Targeting Metabolic Dysfunction and Inflammation with Sotagliflozin Reverses Diastolic Dysfunction in Experimental HFpEF

Background: Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent and strongly associated with cardiometabolic comorbidities including obesity, hypertension, and metabolic dysfunction. While SGLT2 inhibitors have demonstrated clinical benefits in HFpEF, the mechanisms underlying dual SGLT1/2 inhibition remain incompletely understood. Methods: We utilized a murine model of cardiometabolic HFpEF induced by high-fat diet combined with L-NAME administration. Following disease establishment, mice received sotagliflozin (30 mg/kg) or vehicle for 10 weeks. Comprehensive assessments included echocardiography, indirect calorimetry, cardiac metabolomics, bulk RNA sequencing with cell-type deconvolution, and high-dimensional immune profiling by flow cytometry and CyTOF. Results: Sotagliflozin significantly attenuated weight gain and improved glucose tolerance without normalizing blood pressure. Metabolic cage analyses revealed a sustained reduction in respiratory exchange ratio, indicating enhanced fatty acid oxidation, corroborated by elevated cardiac acylcarnitine intermediates including palmitoylcarnitine and dodecanoylcarnitine. Echocardiography demonstrated that sotagliflozin protected against diastolic dysfunction, normalizing isovolumic relaxation time and E/e' ratio while reducing left ventricular mass and myocardial fibrosis. Transcriptomic profiling revealed upregulation of mitochondrial fatty acid β-oxidation pathways and suppression of inflammatory signaling cascades including IL-1 processing and TLR pathways. Flow cytometric analysis demonstrated reduced cardiac infiltration of neutrophils, CCR2+ inflammatory monocytes/macrophages, and IL-1β-expressing immune cells. Splenic immune cell expansion characteristic of systemic inflammation was similarly attenuated. Conclusions: Dual SGLT1/2 inhibition with sotagliflozin exerts coordinated cardiometabolic benefits in experimental HFpEF through metabolic reprogramming toward enhanced lipid utilization and suppression of cardiac and systemic inflammation. These findings establish that sotagliflozin targets the intertwined metabolic-inflammatory axis central to HFpEF pathogenesis, providing mechanistic insight into the therapeutic efficacy of dual SGLT inhibition in cardiometabolic heart failure.