Dapagliflozin in Heart Failure with Reduced Ejection Fraction (HFrEF): A Systematic Review of Its Mechanisms and Clinical Effectiveness
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Abstract
Background: Heart failure with reduced ejection fraction (HFrEF) is a serious condition associated with high morbidity and mortality. Dapagliflozin has demonstrated cardioprotective effects in patients with HFrEF. Objective: This review explores the mechanisms underlying the clinical benefits of dapagliflozin and summarizes current evidence from the DAPA-HF trial and its sub-analyses regarding its effectiveness in patients with HFrEF. Methods: Relevant literature was systematically searched in PubMed, Google Scholar, and Scopus. Eligible studies were analyzed using a narrative approach to summarize the drug’s mechanisms of action and clinical outcomes. Results: Dapagliflozin improves cardiac energy efficiency, stimulates erythropoiesis, reduces myocardial fibrosis, and lowers oxidative stress and NT-proBNP levels. Clinically, 10 mg/day therapy reduces heart failure hospitalizations and cardiovascular mortality by 26% (HR: 0.74), with recently hospitalized patients experiencing benefits up to 49% (HR: 0.51), consistent across subpopulations and providing added advantages to standard therapy. Conclusion: Dapagliflozin serves as an effective adjunct therapy for HFrEF, offering rapid and sustained benefits, reducing morbidity and mortality, and improving patients’ quality of life. Further research is warranted to expand its clinical application.
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References
Corneanu LE, Sîngeap MS, Mutruc V, Petriș OR, Toma TP, Șorodoc V, et al. The Complex Relationship Between Heart Failure and Chronic Obstructive Pulmonary Disease: A Comprehensive Review. J Clin Med 2025;14:4774. https://doi.org/10.3390/jcm14134774. DOI: https://doi.org/10.3390/jcm14134774
Shang Z, Wang X, Gao W. Heart failure with mildly reduced ejection fraction: Emerging frontiers in clinical characteristics, prognosis, and treatment. Rev Cardiovasc Med 2022;23. https://doi.org/10.31083/j.rcm2301030. DOI: https://doi.org/10.31083/j.rcm2301030
Savarese G, Becher PM, Lund LH, Seferovic P, Rosano GMC, Coats AJS. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovasc Res 2022;118:3272–87. https://doi.org/10.1093/cvr/cvac013. DOI: https://doi.org/10.1093/cvr/cvac013
Kerr B, Pharithi RB, Barrett M, Halley C, Gallagher J, Ledwidge M, et al. Angiotensin Receptor Neprilysin Inhibitors in HFrEF: Is This the First Disease Modifying Therapy Drug Class Leading to a Substantial Reduction in Diuretic Need? International Journal of Heart Failure 2021;3:106–16. https://doi.org/10.36628/ijhf.2020.0043. DOI: https://doi.org/10.36628/ijhf.2020.0043
Wirtz HS, Sheer R, Honarpour N, Casebeer AW, Simmons JD, Kurtz CE, et al. Real-world analysis of guideline-based therapy after hospitalization for heart failure. J Am Heart Assoc 2020;9. https://doi.org/10.1161/JAHA.119.015042. DOI: https://doi.org/10.1161/JAHA.119.015042
Maddox TM, Januzzi JL, Allen LA, Breathett K, Brouse S, Butler J, et al. 2024 ACC Expert Consensus Decision Pathway for Treatment of Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2024;83:1444–88. https://doi.org/10.1016/j.jacc.2023.12.024. DOI: https://doi.org/10.1016/j.jacc.2023.12.024
McMurray JJ V, DeMets DL, Inzucchi SE, Køber L, Kosiborod MN, Langkilde AM, et al. The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial: baseline characteristics. Eur J Heart Fail 2019;21:1402–11. https://doi.org/10.1002/ejhf.1548. DOI: https://doi.org/10.1002/ejhf.1548
Selvaraj S, Fu Z, Jones P, Kwee LC, Windsor SL, Ilkayeva O, et al. Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF. Circulation 2022;146:808–18. https://doi.org/10.1161/CIRCULATIONAHA.122.060402. DOI: https://doi.org/10.1161/CIRCULATIONAHA.122.060402
Aberle J, Menzen M, Schmid SM, Terkamp C, Jaeckel E, Rohwedder K, et al. Dapagliflozin effects on haematocrit, red blood cell count and reticulocytes in insulin-treated patients with type 2 diabetes. Sci Rep 2020;10. https://doi.org/10.1038/s41598-020-78734-z. DOI: https://doi.org/10.1038/s41598-020-78734-z
Ortega-Paz L, Laudani C, Sionis A, Vidal-Cales P, Arevalos V, Andrea R, et al. Effect of DAPAgliflozin on Myocardial Fibrosis and Ventricular Function in Patients with ST-Segment Elevation Myocardial Infarction—DAPA-STEMI Trial. J Cardiovasc Dev Dis 2025;12. https://doi.org/10.3390/jcdd12060220. DOI: https://doi.org/10.3390/jcdd12060220
Butt JH, Docherty KF, Petrie MC, Schou M, Kosiborod MN, O’Meara E, et al. Efficacy and Safety of Dapagliflozin in Men and Women with Heart Failure with Reduced Ejection Fraction: A Prespecified Analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial. JAMA Cardiol 2021;6:678–89. https://doi.org/10.1001/jamacardio.2021.0379. DOI: https://doi.org/10.1001/jamacardio.2021.0379
Petrie MC, Verma S, Docherty KF, Inzucchi SE, Anand I, Bělohlávek J, et al. Effect of Dapagliflozin on Worsening Heart Failure and Cardiovascular Death in Patients with Heart Failure with and Without Diabetes. JAMA - Journal of the American Medical Association 2020;323:1353–68. https://doi.org/10.1001/jama.2020.1906. DOI: https://doi.org/10.1001/jama.2019.22087
Jhund PS, Ponikowski P, Docherty KF, Gasparyan SB, Böhm M, Chiang CE, et al. Dapagliflozin and Recurrent Heart Failure Hospitalizations in Heart Failure with Reduced Ejection Fraction: An Analysis of DAPA-HF. Circulation 2021;143:1962–72. https://doi.org/10.1161/CIRCULATIONAHA.121.053659. DOI: https://doi.org/10.1161/CIRCULATIONAHA.121.053659
Butt JH, Nicolau JC, Verma S, Docherty KF, Petrie MC, Inzucchi SE, et al. Efficacy and safety of dapagliflozin according to aetiology in heart failure with reduced ejection fraction: insights from the DAPA-HF trial. Eur J Heart Fail 2021;23:601–13. https://doi.org/10.1002/ejhf.2124. DOI: https://doi.org/10.1002/ejhf.2124
Butt JH, Docherty KF, Jhund PS, de Boer RA, Böhm M, Desai AS, et al. Dapagliflozin and atrial fibrillation in heart failure with reduced ejection fraction: insights from DAPA-HF. Eur J Heart Fail 2022;24:513–25. https://doi.org/10.1002/ejhf.2381. DOI: https://doi.org/10.1002/ejhf.2381
Berg DD, Jhund PS, Docherty KF, Murphy SA, Verma S, Inzucchi SE, et al. Time to Clinical Benefit of Dapagliflozin and Significance of Prior Heart Failure Hospitalization in Patients with Heart Failure with Reduced Ejection Fraction. JAMA Cardiol 2021;6:499–507. https://doi.org/10.1001/jamacardio.2020.7585. DOI: https://doi.org/10.1001/jamacardio.2020.7585
Dewan P, Docherty KF, Bengtsson O, de Boer RA, Desai AS, Drozdz J, et al. Effects of dapagliflozin in heart failure with reduced ejection fraction and chronic obstructive pulmonary disease: an analysis of DAPA-HF. Eur J Heart Fail 2021;23:632–43. https://doi.org/10.1002/ejhf.2083. DOI: https://doi.org/10.1002/ejhf.2083
Jhund PS, Solomon SD, Docherty KF, Heerspink HJL, Anand IS, Böhm M, et al. Efficacy of Dapagliflozin on Renal Function and Outcomes in Patients with Heart Failure with Reduced Ejection Fraction: Results of DAPA-HF. Circulation 2021;143:298–309. https://doi.org/10.1161/CIRCULATIONAHA.120.050391. DOI: https://doi.org/10.1161/CIRCULATIONAHA.120.050391
Solomon SD, Jhund PS, Claggett BL, Dewan P, Køber L, Kosiborod MN, et al. Effect of Dapagliflozin in Patients With HFrEF Treated With Sacubitril/Valsartan: The DAPA-HF Trial. JACC Heart Fail 2020;8:811–8. https://doi.org/10.1016/j.jchf.2020.04.008. DOI: https://doi.org/10.1016/j.jchf.2020.04.008
Ansar F, Azzam A, Zafar U, Ahmed S, Ghauri FK, Khan AM, et al. Empagliflozin and Cardiovascular Outcomes: A Systematic Review of Randomized Controlled Trials in Populations With Diabetes and Heart Failure. Cureus 2025. https://doi.org/10.7759/cureus.90150. DOI: https://doi.org/10.7759/cureus.90150
Docherty KF, McMurray JJV. SOLOIST-WHF and updated meta-analysis: sodium–glucose co-transporter 2 inhibitors should be initiated in patients hospitalized with worsening heart failure. Eur J Heart Fail 2021;23:27–30. https://doi.org/10.1002/ejhf.2075. DOI: https://doi.org/10.1002/ejhf.2075