Clinical pharmacology of SGLT-2 inhibitors in heart failure

References

• Trum M, Riechel J, Wagner S. Cardioprotection by SGLT2 Inhibitors-Does It All Come Down to Na(+)? Int J Mol Sci. 2021 Jul 26;22(15):7976.
   PubMed Web of Science ®Google Scholar
• McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021 Sep 21;42(36):3599–3726.
   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 Feb 26;107(13):1032–1038.
   PubMed Web of Science ®Google Scholar
• Lopaschuk GD, Verma S. Mechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: a State-of-the-Art Review. JACC Basic Transl Sci. 2020 Jun;5(6):632–644.
   PubMedGoogle Scholar
• Lahoz R, Fagan A, McSharry M, et al. Recurrent heart failure hospitalizations are associated with increased cardiovascular mortality in patients with heart failure in Clinical Practice Research Datalink. ESC Heart Fail. 2020 Aug;7(4):1688–1699.
   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 Nov 26;373(22):2117–2128.
   PubMed Web of Science ®Google Scholar
• Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020 Oct 8;383(15):1413–1424.
   PubMed Web of Science ®Google Scholar
• Anker SD, Butler J, Filippatos G, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021 Oct 14;385(16):1451–1461.
   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 Mar;28(3):568–574.
   PubMed Web of Science ®Google Scholar
• Group E-KC, Herrington WG, Staplin N, et al. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med 2022 Nov;4.
   PubMedGoogle Scholar
• Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019 Jan 24;380(4):347–357.
   PubMed Web of Science ®Google Scholar
• JJV M, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019 Nov 21;381(21):1995–2008.
   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 May 18;143(20):1962–1972.
   PubMed Web of Science ®Google Scholar
• Solomon SD, Jjv M, Claggett B, et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022 Sep 27;387(12):1089–1098.
   PubMed Web of Science ®Google Scholar
• Heerspink HJL, Stefansson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 Oct 8;383(15):1436–1446.
   PubMed Web of Science ®Google Scholar
• Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. N Engl J Med. 2021 Jan 14;384(2):117–128.
   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 Jan 14;384(2):129–139.
   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 Aug 17;377(7):644–657.
   PubMed Web of Science ®Google Scholar
• Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019 Jun 13;380(24):2295–2306.
   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 Oct 8;383(15):1425–1435.
   PubMed Web of Science ®Google Scholar
• Cosentino F, Cannon CP, Cherney DZI, et al. Efficacy of Ertugliflozin on Heart Failure-Related Events in Patients With Type 2 Diabetes Mellitus and Established Atherosclerotic Cardiovascular Disease: results of the VERTIS CV Trial. Circulation. 2020 Dec 8;142(23):2205–2215.
   PubMed Web of Science ®Google Scholar
• Williams DM, Nawaz A, Sodium-Glucose Co-Transporter EM. 2 (SGLT2) Inhibitors: are They All the Same? A Narrative Review of Cardiovascular Outcome Trials. Diabetes Ther. 2021 Jan;12(1):55–70.
   PubMed Web of Science ®Google Scholar
• Srinivas N, Sarnaik MK, Modi S, et al. Sodium-Glucose Cotransporter 2 (SGLT-2) Inhibitors: delving Into the Potential Benefits of Cardiorenal Protection Beyond the Treatment of Type-2 Diabetes Mellitus. Cureus. 2021 Aug;13(8):e16868.
   PubMed Web of Science ®Google Scholar
• Pabel S, Hamdani N, Luedde M, et al. SGLT2 Inhibitors and Their Mode of Action in Heart Failure-Has the Mystery Been Unravelled? Curr Heart Fail Rep. 2021 Oct;18(5):315–328.
   PubMed Web of Science ®Google Scholar
• Varadhan A, Stephan K, Gupta R, et al. Growing role of SGLT2i in heart failure: evidence from clinical trials. Expert Rev Clin Pharmacol. 2022 Feb;15(2):147–159.
   PubMed Web of Science ®Google Scholar
• Lopaschuk GD, Karwi QG, Tian R, et al. Cardiac Energy Metabolism in Heart Failure. Circ Res. 2021 May 14;128(10):1487–1513.
   PubMed Web of Science ®Google Scholar
• Ferrannini E, Baldi S, Frascerra S, et al. Shift to Fatty Substrate Utilization in Response to Sodium-Glucose Cotransporter 2 Inhibition in Subjects Without Diabetes and Patients With Type 2 Diabetes. Diabetes. 2016 May;65(5):1190–1195.
   PubMed Web of Science ®Google Scholar
• Verma S, Rawat S, Ho KL, et al. Empagliflozin Increases Cardiac Energy Production in Diabetes: novel Translational Insights Into the Heart Failure Benefits of SGLT2 Inhibitors. JACC Basic Transl Sci. 2018 Oct;3(5):575–587.
   PubMedGoogle Scholar
• Nielsen R, Moller N, Gormsen LC, et al. Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients. Circulation. 2019 Apr 30;139(18):2129–2141.
   PubMed Web of Science ®Google Scholar
• Wakabayashi S, Hisamitsu T, Nakamura TY. Regulation of the cardiac Na(+)/H(+) exchanger in health and disease. J Mol Cell Cardiol. 2013 Aug;61:68–76.
   PubMed Web of Science ®Google Scholar
• Baartscheer A, Schumacher CA, Wust RC, et al. Empagliflozin decreases myocardial cytoplasmic Na(+) through inhibition of the cardiac Na(+)/H(+) exchanger in rats and rabbits. Diabetologia. 2017 Mar;60(3):568–573.
   PubMed Web of Science ®Google Scholar
• Bertero E, Prates Roma L, Ameri P, et al. Cardiac effects of SGLT2 inhibitors: the sodium hypothesis. Cardiovasc Res. 2018 Jan 1;114(1):12–18.
   PubMed Web of Science ®Google Scholar
• Uthman L, Baartscheer A, Bleijlevens B, et al. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na(+)/H(+) exchanger, lowering of cytosolic Na(+) and vasodilation. Diabetologia. 2018 Mar;61(3):722–726.
   PubMed Web of Science ®Google Scholar
• Bell RM, Yellon DM. SGLT2 inhibitors: hypotheses on the mechanism of cardiovascular protection. Lancet Diabetes Endocrinol. 2018 6;Jun(6):435–437.
   Google Scholar
• Pitt B, Bhatt DL. Does SGLT1 Inhibition Add Benefit to SGLT2 Inhibition in Type 2 Diabetes? Circulation. 2021 Jul 6;144(1):4–6.
   PubMed Web of Science ®Google Scholar
• van Woerden G, van Veldhuisen DJ, Manintveld OC, et al. Epicardial Adipose Tissue and Outcome in Heart Failure With Mid-Range and Preserved Ejection Fraction. Circ Heart Fail. 2022 Mar;15(3):e009238.
   PubMed Web of Science ®Google Scholar
• Van de Voorde J, Pauwels B, Boydens C, et al. Adipocytokines in relation to cardiovascular disease. Metabolism. 2013 Nov;62(11):1513–1521.
   PubMed Web of Science ®Google Scholar
• Sato T, Aizawa Y, Yuasa S, et al. The effect of dapagliflozin treatment on epicardial adipose tissue volume. Cardiovasc Diabetol. 2018 Jan 4;17(1):6.
   PubMed Web of Science ®Google Scholar
• Wu P, Wen W, Li J, et al. Systematic Review and Meta-Analysis of Randomized Controlled Trials on the Effect of SGLT2 Inhibitor on Blood Leptin and Adiponectin Level in Patients with Type 2 Diabetes. Horm Metab Res. 2019 Aug;51(8):487–494.
   PubMed Web of Science ®Google Scholar
• Requena-Ibanez JA, Santos-Gallego CG, Rodriguez-Cordero A, et al. Mechanistic Insights of Empagliflozin in Nondiabetic Patients With HFrEF: from the EMPA-TROPISM Study. JACC Heart Fail. 2021 Aug;9(8):578–589.
   PubMed Web of Science ®Google Scholar
• Luo G, Jian Z, Zhu Y, et al. Sirt1 promotes autophagy and inhibits apoptosis to protect cardiomyocytes from hypoxic stress. Int J Mol Med. 2019 May;43(5):2033–2043.
   PubMed Web of Science ®Google Scholar
• Cardioprotective PM. Effects of Sirtuin-1 and Its Downstream Effectors: potential Role in Mediating the Heart Failure Benefits of SGLT2 (Sodium-Glucose Cotransporter 2) Inhibitors. Circ Heart Fail. 2020 Sep;13(9):e007197.
   PubMed Web of Science ®Google Scholar
• Esterline RL, Vaag A, Oscarsson J, et al. MECHANISMS IN ENDOCRINOLOGY: SGLT2 inhibitors: clinical benefits by restoration of normal diurnal metabolism? Eur J Endocrinol. 2018 Apr;178(4):R113–R125.
   PubMedGoogle Scholar
• Santulli G. Cardioprotective effects of autophagy: eat your heart out, heart failure! Sci Transl Med. 2018 May 30;10(443):eaau00462.
   Google Scholar
• Zhou H, Wang S, Zhu P, et al. Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission. Redox Biol. 2018 May;15:335–346.
   PubMed Web of Science ®Google Scholar
• Hawley SA, Ford RJ, Smith BK, et al. The Na+/Glucose Cotransporter Inhibitor Canagliflozin Activates AMPK by Inhibiting Mitochondrial Function and Increasing Cellular AMP Levels. Diabetes. 2016 Sep;65(9):2784–2794.
   PubMed Web of Science ®Google Scholar
• Li C, Zhang J, Xue M, et al. SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart. Cardiovasc Diabetol. 2019 Feb 2;18(1):15.
   PubMedGoogle Scholar
• Uthman L, Homayr A, Juni RP, et al. Empagliflozin and dapagliflozin reduce ROS generation and restore NO bioavailability in tumor necrosis factor alpha-stimulated human coronary arterial endothelial cells. Cell Physiol Biochem. 2019;53(5):865–886.
   PubMedGoogle Scholar
• Verma S, Garg A, Yan AT, et al. Effect of empagliflozin on left ventricular mass and diastolic function in individuals with diabetes: an important clue to the EMPA-REG OUTCOME Trial? Diabetes Care. 2016 Dec;39(12):e212–e213.
   PubMed Web of Science ®Google Scholar
• Shao Q, Meng L, Lee S, et al. Empagliflozin, a sodium glucose co-transporter-2 inhibitor, alleviates atrial remodeling and improves mitochondrial function in high-fat diet/streptozotocin-induced diabetic rats. Cardiovasc Diabetol. 2019 Nov 28;18(1):165.
   PubMed Web of Science ®Google Scholar
• Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, et al. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. J Am Coll Cardiol. 2019 Apr 23;73(15):1931–1944.
   PubMed Web of Science ®Google Scholar
• Gaspari T, Spizzo I, Liu H, et al. Dapagliflozin attenuates human vascular endothelial cell activation and induces vasorelaxation: a potential mechanism for inhibition of atherogenesis. Diab Vasc Dis Res. 2018 Jan;15(1):64–73.
   PubMed Web of Science ®Google Scholar
• Li H, Shin SE, Seo MS, et al. The anti-diabetic drug dapagliflozin induces vasodilation via activation of PKG and Kv channels. Life Sci. 2018 Mar;15(197):46–55.
   Google Scholar
• Durante W, Behnammanesh G, Peyton KJ. Effects of sodium-glucose co-transporter 2 inhibitors on vascular cell function and Arterial Remodeling. Int J Mol Sci. 2021 Aug 16;22(16):8786.
   PubMed Web of Science ®Google Scholar
• Bosch A, Ott C, Jung S, et al. How does empagliflozin improve arterial stiffness in patients with type 2 diabetes mellitus? Sub analysis of a clinical trial. Cardiovasc Diabetol. 2019 Mar 29;18(1):44.
   PubMedGoogle Scholar
• Tsimihodimos V, Filippatos TD, Filippas-Ntekouan S, et al. Renoprotective effects of SGLT2 inhibitors: beyond glucose reabsorption inhibition. Curr Vasc Pharmacol. 2017;15(2):96–102.
   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 Nov 3;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 Sep 15;142(11):1028–1039.
   PubMed Web of Science ®Google Scholar
• Activation PM. and Inhibition of sodium-hydrogen exchanger is a mechanism that links the pathophysiology and treatment of diabetes mellitus with that of heart failure. Circulation. 2017 Oct 17;136(16):1548–1559.
   PubMed Web of Science ®Google Scholar
• Thomas MC. Renal effects of dapagliflozin in patients with type 2 diabetes. Ther Adv Endocrinol Metab. 2014 Jun;5(3):53–61.
   PubMedGoogle Scholar
• Fathi A, Vickneson K, Singh JS. SGLT2-inhibitors; more than just glycosuria and diuresis. Heart Fail Rev. 2021 May;26(3):623–642.
   PubMed Web of Science ®Google Scholar
• Filippatos TD, Liontos A, Papakitsou I, et al. SGLT2 inhibitors and cardioprotection: a matter of debate and multiple hypotheses. Postgrad Med. 2019 Mar;131(2):82–88.
   PubMed Web of Science ®Google Scholar
• Hallow KM, Helmlinger G, Greasley PJ, et al. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes Metab. 2018 Mar;20(3):479–487.
   PubMed Web of Science ®Google Scholar
• Chino Y, Samukawa Y, Sakai S, et al. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. Biopharm Drug Dispos. 2014 Oct;35(7):391–404.
   PubMed Web of Science ®Google Scholar
• Hare JM, Johnson RJ. Uric acid predicts clinical outcomes in heart failure: insights regarding the role of xanthine oxidase and uric acid in disease pathophysiology. Circulation. 2003 Apr 22;107(15):1951–1953.
   PubMed Web of Science ®Google Scholar
• Sanidas EA, Papadopoulos DP, Hatziagelaki E, et al. Sodium glucose cotransporter 2 (SGLT2) inhibitors across the spectrum of Hypertension. Am J Hypertens. 2020 Mar 13;33(3):207–213.
   PubMed Web of Science ®Google Scholar
• Liakos CI, Papadopoulos DP, Sanidas EA, et al. Blood pressure-lowering effect of newer antihyperglycemic Agents (SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 Inhibitors). Am J Cardiovasc Drugs. 2021 Mar;21(2):123–137.
   PubMed Web of Science ®Google Scholar
• Weber MA, Mansfield TA, Cain VA, et al. Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Diabetes Endocrinol. 2016 Mar;4(3):211–220.
   PubMed Web of Science ®Google Scholar
• Mazer CD, Hare GMT, Connelly PW, et al. Effect of empagliflozin on erythropoietin levels, iron stores, and red blood cell morphology in patients with type 2 diabetes mellitus and coronary artery disease. Circulation. 2020 Feb 25;141(8):704–707.
   PubMed Web of Science ®Google Scholar
• Dick SA, Epelman S. Chronic heart failure and inflammation: what do we really know? Circ Res. 2016 Jun 24;119(1):159–176.
   PubMed Web of Science ®Google Scholar
• Iannantuoni F, MdM A, Diaz-Morales N, et al. The SGLT2 inhibitor empagliflozin ameliorates the inflammatory profile in type 2 diabetic patients and promotes an antioxidant response in leukocytes. J Clin Med. 2019 Nov 1;8(11):1814.
   PubMed Web of Science ®Google Scholar
• Heerspink HJL, Perco P, Mulder S, et al. Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease. Diabetologia. 2019 Jul;62(7):1154–1166.
   PubMed Web of Science ®Google Scholar
• Leng W, Wu M, Pan H, et al. The SGLT2 inhibitor dapagliflozin attenuates the activity of ROS-NLRP3 inflammasome axis in steatohepatitis with diabetes mellitus. Ann Transl Med. 2019 Sep;7(18):429.
   PubMed Web of Science ®Google Scholar
• Lee N, Heo YJ, Choi SE, et al. Anti-inflammatory effects of empagliflozin and gemigliptin on LPS-stimulated macrophage via the IKK/NF-kappaB, MKK7/JNK, and JAK2/STAT1 signalling pathways. J Immunol Res. 2021;2021:9944880.
   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 Jan;13(1):e006277.
   PubMed Web of Science ®Google Scholar
• Butts B, Gary RA, Dunbar SB, et al. The Importance of NLRP3 inflammasome in heart failure. J Card Fail. 2015 Jul;21(7):586–593.
   PubMed Web of Science ®Google Scholar
• Youm YH, Nguyen KY, Grant RW, et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015 Mar;21(3):263–269.
   PubMed Web of Science ®Google Scholar
• Cefalu WT, Stenlof K, Leiter LA, et al. Effects of canagliflozin on body weight and relationship to HbA1c and blood pressure changes in patients with type 2 diabetes. Diabetologia. 2015 Jun;58(6):1183–1187.
   PubMed Web of Science ®Google Scholar
• Yan Y, Liu B, Du J, et al. SGLT2i versus ARNI in heart failure with reduced ejection fraction: a systematic review and meta-analysis. ESC Heart Fail. 2021 Jun;8(3):2210–2219.
   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 Feb;232:116–124.
   PubMed Web of Science ®Google Scholar
• Dapagliflozin and effect on cardiovascular events in acute heart failure - thrombolysis in myocardial infarction 68 (DAPA ACT HF-TIMI 68 trial). ClinicalTrials.gov. [cited 2021 Dec 20]. Available from: https://clinicaltrials.gov/ct2/show/NCT04363697
   Google Scholar
• Harrington J, Udell JA, Jones WS, et al. Empagliflozin in patients post myocardial infarction rationale and design of the EMPACT-MI trial. Am Heart J. 2022 May;17(253):86–98.
   Google Scholar
• Dapagliflozin Effects on Cardiovascular Events in Patients With an Acute Heart Attack (DAPA-MI). ClinicalTrials.gov. [cited 2023 Jan 6]. Available from: https://clinicaltrials.gov/ct2/show/NCT04564742
   Google Scholar
• Unnikrishnan AG, Kalra S, Purandare V, et al. Genital Infections with Sodium Glucose Cotransporter-2 Inhibitors: occurrence and Management in Patients with Type 2 Diabetes Mellitus. Indian J Endocrinol Metab. 2018 Nov-Dec;22(6):837–842.
   PubMedGoogle Scholar
• Plewa MC, Bryant M, King-Thiele R. Euglycemic Diabetic Ketoacidosis. StatPearls. Treasure Island (FL) 2022.
   Google Scholar
• Bailey CJ, Day C, Bellary S. Renal protection with SGLT2 inhibitors: effects in acute and chronic kidney disease. Curr Diab Rep. 2022 Jan;22(1):39–52.
   PubMed Web of Science ®Google Scholar