Aims: High myocardial stiffness in heart failure with preserved ejection fraction (HFpEF) is attributed to comorbidity-induced structural and functional remodelling through inflammation and oxidative stress affecting coronary microvascular endothelial cells and cardiomyocytes, which augments interstitial fibrosis and cardiomyocyte stiffness. In murine and human HFpEF myocardium, sodium glucose co-transporter 2 (SGLT2) inhibition ameliorates cardiac microvascular endothelial cell and cardiomyocyte oxidative stress, while enhancing myocardial protein kinase G activity and lowering titin-based cardiomyocyte stiffness. Failure of previous HFpEF outcome trials refocuses attention to improving pathophysiological insight and trial design with better phenotyping of patients and matching of therapeutic targets to prevailing pathogenetic mechanisms. SGLT2 inhibition could represent a viable therapeutic option especially in HFpEF patients in whom high diastolic left ventricular (LV) stiffness is predominantly caused by elevated cardiomyocyte stiffness and associated endothelial dysfunction, whereas HFpEF patients with extensive myocardial fibrosis might be less responsive. This study aims to investigate a stratified treatment approach, using dapagliflozin in heart failure patients with preserved ejection fraction without evidence of significant myocardial fibrosis. Methods and results: The Stratified Treatment to Ameliorate DIAstolic left ventricular stiffness in early Heart Failure with preserved Ejection Fraction (STADIA-HFpEF) is a Phase II, randomized, 2 × 2 crossover trial, evaluating the efficacy of 13 weeks of treatment with dapagliflozin 10 mg od in 26 patients with HFpEF, with normal cardiac magnetic resonance imaging-derived extracellular volume. The co-primary endpoint is echocardiographically derived change in E/e'/LV end-diastolic volume index and change in mean LV e'. Conclusions: The STADIA-HFpEF trial will be the first study to evaluate the direct effects of dapagliflozin on amelioration of LV stiffness, using histological phenotyping to discern early HFpEF.