SGLT2 Inhibition in the Fontan Population: A New Dawn for the Single Ventricle

Addressing the Clinical Dilemma of Fontan Circulation: Few innovations in modern cardiac surgery have had as profound and transformative an impact on the management of congenital heart disease as the Fontan procedure. It has converted what was once a uniformly fatal form of single-ventricle heart disease into a chronic condition compatible with long-term survival [1,2]. However, for clinicians working at the interface of pediatric and adult congenital cardiology, Fontan completion does not represent the end of treatment—it marks the beginning of a lifelong physiological journey. This journey is increasingly characterized by Fontan failure, a multisystem syndrome driven by chronic venous congestion, reduced cardiac output, and progressive end-organ dysfunction [3,4]. Historically, the pharmacological management of Fontan failure has been challenging. For decades, clinicians have attempted to apply the traditional "four pillars" of heart failure therapy, developed for patients with biventricular circulation, to those with Fontan physiology. Unfortunately, these therapies have generally failed to produce meaningful improvements in mortality, exercise capacity, or quality of life [2]. Angiotensin-converting enzyme (ACE) inhibitors and beta-blockers have demonstrated only limited clinical benefit because they do not address the unique hemodynamic characteristics of the Fontan circulation [3]. Physiological Challenges: The Fontan circulation is fundamentally different from normal cardiovascular physiology because it lacks a subpulmonary ventricle. Pulmonary blood flow is entirely passive and depends on elevated central venous pressure to drive blood through the pulmonary vascular bed [3]. Consequently, conventional heart failure therapies that reduce preload may inadvertently compromise pulmonary blood flow and systemic cardiac output. This unique physiology has created a substantial therapeutic gap for the growing population of adults with congenital heart disease, who continue to lack pharmacological therapies capable of improving systemic outcomes without destabilizing Fontan hemodynamics [3,4]. A New Therapeutic Horizon: SGLT2 Inhibitors: Sodium-glucose cotransporter-2 (SGLT2) inhibitors were originally developed as glucose-lowering agents for patients with type 2 diabetes mellitus. However, they have rapidly emerged as a cornerstone of therapy for patients with heart failure across the spectrum of left ventricular ejection fraction because of their cardiovascular and renal protective effects [5,6]. Their potential application in adults with congenital heart disease represents an exciting new frontier. A landmark multicenter study by Neijenhuis et al., published in the Journal of the American College of Cardiology in 2024, entitled "Effects of Sodium-Glucose Cotransporter-2 Inhibitors in Adults with Congenital Heart Disease," provides some of the earliest and most comprehensive evidence regarding the safety and efficacy of these agents in this unique population [7]. The study evaluated 174 adults with congenital heart disease, including patients with complex univentricular physiology. Importantly, treatment with SGLT2 inhibitors was associated with a significant reduction in heart failure hospitalizations over a six-month follow-up period. Equally encouraging was the favorable safety profile, with minimal incidences of symptomatic hypotension or clinically significant renal dysfunction—complications that frequently limit the use of conventional heart failure therapies in Fontan patients [7]. Early Clinical Evidence in Adult Congenital Heart Disease: The multicenter cohort by Neijenhuis et al. may represent an important turning point in the management of adult congenital heart disease [7]. Among 174 adults, the majority receiving SGLT2 inhibitors for symptomatic heart failure, treatment was associated with an approximately threefold reduction in heart failure hospitalization during the six months following treatment initiation compared with the preceding six months (rate ratio 0.30; 95% CI 0.14–0.62) [7]. Mortality remained low (2.3%) and none of the reported deaths were attributed to SGLT2 inhibitor therapy [7]. These findings suggest that SGLT2 inhibitors function not merely as antidiabetic agents but as clinically meaningful modulators of cardiovascular physiology. For Fontan patients, whose circulation depends upon a delicate balance between central venous pressure, pulmonary blood flow, and systemic cardiac output, these observations are particularly relevant [7]. Changes in Ventricular Function: Additional evidence supporting SGLT2 inhibitor therapy has emerged from smaller observational studies focusing on systemic right ventricular and single-ventricle failure. In a cohort of ten patients with systemic right ventricular dysfunction treated with dapagliflozin, median NT-proBNP concentrations decreased substantially over six months (736.6 to 531.6 ng/L), while approximately half of the patients experienced improvement in New York Heart Association (NYHA) functional class [8]. Similarly, short-term imaging studies have demonstrated early improvements in ventricular performance. Significant enhancements in global longitudinal strain, tricuspid annular plane systolic excursion (TAPSE), and fractional area change have been reported within 50 days in patients with systemic right ventricular failure. In patients with single-ventricle physiology, improvements in end-systolic area, fractional area change, free-wall strain, and isovolumic acceleration have been observed within approximately 100 days of therapy, particularly among individuals with reduced ventricular systolic function [9,10]. Safety and Tolerability: Safety remains a critical consideration in patients with complex congenital heart disease. In the multicenter ACHD cohort, adverse events were reported in approximately 10% of patients, while only 6.9% discontinued treatment because of side effects [7]. Importantly, the few deaths