ESC Congress 2026 Abstract · Oct 26, 2026
Combined SGLT2 inhibition and GLP-1 receptor agonism synergistically reduce rejection-associated oxidative stress in cardiac allografts of heart transplant recipients
By Gong D, Mroueh A, Fakih W et al.
Background: Cardiac allograft rejection is characterized by immune activation, oxidative injury, endothelial dysfunction, and progressive adverse remodeling. While SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1Ra) confer cardiometabolic protection in clinical trials, a potential protective role in cardiac allografts remains undefined. Purpose: Characterize cardiac SGLT2 (SLC5A2) and GLP-1R (GLP1R) pattern of expression across different allograft rejection grades and evaluate ex vivo the effects of combined SGLT2i and GLP-1Ra. Methods: The cohort comprised 100 heart transplant recipients (median age 58 years [53–66], 71% male) with substantial cardiometabolic burden, including hypertension (49%), dyslipidemia (56%), diabetes (29%), and median BMI 27.0 kg/m² [23.5–30.8]. Endomyocardial biopsies were classified as Grade 0, Quilty lesions, cellular rejection (CMR), or antibody-mediated rejection (pAMR) based on conventional histological assessment. Gene expression (RT-qPCR), reactive oxygen species (ROS) formation (dihydroethidium staining), and ex vivo pharmacological modulation with SGLT2i empagliflozin and GLP-1Ra semaglutide at different concentrations as well as a potential synergy were assessed. Results: Compared with Grade 0 biopsies, samples classified as CMR and pAMR exhibited significantly higher expression of pro-inflammatory cytokines (IL1B, IL6, TNFA), pro-inflammatory macrophage marker (CD68, CD86), RAAS-related genes (AT1R, NR3C2), NADPH oxidase subunits (CYBA, CYBB), endothelial adhesion molecules (ICAM1, VCAM1), and remodeling and fibrosis mediators (MMP2, MMP9, TGFB1), SLC5A2 (SGLT2) and GLP1R (GLP-1R) alongside reduced NOS3 (eNOS) expression. Interestingly, SLC5A2 and GLP1R expression correlated positively and robustly with TNFA (r² = 0.9619 and 0.9330, respectively; both P < 0.0001) and CD86 (r² = 0.9243 and 0.9575, respectively; both P < 0.0001). Similarly, ROS levels were approximately 4-fold higher in CMR and 6-fold higher in pAMR compared with Grade 0 biopsies and showed strong positive correlations with TNFA, CD86, SLC5A2, and GLP1R (all P < 0.0001). On the other hand, in CMR and pAMR biopsies, ROS levels were significantly reduced by 100 nM of either empagliflozin (-49.3 %) or semaglutide (-46.4%), whereas each compound alone at 10 nM was without effect. Notably, combining both empagliflozin and semaglutide at 10 nM each produced synergistic suppression of oxidative stress beyond single-agent treatment reaching 68.5% reduction. Conclusion: Cardiac allograft rejection is characterized by coordinated inflammatory, pro-oxidant, pro-fibrotic and pro-remodeling activation tightly associated with SGLT2 and GLP-1R expression. Combined SGLT2i and GLP-1Ra exert synergistic antioxidant effects, highlighting a potential adjunctive strategy to attenuate inflammatory injury in transplanted hearts.