Efficacy and Safety of Sodium-Glucose Cotransporter-2 Inhibitors for Heart Failure in Children and Adolescents: A Single-Arm and Pairwise Systematic Review and Meta-Analysis with GRADE Assessment of the Evidence

Abstract: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a cornerstone of adult heart failure (HF) therapy and are increasingly prescribed off-label to children, yet pediatric outcomes have never been pooled. We searched PubMed/MEDLINE, Embase, Scopus, and Web of Science to 14 August 2026 for studies of any SGLT2 inhibitor in children or adolescents with HF and performed a single-arm meta-analysis of all exposed patients and a pairwise meta-analysis of the comparative studies with random-effects models. Nine studies contributed 599 exposed patients and 97 controls. Pooled rates were 3.8% (95% confidence interval [CI] 1.6–8.4) for mortality, 8.5% (6.2–11.5) for transplantation, 11.2% (8.2–15.1) for worsening HF, 0.2% (0.03–1.6) for ketoacidosis, 4.5% (1.2–14.9) for acute kidney injury, 3.7% (1.1–11.7) for urinary tract infection, and 4.1% (1.4–11.2) for discontinuation because of an adverse event. After initiation, left ventricular ejection fraction rose by 7.7 percentage points (3.6–11.8) and natriuretic peptide fell by 0.42 standard deviations (0.34–0.49). In the comparative synthesis (63 exposed, 97 unexposed), risk ratios were 0.80 (0.11–6.07) for mortality and 0.21 (0.03–1.68) for worsening HF; ejection fraction improved 3.34 percentage points more with SGLT2 inhibitors (0.22–6.46) whereas natriuretic peptide did not differ (standardized mean difference −0.09, −0.50 to 0.33).