Impact of Dapagliflozin on Diuretic Needs in Children and Adolescents with Heart Failure 

Impact of Dapagliflozin on Diuretic Needs in Children and Adolescents with Heart Failure | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of Dapagliflozin on Diuretic Needs in Children and Adolescents with Heart Failure Collin Strickland, Madeline Mackin, Danielle Briney, McKenzie Harris, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8750393/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction: Dapagliflozin is recommended in the treatment of adult heart failure (HF) based on evidence from large clinical trials. Newland and colleagues demonstrated improvement in BNP and LVEF after initiating dapagliflozin in pediatric HF patients, but further benefit remains unknown. Given the suspected natriuretic effects, the primary objective of this study was to determine the impact of dapagliflozin on diuretic needs in pediatric patients with HF, with secondary assessment of adverse events. Methods: This retrospective, single-center cohort study included patients ≤ 21 years of age who were initiated on dapagliflozin for the treatment of HF from January 1, 2022, to June 30, 2024. Loop diuretic doses were converted to oral furosemide equivalents (OFE) and compared at baseline, 30- and 90-days, and a median final follow-up of 10.8 months post-dapagliflozin initiation. Results: Median baseline diuretic requirement was 0.85 mg/kg/day OFE [IQR: 0.38–4.3 mg/kg/day OFE]. At 30-days, the median dose decreased significantly to 0.45 mg/kg/day OFE [IQR: 0.2–2.2 mg/kg/day OFE; p = 0.003]. A significant reduction was observed at 90 days to 0.45 mg/kg/day OFE [IQR: 0.2–2.3 mg/kg/day; p = 0.002]. At final study follow-up of 10.8 months, median diuretic dose decreased to 0.29 mg/kg/day [IQR 0–2 mg/kg/day; p = 0.055]. Adverse events included urinary tract infections in 2 patients (8%), hypovolemia in 7 patients (29%), and one case of euglycemic ketoacidosis (4%), with no hypoglycemia reported. Conclusion: Dapagliflozin significantly lowers diuretic needs in pediatric HF patients at 30- and 90-day post-initiation, and aids in a clinically meaningful decrease in diuretics at final study follow-up. SGLT2 inhibitors dapagliflozin loop diuretics pediatric heart failure congenital heart disease heart transplant Figures Figure 1 Figure 2 Introduction Dapagliflozin, an oral SGLT2 inhibitor known to decrease plasma glucose and aid diabetes management, has also been studied in the treatment of heart failure due to suspected natriuretic effects associated with renal excretion of sodium and glucose. This natriuretic effect reduces preload and afterload, while also improving cardiac metabolism, leading to an overall cardioprotective effect [ 1 ]. McMurray and colleagues first demonstrated the efficacy of dapagliflozin on reducing cardiovascular death and worsening heart failure in the Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) trial [ 2 ]. This multicenter, double blinded, parallel group, randomized, controlled trial included 4,744 adult patients [ 3 ]. Following DAPA-HF, dapagliflozin was added to the 2022 American College of Cardiology, American Heart Association, and Heart Failure Society of America (ACC/AHA/HFSA) Guidelines for the Management of Heart Failure, as a recommended agent for heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF)[ 2 ]. However, for pediatric heart failure (HF) patients, the implementation of dapagliflozin to the HF medical regimen has largely been based on clinical judgement and extrapolation from adult literature. Recently, Newland and colleagues examined dapagliflozin use in 38 pediatric HF patients and found significant decreases in B-type natriuretic peptide (BNP) and significantly increased left ventricular ejection fraction (LVEF) in patients with dilated cardiomyopathy. Despite the promising results from this study, there was still some uncertainty regarding which pediatric HF patient population this is most likely to benefit, the impact on diuretic requirements, and which patients are likely to experience an adverse event [ 4 ]. Based on the results found by Newland and colleagues, Norton Children’s Hospital began utilizing dapagliflozin for pediatric heart failure in 2022. To evaluate the use at our institution, we implemented a single-center, retrospective chart review of the pediatric heart failure patients who were prescribed dapagliflozin between January 1, 2022, to June 30, 2024, at our center. Given the suspected natriuretic effects of dapagliflozin, the primary objective of this study was to determine the impact of dapagliflozin on diuretic needs in pediatric patients with dilated cardiomyopathy, heart failure secondary to congenital heart disease, and impaired cardiac function post-heart transplant (HT). Secondary outcomes included efficacy and safety measures. We hypothesized that the addition of dapagliflozin to guideline-directed medical therapy for heart failure would result in a significant decrease in diuretic requirements for these patients. Methods This is a retrospective single-center cohort study of patients started on dapagliflozin for the treatment of pediatric heart failure patients at our center from January 1, 2022, to June 30, 2024. Patients were identified through electronic medical record search for those patients less than or equal to 21 years of age, receiving dapagliflozin for greater than or equal to 30 days with a diagnosis of dilated cardiomyopathy, post-orthotopic heart transplant, or congenital heart disease, and were on guideline directed medical therapy (aldosterone receptor antagonist, beta-blocker, and angiotensin-converting enzyme inhibitor/angiotensin receptor-neprilysin inhibitor). Patients were excluded from this study if they carried a diagnosis of diabetes. This study was approved by the Institutional Review Board at Norton Healthcare IRB# 24-N0314. Consent requirements were waived. Data for this study was obtained from Epic Hyperspace® electronic medical records. Demographic and inpatient and outpatient clinical data were recorded, specifically, from dapagliflozin prescription information including age; gender; weight; past dapagliflozin dose (mg) was recorded as absolute and per body weight (mg/kg) using the hospital dosing weight at the time and outpatient weight. Dosing was determined utilizing the dosing scheme Newland and colleagues examined [ 4 ]. Loop diuretic dosing was converted to daily oral furosemide equivalents (OFE) (mg/kg) using a conversion factor of 40 mg oral furosemide = 20 mg of IV furosemide = 1 mg of oral/IV bumetanide. Additionally, serum creatinine (SCr), blood urea nitrogen (BUN) was converted to estimated glomerular filtration rate (eGFR) as a measure of renal function using the bedside Schwartz equation. The primary endpoint was diuretic use in OFE at initiation of dapagliflozin, day 30, day 90, and final study follow-up at 10.8 months. Secondary endpoints include measures of BNP (pg/dL) and LVEF reported by echocardiography, when available. Most recent BNP obtained prior to dapagliflozin initiation was used for study comparison to BNP post-dapagliflozin initiation. LVEF was unable to be obtained for patients with single ventricle physiology in this study. Adverse events were defined as treated urinary tract infections (UTI) with a positive urine culture; hypoglycemia (defined as blood glucose < 70 mg/dL); treated hypovolemia (defined as requiring IV volume expansion); and euglycemic ketoacidosis (defined as normal blood glucose values of ≤ 250 mg/dL, presence of anion-gap metabolic acidosis, and ketonuria). Since our data is not normally distributed, we elected to use nonparametric statistics; therefore, descriptive statistics presented as percentages for categorical variables and median [IQR] for continuous variables. Endpoint analysis of continuous variables includes Friedman test for overall differences and if significant, Wilcoxon-Signed Rank analysis for pairwise comparison between timepoints (with Bonferroni correction). For group comparisons, Chi-square analysis or Fisher exact test was used when appropriate. Statistical significance is set for a p-value of < 0.05. Results Dapagliflozin was initiated in 35 patients at Norton Children’s Hospital during the study period, with 25 meeting inclusion criteria. Among the 10 excluded patients, 3 had a treatment duration of less than 30 days, 5 lacked follow-up at 30 days, and 2 did not meet the specified diagnoses. Of the patients on therapy for less than 30 days, one patient received a heart transplant (HT) on day 22 and had therapy discontinued prior to transplant, one patient had significantly improved systolic function post-viral myocarditis by day 27 and had therapy discontinued upon recovery, and one patient was deceased 9 days after starting unrelated to dapagliflozin therapy ( Fig. 1 ) . The median age at therapy initiation was 11.1 years [IQR: 9.2–15.9], with 14 males (56%). The cohort included 9 post-HT patients (36%), 9 patients with dilated cardiomyopathy (36%), and 12 patients with congenital heart disease (48%) ( Table 1 ) . Dapagliflozin was started post-HT for several reasons, including diastolic dysfunction, and to slow progression of chronic kidney disease and minimize diuretic needs. Notably, 2 patients from the dilated cardiomyopathy and 1 patient from the congenital heart disease groups also underwent HT, and dapagliflozin was not re-started post-HT. The median dose of dapagliflozin administered was 10 mg [IQR: 5–10 mg], added to a heart failure regimen that included a beta-blocker in 16 patients (64%), an angiotensin receptor neprilysin inhibitor or renin-angiotensin-aldosterone system inhibitor in 13 patients (52%), and a mineralocorticoid antagonist in 22 patients (88%). Complete guideline-directed medical therapy, defined by the patient being on all three agents listed above, was achieved in 9 patients (36%), while 2 agents were prescribed in 9 patients (36%), 1 agent in 6 patients (24%), and no guideline-directed therapy agents in 1 patient (4%) ( Table 2 ). Diuretic needs were assessed in terms of weight-based OFE per day. The median dose of diuretics at baseline was 0.85 mg/kg/day OFE [IQR: 0.38–4.3 mg/kg/day OFE]. At 30-day follow-up, median diuretic dose significantly decreased to 0.45 mg/kg/day OFE from baseline [IQR: 0.2–2.2 mg/kg/day OFE; p = 0.003]. At 90-day follow-up, median diuretic dose significantly decreased from baseline to 0.45 mg/kg/day OFE from baseline [IQR: 0.2–2.3 mg/kg/day; p = 0.002]. Over the entire study period of a median of 10.8 months, median diuretic dose decreased from baseline to 0.29 mg/kg/day [IQR 0–2 mg/kg/day; p = 0.055] ( Fig. 2 ). Median follow-up duration varied across other efficacy outcome measures. For BNP monitoring, the median follow-up was 323 days [IQR: 194–372 days]. BNP levels were assessed in 24 of the 25 patients included and showed a significant reduction from a median of 263.1 pg/mL [IQR: 90.7–854 pg/mL] to 90.9 pg/mL [IQR: 64–250 pg/mL, p = 0.01174]. LVEF was monitored in 17 of 25 patients, demonstrating a significant increase from a median of 45.2% [IQR: 35–57%] to 56.7% [IQR: 41–60%, p = 0.0045] at a median follow-up of 363 days [IQR: 154–385 days] ( Table 3 ). LVEF could not be evaluated in 7 patients due to single ventricle physiology. Renal function parameters were assessed in all patients at baseline and after initiation of dapagliflozin. However, not all patients had follow-up measures at the three specified timepoints. Baseline median BUN prior to initiating dapagliflozin in all patients was 16 mg/dL [IQR: 11–26 mg/dL]. Median BUN at 30-day follow-up was 15 mg/dL [IQR: 14–28 mg/dL]. Median BUN at 60-day follow-up was 19 mg/dL [IQR: 13–25.25 mg/dL]. Median BUN at 90-day follow-up was 18 mg/dL [IQR: 13–23 mg/dL]. Baseline serum creatinine prior to initiating dapagliflozin in all patients was 0.61 mg/dL [IQR: 0.45–0.79 mg/dL], then 0.72 mg/dL [IQR: 0.58–0.88 mg/dL] at 30-day follow-up, 0.63 mg/dL [IQR: 0.5–0.87 mg/dL] at 60-day follow-up, and 0.64 mg/dL [IQR:0.41–0.79 mg/dL] at 90-day follow-up. Baseline eGFR prior to dapagliflozin initiation in all patients was 102 mL/min/1.73 m 2 [IQR: 84–130 mL/min/1.73 m 2 ]. Median eGFR 30 days after dapagliflozin initiation in all patients was 82 mL/min/1.73 m 2 [IQR: 72–97 mL/min/1.73 m 2 ], then 91.5 mL/min/1.73 m 2 [IQR: 76.5–106.25 mL/min/1.73 m 2 ] at 60 days post-dapagliflozin initiation, and 95 mL/min/1.73 m 2 [IQR: 79.5–118 mL/min/1.73 m 2 ] at 90 days post-dapagliflozin initiation. Dapagliflozin was temporarily discontinued for surgery or cardiac catheterization in 8 (33%) patients. Adverse events observed during dapagliflozin treatment included urinary tract infections in 2 patients (8%), episodes of hypovolemia in 7 patients (29%), and one case (4%) of euglycemic ketoacidosis. The euglycemic ketoacidosis was an incidental finding found post-HT because urine ketones were checked pre-operatively for the case. Notably, no instances of hypoglycemia were reported among the study participants ( Table 4 ). Discussion This study is unique compared to previous literature examining dapagliflozin in pediatric HF as it evaluates patients with dilated cardiomyopathy, congenital heart disease, and post-orthotopic heart transplant with longer follow-up parameters. This study evaluated the natriuretic effect of dapagliflozin by assessing the decrease in diuretic requirements for pediatric HF patients. The results of this study demonstrated a significant decrease in loop diuretic requirements at 30-days and 90-days post-dapagliflozin initiation and trended towards a decrease in diuretics at final study follow-up of 10.8 months. The observed reduction in loop diuretic use is noteworthy, as it indicates that dapagliflozin may mitigate exposure to nephrotoxic agents in this patient population. When evaluating the impact dapagliflozin has on decreasing loop diuretic requirements, it is important to note that of the 25 patients on initial loop diuretic therapy, 18 patients had decreased loop diuretic requirements, 2 were kept on the same loop diuretic regimen during dapagliflozin therapy, and 5 required an increase in loop diuretic doses. This change had not been previously documented in pediatric studies but was first recognized in the DICTATE-AHF trial where the dapagliflozin arm required significantly less loop diuretics to achieve the primary outcome of diuretic efficiency. Further, in the DICTATE-AHF trial, dapagliflozin was also associated with improved 24-hour natriuresis and urine output, expediting hospital discharge [ 14 ]. While this study did not evaluate 24-hour natriuresis or urine output upon starting dapagliflozin, the decreased requirements of loop diuretics overall suggest that dapagliflozin’s natriuretic effects should be respected for the management of HF in pediatrics. Our findings also demonstrate significant improvements in several key heart failure parameters, such as a significant reduction in BNP and a significant increase in LVEF, further cementing dapagliflozin’s role within GDMT in pediatric patients. There appeared to be no significant impact on renal function based on changes in serum creatinine, BUN, and eGFR over the study period. Dapagliflozin was well-tolerated within these patients with hypovolemia being the most common documented adverse effect in this study. The occurrence of this adverse event may be due to cumulative natriuretic effects of dapagliflozin in combination with further diuretic therapy. The doses used for dapagliflozin within this study were first established in Newland and Colleagues pediatric HF study with target doses of 0.1 to 0.2 mg/kg daily with a maximum of 10 mg [ 5 , 6 ]. Doses were rounded to the nearest tablet size, with the lowest dose received being 1.25 mg. The goal for patients with pediatric HF is to establish full GDMT but due to intolerances such as hypotension and bradycardia, not all patients achieve this goal 7 . Not all patients at this institution were on GDMT. Despite this, we still saw improvements in LVEF with the addition of dapagliflozin to incomplete GDMT regimens. This suggests that dapagliflozin may have benefit alone for LVEF, adding to the benefit seen in the adult literature for renin-angiotensin aldosterone system medications, beta-blockers, and aldosterone antagonists [ 9 – 13 ]. The reductions in BNP levels and improvements in LVEF suggest that dapagliflozin may contribute to positive cardiac reverse remodeling and enhanced cardiac function. This mechanism of improvement occurs as there is a downregulation in sympathetic activity, leading to a reduction in cardiac stretching resulting in decreased BNP levels 8 . Further, inhibiting sodium-glucose co-transporters within the renal tubules, natriuresis, and osmotic diuresis is promoted to decrease both preload and afterload. In doing this, there is an alleviation of volume overload, reduced ventricular wall stress, and overall improvements in cardiac function as seen with improvements in LVEF [ 3 , 8 ]. However, since this study included patients with single ventricle physiology, LVEF was not able to be recorded in 7 of the 12 included patients with congenital heart disease. This retrospective, single-center study has inherent limitations including the observational nature and relatively small sample size. Due to the small sample size and limited timeframe of this study, it is difficult to draw a direct correlation with the initiation of dapagliflozin and decreased diuretic requirements. There are many confounding variables in the pediatric heart failure patient population that may lead to decreased diuretic requirements over time, such as other GDMT regimens. There were also many variations within the follow-up durations for each efficacy measure which may have impacted outcome assessments. Further, dapagliflozin must be held prior to any procedure requiring anesthesia 72 hours prior to the procedure due to the risk of euglycemic ketoacidosis, but this study did not evaluate the appropriate holding mechanism or adverse events when the medication was not appropriately held as a part of safety outcomes. Additionally, LVEF could not be collected on every patient due to 7 included patients having single ventricle physiology. Conclusion This study highlights the suspected additive diuretic and natriuretic effects of dapagliflozin therapy by demonstrating significant decreases in OFE at 30-days and 90-days post-dapagliflozin initiation, and although not statistically significant, a clinically significant decrease in loop diuretic requirements at final follow-up. The results of this study were also congruent with previous pediatric literature demonstrating a significant decrease in BNP and significant increase in LVEF over the study period. However, given the limitations of this study, larger, prospective, pediatric heart failure studies including multi-center registry data would be needed to characterize the true natriuretic effect of dapagliflozin and decrease in loop diuretic requirements. Declarations Disclosures The authors declare that there are no conflicts of interest regarding this study. Authors received no specific grant from any funding agency. Author Contribution C.S., M.M., and D.B. collected data for the manuscript. C.S., M.M., M.H., and S.J. analyzed data for the manuscript. C.S., M.H., and S.J. wrote the main manuscript text, prepared figures, and data tables reflected in the manuscript. C.S., M.H., J.K., J.S., S.W., and S.J. reviewed the manuscript. Data Availability Data for this study was obtained from Epic Hyperspace® electronic medical records and stored in a password protected Microsoft Excel® document. Data for this study are not available to be shared per approval from the Institutional Review Board at Norton Healthcare. The data are, however, available upon request and with the permission of the Institutional Review Board at Norton Healthcare. References Sano R, Shinozaki Y, Ohta T (2020) Sodium-glucose cotransporters: Functional properties and pharmaceutical potential. J Diabetes Investig 11(4):770–782. 10.1111/jdi.13255 Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Yancy CW (2022) 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 79(17):e263–e421 McMurray JJ, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Langkilde AM (2019) Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 381(21):1995–2008 Newland DM, Hong BJ, Albers EL, Friedland-Little JM, Kemna MS, Law YM (2021) Safety of dapagliflozin in children with heart failure. J Heart Lung Transplantation 40(4):S280 Newland DM, Law YM, Albers EL, Friedland-Little JM, Ahmed H, Kemna MS, Hong BJ (2023) Early clinical experience with dapagliflozin in children with heart failure. Pediatr Cardiol 44(1):146–141 Shaddy R, Burch M, Kantor PF, Solar-Yohay S, Garito T, Zhang S, Bonnet D (2024) Sacubitril/Valsartan in pediatric heart failure (PANORAMA-HF): a randomized, multicenter, double-blind trial. Circulation 150(22):1756–1766 Maddox TM, Januzzi Jr JL, Allen LA, Breathett K, Butler J, Davis LL, Youmans QR (2021) 2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 77(6):772–810 Yu YW, Zhao XM, Wang YH et al (2021) Effect of sodium-glucose cotransporter 2 inhibitors on cardiac structure and function in type 2 diabetes mellitus patients with or without chronic heart failure: a meta-analysis. Cardiovasc Diabetol 20(1):25 Zhang N, Wang Y, Tse G et al (2022) Effect of sodium-glucose cotransporter-2 inhibitors on cardiac remodelling: a systematic review and meta-analysis. Eur J Prev Cardiol 28(17):1961–1973 Yu YW, Zhao XM, Wang YH et al (2021) Effect of sodium-glucose cotransporter 2 inhibitors on cardiac structure and function in type 2 diabetes mellitus patients with or without chronic heart failure: a meta-analysis. Cardiovasc Diabetol 20(1):25 Januzzi JL Jr, Prescott MF, Butler J et al (2019) Association of change in n-terminal pro-B-type natriuretic peptide following initiation of sacubitril-valsartan treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction. JAMA 322(11):1085–1095 Cleland JGF, Bunting KV, Flather MD et al (2018) Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Eur Heart J 39(1):26–35 Vizzardi E, D’Aloia A, Giubbini R et al (2010) Effect of spironolactone on left ventricular ejection fraction and volumes in patients with class I or II heart failure. Am J Cardiol 106(9):1292–1296 Cox ZL, Collins SP, Hernandez GA, McRae AT III, Davidson BT, Adams K, Lindenfeld J (2024) Efficacy and safety of dapagliflozin in patients with acute heart failure. J Am Coll Cardiol 83(14):1295–1306 Tables Table 1: Baseline Characteristics Values Age (median years, range) 11.1 (0.5-18.6) Sex Male (n, %) 14 (58%) Female (n, %) 11 (42%) Past Medical History Dilated Cardiomyopathy (n) 9 Congenital Heart Disease (n) 12 Post Heart Transplant (n) 9* *3 patients had diagnosis of only post-heart transplant Table 1: Baseline characteristics of pediatric heart failure patients treated with dapagliflozin. Table 2: Medications Values Dose of dapagliflozin (median mg, range) 10 mg (1.25-10) GDMT Beta-blocker (n, %) 16 (63%) ARNI/RAAS inhibitor (n, %) 13 (54%) Mineralocorticoid antagonist (n, %) 22 (92%) Sum of GDMT All (3) additional agents (n, %) 9 (38%) 2 additional agents (n, %) 9 (38%) 1 additional agent (n, %) 6 (21%) 0 additional agents (n, %) 1 (4%) Table 2: Dapagliflozin dosing and guideline-directed medical therapy in pediatric heart failure patients. Table 3: Efficacy Measures n Baseline Follow-up Days p-value BNP (median, range) 24 263.1 (0-2363) 90.9 (0-755) 323 (96-556) 0.01174 # LVEF (median, range) 17 45.2 (15-65) 56.7 (13-66) 363 (105-566) 0.0045 # # p-values are the result of Wilcoxon-Signed Ranked Test Table 3: Baseline and follow-up of BNP and LVEF in pediatric heart failure patients initiated on dapagliflozin. Table 4: Adverse Events Values Urinary Tract Infection (n, %) 2 (8%) Hypovolemia (n, %) 7 (29%) Hypoglycemia (n, %) 0 (0%) Euglycemic ketoacidosis (n, %) 1 (4%) Held for surgery (n, %) 8 (33%) Table 4: Incidence of adverse events in pediatric heart failure patients initiated on dapagliflozin. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8750393","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":585189309,"identity":"b4aff2f6-9d11-4c96-87a2-41244115e9c4","order_by":0,"name":"Collin 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Joshua","middleName":"","lastName":"Sparks","suffix":""},{"id":585189315,"identity":"c0d9c95e-664a-4c72-b20d-56b5aa27ffbb","order_by":6,"name":"Sarah Wilkens","email":"","orcid":"","institution":"Norton Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sarah","middleName":"","lastName":"Wilkens","suffix":""},{"id":585189316,"identity":"d49cfc8f-b107-46da-8c50-a1d63e4ad91b","order_by":7,"name":"Stephanie Johnson","email":"","orcid":"","institution":"Norton Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Stephanie","middleName":"","lastName":"Johnson","suffix":""}],"badges":[],"createdAt":"2026-01-31 13:53:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8750393/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8750393/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101874681,"identity":"f5a9da5a-c49a-4ea6-89e3-3a71dc1dac03","added_by":"auto","created_at":"2026-02-04 14:01:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":26745,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePatient Cohort\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFlow diagram showing identification, inclusion, and exclusion of pediatric heart failure patients, with reasons for exclusion detailed.\u003c/p\u003e","description":"","filename":"floatimage152.png","url":"https://assets-eu.researchsquare.com/files/rs-8750393/v1/85bc32c169bf8773ce8b4c27.png"},{"id":101874683,"identity":"8c04792e-3024-4f63-83e9-93d2d9925f84","added_by":"auto","created_at":"2026-02-04 14:01:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":34970,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDiuretic Requirements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBox-and-whisker plot indicating oral furosemide equivalents at baseline, 30 days, 90 days, and final follow-up post-initiation of dapagliflozin in pediatric heart failure patients.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8750393/v1/0ab5a9dbe40e7086c077cb5e.png"},{"id":104436808,"identity":"f04057ab-7c75-4e48-b896-53b5ed9a6eb3","added_by":"auto","created_at":"2026-03-11 16:55:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":684435,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8750393/v1/d35a1786-976d-4aa8-aafe-88f875c8a75d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":" Impact of Dapagliflozin on Diuretic Needs in Children and Adolescents with Heart Failure ","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDapagliflozin, an oral SGLT2 inhibitor known to decrease plasma glucose and aid diabetes management, has also been studied in the treatment of heart failure due to suspected natriuretic effects associated with renal excretion of sodium and glucose. This natriuretic effect reduces preload and afterload, while also improving cardiac metabolism, leading to an overall cardioprotective effect [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. McMurray and colleagues first demonstrated the efficacy of dapagliflozin on reducing cardiovascular death and worsening heart failure in the Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) trial [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This multicenter, double blinded, parallel group, randomized, controlled trial included 4,744 adult patients [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFollowing DAPA-HF, dapagliflozin was added to the 2022 American College of Cardiology, American Heart Association, and Heart Failure Society of America (ACC/AHA/HFSA) Guidelines for the Management of Heart Failure, as a recommended agent for heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF)[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, for pediatric heart failure (HF) patients, the implementation of dapagliflozin to the HF medical regimen has largely been based on clinical judgement and extrapolation from adult literature. Recently, Newland and colleagues examined dapagliflozin use in 38 pediatric HF patients and found significant decreases in B-type natriuretic peptide (BNP) and significantly increased left ventricular ejection fraction (LVEF) in patients with dilated cardiomyopathy. Despite the promising results from this study, there was still some uncertainty regarding which pediatric HF patient population this is most likely to benefit, the impact on diuretic requirements, and which patients are likely to experience an adverse event [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBased on the results found by Newland and colleagues, Norton Children\u0026rsquo;s Hospital began utilizing dapagliflozin for pediatric heart failure in 2022. To evaluate the use at our institution, we implemented a single-center, retrospective chart review of the pediatric heart failure patients who were prescribed dapagliflozin between January 1, 2022, to June 30, 2024, at our center. Given the suspected natriuretic effects of dapagliflozin, the primary objective of this study was to determine the impact of dapagliflozin on diuretic needs in pediatric patients with dilated cardiomyopathy, heart failure secondary to congenital heart disease, and impaired cardiac function post-heart transplant (HT). Secondary outcomes included efficacy and safety measures. We hypothesized that the addition of dapagliflozin to guideline-directed medical therapy for heart failure would result in a significant decrease in diuretic requirements for these patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis is a retrospective single-center cohort study of patients started on dapagliflozin for the treatment of pediatric heart failure patients at our center from January 1, 2022, to June 30, 2024. Patients were identified through electronic medical record search for those patients less than or equal to 21 years of age, receiving dapagliflozin for greater than or equal to 30 days with a diagnosis of dilated cardiomyopathy, post-orthotopic heart transplant, or congenital heart disease, and were on guideline directed medical therapy (aldosterone receptor antagonist, beta-blocker, and angiotensin-converting enzyme inhibitor/angiotensin receptor-neprilysin inhibitor). Patients were excluded from this study if they carried a diagnosis of diabetes. This study was approved by the Institutional Review Board at Norton Healthcare IRB# 24-N0314. Consent requirements were waived.\u003c/p\u003e \u003cp\u003eData for this study was obtained from Epic Hyperspace\u0026reg; electronic medical records. Demographic and inpatient and outpatient clinical data were recorded, specifically, from dapagliflozin prescription information including age; gender; weight; past dapagliflozin dose (mg) was recorded as absolute and per body weight (mg/kg) using the hospital dosing weight at the time and outpatient weight. Dosing was determined utilizing the dosing scheme Newland and colleagues examined [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Loop diuretic dosing was converted to daily oral furosemide equivalents (OFE) (mg/kg) using a conversion factor of 40 mg oral furosemide\u0026thinsp;=\u0026thinsp;20 mg of IV furosemide\u0026thinsp;=\u0026thinsp;1 mg of oral/IV bumetanide. Additionally, serum creatinine (SCr), blood urea nitrogen (BUN) was converted to estimated glomerular filtration rate (eGFR) as a measure of renal function using the bedside Schwartz equation.\u003c/p\u003e \u003cp\u003eThe primary endpoint was diuretic use in OFE at initiation of dapagliflozin, day 30, day 90, and final study follow-up at 10.8 months. Secondary endpoints include measures of BNP (pg/dL) and LVEF reported by echocardiography, when available. Most recent BNP obtained prior to dapagliflozin initiation was used for study comparison to BNP post-dapagliflozin initiation. LVEF was unable to be obtained for patients with single ventricle physiology in this study.\u003c/p\u003e \u003cp\u003eAdverse events were defined as treated urinary tract infections (UTI) with a positive urine culture; hypoglycemia (defined as blood glucose\u0026thinsp;\u0026lt;\u0026thinsp;70 mg/dL); treated hypovolemia (defined as requiring IV volume expansion); and euglycemic ketoacidosis (defined as normal blood glucose values of \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;250 mg/dL, presence of anion-gap metabolic acidosis, and ketonuria).\u003c/p\u003e \u003cp\u003eSince our data is not normally distributed, we elected to use nonparametric statistics; therefore, descriptive statistics presented as percentages for categorical variables and median [IQR] for continuous variables. Endpoint analysis of continuous variables includes Friedman test for overall differences and if significant, Wilcoxon-Signed Rank analysis for pairwise comparison between timepoints (with Bonferroni correction). For group comparisons, Chi-square analysis or Fisher exact test was used when appropriate. Statistical significance is set for a p-value of \u0026lt;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eDapagliflozin was initiated in 35 patients at Norton Children\u0026rsquo;s Hospital during the study period, with 25 meeting inclusion criteria. Among the 10 excluded patients, 3 had a treatment duration of less than 30 days, 5 lacked follow-up at 30 days, and 2 did not meet the specified diagnoses. Of the patients on therapy for less than 30 days, one patient received a heart transplant (HT) on day 22 and had therapy discontinued prior to transplant, one patient had significantly improved systolic function post-viral myocarditis by day 27 and had therapy discontinued upon recovery, and one patient was deceased 9 days after starting unrelated to dapagliflozin therapy \u003cem\u003e(\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. The median age at therapy initiation was 11.1 years [IQR: 9.2\u0026ndash;15.9], with 14 males (56%). The cohort included 9 post-HT patients (36%), 9 patients with dilated cardiomyopathy (36%), and 12 patients with congenital heart disease (48%) \u003cem\u003e(\u003c/em\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cem\u003e)\u003c/em\u003e. Dapagliflozin was started post-HT for several reasons, including diastolic dysfunction, and to slow progression of chronic kidney disease and minimize diuretic needs. Notably, 2 patients from the dilated cardiomyopathy and 1 patient from the congenital heart disease groups also underwent HT, and dapagliflozin was not re-started post-HT.\u003c/p\u003e \u003cp\u003eThe median dose of dapagliflozin administered was 10 mg [IQR: 5\u0026ndash;10 mg], added to a heart failure regimen that included a beta-blocker in 16 patients (64%), an angiotensin receptor neprilysin inhibitor or renin-angiotensin-aldosterone system inhibitor in 13 patients (52%), and a mineralocorticoid antagonist in 22 patients (88%). Complete guideline-directed medical therapy, defined by the patient being on all three agents listed above, was achieved in 9 patients (36%), while 2 agents were prescribed in 9 patients (36%), 1 agent in 6 patients (24%), and no guideline-directed therapy agents in 1 patient (4%) \u003cem\u003e(\u003c/em\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e\u003c/p\u003e \u003cp\u003eDiuretic needs were assessed in terms of weight-based OFE per day. The median dose of diuretics at baseline was 0.85 mg/kg/day OFE [IQR: 0.38\u0026ndash;4.3 mg/kg/day OFE]. At 30-day follow-up, median diuretic dose significantly decreased to 0.45 mg/kg/day OFE from baseline [IQR: 0.2\u0026ndash;2.2 mg/kg/day OFE; p\u0026thinsp;=\u0026thinsp;0.003]. At 90-day follow-up, median diuretic dose significantly decreased from baseline to 0.45 mg/kg/day OFE from baseline [IQR: 0.2\u0026ndash;2.3 mg/kg/day; p\u0026thinsp;=\u0026thinsp;0.002]. Over the entire study period of a median of 10.8 months, median diuretic dose decreased from baseline to 0.29 mg/kg/day [IQR 0\u0026ndash;2 mg/kg/day; p\u0026thinsp;=\u0026thinsp;0.055] \u003cem\u003e(\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e Median follow-up duration varied across other efficacy outcome measures. For BNP monitoring, the median follow-up was 323 days [IQR: 194\u0026ndash;372 days]. BNP levels were assessed in 24 of the 25 patients included and showed a significant reduction from a median of 263.1 pg/mL [IQR: 90.7\u0026ndash;854 pg/mL] to 90.9 pg/mL [IQR: 64\u0026ndash;250 pg/mL, p\u0026thinsp;=\u0026thinsp;0.01174]. LVEF was monitored in 17 of 25 patients, demonstrating a significant increase from a median of 45.2% [IQR: 35\u0026ndash;57%] to 56.7% [IQR: 41\u0026ndash;60%, p\u0026thinsp;=\u0026thinsp;0.0045] at a median follow-up of 363 days [IQR: 154\u0026ndash;385 days] \u003cem\u003e(\u003c/em\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e LVEF could not be evaluated in 7 patients due to single ventricle physiology. Renal function parameters were assessed in all patients at baseline and after initiation of dapagliflozin. However, not all patients had follow-up measures at the three specified timepoints. Baseline median BUN prior to initiating dapagliflozin in all patients was 16 mg/dL [IQR: 11\u0026ndash;26 mg/dL]. Median BUN at 30-day follow-up was 15 mg/dL [IQR: 14\u0026ndash;28 mg/dL]. Median BUN at 60-day follow-up was 19 mg/dL [IQR: 13\u0026ndash;25.25 mg/dL]. Median BUN at 90-day follow-up was 18 mg/dL [IQR: 13\u0026ndash;23 mg/dL]. Baseline serum creatinine prior to initiating dapagliflozin in all patients was 0.61 mg/dL [IQR: 0.45\u0026ndash;0.79 mg/dL], then 0.72 mg/dL [IQR: 0.58\u0026ndash;0.88 mg/dL] at 30-day follow-up, 0.63 mg/dL [IQR: 0.5\u0026ndash;0.87 mg/dL] at 60-day follow-up, and 0.64 mg/dL [IQR:0.41\u0026ndash;0.79 mg/dL] at 90-day follow-up. Baseline eGFR prior to dapagliflozin initiation in all patients was 102 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e [IQR: 84\u0026ndash;130 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e]. Median eGFR 30 days after dapagliflozin initiation in all patients was 82 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e [IQR: 72\u0026ndash;97 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e], then 91.5 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e [IQR: 76.5\u0026ndash;106.25 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e] at 60 days post-dapagliflozin initiation, and 95 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e [IQR: 79.5\u0026ndash;118 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e] at 90 days post-dapagliflozin initiation.\u003c/p\u003e \u003cp\u003eDapagliflozin was temporarily discontinued for surgery or cardiac catheterization in 8 (33%) patients. Adverse events observed during dapagliflozin treatment included urinary tract infections in 2 patients (8%), episodes of hypovolemia in 7 patients (29%), and one case (4%) of euglycemic ketoacidosis. The euglycemic ketoacidosis was an incidental finding found post-HT because urine ketones were checked pre-operatively for the case. Notably, no instances of hypoglycemia were reported among the study participants \u003cem\u003e(\u003c/em\u003eTable\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study is unique compared to previous literature examining dapagliflozin in pediatric HF as it evaluates patients with dilated cardiomyopathy, congenital heart disease, and post-orthotopic heart transplant with longer follow-up parameters. This study evaluated the natriuretic effect of dapagliflozin by assessing the decrease in diuretic requirements for pediatric HF patients. The results of this study demonstrated a significant decrease in loop diuretic requirements at 30-days and 90-days post-dapagliflozin initiation and trended towards a decrease in diuretics at final study follow-up of 10.8 months. The observed reduction in loop diuretic use is noteworthy, as it indicates that dapagliflozin may mitigate exposure to nephrotoxic agents in this patient population.\u003c/p\u003e \u003cp\u003eWhen evaluating the impact dapagliflozin has on decreasing loop diuretic requirements, it is important to note that of the 25 patients on initial loop diuretic therapy, 18 patients had decreased loop diuretic requirements, 2 were kept on the same loop diuretic regimen during dapagliflozin therapy, and 5 required an increase in loop diuretic doses. This change had not been previously documented in pediatric studies but was first recognized in the DICTATE-AHF trial where the dapagliflozin arm required significantly less loop diuretics to achieve the primary outcome of diuretic efficiency. Further, in the DICTATE-AHF trial, dapagliflozin was also associated with improved 24-hour natriuresis and urine output, expediting hospital discharge [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. While this study did not evaluate 24-hour natriuresis or urine output upon starting dapagliflozin, the decreased requirements of loop diuretics overall suggest that dapagliflozin\u0026rsquo;s natriuretic effects should be respected for the management of HF in pediatrics.\u003c/p\u003e \u003cp\u003eOur findings also demonstrate significant improvements in several key heart failure parameters, such as a significant reduction in BNP and a significant increase in LVEF, further cementing dapagliflozin\u0026rsquo;s role within GDMT in pediatric patients. There appeared to be no significant impact on renal function based on changes in serum creatinine, BUN, and eGFR over the study period. Dapagliflozin was well-tolerated within these patients with hypovolemia being the most common documented adverse effect in this study. The occurrence of this adverse event may be due to cumulative natriuretic effects of dapagliflozin in combination with further diuretic therapy.\u003c/p\u003e \u003cp\u003eThe doses used for dapagliflozin within this study were first established in Newland and Colleagues pediatric HF study with target doses of 0.1 to 0.2 mg/kg daily with a maximum of 10 mg [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Doses were rounded to the nearest tablet size, with the lowest dose received being 1.25 mg. The goal for patients with pediatric HF is to establish full GDMT but due to intolerances such as hypotension and bradycardia, not all patients achieve this goal\u003csup\u003e7\u003c/sup\u003e. Not all patients at this institution were on GDMT. Despite this, we still saw improvements in LVEF with the addition of dapagliflozin to incomplete GDMT regimens. This suggests that dapagliflozin may have benefit alone for LVEF, adding to the benefit seen in the adult literature for renin-angiotensin aldosterone system medications, beta-blockers, and aldosterone antagonists [\u003cspan additionalcitationids=\"CR10 CR11 CR12\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe reductions in BNP levels and improvements in LVEF suggest that dapagliflozin may contribute to positive cardiac reverse remodeling and enhanced cardiac function. This mechanism of improvement occurs as there is a downregulation in sympathetic activity, leading to a reduction in cardiac stretching resulting in decreased BNP levels\u003csup\u003e8\u003c/sup\u003e. Further, inhibiting sodium-glucose co-transporters within the renal tubules, natriuresis, and osmotic diuresis is promoted to decrease both preload and afterload. In doing this, there is an alleviation of volume overload, reduced ventricular wall stress, and overall improvements in cardiac function as seen with improvements in LVEF [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, since this study included patients with single ventricle physiology, LVEF was not able to be recorded in 7 of the 12 included patients with congenital heart disease.\u003c/p\u003e \u003cp\u003eThis retrospective, single-center study has inherent limitations including the observational nature and relatively small sample size. Due to the small sample size and limited timeframe of this study, it is difficult to draw a direct correlation with the initiation of dapagliflozin and decreased diuretic requirements. There are many confounding variables in the pediatric heart failure patient population that may lead to decreased diuretic requirements over time, such as other GDMT regimens. There were also many variations within the follow-up durations for each efficacy measure which may have impacted outcome assessments. Further, dapagliflozin must be held prior to any procedure requiring anesthesia 72 hours prior to the procedure due to the risk of euglycemic ketoacidosis, but this study did not evaluate the appropriate holding mechanism or adverse events when the medication was not appropriately held as a part of safety outcomes. Additionally, LVEF could not be collected on every patient due to 7 included patients having single ventricle physiology.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study highlights the suspected additive diuretic and natriuretic effects of dapagliflozin therapy by demonstrating significant decreases in OFE at 30-days and 90-days post-dapagliflozin initiation, and although not statistically significant, a clinically significant decrease in loop diuretic requirements at final follow-up. The results of this study were also congruent with previous pediatric literature demonstrating a significant decrease in BNP and significant increase in LVEF over the study period. However, given the limitations of this study, larger, prospective, pediatric heart failure studies including multi-center registry data would be needed to characterize the true natriuretic effect of dapagliflozin and decrease in loop diuretic requirements.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eDisclosures\u003c/h2\u003e \u003cp\u003eThe authors declare that there are no conflicts of interest regarding this study. Authors received no specific grant from any funding agency.\u003c/p\u003e \u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eC.S., M.M., and D.B. collected data for the manuscript. C.S., M.M., M.H., and S.J. analyzed data for the manuscript. C.S., M.H., and S.J. wrote the main manuscript text, prepared figures, and data tables reflected in the manuscript. C.S., M.H., J.K., J.S., S.W., and S.J. reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData for this study was obtained from Epic Hyperspace\u0026reg; electronic medical records and stored in a password protected Microsoft Excel\u0026reg; document. Data for this study are not available to be shared per approval from the Institutional Review Board at Norton Healthcare. The data are, however, available upon request and with the permission of the Institutional Review Board at Norton Healthcare.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSano R, Shinozaki Y, Ohta T (2020) Sodium-glucose cotransporters: Functional properties and pharmaceutical potential. J Diabetes Investig 11(4):770\u0026ndash;782. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/jdi.13255\u003c/span\u003e\u003cspan address=\"10.1111/jdi.13255\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHeidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Yancy CW (2022) 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 79(17):e263\u0026ndash;e421\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcMurray JJ, Solomon SD, Inzucchi SE, K\u0026oslash;ber L, Kosiborod MN, Martinez FA, Langkilde AM (2019) Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 381(21):1995\u0026ndash;2008\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNewland DM, Hong BJ, Albers EL, Friedland-Little JM, Kemna MS, Law YM (2021) Safety of dapagliflozin in children with heart failure. J Heart Lung Transplantation 40(4):S280\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNewland DM, Law YM, Albers EL, Friedland-Little JM, Ahmed H, Kemna MS, Hong BJ (2023) Early clinical experience with dapagliflozin in children with heart failure. Pediatr Cardiol 44(1):146\u0026ndash;141\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShaddy R, Burch M, Kantor PF, Solar-Yohay S, Garito T, Zhang S, Bonnet D (2024) Sacubitril/Valsartan in pediatric heart failure (PANORAMA-HF): a randomized, multicenter, double-blind trial. Circulation 150(22):1756\u0026ndash;1766\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaddox TM, Januzzi Jr JL, Allen LA, Breathett K, Butler J, Davis LL, Youmans QR (2021) 2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 77(6):772\u0026ndash;810\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYu YW, Zhao XM, Wang YH et al (2021) Effect of sodium-glucose cotransporter 2 inhibitors on cardiac structure and function in type 2 diabetes mellitus patients with or without chronic heart failure: a meta-analysis. Cardiovasc Diabetol 20(1):25\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang N, Wang Y, Tse G et al (2022) Effect of sodium-glucose cotransporter-2 inhibitors on cardiac remodelling: a systematic review and meta-analysis. Eur J Prev Cardiol 28(17):1961\u0026ndash;1973\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYu YW, Zhao XM, Wang YH et al (2021) Effect of sodium-glucose cotransporter 2 inhibitors on cardiac structure and function in type 2 diabetes mellitus patients with or without chronic heart failure: a meta-analysis. Cardiovasc Diabetol 20(1):25\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJanuzzi JL Jr, Prescott MF, Butler J et al (2019) Association of change in n-terminal pro-B-type natriuretic peptide following initiation of sacubitril-valsartan treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction. JAMA 322(11):1085\u0026ndash;1095\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCleland JGF, Bunting KV, Flather MD et al (2018) Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Eur Heart J 39(1):26\u0026ndash;35\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVizzardi E, D\u0026rsquo;Aloia A, Giubbini R et al (2010) Effect of spironolactone on left ventricular ejection fraction and volumes in patients with class I or II heart failure. Am J Cardiol 106(9):1292\u0026ndash;1296\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCox ZL, Collins SP, Hernandez GA, McRae AT III, Davidson BT, Adams K, Lindenfeld J (2024) Efficacy and safety of dapagliflozin in patients with acute heart failure. J Am Coll Cardiol 83(14):1295\u0026ndash;1306\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Baseline Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 362px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eValues\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 362px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e (median years, range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e11.1 (0.5-18.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 362px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 362px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale\u0026nbsp;\u003c/strong\u003e(n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e14 (58%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 362px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFemale\u0026nbsp;\u003c/strong\u003e(n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e11 (42%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 362px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePast Medical History\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 362px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDilated Cardiomyopathy\u0026nbsp;\u003c/strong\u003e(n)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 362px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCongenital Heart Disease\u0026nbsp;\u003c/strong\u003e(n)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 362px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePost Heart Transplant\u0026nbsp;\u003c/strong\u003e(n)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e9*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 551px;\"\u003e\n \u003cp\u003e*3 patients had diagnosis of only post-heart transplant\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 1: Baseline characteristics of pediatric heart failure patients treated with dapagliflozin.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Medications\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eValues\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDose of dapagliflozin\u0026nbsp;\u003c/strong\u003e(median mg, range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e10 mg (1.25-10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGDMT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBeta-blocker\u003c/strong\u003e (n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e16 (63%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eARNI/RAAS inhibitor\u003c/strong\u003e (n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e13 (54%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMineralocorticoid\u003c/strong\u003e \u003cstrong\u003eantagonist\u0026nbsp;\u003c/strong\u003e(n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e22 (92%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSum of GDMT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll (3) additional agents\u0026nbsp;\u003c/strong\u003e(n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e9 (38%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2 additional agents\u0026nbsp;\u003c/strong\u003e(n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e9 (38%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1 additional agent\u0026nbsp;\u003c/strong\u003e(n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e6 (21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0 additional agents\u0026nbsp;\u003c/strong\u003e(n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e1 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 2: Dapagliflozin dosing and guideline-directed medical therapy in pediatric heart failure patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3: Efficacy Measures\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"634\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-up\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDays\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBNP\u003c/strong\u003e (median, range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e263.1 (0-2363)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e90.9 (0-755)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e323 (96-556)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e0.01174\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLVEF\u0026nbsp;\u003c/strong\u003e(median, range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e45.2 (15-65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e56.7 (13-66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e363 (105-566)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e0.0045\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 634px;\"\u003e\n \u003cp\u003e\u003csup\u003e#\u003c/sup\u003ep-values are the result of Wilcoxon-Signed Ranked Test\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 3: Baseline and follow-up of BNP and LVEF in pediatric heart failure patients initiated on dapagliflozin.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4: Adverse Events\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 260px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eValues\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 260px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUrinary Tract Infection\u0026nbsp;\u003c/strong\u003e(n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e2 (8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 260px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHypovolemia\u0026nbsp;\u003c/strong\u003e(n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e7 (29%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 260px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHypoglycemia\u0026nbsp;\u003c/strong\u003e(n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 260px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEuglycemic ketoacidosis\u0026nbsp;\u003c/strong\u003e(n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e1 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 260px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHeld for surgery\u0026nbsp;\u003c/strong\u003e(n, %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e8 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 4: Incidence of adverse events in pediatric heart failure patients initiated on dapagliflozin.\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"SGLT2 inhibitors, dapagliflozin, loop diuretics, pediatric heart failure, congenital heart disease, heart transplant","lastPublishedDoi":"10.21203/rs.3.rs-8750393/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8750393/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIntroduction: Dapagliflozin is recommended in the treatment of adult heart failure (HF) based on evidence from large clinical trials. Newland and colleagues demonstrated improvement in BNP and LVEF after initiating dapagliflozin in pediatric HF patients, but further benefit remains unknown. Given the suspected natriuretic effects, the primary objective of this study was to determine the impact of dapagliflozin on diuretic needs in pediatric patients with HF, with secondary assessment of adverse events.\u003c/p\u003e \u003cp\u003eMethods: This retrospective, single-center cohort study included patients\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;21 years of age who were initiated on dapagliflozin for the treatment of HF from January 1, 2022, to June 30, 2024. Loop diuretic doses were converted to oral furosemide equivalents (OFE) and compared at baseline, 30- and 90-days, and a median final follow-up of 10.8 months post-dapagliflozin initiation.\u003c/p\u003e \u003cp\u003eResults: Median baseline diuretic requirement was 0.85 mg/kg/day OFE [IQR: 0.38\u0026ndash;4.3 mg/kg/day OFE]. At 30-days, the median dose decreased significantly to 0.45 mg/kg/day OFE [IQR: 0.2\u0026ndash;2.2 mg/kg/day OFE; p\u0026thinsp;=\u0026thinsp;0.003]. A significant reduction was observed at 90 days to 0.45 mg/kg/day OFE [IQR: 0.2\u0026ndash;2.3 mg/kg/day; p\u0026thinsp;=\u0026thinsp;0.002]. At final study follow-up of 10.8 months, median diuretic dose decreased to 0.29 mg/kg/day [IQR 0\u0026ndash;2 mg/kg/day; p\u0026thinsp;=\u0026thinsp;0.055]. Adverse events included urinary tract infections in 2 patients (8%), hypovolemia in 7 patients (29%), and one case of euglycemic ketoacidosis (4%), with no hypoglycemia reported.\u003c/p\u003e \u003cp\u003eConclusion: Dapagliflozin significantly lowers diuretic needs in pediatric HF patients at 30- and 90-day post-initiation, and aids in a clinically meaningful decrease in diuretics at final study follow-up.\u003c/p\u003e","manuscriptTitle":" Impact of Dapagliflozin on Diuretic Needs in Children and Adolescents with Heart Failure ","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-04 14:01:21","doi":"10.21203/rs.3.rs-8750393/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3803f68f-012d-4eab-83e2-ab334cba4b59","owner":[],"postedDate":"February 4th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-11T16:54:56+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-04 14:01:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8750393","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8750393","identity":"rs-8750393","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}