SGLT2 Inhibitors in Fontan Circulation: Bridging the Evidence Gap Between Adult Heart Failure Data and Single-Ventricle Physiology

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have transformed the management of heart failure in adults and are now used empirically in children with Fontan-palliated single-ventricle circulation, despite an absence of trials in this population. Early observational data suggest that SGLT2 inhibitors are well tolerated in Fontan circulatory failure, with signals of reduced natriuretic peptide levels and modest improvement in ventricular function, but no study has been designed or powered to establish efficacy. This gap is compounded by a physiological mismatch: the Fontan circulation is characterized by the absence of a subpulmonary pumping chamber, resulting in passive pulmonary blood flow. Under these unique hemodynamic conditions, systemic ventricular preload is primarily determined by pulmonary vascular resistance, ventricular diastolic properties, and atrial filling pressures. These distinctive physiological characteristics may have important implications for the mechanisms underlying the effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors. Notably, diastolic dysfunction is increasingly recognized as a prevalent feature of Fontan circulatory failure. Given the established clinical benefits of SGLT2 inhibitors in adults with heart failure with preserved ejection fraction, their potential therapeutic effects in the Fontan population may extend beyond conventional preload modulation to include improvements in diastolic function and ventricular filling dynamics. In this Perspective, we examine whether the principal mechanisms of SGLT2 inhibitor benefit described in adults-osmotic diuresis and preload reduction, a myocardial substrate shift toward ketone metabolism, and blockade of the cardiac sodium-hydrogen exchanger-plausibly translate to Fontan physiology, review the available pediatric evidence and its limitations, and outline a framework for a prospective, phenotype-stratified multicenter trial. We argue that current practice has outpaced the evidence specific to this population, and that closing this gap requires a Fontan-specific research agenda rather than continued extrapolation from adult heart failure trials.