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Here the authors provide real-world evidence through a target trial emulation study using the TriNetX federated electronic health record network to show that glucagon-like peptide-1 receptor agonists is associated with a lower risk of the primary composite ischemic cardiovascular events plus heart failure exacerbations compared with dipeptidyl peptidase-4 inhibitors.
Patients with end-stage kidney disease (ESKD) receiving maintenance dialysis have a high burden of heart failure (HF), with cardiovascular disease the leading cause of death, yet are largely excluded from randomized trials. Using the TriNetX federated electronic health record network, we emulate a target trial comparing initiation of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus dipeptidyl peptidase-4 inhibitors (DPP-4is) in diabetic ESKD patients with HF, undergoing maintenance dialysis. We identify a primary ESKD-HF population and a confirmatory dialysis-dependence-coded HF subset, and apply a new-user, active-comparator design and use propensity score matching to balance baseline characteristics. In the primary ESKD-HF population, GLP-1RAs use is associated with a lower risk of the primary composite ischemic cardiovascular events plus HF exacerbations, than DPP-4i initiation (31.7% vs. 41.4%; HR 0.72[0.64–0.82], P < 0.0001), with concordance reductions in ischemic events (HR 0.74), HF exacerbations (HR 0.76), all-cause mortality (HR 0.68), and a death-inclusive composite (HR 0.72). Results are consistent in multivariable models, across prespecified subgroups, and in extensive sensitivity analyses, and are corroborated in the confirmatory dialysis-dependence–coded HF subset HR (0.71[0.60–0.85]). These findings provide real-world evidence suggesting GLP-1RAs may improve cardiovascular outcomes in dialysis-dependent diabetic ESKD with HF and support prospective randomized evaluation.