Understanding Rebound Cardiovascular Risk After GLP-1 RA Discontinuation Using Target Trial Emulation
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have transformed the management of cardiovascular-kidney-metabolic (CKM) syndrome, with randomized trials establishing clear cardiovascular benefit in patients with diabetes, obesity, and related conditions. Yet real-world persistence with GLP-1 RA therapy is often poor, driven by cost, supply shortages, side effects, and shifting insurance coverage. While withdrawal studies show rapid metabolic deterioration after discontinuation, the cardiovascular consequences of stopping therapy remain largely uncharacterized. 
Dr. Andreas Kalogeropoulos, a clinical researcher in the Department of Medicine, Division of Cardiology, has been awarded funding from the American Heart Association to address this gap. Preliminary analyses using real-world data show a substantial rise in cardiovascular events following GLP-1 RA discontinuation relative to continued treatment — but a central question remains unanswered: does this reflect a true rebound above baseline risk, or simply a return to the risk level of patients who never initiated therapy at all?
Using a sequential target trial emulation framework applied to de-identified electronic health records from more than 100 million patients across 30 US health systems, Dr. Kalogeropoulos will benchmark post-discontinuation cardiovascular risk against matched, never-treated patients and identify which patient subgroups are most vulnerable. The findings are expected to inform clinical counseling, coverage policy, and strategies for supporting patients who cannot sustain long-term GLP-1 RA therapy.