Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2is) reduce cardiovascular events in nonsurgical populations, yet their comparative effects as combination versus monotherapy after cardiac surgery remain unknown. Using the TriNetX US Collaborative Network (115 million patients, 67 healthcare organizations), we conducted a retrospective propensity score-matched cohort study of adults undergoing coronary artery bypass grafting or open valve surgery between January 2018 and January 2026, excluding transcatheter aortic valve replacement. Two prespecified analyses compared combination therapy (GLP-1 RA plus SGLT2i) with each monotherapy. One-to-one nearest-neighbor matching (caliper 0.1) balanced age, sex, race, ethnicity, comorbidities, and glycemic control. The primary outcome was all-cause mortality at 365 days, with prespecified subgroup analyses by heart failure (HF) and chronic kidney disease (CKD) status and sensitivity analyses at 180 and 600 days. After matching, Analysis 1 (combination vs GLP-1 RA monotherapy) included 6974 patients, and Analysis 2 (combination vs SGLT2i monotherapy) included 12,682 patients. Combination therapy was not associated with reduced mortality versus GLP-1 RA monotherapy overall (HR, 0.93; P = 0.587) but was associated with lower mortality versus SGLT2i monotherapy (HR, 0.60; P < 0.001), along with lower atrial fibrillation and major adverse cardiovascular events. The Analysis 1 mortality benefit emerged only in HF and CKD subgroups, with an acute kidney injury signal at 600 days. GLP-1 RA add-on therapy was associated with broad mortality reduction after cardiac surgery, whereas SGLT2i add-on benefit was confined to patients with HF or CKD, with potential renal risk in unselected patients. Prospective trials are warranted.
