Dapagliflozin in phenotypically stratified HFpEF without myocardial fibrosis: the STADIA-HFpEF randomized crossover trial

AIMS: Heart failure with preserved ejection fraction(HFpEF) is characterized by increased diastolic left ventricular(LV) stiffness resulting from variable contributions of myocardial extracellular matrix(ECM) remodeling and titin-based cardiomyocyte stiffness. Sodium-glucose cotransporter-2 inhibitors(SGLT2i) improved cardiomyocyte distensibility, inflammation, and oxidative stress in experimental and human HFpEF myocardium. We investigated whether dapagliflozin improves LV distensibility in phenotypically stratified HFpEF patients without significant myocardial fibrosis. METHODS: STADIA-HFpEF was a 34-week, randomized, double-blind, placebo-controlled crossover trial. HFpEF patients underwent multi-level phenotypic stratification including cardiac magnetic resonance imaging to exclude structural cardiomyopathies and significant myocardial ECM remodeling. Participants were randomized to dapagliflozin 10 mg or placebo for two 13-week treatment periods separated by an 8-week washout.The co-primary endpoints were changes in E/e'/LV end-diastolic volume index(LVEDVi) and mean LV e', reflecting LV distensibility and relaxation. Secondary endpoints included echocardiographic variables, quality of life, 6-minute walk distance, and inflammatory biomarkers. RESULTS: Between February 2020 and October 2022, 32 patients were randomized and 29 completed the study protocol. Median age was 73(68-76) years including 28 women(88%). Dapagliflozin did not significantly modify E/e'/LVEDVi compared with placebo 0.24 (0.20-0.32) to 0.26 (0.22-0.34) vs. 0.23 (0.22-0.29) to 0.25 (0.21-0.31); p=0.370 nor did it change mean LV e' 6.2 (5.6-7.5) to 6.2 (5.7-7.1) vs. 6.6 (5.6-7.4) to 6.7 (5.4-7.5); p=0.448. Most secondary outcomes were neutral. However, an isolated improvement in LA conduit strain and numerical reductions in inflammatory biomarkers were observed during dapagliflozin treatment. CONCLUSIONS: In phenotypically stratified HFpEF patients without significant myocardial fibrosis, dapagliflozin did not improve LV distensibility or relaxation. An isolated improvement in LA conduit strain and numerical reductions in inflammatory biomarkers were observed; however, these exploratory findings require confirmation in larger studies.