SGLT2 Inhibition as a Perioperative Cardiorenal Stabilizer in Cardiac Surgery: Integrated Clinical Cohort and Pleiotropic Network-Based Pharmacological Analysis

Background: Patients with type 2 diabetes mellitus (T2DM) undergoing cardiac surgery represent a high-risk population characterized by substantial cardiometabolic stress and increased susceptibility to postoperative heart failure, renal dysfunction, and unplanned rehospitalization. Although sodium-glucose cotransporter 2 (SGLT2) inhibitors provide established cardiorenal protection in ambulatory populations, their perioperative impact in cardiac surgery cohorts remains insufficiently defined. Methods: In a single-center retrospective cohort of 620 T2DM patients, inverse probability of treatment weighting and time-dependent Cox regression were applied to account for perioperative treatment interruption and delayed postoperative reinitiation when evaluating the association between chronic SGLT2 inhibitor therapy and 12-month rehospitalization risk. To provide biological context for the observed clinical associations, target-driven systems pharmacology, molecular docking against SGLT2, NHE1, AMPK, and NLRP3, and protein–protein interaction (PPI) network analysis were performed. Hub proteins were identified using Maximal Clique Centrality, followed by functional enrichment (GO/KEGG) analysis. Results: Chronic SGLT2 inhibitor therapy was associated with reduced first rehospitalization (HR 0.64; 95% CI 0.48–0.85; p = 0.002) and a lower cumulative rehospitalization burden (IRR 0.61; 95% CI 0.46–0.82; p = 0.001), primarily driven by heart failure-related and metabolic phenotypes. Molecular docking analyses identified favorable binding with SGLT2 and additional cardiometabolic and inflammatory targets, including NHE1, AMPK, NLRP3, IKKβ, IL-6Rα, and PPAR isoforms, suggesting modulation of myocardial ion homeostasis, metabolic resilience, and inflammatory signaling. PPI analysis identified eight hub proteins (AKT1, MTOR, STAT3, EGFR, PIK3CA, SRC, MAPK1, and MAPK3) significantly enriched in PI3K/AKT, MAPK/ERK, and ErbB signaling pathways. Conclusions: Chronic SGLT2 inhibitor therapy was independently associated with reduced postoperative rehospitalization and cumulative event burden in T2DM patients undergoing cardiac surgery. Integrated in silico analyses offer mechanistic hypotheses consistent with the observed clinical associations. These findings suggest that structured perioperative SGLT2 inhibitor management may contribute to improved postoperative outcomes, while prospective validation in future studies would strengthen these findings. However, given the retrospective observational design, these findings should be interpreted as associative rather than causal.