SUN-559 Empagliflozin Reduces Monocyte-Platelet Aggregates: A Link to Cardiometabolic Benefits

Abstract Disclosure: B. Safa: None. J. Oakes: None. J.D. Simmons: None. H. Nian: None. L.A. Kirk: None. E. Olson: None. M. Gonzales: None. R.D. Gangula: None. A.C. Cassidy: None. L. Zhu: None. A. Matta: None. S. Bailin: None. C.L. Gabriel: None. C.N. Wanjalla: None. M. Luther: None. J.R. Koethe: None. S.A. Kalams: None. M. Mashayekhi: None. Monocyte-platelet aggregates (MPAs) are increasingly recognized as contributors to inflammation and thrombosis, and are increased in obesity. These aggregates increase inflammation through cytokine and chemokine secretion, contributing to vascular inflammation and the recruitment of leukocytes, linking immune dysregulation to cardiometabolic diseases. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have beneficial effects on cardiometabolic diseases, though the mechanisms are not fully understood. This study tests the hypothesis that the SGLT2 inhibitor empagliflozin reduces inflammation by modulating monocyte-platelet aggregates (MPAs), which is a potential mechanism for the observed cardiometabolic benefits. This pilot study involved eight women with obesity and pre-diabetes as defined by the ADA criteria. Baseline characteristics included mean age of 61±6.1 years, weight of 93±16.9 kg, and BMI of 35.6±4 kg/m2. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, after 2 and 12 weeks of treatment with empagliflozin (25mg/day). Single-cell RNA sequencing was performed to identify and characterize immune cell populations. We used the SCENITH protocol (Single Cell ENergetic metabolism by profilIng Translation inHibition) to define the metabolic profile of MPAs using PBMCs from healthy controls. Metabolic difference was tested using paired t-test. Empagliflozin significantly reduced MPAs at 2 weeks (-2.88% ± 2.11, p = 0.018) and 12 weeks (-4.06% ± 2.11, p = 0.002). Pathway enrichment analysis of differentially expressed genes in MPAs revealed heightened signatures of metabolic activity compared to classical monocytes. Metabolic activity using the SCENITH protocol revealed increased fatty acid oxidation capacity in MPAs compared to classical monocytes (3.92% ±1.67, p= 0.002). This study provides the first human evidence that empagliflozin reduces MPAs, mediators of inflammation and thrombosis. We further demonstrate that MPAs have heightened fatty acid oxidation capacity. The ability of empagliflozin to reduce MPAs and modulate their metabolic activity is a mechanism that may contribute to its cardiometabolic benefits. A randomized controlled trial to explore the broader mechanistic effects of empagliflozin on immune function and metabolism is ongoing. Presentation: Sunday, July 13, 2025