Effect of Sodium-Glucose Cotransporter-2 Inhibitors on the Progression of Aortic Stenosis

BACKGROUND Aortic stenosis (AS) is the leading cause of valvular heart disease-related morbidity and mortality, but there are no medical treatments to slow its progression. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have pleiotropic effects which could be disease modifying in AS. OBJECTIVES The purpose of this study was to determine if SGLT2i usage is associated with slower progression of AS. METHODS A target trial emulation comparing the effect of the initiation of SGLT2i compared with no SGLT2i in patients with nonsevere AS was performed using retrospective electronic medical record data from the Yale New Haven Health System from January 2016 to September 2022. Patients with native aortic valve sclerosis or nonsevere AS with at least 12 months of echocardiographic follow-up were included. Patients were excluded if they had an estimated glomerular filtration rate <30 mL/min/1.73 m2 or had initiated SGLT2i >1 year before the index echocardiogram. The prespecified primary outcome was progression to severe AS. RESULTS A total of 458 patients prescribed SGLT2i and 11,240 patients never prescribed SGLT2i were included. Patients were on SGLT2i for a median of 0.9 years. Patients on SGLT2i were younger and had higher rates of diabetes and chronic kidney disease. Patients on SGLT2i were more likely to have ejection fraction <= 40%. There were no differences between groups in baseline AS severity (66% sclerosis, 23% mild stenosis, and 11% moderate in overall cohort). Patients ever prescribed SGLT2i were less likely to progress to severe AS (HR: 0.61; 95% CI: 0.39-0.94; P 1/4 0.03) with a progressively lower risk among patients on SGLT2i for >3, 6, and 12 months (HR: 0.54, 0.48, and 0.27, respectively). CONCLUSIONS This retrospective, multicenter, observational study suggests that SGLT2i may slow the progression of nonsevere AS. (JACC Cardiovasc Interv. 2025;18:738-748) (c) 2025 by the American College of Cardiology Foundation.