Early Weight Regain After GLP-1 Receptor Agonist Discontinuation: Mechanisms and Implications for Treatment...

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the pharmacological management of obesity, producing substantial and sustained weight loss during active treatment. However, discontinuation of therapy is frequently followed by significant weight regain, raising important questions regarding the durability of treatment effects and optimal strategies for treatment withdrawal. Recent systematic reviews and meta-analyses consistently demonstrate that weight regain after GLP-1RA discontinuation is substantial and follows a characteristic trajectory, with a large proportion occurring during the early post-cessation period. This front-loaded pattern suggests that the initial months after treatment cessation represent a critical window influencing long-term outcomes. Mechanistically, post-cessation weight regain appears to reflect the interaction of multiple processes. These include restoration of appetite following withdrawal of pharmacological GLP-1 signalling, compensatory increases in orexigenic hormones such as ghrelin, alterations in incretin balance including glucose-dependent insulinotropic polypeptide (GIP) and potential adaptive changes in GLP-1 receptor signalling pathways during prolonged pharmacological exposure, although evidence for a direct role in post-cessation weight regain remains limited. These converging mechanisms have important clinical implications, as abrupt discontinuation may result in a transient mismatch between increased biological drive for weight regain and the sudden loss of pharmacological appetite suppression. In this context, strategies aimed at mitigating early weight regain are of increasing interest. Recent randomised evidence suggests that reduced-intensity pharmacological maintenance may attenuate weight regain compared with abrupt discontinuation. However, whether structured tapering strategies can successfully facilitate treatment discontinuation remains unknown and requires prospective evaluation.