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SGLT2-Inhibitors on HFpEF Patients. Role of Ejection Fraction

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Abstract

Results from DELIVER trial and publication of EMPEROR-Preserved with sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with heart failure (HF) with ejection fraction (EF) > 40% represent a significant step forward in the treatment of HF with preserved EF (HFpEF). However, detailed analysis and attenuation of effect at higher EF levels have sparked some doubts about whether empagliflozin is effective across the entire spectrum of EF. HFpEF is no longer considered as one disease entity, but has been reconceptualized as a heterogenous group of phenotypes with derangements in multiple organ systems, driven by comorbidities. This heterogeneity suggests that it should not be considered as a single group in terms of treatment goals or clinical approach. Future research at the higher range of EF should ideally tailor investigations for unequivocally preserved EF (> 50%), consider the dynamic nature of EF over time, and use low-variability imaging techniques such as CMR. Furthermore, classifications based on pathophysiology and HF phenotypes beyond the EF construct will shape the design of future trials and help narrow down groups of patients who may respond to personalized treatment.

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References

  1. van Woerden G, van Veldhuisen DJ, Manintveld OC, van Empel VPM, Willems TP, de Boer RA, et al. Epicardial adipose tissue and outcome in heart failure with mid-range and preserved ejection fraction. Circ Heart Fail. 2021;CIRCHEARTFAILURE121009238.

  2. Triposkiadis F, Butler J, Abboud FM, Armstrong PW, Adamopoulos S, Atherton JJ, et al. The continuous heart failure spectrum: moving beyond an ejection fraction classification. Eur Heart J. 2019;40(26):2155–63.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, Fang JC, Fedson SE, Fonarow GC, Hayek SS, Hernandez AF, Khazanie P, Kittleson MM, Lee CS, Link MS, Milano CA, Nnacheta LC, Sandhu AT, Stevenson LW, Vardeny O, Vest AR, Yancy CW. 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. 2022 May 3;79(17):e263–e21. https://doi.org/10.1016/j.jacc.2021.12.012.

  4. Vasan RS, Xanthakis V, Lyass A, Andersson C, Tsao C, Cheng S, et al. Epidemiology of left ventricular systolic dysfunction and heart failure in the Framingham study: an echocardiographic study over 3 decades. JACC Cardiovasc Imaging. 2018;11(1):1–11.

    Article  PubMed  Google Scholar 

  5. Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, et al. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019;381(17):1609–20.

    Article  CAS  PubMed  Google Scholar 

  6. Bozkurt B, Ezekowitz J. Substance and substrate: LVEF and sex subgroup analyses of PARAGON-HF and PARADIGM-HF trials. Circulation. 2020;141(5):362–6.

    Article  PubMed  Google Scholar 

  7. Gori M, Senni M, Claggett B, Liu J, Maggioni AP, Zile M, et al. Integrating high-sensitivity troponin T and sacubitril/valsartan treatment in HFpEF: the PARAGON-HF trial. JACC Heart Fail. 2021;9(9):627–35.

    Article  PubMed  Google Scholar 

  8. Vaduganathan M, Claggett BL, Desai AS, Anker SD, Perrone SV, Janssens S, et al. Prior heart failure hospitalization, clinical outcomes, and response to sacubitril/valsartan compared with valsartan in HFpEF. J Am Coll Cardiol. 2020;75(3):245–54.

    Article  CAS  PubMed  Google Scholar 

  9. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383–92.

    Article  CAS  PubMed  Google Scholar 

  10. de Denus S, O’Meara E, Desai AS, Claggett B, Lewis EF, Leclair G, et al. Spironolactone Metabolites in TOPCAT - new insights into regional variation. N Engl J Med. 2017;376(17):1690–2.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Cohen JB, Schrauben SJ, Zhao L, Basso MD, Cvijic ME, Li Z, et al. Clinical phenogroups in heart failure with preserved ejection fraction: detailed phenotypes, prognosis, and response to spironolactone. JACC Heart Fail. 2020;8(3):172–84.

    Article  PubMed  PubMed Central  Google Scholar 

  12. McMurray JJV, Docherty KF, Jhund PS. Dapagliflozin in patients with heart failure and reduced ejection fraction. Reply N Engl J Med. 2020;382(10):973.

    PubMed  Google Scholar 

  13. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383(15):1413–24.

    Article  CAS  PubMed  Google Scholar 

  14. Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021;384(2):117–28.

    Article  CAS  PubMed  Google Scholar 

  15. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Bohm M, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451–61.

    Article  CAS  PubMed  Google Scholar 

  16. Dewan P, Solomon SD, Jhund PS, Inzucchi SE, Kober L, Kosiborod MN, et al. Efficacy and safety of sodium-glucose co-transporter 2 inhibition according to left ventricular ejection fraction in DAPA-HF. Eur J Heart Fail. 2020;22(7):1247–58.

    Article  CAS  PubMed  Google Scholar 

  17. Butler J, Packer M, Filippatos G, Ferreira JP, Zeller C, Schnee J, et al. Effect of empagliflozin in patients with heart failure across the spectrum of left ventricular ejection fraction. Eur Heart J. 2022;43(5):416–26.

    Article  CAS  PubMed  Google Scholar 

  18. Gevaert AB, Kataria R, Zannad F, Sauer AJ, Damman K, Kavita Sharma K, Shah SJ, Van Spall HCG. Heart failure with preserved ejection fraction: recent concepts in diagnosis, mechanisms and management Heart. 2022;0:1–9. https://doi.org/10.1136/heartjnl-2021-319605.

  19. Shah SJ, Katz DH, Selvaraj S, Burke MA, Yancy CW, Gheorghiade M, et al. Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation. 2015;131(3):269–79.

    Article  PubMed  Google Scholar 

  20. Obokata M, Reddy YNV, Pislaru SV, Melenovsky V, Borlaug BA. Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation. 2017;136(1):6–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Packer M, Lam CSP, Lund LH, Maurer MS, Borlaug BA. Characterization of the inflammatory-metabolic phenotype of heart failure with a preserved ejection fraction: a hypothesis to explain influence of sex on the evolution and potential treatment of the disease. Eur J Heart Fail. 2020;22(9):1551–67.

    Article  PubMed  Google Scholar 

  22. Pabel S, Hamdani N, Sossalla S. A mechanistic rationale for the investigation of sodium-glucose co-transporter 2 inhibitors in heart failure with preserved ejection fraction. Letter regarding the article ‘Baseline characteristics of patients with heart failure with preserved ejection fraction in the EMPEROR-Preserved trial.’ Eur J Heart Fail. 2021;23(5):841.

    Article  CAS  PubMed  Google Scholar 

  23. Salerno M, Kramer CM. Myocardial extracellular volume: unifying form and function in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2016;67(15):1826–8.

    Article  PubMed  Google Scholar 

  24. Aoki T, Fukumoto Y, Sugimura K, Oikawa M, Satoh K, Nakano M, et al. Prognostic impact of myocardial interstitial fibrosis in non-ischemic heart failure. Comparison between preserved and reduced ejection fraction heart failure. Circ J. 2011;75(11):2605–13.

    Article  CAS  PubMed  Google Scholar 

  25. Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, Garcia-Ropero A, Ishikawa K, Watanabe S, et al. Empagliflozin ameliorates diastolic dysfunction and left ventricular fibrosis/stiffness in nondiabetic heart failure: a multimodality study. JACC Cardiovasc Imaging. 2021;14(2):393–407.

    Article  PubMed  Google Scholar 

  26. Santos-Gallego CG, Vargas-Delgado AP, Requena-Ibanez JA, Garcia-Ropero A, Mancini D, Pinney S, et al. Randomized trial of empagliflozin in nondiabetic patients with heart failure and reduced ejection fraction. J Am Coll Cardiol. 2021;77(3):243–55.

    Article  CAS  PubMed  Google Scholar 

  27. Requena-Ibanez JA, Santos-Gallego CG, Rodriguez-Cordero A, Vargas-Delgado AP, Mancini D, Sartori S, et al. Mechanistic insights of empagliflozin in nondiabetic patients with HFrEF: from the EMPA-TROPISM study. JACC Heart Fail. 2021;9(8):578–89.

    Article  PubMed  Google Scholar 

  28. Packer M, Kitzman DW. Obesity-related heart failure with a preserved ejection fraction: the mechanistic rationale for combining inhibitors of aldosterone, neprilysin, and sodium-glucose cotransporter-2. JACC Heart Fail. 2018;6(8):633–9.

    Article  PubMed  Google Scholar 

  29. Iacobellis G. Epicardial adipose tissue in contemporary cardiology. Nat Rev Cardiol. 2022 Mar 16;1–14. https://doi.org/10.1038/s41569-022-00679-9.

  30. van Woerden G, Gorter TM, Westenbrink BD, Willems TP, van Veldhuisen DJ, Rienstra M. Epicardial fat in heart failure patients with mid-range and preserved ejection fraction. Eur J Heart Fail. 2018;20(11):1559–66.

    Article  PubMed  Google Scholar 

  31. Requena-Ibanez JA, Santos-Gallego CG, Rodriguez Cordero AJ, Fardman B, Sartori S, Sanz J, et al. Not only how much, but also how to, when measuring epicardial adipose tissue. Magn Reson Imaging. 2022;86:149–51.

    Article  PubMed  Google Scholar 

  32. Fukuda T, Bouchi R, Terashima M, Sasahara Y, Asakawa M, Takeuchi T, et al. Ipragliflozin reduces epicardial fat accumulation in non-obese type 2 diabetic patients with visceral obesity: a pilot study. Diabetes Ther. 2017;8(4):851–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bouchi R, Terashima M, Sasahara Y, Asakawa M, Fukuda T, Takeuchi T, et al. Luseogliflozin reduces epicardial fat accumulation in patients with type 2 diabetes: a pilot study. Cardiovasc Diabetol. 2017;16(1):32.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Sato T, Aizawa Y, Yuasa S, Fujita S, Ikeda Y, Okabe M. The effect of dapagliflozin treatment on epicardial adipose tissue volume and p-wave indices: an ad-hoc analysis of the previous randomized clinical trial. J Atheroscler Thromb. 2020;27(12):1348–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yagi S, Hirata Y, Ise T, Kusunose K, Yamada H, Fukuda D, et al. Canagliflozin reduces epicardial fat in patients with type 2 diabetes mellitus. Diabetol Metab Syndr. 2017;9:78.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Diaz-Rodriguez E, Agra RM, Fernandez AL, Adrio B, Garcia-Caballero T, Gonzalez-Juanatey JR, et al. Effects of dapagliflozin on human epicardial adipose tissue: modulation of insulin resistance, inflammatory chemokine production, and differentiation ability. Cardiovasc Res. 2018;114(2):336–46.

    Article  CAS  PubMed  Google Scholar 

  37. Konstam MA, Kramer DG, Patel AR, Maron MS, Udelson JE. Left ventricular remodeling in heart failure: current concepts in clinical significance and assessment. JACC Cardiovasc Imaging. 2011;4(1):98–108.

    Article  PubMed  Google Scholar 

  38. Dhingra NK, Mistry N, Puar P, Verma R, Anker S, Mazer CD, et al. SGLT2 inhibitors and cardiac remodelling: a systematic review and meta-analysis of randomized cardiac magnetic resonance imaging trials. ESC Heart Fail. 2021;8(6):4693–700.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, Ishikawa K, Watanabe S, Picatoste B, et al. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. J Am Coll Cardiol. 2019;73(15):1931–44.

    Article  CAS  PubMed  Google Scholar 

  40. Requena-Ibanez JA, Santos-Gallego CG, Rodriguez-Cordero A, Vargas-Delgado AP, Badimon JJ. Empagliflozin improves quality of life in nondiabetic HFrEF patients. Sub-analysis of the EMPATROPISM trial. Diabetes Metab Syndr. 2022;16(2):102417.

    Article  CAS  PubMed  Google Scholar 

  41. Lee MMY, Brooksbank KJM, Wetherall K, Mangion K, Roditi G, Campbell RT, et al. Effect of empagliflozin on left ventricular volumes in patients with type 2 diabetes, or prediabetes, and heart failure with reduced ejection fraction (SUGAR-DM-HF). Circulation. 2021;143(6):516–25.

    Article  CAS  PubMed  Google Scholar 

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Funding

Dr. Requena was funded by Sociedad Española de Cardiología through a mobility grant (SEC/PRS-MOV-INT 21/004).

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  1. Atherothrombosis Research Unit, Icahn School of Medicine at Mount Sinai, Mount Sinai Heart, New York, NY, 10029, USA

    Juan Antonio Requena-Ibanez, Carlos G. Santos-Gallego, M. Urooj Zafar & Juan J. Badimon

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  1. Juan Antonio Requena-Ibanez
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Requena-Ibanez, J.A., Santos-Gallego, C.G., Zafar, M.U. et al. SGLT2-Inhibitors on HFpEF Patients. Role of Ejection Fraction. Cardiovasc Drugs Ther 37, 989–996 (2023). https://doi.org/10.1007/s10557-022-07371-7

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