Discontinuation of incretin-based therapies in obesity: the complexity of a breakup.

Abstract

Incretin-based therapies, including mono-, dual-, and emerging triple-agonists, have transformed the pharmacological management of obesity by inducing substantial and sustained weight loss together with marked improvements in cardiometabolic risk factors. However, growing evidence from randomized withdrawal trials and meta-analyses demonstrates that discontinuation of these agents is consistently followed by rapid and clinically meaningful weight regain, often approaching two-thirds of the initial weight loss within one year, alongside early deterioration of cardiometabolic parameters. These observations reinforce the concept of obesity as a chronic, relapsing disease that generally requires long-term pharmacological management rather than time-limited treatment. This Opinion article examines the biological, clinical, and health-system factors that complicate discontinuation of incretin-based therapies, including adaptive neuroendocrine responses to weight loss, interindividual variability in treatment response, persistence of "obesity memory" at the adipose tissue level, and real-world challenges related to adherence, tolerability, and cost. We discuss emerging strategies aimed at mitigating post-withdrawal weight regain, such as dose de-escalation, low-dose maintenance, extended dosing intervals, and intensive lifestyle interventions, while highlighting the current lack of robust randomized evidence supporting these approaches. Finally, we propose reframing the concept of precision medicine in obesity toward a "precision physician-patient relationship," emphasizing individualized, longitudinal decision-making to guide treatment continuation, tapering, or discontinuation in the absence of reliable predictive biomarkers.