharmacological, behavioral, and psychological interventions may mitigate post-discontinuation relapse. Conclusion GLP-1RA discontinuation should be considered a high-risk clinical transition rather than a treatment endpoint. Structured follow-up and multidisciplinary management are essential to preserve long-term cardiometabolic benefits.