New hope for young hearts: A systematic review of sodium glucose cotransporter 2 inhibitors in pediatric heart failure

Abstract

Current management of pediatric heart failure (HF) remains challenging. The emergence of sodium glucose cotransporter 2 inhibitors (SGLT2i) offers potential benefits beyond their traditional use in diabetes care. This review aims to provide a comprehensive perspective on the potential of SGLT2i to address pediatric HF. A literature search was conducted across PubMed/MedLine, Scopus, Cochrane Library, and gray literature repositories. This review included studies on SGLT2i use in pediatric HF, focusing on patients aged 18 or younger. The quality of the studies was independently assessed by four reviewers, with discrepancies resolved by consensus. A narrative synthesis was conducted to evaluate the clinical outcomes reported across the included studies. The protocol was registered in the Prospective Register of Systematic Reviews (CRD420251051396). Five studies were included in the analysis. Studies have reported an increase in ejection fractions and a decrease in natriuretic peptide levels following treatment with SGLT2i. Echocardiographic findings generally suggested a positive impact on the severity of ventricular dilation and atrioventricular valve regurgitation. There were no significant changes in the hemodynamic status, liver function, blood glucose, and electrolyte levels; however, we observed a notable decrease in glomerular filtration rate, an increase in serum creatinine, an elevated risk of acute kidney injury, protein-losing enteropathy, persistent abdominal pain, and urinary tract infection. SGLT2i offers therapeutic promise in pediatric HF with an acceptable safety failure. Preliminary data support further investigations to guide clinical adoption.

INTRODUCTION

Pediatric heart failure (HF) has only a few established treatment options, and current management is largely based on adult data due to its rarity and etiological variability in children.[1,2] Sodium-glucose cotransporter 2 inhibitors (SGLT2i), originally developed for managing type 2 diabetes, have shown significant cardiovascular benefits in adults with HF, including reduced mortality and enhanced cardiac performance.[3,4,5,6,7] Early pediatric data suggest comparable advantages with favorable tolerability.[8,9,10,11,12] This systematic review aims to evaluate the efficacy and safety of SGLT2i in pediatric HF.

METHODS

Protocol approval

This systematic review was conducted following the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement.[13] Institutional review board approval was deemed unnecessary as the study involved secondary analysis of data available from electronic databases. The protocol has been registered in the International Prospective Register of Systematic Reviews (CRD420251051396).

Search strategy, sources, and study selection

A comprehensive literature search was conducted across multiple databases, including PubMed/Medline, Scopus, Cochrane Library, and gray literature repositories such as Google Scholar, WorldCat, and clinical trial registries. Articles published from January 1, 2015 to June 10, 2025 were included in the search. Search terms incorporated combinations of keywords and MeSH terms, including (“SGLT2 inhibitors” OR “sodium-glucose cotransporter 2 inhibitors” OR “empagliflozin” OR “dapagliflozin”) AND (“pediatric heart failure” OR “child heart failure” OR “juvenile heart failure”). No restrictions were applied to the publication date or language.

The search process was carried out independently by three reviewers (GM, FJ, and NA), who screened articles for eligibility based on predefined criteria. Duplicate articles were removed, and the remaining articles were evaluated through title and abstract screening. Full-text articles that met the inclusion criteria underwent a detailed assessment. Discrepancies during study selection were resolved through consensus, with arbitration by a fourth reviewer (IH). Reasons for excluding studies were documented, and the selection process was summarized in a PRISMA flow diagram [Figure 1].

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-analyses flow diagram. The diagram provided an overview of the search strategy and selection process used to identify articles suitable for inclusion in this systematic review

This review included randomized and non-randomized controlled trials as well as observational studies that examined the use of SGLT2i in pediatric HF. Studies were excluded if they were classified as reviews, commentary articles, or book sections. Eligible studies were required to focus on patients aged 18 years or younger, regardless of race, socioeconomic status, religion, geographic location, or underlying health conditions. Studies had to report outcomes related to cardiac function, changes in biomarker (e.g., natriuretic peptides) levels, hospitalization rates, length of stay, and treatment-related adverse events. Comparisons of interest, if any, included SGLT2i versus placebo or other standard treatments for pediatric HF.

Data extraction

Three independent reviewers (GM, FJ, and NA) performed data extraction using a standardized form. Extracted data included: (1) study title and first author; (2) year of publication; (3) geographical region; (4) study design and methodology; (5) sample size and baseline characteristics of participants; (6) Intervention details, including type and dosage of SGLT2i; (7) outcomes of interest, including changes in biomarkers, cardiac function, and clinical endpoints. Disagreements in data extraction were resolved by discussion, with adjudication by a fourth reviewer (IH).

Risk of bias assessment

The quality of included studies was evaluated using the Cochrane Risk of Bias tool for randomized controlled trials, the Newcastle–Ottawa Scale for observational studies, and the Critical Appraisal Skills Programme for case series. Assessments were performed independently by four reviewers (GM, FJ, NA, and IH), with discrepancies resolved by consensus.

Data synthesis

A narrative synthesis was employed to integrate and interpret the findings systematically. This method enabled a comprehensive evaluation of the role of SGLT2i in pediatric HF while accounting for the diverse methodologies and patient populations studied. The results were organized thematically, with a primary focus on clinical efficacy and safety. Findings were presented using descriptive summaries and tabular formats to facilitate comparisons of study characteristics and outcomes. Tables outlined key details for each study, including sample sizes, interventions, and reported results, facilitating a clear understanding of trends across the literature. Accompanying narrative descriptions provided context, offering insights into the broader implications of the data.

RESULTS

Search results

The systematic review identified 145 records through database searches. After removing 25 duplicates, 120 unique records underwent title and abstract screening, resulting in the exclusion of 110 records as irrelevant. Ultimately, 5 studies met the inclusion criteria and were included in the qualitative synthesis [Figure 1].[8,9,10,11,12]

Characteristics of included studies

The use of SGLT2i shows potential in treating adult HF by lowering mortality risk, though its role in pediatric and adolescent cases remains understudied. Current evidence suggests that SGLT2i treatment is predominantly used in male patients, with a median age across studies ranging from 12 to 14 years. The studies were mostly from the United States and reported multiple cardiac diagnoses, including cardiomyopathy, valvular disease, and single-ventricle physiology (with or without Fontan circulation). The severity of HF was stratified based on New York Heart Association functional class stages I-IV.

Before SGLT2i intervention, patients commonly received treatments such as sacubitril/valsartan, beta-blockers, mineralocorticoid antagonists, loop and thiazide diuretics, angiotensin-converting enzyme inhibitors, and other standard therapies. Dapagliflozin was more widely used, typically at a dose of 0.1–0.2 mg/kg/day, up to 10 mg once daily. The median follow-up time across studies varied from 130 days to 9 years. In one case series, the shortest follow-up period was 1 month, while the longest reached 9 months.[12] Table 1 provides detailed characteristics of the included studies.

Table 1.

Characteristics of included studies

First author, publication year		Region		Study design		Groups		Age		Gender (%)		LVEF		NYHA grading		Cardiac diagnosis		Follow-up time		Intervention
Newland et al., 2023[8]		USA		Single-center retrospective study		Dapagliflozin (38)		Median 12.2 (IQR 6.2–17.5) (range 0.27–20.2)		Male (50)		Median baseline: 32% (IQR: 25.75%–36.12%)		NYHA II-IV		Dilated cardiomyopathy (68.4%) and reduced LVEF≤40% (65.8%), 4 cases of diastolic heart failure, and 7 single ventricle		Median: 130 days (IQR: 76–332)		Dapagliflozin 0.1–0.2 mg/kg/day (max 10 mg daily) added to standard heart failure therapy
Newland et al., 2024[9]		USA		Matched case-control study		Dafagliflozin (22)		Median 13.8 (range 0.36–20.7)		Male (50)		NA		NYHA II-IV		Cardiomyopathy (10), fontan failure (9), congenital heart disease (3)		2014–2023		Dapagliflozin 0.17 mg/kg/day before heart transplant (IQR 0.13–0.20)
						Control (44)				Male (55)						Cardiomyopathy (20), fontan failure (18), congenital heart disease (6)
Konduri et al., 2023[10]		USA		Single-center retrospective study		Dapagliflozin (13) or Empagliflozin (1)		Median 14.5 (range 2.0–26.4)		Male (57.1)		50% had FCF with reduced EF, the other half with preserved EF		NYHA I-III		Fontan circulation with systemic ventricle dysfunction		Median: 4.1 months (range: 13 days-7.7 months)		Dapagliflozin/empagliflozin 10 mg once daily for patients ≥50 mg, and 0.1–0.2 mg/kg/day for patients <50 kg
Butts et al.,2024[11]		USA		Multicenter retrospective study		Dapagliflozin (86) or empagliflozin (18)		Baseline median 16.3 (range 11.4–19.3), Follow-up median 16.5 (range 12.5–18.9)		Male (64)		Median baseline: 36% (26.0–42.0), Median follow-up: 37.2% (28.0–49.0)		NA		Dilated cardiomyopathy (31), other cardiomyopathy (11), single ventricle congenital heart disease-Fontan (30), single ventricle congenital heart disease- nonfontan (4), congenital heart disease biventricular circulation (18)		Median: 203.5 days (IQR: 86.3–415.3)		Dapagliflozin was administered to 86 patients, and empagliflozin was given to 18 patients. However, there is no data regarding the dosage
Kurkiewicz-Sawczak et al., 2024[12]		Poland		Case series		Dapagliflozin		P1: 6		Male (100)		P1: 23%		P1: NYHA III/IV		P1: Dilated cardiomyopathy, supravalvular aortic stenosis, obstructed left coronary artery trunk, ventricular arrhythmias, pulmonary hypertension		P1: 1 month		Dapagliflozin was administered to all patients, though the dosage was not specified in this case report
								P2: 17				P2: 29.%		P2: NYHA III/IV		P2: Aortic stenosis, after balloon aortic valvuloplasty (2006), bioprosthetic aortic valve replacement (2022), aortic valve prosthesis dislocation and replacement to mechanical valve prosthesis (2022), two mechanical prosthesis repair surgeries (April 2023, May 2023), third-degree atrioventricular block		P2: 9 months
								P3: 13				P3: 60%		P3: NYHA II/III		P3: Hypertrophic cardiomyopathy		P3: 5 months
								P4: 17				P4: 30%		P4: NYHA II/III		P4: Pulmonary artery atresia with ventricular septal defect, after biventricular repair with xenograft (May 2007), with pulmonary graft stenosis, occluded left pulmonary artery		P4: 1 month

IQR: Interquartile range, LVEF: Left ventricular ejection fraction, NA: Not applicable, NYHA: New York Heart Association, FCF: Fontan circulatory failure

Most of the studies included in this review had good quality. One study raised some concerns regarding the applicability in a general population due to the highly specific study subjects.[12] The risk of bias assessment is presented in Supplementary Tables 1 and 2.

Supplementary Table 1.

Quality assessment of included observational studies

Studies		Selection		Comparability		Outcome		Judgment
Newland et al., 2023[8]		★★★		★★		★★		Good
Newland et al., 2024[9]		★★★★		★★		★★★		Good
Konduri et al., 2023[10]		★★★		★		★★		Good
Butts et al., 2024[11]		★★★		★★		★★		Good

The study is rated either as “good” (3 or 4 points in selection, 1 or 2 points in comparability, and 2 or 3 points in outcomes), “fair” (2 points in selection, 1 or 2 points in comparability, and 2 or 3 points in outcomes) or “poor” (0 or 1 point(s) in selection, or 0 point in comparability, or 0 or 1 point(s) in outcomes)

Supplementary Table 2.

Quality assessment of included case series

Studies		Validity		Outcome reporting		Applicability
Kurkiewicz-Sawczak et al., 2024[12]		Clear objective Importance of the study clearly addressed		Sufficient data to support the findings Ethical issue properly addressed		Added value to current knowledge Limitations to be addressed in future trials

Efficacy of sodium glucose cotransporter 2 inhibitors for pediatric heart failure

Across studies, increases in ejection fraction (EF) were observed, highlighting improved cardiac function. Newland et al. reported that treatment with SGLT2i showed an improvement in EF from 32% to 37.2% (P = 0.006) among subjects with moderate-to-severe left ventricular (LV) dysfunction.[8] Similarly, Kurkiewicz-Sawczak et al. observed a marked improvement in patients with severe LV dysfunction, with a shift to normal-to-mild dysfunction (EF >40%) following treatment with SGLT2i.[12] Another study on a patient with Fontan circulation and HF with reduced EF (HFrEF) showed improved outcomes with the addition of dapagliflozin to the standard HF therapies, including spironolactone, sacubitril/valsartan, and metoprolol succinate. After 1 year, this patient has demonstrated a significant decrease in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and Fontan pressures, as well as improvements in cardiac index, systolic function, and tricuspid regurgitation, which have avoided the need for further hospitalizations.[10]

Treatment with SGLT2i has been associated with reductions in brain natriuretic peptide (BNP) levels, ranging from 25.22% to 64%, alongside a 40.4% decrease in NT-proBNP.[8,10] In addition, NT-proBNP levels declined in three out of four patients in a study by Kurkiewicz-Sawczak et al.[12] Echocardiographic results further support these findings. Before SGLT2i therapy, 33.3% of patients had moderate ventricular dilation, and 22.2% had severe dilation. Posttherapy, severe dilation decreased to 11.1%, whereas mild dilation increased to 33.3%. For atrioventricular (AV) valve regurgitation, mild cases increased from 44.4% to 55.6%, and moderate cases decreased to 0%, although moderate-to-severe regurgitation rose to 33.3%.[10] These mixed changes underscore the therapy’s generally positive effect on cardiac function, despite some variability in the results, as also shown in the study by Butts et al., which showed only a slight increase in EF (from 36% to 37.2%) and a minimal decrease in BNP levels.[11] The length of stay was not significantly different between patients receiving dapagliflozin and those in the control group.[9] Three studies reported rehospitalization rates ranging from 7.14% to 13.1%, with all cases attributed to HF.[8,10,11] The summary of the findings is presented in Supplementary Table 3.

Supplementary Table 3.

Summary of evidence - efficacy of sodium glucose cotransporter 2 inhibitors for pediatric heart failure

First author, publication year		Sample size		Groups		Efficacy
						EF		Natriuretic peptides		Echocardiography		Length of stay		Rehospitalization
Newland et al., 2023[8]		38		Dapagliflozin		LVEF increased significantly from 32% to 37.2% (P=0.006)		Median BNP decreased from 222 pg/mL to 166 pg/mL (P=0.04)		NA		NA		13.1% (5 patients) rehospitalized for heart failure after starting dapagliflozin
Newland et al., 2024[9]		66		Given dafagliflozin (22)		NA		NA		NA		Days spent in the cardiac ICU after heart transplant: 7, days from heart transplant to hospital discharge: 18		NA
				Not-given dapagliflozin/control (44)				NA				Days spent in the cardiac ICU after heart transplant: 7, Days from heart transplant to hospital discharge: 18
Konduri et al., 2023[10]		14		Dapagliflozin (13) or empagliflozin (1)		Before SGLT2i therapy, 22.2% of patients had normal/low normal LVEF, while 33.3% had moderate to severely depressed LVEF, and 11.1% had severely depressed LVEF. After therapy, normal/low normal LVEF increased to 33.3%, mild to moderately depressed LVEF dropped to 0%, and moderate to severely depressed LVEF decreased to 22.2%. Severely depressed LVEF remained at 11.1%		Four out of five patients had significantly reduced natriuretic peptide levels after SGLT2i treatment. (BNP: 214±245 pg/mL versus. 76.5±66.5 pg/mL) (proBNP: 1666±1428 pg/mL versus. 993±752 pg/mL)		Ventricular dilation: Pre-SGLT2i, 33.3% of patients had moderate dilation, and 22.2% had severe dilation. Posttherapy, severe dilation decreased to 11.1%, while mild dilation increased to 33.3%, showing some improvement		NA		One patient was readmitted for heart failure 6.7 months after starting treatment
										AV valve regurgitation: pre-SGLT2i, 44.4% of patients had mild regurgitation, and 22.2% had moderate regurgitation. Posttherapy, mild regurgitation increased to 55.6%, while moderate regurgitation dropped to 0%. However, moderate-severe regurgitation rose to 33.3%
Butts et al., 2024[11]		104		Dapagliflozin (86) or empagliflozin (18)		EF increased slightly from 36% (26.0–42.0) to 37.2% (28.0–49.0)		There was a decrease in BNP levels, from an initial value of 90.4 (32.9–231.7) at baseline to 87.6 (37.0–167.7)		NA		NA		11 patients were hospitalized due to heart failure
Kurkiewicz-Sawczak et al., 2024[12]		4		Dapagliflozin		P1: LVEF improved to 28–29% from 23%		P1: Increased in NT-proBNP from 28,713 pg/mL to 32,043 pg/mL		NA		NA		NA
						P2: LVEF improved from 29% to 50–54% within 9 months		P2: There was a significant decrease of NT-proBNP, with levels dropping from 3,084.6 pg/mL to 441.2 pg/mL		NA		NA		NA
						P3: There was no improvement in LVEF; initially at 60%, it decreased to 50% following treatment		P3: NT-proBNP levels dropped from 26,328.2 pg/mL to 23,066.6 pg/mL		NA		NA		NA
						P4: LVEF increased from 30%–46%		P4: NT-proBNP showed a significant decrease from 972.0 pg/mL to 647.9 pg/mL		NA		NA		NA

LVEF: Left ventricular ejection fraction, NA: Not applicable, NT-proBNP: N-Terminal Pro-B-type natriuretic peptide, EF: Ejection fraction

Safety of sodium glucose cotransporter 2 inhibitors for pediatric heart failure

Regarding cardiovascular side effects, blood pressure was assessed in two studies, both of which showed insignificant changes. In the first study, systolic blood pressure increased slightly from 95 mmHg to 96 mmHg, while diastolic blood pressure remained unchanged at 54 mmHg.[8] In the second study, systolic blood pressure rose slightly from 106 to 108 mmHg, and diastolic blood pressure decreased slightly from 64 to 63 mmHg.[10] Newland et al. also reported a side effect of acute decompensated HF requiring LV assist device placement in one out of 38 patients, which occurred after 24 days of dapagliflozin use.[8]

One study found that 21.4% of patients experienced protein-losing enteropathy, while 7.14% reported persistent abdominal pain, which led to the discontinuation of dapagliflozin therapy.[10] Blood glucose, electrolyte levels, and albumin were assessed as metabolic parameters across three studies, yielding insignificant changes. One study reported a 3.1% decrease in blood glucose, while hemoglobin A1c showed a slight 1.1% increase.[8] In contrast, Konduri et al. indicated a nonsignificant 0.2% increase in glucose levels.[10] Notably, two out of 22 patients (9%) in the dapagliflozin group and four out of 44 patients (9%) in the control group experienced hypoglycemia.[9] Electrolyte measurements (sodium, chloride, potassium, and magnesium) showed clinically insignificant changes across studies.[8,10,11] Similarly, albumin levels remained relatively stable, showing only a 5% increase across two studies.[10,11]

Renal outcomes associated with the use of SGLT2i were evaluated, revealing that blood urea nitrogen levels showed minimal changes compared to baseline, typically fluctuating by only 1 mg/dL or remaining stable after the intervention.[8,10,11] We observed a decline in estimated glomerular filtration rate (eGFR), with values decreasing by approximately 6.8% to 23.9%.[8,10] Furthermore, modest increases in serum creatinine were reported, with values rising by approximately 14.3%–24%.[10,11] In addition, across the studies, acute kidney injury (AKI) was identified as a notable side effect, occurring in three studies with reported cases of 10.5%, 7.14%, and 7.69% patients, respectively.[8,10,11]

The use of SGLT2i was associated with glucosuria (≥1000 mg/dL in 16 out of 22 subjects) and the absence of ketonuria.[9] One study reported that 15.8% of participants experienced urinary tract infections (UTIs) that required antibiotic treatment.[8] In contrast, two other studies reported no cases of UTIs.[9,10] In addition, there was one reported death in the study (2.6%) after 190 days of treatment, with no prior known complications related to dapagliflozin.[8] Notably, no deaths were recorded in the other studies.[9,10,12] The summary of the findings is presented in Supplementary Table 4.

Supplementary Table 4.

Summary of evidence - Safety of sodium glucose cotransporter 2 inhibitors for pediatric heart failure

First author, publication year		Sample size		Groups		Safety
						Cardiovascular		Hematology		Arterial blood gas		Renal		Gastrointestinal		Metabolic		Infection		Death
Newland et al., 2023[8]		38		Dapagliflozin		No significant change in median systolic BP (95 to 96) and diastolic BP (54 to 54), heart rate (91 to 88).		Hemoglobin levels increased from 11.5 mg/dL to 13.3 mg/dL, leading to a corresponding rise in hematocrit from 35.5% to 39.6%.		NA		No significant changes in eGFR from baseline (118) to follow-up (110)		NA		No significant change in blood glucose levels (95.3 to 92.3) and HbA1c (5.28 to 5.24)		6 patients (15.8%) experienced UTI requiring antibiotics		1 patient from cardiac arrest after 190 days without prior known complications from dapagliflozin
						1 Patient experienced acute decompensated HF
												No significant change in BUN (18 mg/dL at baseline to 19 mg/dL in latest followup)				No significant electrolyte imbalances and changes. Sodium (135.8 – > 137.5), Chloride (102.3 – > 102), Potassium (4.29 – > 4.27), Magnesium (2 – > 2.12)
												4 patients experienced AKI
Newland et al., 2024[9]		66		Given dafagliflozin (22)		NA		NA		No significant differences were found in the median arterial blood gas indices (pH, PCO2, and bicarbonate), or peak arterial blood lactic acid levels between dapagliflozin receivers and control groups at any time from POD0 to POD3		91% of dapagliflozin receivers had detectable glucosuria, with 73% showing levels greater than 1000 mg/dL (+3). Urine ketones was absent		NA		Blood glucose nadir: 127 mg/dL. Hypoglycemia (blood glucose <70 mg/dL) was observed in two patients on postoperative day POD 0 and POD1		None had a urine culture with ≥50,000 CFU/mL from a catheter or >100,000 CFU/mL in a clean catch.		None in both groups
				Not-given dapagliflozin/control (44)				NA				No patients was detected with glucosuria and urine ketones				Blood glucose nadir: 123 mg/dL. Three control patients experienced hypoglycemia on POD0, and one control on POD1
Konduri et al., 2023[10]		14		Dapagliflozin (13) or Empagliflozin (1)		There was a slight increase in systolic BP (106±11.8 to 108±13.5) and a small decrease in diastolic BP (64.1±10.9 to 60.3±8.7). No patients with hypotension was found		NA		NA		There was an increase in serum creatinine (0.75±0.35 – >0.93±0.45)		Three patients were found to have protein-losing enteropathy.		There was no signifcant diference in Glucose levels (94.2±29.7 – >94.4±13.3)		There was no genitourinary infections found		None
												Accordingly, there was a reduction in the mean eGFR (113±39.6 – >86.6±26.0)				There was no signifcant diference in electrolyte levels. Sodium (138±3.6 – >139±5.1), Chloride (105±6.1 – >103±5.7)
												There was a slight increase in BUN levels, rising from a baseline of 19.1±8.9–20.1±9.6;		One patient who had baseline abdominal pain that persisted after starting dapaglifozin		Albumin levels showed a slight increase, rising from a baseline of 4.0±0.81–4.2±0.97
												A patient with FCFrEF, PLE, chronic fluid overload, and chronic kidney disease had significant diuresis and AKI				There was no acidosis, hypoglycemia
Butts et al.,2024[11]		104		Dapagliflozin (86) or Empagliflozin (18)		NA		NA		NA		For creatinine, there was a slight increase from a baseline of 0.7–0.8		NA		There was no significant change in sodium levels, which increased from 138.0–138.5		NA		NA
												Meanwhile, cystatin C levels remained unchanged at 1.1 for both baseline and the latest follow-up
												There was no change in the median BUN levels at baseline and the latest follow-up, both remaining at 14.0;				No significant change in albumin (4.0 at baseline to 4.2 in latest followup)
												8 patients experienced AKI
Kurkiewicz-Sawczak et al., 2024[12]		4		Dapagliflozin		NA		NA		NA		NA		NA		NA		No		No
						NA		NA		NA		NA		NA		NA		No		No
						NA		NA		NA		NA		NA		NA		No		No
						NA		NA		NA		NA		NA		NA		No		No

AKI: Acute kidney injury, BP: Blood pressure, BUN: Blood urea nitrogen, eGFR: Estimated glomerular filtration rate, FCFrEF: FONTAN circulatory failure with reduced ejection fraction, HF: Heart failure, NA: Not applicable, PLE: Protein losing enteropathy, UTI: Urinary tract infection

DISCUSSION

SGLT2i, such as dapagliflozin and empagliflozin, exert their therapeutic effects in HF through multiple interconnected mechanisms, which may directly translate into clinical benefits observed in children. By promoting osmotic diuresis and natriuresis, SGLT2i reduces plasma volume, thereby lowering preload and afterload on the heart and alleviating hemodynamic stress.[14] This reduction in cardiac workload contributes to improved LV performance, as evidenced by increases in EF. In addition, SGLT2i enhances myocardial energy metabolism by shifting substrate utilization from fatty acid oxidation to the more efficient ketone body metabolism, which optimizes adenosine triphosphate production and supports systolic function.[15]

The anti-inflammatory and antifibrotic properties of SGLT2i further contribute to their efficacy by reducing myocardial fibrosis and adverse cardiac remodeling.[7] These effects are directly linked to reductions in ventricular dilation.[10] The therapy also mitigates AV valve regurgitation, likely due to reverse remodeling and improved ventricular geometry, as demonstrated by reductions in moderate regurgitation and stabilization of valve function.[16]

Another pivotal mechanism involves the reduction of cardiac stress through decreases in BNP and NT-proBNP, key biomarkers of HF severity. By enhancing natriuresis and reducing systemic congestion, SGLT2i lowers intracardiac pressures, which subsequently decreases the secretion of these biomarkers by ventricular myocytes. These biomarker reductions are a direct consequence of improved cardiac loading conditions and better overall hemodynamics, further validating the mechanistic role of SGLT2i in HF management.[6,17,18]

This systematic review offers emerging insights into how SGLT2i may be incorporated into pediatric HF care. The evidence suggests that SGLT2i may be beneficial for children and adolescents aged 6–18 years with symptomatic HF and reduced EF. Across the reviewed studies, patients often had underlying diagnoses such as dilated cardiomyopathy, single-ventricle congenital heart disease with Fontan circulation, or other congenital defects with ventricular dysfunction.[8,9,10,11,12] Improvements in EF, reductions in natriuretic peptide levels, and echocardiographic markers of remodeling were most evident in this group. These findings align with adult data showing cardiovascular benefits of SGLT2i in HFrEF, independent of glycemic status.[4,17] In most included studies, SGLT2i were added after patients had been stabilized on conventional HF therapies such as angiotensin-converting enzyme inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and diuretics. This suggests a role for SGLT2i as an adjunctive therapy in cases of residual congestion or suboptimal ventricular function. A Phase II trial (NCT06012266), launched in August 2024, is investigating the pharmacokinetics of dapagliflozin and empagliflozin in children aged 6–18 years, with results anticipated by August 2025.[19] Notably, data on children under 5 years, particularly infants, were extremely limited. While a small number of cases included patients as young as 2 years old,[8,9] The pharmacokinetics and tolerability of SGLT2i in this age group remain unknown.

SGLT2i, such as dapagliflozin and empagliflozin, work by inhibiting the SGLT2 protein in the proximal renal tubules, thereby reducing glucose reabsorption and promoting glycosuria. While these mechanisms contribute to their efficacy in HF by decreasing plasma volume, preload, and afterload, they also carry potential risks of adverse effects due to their systemic impact on metabolism and renal function. The diuretic and natriuretic effects of SGLT2i can exacerbate intravascular volume depletion in vulnerable patients, leading to acute decompensated HF or worsening hypotension.[7,16] This hemodynamic alteration can also decrease renal perfusion, contributing to a decline in eGFR and an increase in serum creatinine levels, particularly in those with preexisting kidney disease or volume depletion.[20]

The potential for AKI arises from a combination of volume contraction, altered renal hemodynamics, and increased tubular workload due to glycosuria. Although these changes are often transient and reversible, they underscore the importance of exercising caution when using SGLT2i in patients with impaired renal reserve.[21] In addition, protein-losing enteropathy has been reported in some cases, potentially linked to the drug’s impact on systemic volume regulation and mesenteric blood flow, although this mechanism remains poorly understood. Persistent abdominal pain in some patients may also result from alterations in gut motility or osmotic shifts related to glycosuria-induced fluid loss. However, further research is required to confirm these associations.[16]

Hypoglycemia, although uncommon when SGLT2 inhibitors (SGLT2i) are used as monotherapy, can occur when they are combined with insulin or sulfonylureas, as the increased urinary glucose excretion lowers baseline glucose levels, thereby heightening the risk of hypoglycemic episodes.[15] Similarly, the glycosuric mechanism of SGLT2i increases the risk of UTIs in patients due to the higher concentration of glucose in the urinary tract, which serves as a substrate for bacterial growth. These infections, if severe or recurrent, can exacerbate systemic inflammation and further compromise renal and cardiac function.[21]

Although generally well-tolerated, SGLT2i use should therefore be avoided or closely monitored in patients with: (1) eGFR <60 mL/min/1.73 m²;[7,20] (2) ongoing hypotension or dehydration;[16] (3) active protein-losing enteropathy;[10] (4) recurrent UTIs or genital infections.[8,21] To ensure safety in clinical use, routine monitoring should include baseline and follow-up renal function (serum creatinine and eGFR), electrolytes and blood glucose levels, clinical assessment of hydration status and blood pressure, as well as surveillance for signs of UTIs, gastrointestinal symptoms, or volume depletion.

Our systematic review has several strengths. The review’s methodological rigor, which included adhering to PRISMA guidelines and conducting a comprehensive search across multiple databases without language or date restrictions, strengthened its credibility and minimized selection bias. The inclusion of diverse study designs and independent screening by multiple reviewers enhanced rigor, and validated risk-of-bias tools confirmed the high quality of the majority of the studies. However, there are several limitations. Inconsistent efficacy findings, an overrepresentation of male/U.S. participants, and a tiny, unreliable evidence base restricts the review’s conclusions. It is also important to acknowledge the inherent limitations of drug trials in pediatric HF, which result from the substantial heterogeneity in age range and underlying cardiac conditions such as dilated cardiomyopathy, hypertrophic cardiomyopathy, Fontan failure, and other forms of congenital heart disease. Small sample sizes compromise the credibility of reported safety hazards, and long-term results are obscured by inconsistent follow-up. Moreover, the tendency to report favorable outcomes in these diverse clinical subgroups may lead to interpretation bias, especially when derived from limited data sets. Validity is further limited by the inherent bias risks of observational studies and the extrapolation of mechanisms from adult data, highlighting the necessity of pediatric-specific trials.

CONCLUSIONS

SGLT2 inhibitors show potential in improving cardiac outcomes in pediatric HF, demonstrating an acceptable safety profile. While present evidence remains limited, this review provides a valuable foundation by summarizing early safety signals, trends in efficacy, and key patient selection criteria. It offers practical interim guidance for clinicians and highlights critical knowledge gaps for future research. To enable routine clinical use, rigorous, well-designed pediatric trials are urgently needed to define optimal timing, dosing, and monitoring strategies.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.