Counteracting heart failure with diabetes drugs: a review into the pharmacokinetic and pharmacodynamic properties

References

• Salah HM, Minhas AMK, Khan MS, et al. Trends in hospitalizations for heart failure, acute myocardial infarction, and stroke in the United States from 2004 to 2018. Am Heart J. 2022;243:103–109.
   PubMed Web of Science ®Google Scholar
• McDonagh TA, Metra M, and Adamo M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599–3726.
   PubMed Web of Science ®Google Scholar
• Heidenreich PA, Bozkurt B, and Aguilar D, et al. 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. Circulation. 2022;145(18):e895–e1032.
   PubMed Web of Science ®Google Scholar
• Scheen AJ. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015;75(1):33–59.
   PubMed Web of Science ®Google Scholar
• Scheen AJ. Sodium-glucose co-transporter type 2 inhibitors for the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2020;16(10):556–577.
   PubMed Web of Science ®Google Scholar
• Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–2128.
   PubMed Web of Science ®Google Scholar
• Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–657.
   PubMed Web of Science ®Google Scholar
• Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–357.
   PubMed Web of Science ®Google Scholar
• Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383(15):1425–1435.
   PubMed Web of Science ®Google Scholar
• Seferovic PM, Fragasso G, and Petrie M, et al. Sodium-glucose co-transporter 2 inhibitors in heart failure: beyond glycaemic control. A position paper of the heart failure association of the European society of cardiology. Eur J Heart Fail. 2020;22(9):1495–1503.
   PubMed Web of Science ®Google Scholar
• Giugliano D, Meier JJ, Esposito K. Heart failure and type 2 diabetes: from cardiovascular outcome trials, with hope. Diabetes Obes Metab. 2019;21(5):1081–1087.
   PubMed Web of Science ®Google Scholar
• Lytvyn Y, Bjornstad P, Udell JA, et al. Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials. Circulation. 2017;136(17):1643–1658.
   PubMed Web of Science ®Google Scholar
• Butler J, Hamo CE, Filippatos G, et al. The potential role and rationale for treatment of heart failure with sodium-glucose co-transporter 2 inhibitors. Eur J Heart Fail. 2017;19(11):1390–1400.
   PubMed Web of Science ®Google Scholar
• McMurray JJV, Solomon SD, and Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995–2008.
   PubMed Web of Science ®Google Scholar
• Packer M, Anker SD, and Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383(15):1413–1424 .
   PubMed Web of Science ®Google Scholar
• Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396(10254):819–829.
   PubMed Web of Science ®Google Scholar
• Anker SD, Butler J, and Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451–1461.
   PubMed Web of Science ®Google Scholar
• Giugliano D, Longo M, Scappaticcio L, et al. SGLT-2 inhibitors and cardiorenal outcomes in patients with or without type 2 diabetes: a meta-analysis of 11 CVOTs. Cardiovasc Diabetol. 2021;20(1):236.
   PubMed Web of Science ®Google Scholar
• Scheen AJ. Evaluating SGLT2 inhibitors for type 2 diabetes: pharmacokinetic and toxicological considerations. Expert Opin Drug Metab Toxicol. 2014;10(5):647–663.
   PubMed Web of Science ®Google Scholar
• Galli M, D’Amario D, Sofia C, et al. Clinical potential relevance of metabolic properties of SGLT2 inhibitors in patients with heart failure. Expert Opin Drug Metab Toxicol. 2018;14(12):1273–1285.
   PubMed Web of Science ®Google Scholar
• Scheen AJ. Drug-drug interactions with SGLT-2 inhibitors, new oral glucose-lowering agents for the management of type 2 diabetes. Clin Pharmacokinet. 2014;53(4):295–304.
   PubMed Web of Science ®Google Scholar
• Kasichayanula S, Liu X, Lacreta F, et al. Clinical pharmacokinetics and pharmacodynamics of dapagliflozin, a selective inhibitor of sodium-glucose co-transporter type 2. Clin Pharmacokinet. 2014;53(1):17–27.
   PubMed Web of Science ®Google Scholar
• Maranghi M, Carnovale A, Durante C, et al. Pharmacokinetics, pharmacodynamics and clinical efficacy of dapagliflozin for the treatment of type 2 diabetes. Expert Opin Drug Metab Toxicol. 2015;11(1):125–137.
   PubMed Web of Science ®Google Scholar
• Garcia-Ropero A, Badimon JJ, Santos-Gallego CG. The pharmacokinetics and pharmacodynamics of SGLT2 inhibitors for type 2 diabetes mellitus: the latest developments. Expert Opin Drug Metab Toxicol. 2018;14(12):1287–1302.
   PubMed Web of Science ®Google Scholar
• Sotirakos S. Evaluation of dapagliflozin in the treatment of heart failure. Future Cardiol. 2021;17(3):415–425.
   PubMed Web of Science ®Google Scholar
• Scheen AJ. Pharmacokinetics, pharmacodynamics and clinical use of SGLT2 inhibitors in patients with type 2 diabetes mellitus and chronic kidney disease. Clin Pharmacokinet. 2015;54(7):691–708.
   PubMed Web of Science ®Google Scholar
• Kasichayanula S, Liu X, Pe Benito M, et al. The influence of kidney function on dapagliflozin exposure, metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus. Br J Clin Pharmacol. 2013;76(3):432–444.
   PubMed Web of Science ®Google Scholar
• Kroonen M, Koomen JV, Petrykiv SI, et al. Exposure-response relationships for the sodium-glucose co-transporter-2 inhibitor dapagliflozin with regard to renal risk markers. Diabetes Obes Metab. 2020;22(6):916–921.
   PubMed Web of Science ®Google Scholar
• Kasichayanula S, Liu X, Zhang W, et al. Influence of hepatic impairment on the pharmacokinetics and safety profile of dapagliflozin: an open-label, parallel-group, single-dose study. Clin Ther. 2011;33(11):1798–1808.
   PubMed Web of Science ®Google Scholar
• van der Aart-van der Beek AB, Koomen JV, Dekkers CCJ, et al. Evaluation of the pharmacokinetics and exposure-response relationship of dapagliflozin in patients without diabetes and with chronic kidney disease. Clin Pharmacokinet. 2021;60(4):517–525.
   PubMed Web of Science ®Google Scholar
• van der Walt JS, Hong Y, Zhang L, et al. A nonlinear mixed effects pharmacokinetic model for dapagliflozin and dapagliflozin 3- O -glucuronide in renal or hepatic impairment. CPT Pharmacometrics Syst Pharmacol. 2013;2(5):e42.
   PubMedGoogle Scholar
• Kasichayanula S, Chang M, Liu X, et al. Lack of pharmacokinetic interactions between dapagliflozin and simvastatin, valsartan, warfarin, or digoxin. Adv Ther. 2012;29(2):163–177.
   PubMed Web of Science ®Google Scholar
• Wilcox CS, Shen W, Boulton DW, et al. Interaction between the sodium-glucose-linked transporter 2 inhibitor dapagliflozin and the loop diuretic bumetanide in normal human subjects. J Am Heart Assoc. 2018;7(4).
   Web of Science ®Google Scholar
• Ibrahim A, Ghaleb R, Mansour H, et al. Safety and efficacy of adding dapagliflozin to furosemide in type 2 diabetic patients with decompensated heart failure and reduced ejection fraction. Front Cardiovasc Med. 2020;7:602251.
   PubMed Web of Science ®Google Scholar
• Eickhoff MK, Olsen FJ, Frimodt-Moller M, et al. Effect of dapagliflozin on cardiac function in people with type 2 diabetes and albuminuria - A double blind randomized placebo-controlled crossover trial. J Diabetes Complications. 2020;34(7):107590.
   PubMed Web of Science ®Google Scholar
• Tanaka H, Soga F, Tatsumi K, et al. Positive effect of dapagliflozin on left ventricular longitudinal function for type 2 diabetic mellitus patients with chronic heart failure. Cardiovasc Diabetol. 2020;19(1):6.
   PubMed Web of Science ®Google Scholar
• Solini A, Giannini L, Seghieri M, et al. Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: a pilot study. Cardiovasc Diabetol. 2017;16(1):138.
   PubMed Web of Science ®Google Scholar
• Scheen AJ. Effect of SGLT2 inhibitors on the sympathetic nervous system and blood pressure. Curr Cardiol Rep. 2019;21(8):70.
   PubMed Web of Science ®Google Scholar
• Nassif ME, Windsor SL, Tang F, et al. Dapagliflozin effects on biomarkers, symptoms, and functional status in patients with heart failure with reduced ejection fraction: the DEFINE-HF trial. Circulation. 2019;140(18):1463–1476.
   PubMed Web of Science ®Google Scholar
• Furtado RHM, Bonaca MP, Raz I, et al. Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes mellitus and previous myocardial infarction. Circulation. 2019;139(22):2516–2527.
   PubMed Web of Science ®Google Scholar
• Cahn A, Mosenzon O, Wiviott SD, et al. Efficacy and safety of dapagliflozin in the elderly: analysis from the DECLARE-TIMI 58 study. Diabetes Care. 2020;43(2):468–475.
   PubMed Web of Science ®Google Scholar
• Zelniker TA, Raz I, Mosenzon O, et al. Effect of dapagliflozin on cardiovascular outcomes according to baseline kidney function and albuminuria status in patients with type 2 diabetes: a prespecified secondary analysis of a randomized clinical trial. JAMA Cardiol. 2021;6(7):801–810.
   PubMed Web of Science ®Google Scholar
• Zelniker TA, Morrow DA, Mosenzon O, et al. Relationship between baseline cardiac biomarkers and cardiovascular death or hospitalization for heart failure with and without sodium–glucose co-transporter 2 inhibitor therapy in DECLARE-TIMI 58. Eur J Heart Fail. 2021;23(6):1026–1036.
   PubMed Web of Science ®Google Scholar
• Berg D, Wiviott S, Goodrich E, et al. Mediation analysis for dapagliflozin and the reduction in hospitalization for heart failure in DECLARE-TIMI 58 (Abstract. J Am Coll Cardiol. 2021;77(18):869.
   Web of Science ®Google Scholar
• Kondo H, Takahashi N. Reduced hospitalization for heart failure using anti-diabetic drug dapagliflozin: implications of DECLARE-TIMI 58 for the basic science community. Cardiovasc Res. 2019;115(6):e54–e57.
   PubMed Web of Science ®Google Scholar
• Kato ET, Silverman MG, Mosenzon O, et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation. 2019;139(22):2528–2536.
   PubMed Web of Science ®Google Scholar
• Verma S, McMurray JJV. The serendipitous story of SGLT2 inhibitors in heart failure. Circulation. 2019;139(22):2537–2541.
   PubMed Web of Science ®Google Scholar
• Berg DD, Jhund PS, Docherty KF, 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(5):499–507.
   PubMed Web of Science ®Google Scholar
• Docherty KF, Jhund PS, Claggett B, et al. Extrapolating long-term event-free and overall survival with dapagliflozin in patients with heart failure and reduced ejection fraction: an exploratory analysis of a phase 3 randomized clinical trial. JAMA Cardiol. 2021;6(11):1298–1305.
   PubMed Web of Science ®Google Scholar
• Jhund PS, Ponikowski P, Docherty KF, et al. Dapagliflozin and recurrent heart failure hospitalizations in heart failure with reduced ejection fraction: an analysis of DAPA-HF. Circulation. 2021;143(20):1962–1972.
   PubMed Web of Science ®Google Scholar
• Docherty KF, Simpson J, Jhund PS, et al. Effect of dapagliflozin, compared with placebo, according to baseline risk in DAPA-HF. JACC Heart Fail. 2022;10(2):104–118.
   PubMed Web of Science ®Google Scholar
• Butt JH, Nicolau JC, Verma S, 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(4):601–613.
   PubMed Web of Science ®Google Scholar
• Butt JH, Adamson C, Docherty KF, et al. Efficacy and safety of dapagliflozin in heart failure with reduced ejection fraction according to N-terminal pro-B-type natriuretic peptide: insights from the DAPA-HF trial. Circ Heart Fail. 2021;14(12):e008837.
   PubMed Web of Science ®Google Scholar
• Berg DD, Docherty KF, Sattar N, et al. Serial assessment of high-sensitivity cardiac troponin and the effect of dapagliflozin in patients with heart failure with reduced ejection fraction: an analysis of the DAPA-HF trial. Circulation. 2022;145(3):158–169.
   PubMed Web of Science ®Google Scholar
• Nassif ME, Windsor SL, Borlaug BA, et al. The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial. Nat Med. 2021;27(11):1954–1960.
   PubMed Web of Science ®Google Scholar
• Solomon SD, de Boer RA, DeMets D, et al. Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial. Eur J Heart Fail. 2021;23(7):1217–1225.
   PubMed Web of Science ®Google Scholar
• Cox ZL, Collins SP, Aaron M, et al. Efficacy and safety of dapagliflozin in acute heart failure: rationale and design of the DICTATE-AHF trial. Am Heart J. 2021;232:116–124.
   PubMed Web of Science ®Google Scholar
• Scheen AJ. Pharmacokinetic and pharmacodynamic profile of empagliflozin, a sodium glucose co-transporter 2 inhibitor. Clin Pharmacokinet. 2014;53(3):213–225.
   PubMed Web of Science ®Google Scholar
• Tomlinson B, Hu M, Zhang Y, et al. Evaluation of the pharmacokinetics, pharmacodynamics and clinical efficacy of empagliflozin for the treatment of type 2 diabetes. Expert Opin Drug Metab Toxicol. 2017;13(2):211–223.
   PubMed Web of Science ®Google Scholar
• Macha S, Mattheus M, Halabi A, et al. Pharmacokinetics, pharmacodynamics and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in subjects with renal impairment. Diabetes Obes Metab. 2014;16(3):215–222.
   PubMed Web of Science ®Google Scholar
• Macha S, Rose P, Mattheus M, et al. Pharmacokinetics, safety and tolerability of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with hepatic impairment. Diabetes Obes Metab. 2014;16(2):118–123.
   PubMed Web of Science ®Google Scholar
• Macha S, Sennewald R, Rose P, et al. Lack of clinically relevant drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and verapamil, ramipril, or digoxin in healthy volunteers. Clin Ther. 2013;35(3):226–235.
   PubMed Web of Science ®Google Scholar
• Heise T, Mattheus M, Woerle HJ, et al. Assessing pharmacokinetic interactions between the sodium glucose cotransporter 2 inhibitor empagliflozin and hydrochlorothiazide or torasemide in patients with type 2 diabetes mellitus: a randomized, open-label, crossover study. Clin Ther. 2015;37(4):793–803.
   PubMed Web of Science ®Google Scholar
• Jensen J, Omar M, Kistorp C, et al. Metabolic effects of empagliflozin in heart failure: a randomized, double-blind, and placebo-controlled trial (Empire HF Metabolic). Circulation. 2021;143(22):2208–2210.
   PubMed Web of Science ®Google Scholar
• Boorsma EM, Beusekamp JC, Ter Maaten JM, et al. Effects of empagliflozin on renal sodium and glucose handling in patients with acute heart failure. Eur J Heart Fail. 2021;23(1):68–78.
   PubMed Web of Science ®Google Scholar
• Mordi NA, Mordi IR, Singh JS, et al. Renal and cardiovascular effects of SGLT2 inhibition in combination with loop diuretics in patients with type 2 diabetes and chronic heart failure: the RECEDE-CHF trial. Circulation. 2020;142(18):1713–1724.
   PubMed Web of Science ®Google Scholar
• Griffin M, Rao VS, Ivey-Miranda J, et al. Empagliflozin in heart failure: diuretic and cardiorenal effects. Circulation. 2020;142(11):1028–1039.
   PubMed Web of Science ®Google Scholar
• Packer M, Anker SD, Butler J, et al. Empagliflozin in patients with heart failure, reduced ejection fraction, and volume overload: EMPEROR-Reduced trial. J Am Coll Cardiol. 2021;77(11):1381–1392.
   PubMed Web of Science ®Google Scholar
• Thirunavukarasu S, Jex N, Chowdhary A, et al. Empagliflozin treatment is associated with improvements in cardiac energetics and function and reductions in myocardial cellular volume in patients with type 2 diabetes. Diabetes. 2021;70(12):2810–2822.
   PubMed Web of Science ®Google Scholar
• Lee MMY, Brooksbank KJM, Wetherall K, 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):516–525.
   PubMed Web of Science ®Google Scholar
• Kolwelter J, Bosch A, Jung S, et al. Effects of the sodium-glucose cotransporter 2 inhibitor empagliflozin on vascular function in patients with chronic heart failure. ESC Heart Fail. 2021;8(6):5327–5337.
   PubMedGoogle Scholar
• Jensen J, Omar M, Kistorp C, et al. Effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate in patients with heart failure (Empire HF Renal): a prespecified substudy of a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2021;9(2):106–116.
   PubMed Web of Science ®Google Scholar
• Tamaki S, Yamada T, Watanabe T, et al. Effect of empagliflozin as an add-on therapy on decongestion and renal function in patients with diabetes hospitalized for acute decompensated heart failure: a prospective randomized controlled study. Circ Heart Fail. 2021;14(3):e007048.
   PubMed Web of Science ®Google Scholar
• Jensen J, Omar M, Kistorp C, et al. Twelve weeks of treatment with empagliflozin in patients with heart failure and reduced ejection fraction: a double-blinded, randomized, and placebo-controlled trial. Am Heart J. 2020;228:47–56.
   PubMed Web of Science ®Google Scholar
• Abraham WT, Lindenfeld J, Ponikowski P, et al. Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes. Eur Heart J. 2021;42(6):700–710.
   PubMed Web of Science ®Google Scholar
• Santos-Gallego CG, Vargas-Delgado AP, Requena-Ibanez JA, et al. Randomized trial of empagliflozin in nondiabetic patients with heart failure and reduced ejection fraction. J Am Coll Cardiol. 2021;77(3):243–255.
   PubMed Web of Science ®Google Scholar
• Scheen AJ. Reduction in cardiovascular and all-cause mortality in the EMPA-REG OUTCOME trial: a critical analysis. Diabetes Metab. 2016;42(2):71–76.
   PubMed Web of Science ®Google Scholar
• McMurray J. EMPA-REG - the “diuretic hypothesis.” J Diabetes Complications. 2016;30(1):3–4.
   PubMed Web of Science ®Google Scholar
• Scheen AJ. Reappraisal of the diuretic effect of empagliflozin in EMPA-REG OUTCOME: comparison with classic diuretics. Diabetes Metab. 2016;42(4):224–233.
   PubMed Web of Science ®Google Scholar
• Fitchett D, Inzucchi SE, Zinman B, et al. Mediators of the improvement in heart failure outcomes with empagliflozin in the EMPA-REG OUTCOME trial. ESC Heart Fail. 2021;8(6):4517–4527.
   PubMedGoogle Scholar
• Pellicori P, Ofstad AP, Fitchett D, et al. Early benefits of empagliflozin in patients with or without heart failure: findings from EMPA-REG OUTCOME. ESC Heart Fail. 2020;7(6):3401–3407.
   Web of Science ®Google Scholar
• Fitchett D, Butler J, van de Borne P, et al. Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME(R) trial. Eur Heart J. 2018;39(5):363–370.
   PubMed Web of Science ®Google Scholar
• Pellicori P, Fitchett D, Kosiborod MN, et al. Use of diuretics and outcomes in patients with type 2 diabetes: findings from the EMPA-REG OUTCOME trial. Eur J Heart Fail. 2021;23(7):1085–1093.
   PubMed Web of Science ®Google Scholar
• Bohm M, Fitchett D, Ofstad AP, et al. Heart failure and renal outcomes according to baseline and achieved blood pressure in patients with type 2 diabetes: results from EMPA-REG OUTCOME. J Hypertens. 2020;38(9):1829–1840.
   PubMed Web of Science ®Google Scholar
• Scheen AJ. Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: focus on SGLT2 inhibitors and EMPA-REG OUTCOME. Diabetes Res Clin Pract. 2016;121:204–214.
   PubMed Web of Science ®Google Scholar
• Savarese G, Sattar N, Januzzi J, et al. Empagliflozin is associated with a lower risk of post-acute heart failure rehospitalization and mortality. Circulation. 2019;139(11):1458–1460.
   PubMed Web of Science ®Google Scholar
• Savarese G, Uijl A, Lund LH, et al. Empagliflozin in heart failure with predicted preserved versus reduced ejection fraction: data from the EMPA-REG OUTCOME trial. J Card Fail. 2021;27(8):888–895.
   PubMed Web of Science ®Google Scholar
• Anker SD, Butler J, Filippatos G, et al. Effect of empagliflozin on cardiovascular and renal outcomes in patients with heart failure by baseline diabetes status - Results from the EMPEROR-Reduced trial. Circulation. 2021;143(4):337–349.
   PubMed Web of Science ®Google Scholar
• Zannad F, Ferreira JP, Pocock SJ, et al. Cardiac and kidney benefits of empagliflozin in heart failure across the spectrum of kidney function: insights from EMPEROR-Reduced. Circulation. 2021;143(4):310–321.
   PubMed Web of Science ®Google Scholar
• Bohm M, Anker SD, Butler J, et al. Empagliflozin improves cardiovascular and renal outcomes in heart failure irrespective of systolic blood pressure. J Am Coll Cardiol. 2021;78(13):1337–1348.
   PubMed Web of Science ®Google Scholar
• Januzzi JL Jr., Zannad F, Anker SD, et al. Prognostic importance of NT-proBNP and effect of empagliflozin in the EMPEROR-Reduced trial. J Am Coll Cardiol. 2021;78(13):1321–1332.
   PubMed Web of Science ®Google Scholar
• Verma S, Dhingra NK, Butler J, et al. Empagliflozin in the treatment of heart failure with reduced ejection fraction in addition to background therapies and therapeutic combinations (EMPEROR-Reduced): a post-hoc analysis of a randomised, double-blind trial. Lancet Diabetes Endocrinol. 2022;10:35–45.
   PubMed Web of Science ®Google Scholar
• Butler J, Siddiqi TJ, Filippatos G, et al. Early benefit with empagliflozin in heart failure with preserved ejection fraction: insights from the EMPEROR-Preserved trial. Eur J Heart Fail. 2022. published on line. DOI:10.1002/ejhf.2420.
   Google Scholar
• Packer M, Butler J, Zannad F, et al. Effect of empagliflozin on worsening heart failure events in patients with heart failure and a preserved ejection fraction: the EMPEROR-Preserved trial. Circulation. 2021;144(16):1284–1294.
   PubMed Web of Science ®Google Scholar
• Hias J, Hellemans L, Walgraeve K, et al. SGLT2 inhibitors in older adults with heart failure with preserved ejection fraction. Drugs Aging. 2022. published on line.
   Web of Science ®Google Scholar
• Damman K, Beusekamp JC, Boorsma EM, et al. Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF). Eur J Heart Fail. 2020;22(4):713–722.
   PubMed Web of Science ®Google Scholar
• Voors AA, Angermann CE, Teerlink JR, et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med. 2022;28(3):568–574.
   PubMed Web of Science ®Google Scholar
• Nakagaito M, Imamura T, Joho S, et al. Efficacy of continuing SGLT2 Inhibitors on outcomes in patients with acute decompensated heart failure. Int Heart J. 2021;62(4):885–890.
   PubMed Web of Science ®Google Scholar
• Avgerinos I, Karagiannis T, Kakotrichi P, et al. Sotagliflozin for patients with type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2022;24(1):106–114.
   PubMed Web of Science ®Google Scholar
• Tager T, Frankenstein L, Atar D, et al. Influence of receptor selectivity on benefits from SGLT2 inhibitors in patients with heart failure: a systematic review and head-to-head comparative efficacy network meta-analysis. Clin Res Cardiol. 2022;111(4):428–439.
   PubMed Web of Science ®Google Scholar
• Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med. 2021;384(2):129–139.
   PubMed Web of Science ®Google Scholar
• Bhatt DL, Szarek M, and Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021;384(2):117–128.
   PubMed Web of Science ®Google Scholar
• Salah HM, Al’Aref SJ, Khan MS, et al. Efficacy and safety of sodium-glucose cotransporter 2 inhibitors initiation in patients with acute heart failure, with and without type 2 diabetes: a systematic review and meta-analysis. Cardiovasc Diabetol. 2022;21(1):20.
   PubMed Web of Science ®Google Scholar
• Bhattarai M, Salih M, Regmi M, et al. Association of sodium-glucose cotransporter 2 inhibitors with cardiovascular outcomes in patients with type 2 diabetes and other risk factors for cardiovascular disease: a meta-analysis. JAMA Network Open. 2022;5(1):e2142078.
   PubMed Web of Science ®Google Scholar
• Scheen AJ. An update on the safety of SGLT2 inhibitors. Expert Opin Drug Safety. 2019;18(4):295–311.
   PubMed Web of Science ®Google Scholar
• Shen L, Kristensen SL, Bengtsson O, et al. Dapagliflozin in HFrEF patients treated with mineralocorticoid receptor antagonists: an analysis of DAPA-HF. JACC Heart Fail. 2021;9(4):254–264.
   PubMed Web of Science ®Google Scholar
• Scheen AJ, Delanaye P. Acute renal injury events in diabetic patients treated with SGLT2 inhibitors: a comprehensive review with a special reference to RAAS blockers. Diabetes Metab. 2022;48(2):101315.
   PubMed Web of Science ®Google Scholar
• Lan NSR, Fegan PG, Yeap BB, et al. The effects of sodium-glucose cotransporter 2 inhibitors on left ventricular function: current evidence and future directions. ESC Heart Fail. 2019;6(5):927–935.
   PubMed Web of Science ®Google Scholar
• Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61(10):2108–2117.
   PubMed Web of Science ®Google Scholar
• Joshi SS, Singh T, Newby DE, et al. Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure. Heart. 2021;107(13):1032–1038.
   PubMed Web of Science ®Google Scholar
• Uthman L, Baartscheer A, Schumacher CA, et al. Direct cardiac actions of sodium glucose cotransporter 2 inhibitors target pathogenic mechanisms underlying heart failure in diabetic patients. Front Physiol. 2018;9:1575.
   PubMed Web of Science ®Google Scholar
• Olsen MB, Gregersen I, Sandanger O, et al. Targeting the inflammasome in cardiovascular disease. JACC Basic Transl Sci. 2022;7(1):84–98.
   PubMedGoogle Scholar
• Wang S, Zhang J, Wang Y, et al. NLRP3 inflammasome as a novel therapeutic target for heart failure. Anatol J Cardiol. 2022;26(1):15–22.
   PubMed Web of Science ®Google Scholar
• Byrne NJ, Matsumura N, Maayah ZH, et al. Empagliflozin blunts worsening cardiac dysfunction associated with reduced NLRP3 (nucleotide-binding domain-like receptor protein 3) inflammasome activation in heart failure. Circ Heart Fail. 2020;13(1):e006277.
   PubMed Web of Science ®Google Scholar
• Feijoo-Bandin S, Aragon-Herrera A, and Otero-Santiago M, et al. Role of sodium-glucose co-transporter 2 inhibitors in the regulation of inflammatory processes in animal models. Int J Mol Sci. 2022;23(10):5634.
   Web of Science ®Google Scholar
• Delanaye P, Scheen AJ. The diuretic effect of SGLT2 inhibitors: a comprehensive review of their specificities and their role in renal protection. Diabetes Metab. 2021;47(6):101285.
   PubMed Web of Science ®Google Scholar
• Jackson AM, Dewan P, Anand IS, et al. Dapagliflozin and diuretic use in patients with heart failure and reduced ejection fraction in DAPA-HF. Circulation. 2020;142(11):1040–1054.
   PubMed Web of Science ®Google Scholar
• Zannad F, Rossignol P. Cardiorenal syndrome revisited. Circulation. 2018;138(9):929–944.
   PubMed Web of Science ®Google Scholar
• Fontes-Carvalho R, Santos-Ferreira D, Raz I, et al. Protective effects of SGLT-2 inhibitors across the cardiorenal continuum: two faces of the same coin. Eur J Prev Cardiol. 2021. published on line. DOI:10.1093/eurjpc/zwab034.
   Web of Science ®Google Scholar
• Scheen AJ, Delanaye P. Acute renal injury events in diabetic patients treated with SGLT2 inhibitors: a comprehensive review with a special reference to RAAS blockers. Diabetes Metab. 2021;48(2):101315.
   PubMed Web of Science ®Google Scholar
• Bonnet F, Scheen AJ. Effects of SGLT2 inhibitors on systemic and tissue low-grade inflammation: potential contribution for diabetic complications and cardiovascular disease. Diabetes Metab. 2018;44(6):457–464.
   PubMed Web of Science ®Google Scholar
• Norre T, Grimm D, Simonsen U. Sacubitril/valsartan, sodium-glucose cotransporter 2 inhibitors and vericiguat for congestive heart failure therapy. Basic Clin Pharmacol Toxicol. 2022;130(4):425–438.
   PubMed Web of Science ®Google Scholar
• Aimo A, Pateras K, Stamatelopoulos K, et al. Relative efficacy of sacubitril-valsartan, vericiguat, and SGLT2 inhibitors in heart failure with reduced ejection fraction: a systematic review and network meta-analysis. Cardiovasc Drugs Ther. 2021;35(5):1067–1076.
   PubMed Web of Science ®Google Scholar
• Packer M, Anker SD, Butler J, et al. Influence of neprilysin inhibition on the efficacy and safety of empagliflozin in patients with chronic heart failure and a reduced ejection fraction: the EMPEROR-reduced trial. Eur Heart J. 2021;42(6):671–680.
   PubMed Web of Science ®Google Scholar
• Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019;381(17):1609–1620.
   PubMed Web of Science ®Google Scholar
• Teo YN, Teo YH, Syn NL, et al. Comparing sacubitril/valsartan against sodium-glucose cotransporter 2 inhibitors in heart failure: a systematic review and network meta-analysis. Clin Drug Investig. 2022;42(1):1–16.
   PubMed Web of Science ®Google Scholar
• Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med. 2021;385(24):2252–2263.
   PubMed Web of Science ®Google Scholar
• Sarafidis P, Papadopoulos CE, Kamperidis V, et al. Cardiovascular protection with sodium-glucose cotransporter-2 inhibitors and mineralocorticoid receptor antagonists in chronic kidney disease: a milestone achieved. Hypertension. 2021;77(5):1442–1455.
   PubMed Web of Science ®Google Scholar