Promise of SGLT2 Inhibitors in Heart Failure: Diabetes and Beyond

Current Treatment Options in Cardiovascular Medicine

Volumn 19, Issue 3, 2017, Pages

  Martens, Pieter ^a,b   Mathieu, Chantal ^c   Verbrugge, Frederik H ^a  

^a DEPARTMENT OF CARDIOLOGY   (Belgium)

^b HASSELT UNIVERSITY   (Belgium)

^c UNIVERSITY HOSPITALS LEUVEN   (Belgium)

Author keywords

Diabetes mellitus; Energy metabolism; Glomerular filtration rate; Heart failure; Plasma volume; Sodium glucose transporter 2

Indexed keywords

CANAGLIFLOZIN; DAPAGLIFLOZIN; EMPAGLIFLOZIN; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR;

ADRENERGIC SYSTEM; ARTERIAL STIFFNESS; CARDIOVASCULAR MORTALITY; CARDIOVASCULAR RISK; DIABETES MELLITUS; DIURESIS; DRUG EFFICACY; DRUG MECHANISM; END STAGE RENAL DISEASE; ENDOTHELIAL DYSFUNCTION; GLUCOSE TRANSPORT; GLYCEMIC CONTROL; HEART FAILURE; HEART MUSCLE METABOLISM; HEMATOCRIT; HOSPITAL ADMISSION; HOSPITAL READMISSION; HUMAN; KIDNEY PROXIMAL TUBULE; NEPHRON; NONHUMAN; PLASMA VOLUME; PLEIOTROPY; RENOVASCULAR HYPERTENSION; REVIEW; RISK REDUCTION; SODIUM TRANSPORT;

EID: 85015967268     PISSN: 10928464     EISSN: 15343189     Source Type: Journal    
DOI: 10.1007/s11936-017-0522-x     Document Type: Review

References (67)

1. Mentz RJ, Kelly JP, von Lueder TG, Voors AA, Lam CS, Cowie MR, et al. Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol. 2014;64(21):2281–93.
2. Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database. J Am Coll Cardiol. 2006;47(1):76–84.
3. Fonarow GC, Stough WG, Abraham WT, Albert NM, Gheorghiade M, Greenberg BH, et al. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol. 2007;50(8):768–77.
4. Ather S, Chan W, Bozkurt B, Aguilar D, Ramasubbu K, Zachariah AA, et al. Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol. 2012;59(11):998–1005.
5. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol. 1974;34(1):29–34.
6. Cubbon RM, Woolston A, Adams B, Gale CP, Gilthorpe MS, Baxter PD, et al. Prospective development and validation of a model to predict heart failure hospitalisation. Heart. 2014;100(12):923–9.
7. • Fitchett DH, Udell JA, Inzucchi SE. Heart failure outcomes in clinical trials of glucose-lowering agents in patients with diabetes. Eur J Heart Fail. 2016. Recent meta-analysis providing an insightful overview of heart failure outcomes in clinical trials with glucose lowering drugs in patients with diabetes.
8. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279–89.
9. Komajda M, McMurray JJ, Beck-Nielsen H, Gomis R, Hanefeld M, Pocock SJ, et al. Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial. Eur Heart J. 2010;31(7):824–31.
10. • Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26. Large trial designed to prove cardiovascular safety of the dipeptidyl peptidase-4 inhibitor saxagliptin that showed an increased risk for heart failure.
11. •• Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28. The only trial powered for cardiovascular end-points evaluation with a sodium-glucose transporter-2 inhibitor showing an unprecedented 38% reduction in cardiovascular mortality.
12. Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91(2):733–94.
13. Freitas HS, Anhe GF, Melo KF, Okamoto MM, Oliveira-Souza M, Bordin S, et al. Na(+) -glucose transporter-2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor-1alpha expression and activity. Endocrinology. 2008;149(2):717–24.
14. Vidotti DB, Arnoni CP, Maquigussa E, Boim MA. Effect of long-term type 1 diabetes on renal sodium and water transporters in rats. Am J Nephrol. 2008;28(1):107–14.
15. Schnermann J. Juxtaglomerular cell complex in the regulation of renal salt excretion. Am J Physiol. 1998;274(2 Pt 2):R263–79.
16. Vallon V, Richter K, Blantz RC, Thomson S, Osswald H. Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption. J Am Soc Nephrol. 1999;10(12):2569–76.
17. Vallon V, Rose M, Gerasimova M, Satriano J, Platt KA, Koepsell H, et al. Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus. Am J Physiol Ren Physiol. 2013;304(2):F156–67.
18. Vallon V, Gerasimova M, Rose MA, Masuda T, Satriano J, Mayoux E, et al. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Ren Physiol. 2014;306(2):F194–204.
19. Tahrani AA, Barnett AH, Bailey CJ. SGLT inhibitors in management of diabetes. Lancet Diabetes Endocrinol. 2013;1(2):140–51.
20. Monami M, Nardini C, Mannucci E. Efficacy and safety of sodium glucose co-transport-2 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2014;16(5):457–66.
21. Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens. 2014;8(4):262–75. e9.
22. Oliva RV, Bakris GL. Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. J Am Soc Hypertens. 2014;8(5):330–9.
23. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837–53.
24. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577–89.
25. Group AS, Gerstein HC, Miller ME, Genuth S, Ismail-Beigi F, Buse JB, et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011;364(9):818–28.
26. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457–71.
27. Control G, Turnbull FM, Abraira C, Anderson RJ, Byington RP, Chalmers JP, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52(11):2288–98.
28. • Udell JA, Cavender MA, Bhatt DL, Chatterjee S, Farkouh ME, Scirica BM. Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol. 2015;3(5):356–66. Recent meta-analysis providing an insightful overview of cardiovascular outcomes in clinical trials with glucose lowering drugs in patients with diabetes.
29. Hippisley-Cox J, Coupland C. Diabetes treatments and risk of heart failure, cardiovascular disease, and all cause mortality: cohort study in primary care. BMJ. 2016;354:i3477.
30. Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care. 2004;27(1):256–63.
31. • Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial. Eur Heart J. 2016;37(19):1526–34. Subanalysis of the EMPA-REG trial with empagliflozin (reference 11) with focus on heart failure reduction achieved with this medication.
32. •• Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016;375(4):323–34. Subanalysis of the EMPA-REG trial with empagliflozin (reference 11) clearly demonstrating the renoprotective effect of empagliflozin in diabetes.
33. • Verbrugge FH, Dupont M, Steels P, Grieten L, Swennen Q, Tang WH, et al. The kidney in congestive heart failure: ‘are natriuresis, sodium, and diuretics really the good, the bad and the ugly?’. Eur J Heart Fail. 2014;16(2):133–42. This review on renal sodium handling in heart failure comprehensively explains the rationale behind inhibition of proximal tubular sodium reabsorption in heart failure which is a major effect of sodium-glucose transporter-2 inhibitors.
34. Miller WL, Mullan BP. Understanding the heterogeneity in volume overload and fluid distribution in decompensated heart failure is key to optimal volume management: role for blood volume quantitation. JACC Heart Fail. 2014;2(3):298–305.
35. Nijst P, Verbrugge FH, Grieten L, Dupont M, Steels P, Tang WH, et al. The pathophysiological role of interstitial sodium in heart failure. J Am Coll Cardiol. 2015;65(4):378–88.
36. Kalra PR, Anagnostopoulos C, Bolger AP, Coats AJ, Anker SD. The regulation and measurement of plasma volume in heart failure. J Am Coll Cardiol. 2002;39(12):1901–8.
37. Testani JM, Chen J, McCauley BD, Kimmel SE, Shannon RP. Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival. Circulation. 2010;122(3):265–72.
38. van der Meer P, Postmus D, Ponikowski P, Cleland JG, O’Connor CM, Cotter G, et al. The predictive value of short-term changes in hemoglobin concentration in patients presenting with acute decompensated heart failure. J Am Coll Cardiol. 2013;61(19):1973–81.
39. Testani JM, Brisco MA, Chen J, McCauley BD, Parikh CR, Tang WH. Timing of hemoconcentration during treatment of acute decompensated heart failure and subsequent survival: importance of sustained decongestion. J Am Coll Cardiol. 2013;62(6):516–24.
40. Verbrugge FH, Vangoitsenhoven R, Mullens W, Van der Schueren BJ, Mathieu C, Tang WH. SGLT-2 inhibitors: potential novel strategy to prevent congestive heart failure in diabetes? Curr Cardiovasc Risk Rep. 2015;9:38.
41. • Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013;15(9):853–62. Important study highlighting that plasma volume is decreased after treatment with the sodium-glucose transporter-2 inhibitor dapagliflozin in diabetes.
42. Cheungpasitporn W, Thongprayoon C, Chiasakul T, Korpaisarn S, Erickson SB. Renin-angiotensin system inhibitors linked to anemia: a systematic review and meta-analysis. QJM. 2015;108(11):879–84.
43. • Cherney DZ, Scholey JW, Jiang S, Har R, Lai V, Sochett EB, et al. The effect of direct renin inhibition alone and in combination with ACE inhibition on endothelial function, arterial stiffness, and renal function in type 1 diabetes. Diabetes Care. 2012;35(11):2324–30. Insightful study demonstrating that the sodium-glucose transporter-2 inhibitor empagliflozin was able to reverse glomerular hyperfiltration in diabetes.
44. • Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care. 2016;39(7):1108–14. Interesting review explaining the hypothesis that sodium-glucose transporter-2 inhibitors improve cardiac metabolism in diabetes by stimulating β-hydroxybutyrate oxidation as an efficient energy fuel.
45. Carlstrom M, Wilcox CS, Arendshorst WJ. Renal autoregulation in health and disease. Physiol Rev. 2015;95(2):405–511.
46. Kriz W, Shirato I, Nagata M, LeHir M, Lemley KV. The podocyte’s response to stress: the enigma of foot process effacement. Am J Physiol Ren Physiol. 2013;304(4):F333–47.
47. Holtkamp FA, de Zeeuw D, Thomas MC, Cooper ME, de Graeff PA, Hillege HJ, et al. An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function. Kidney Int. 2011;80(3):282–7.
48. Testani JM, Kimmel SE, Dries DL, Coca SG. Prognostic importance of early worsening renal function after initiation of angiotensin-converting enzyme inhibitor therapy in patients with cardiac dysfunction. Circ Heart Fail. 2011;4(6):685–91.
49. Zingerman B, Herman-Edelstein M, Erman A, Bar Sheshet Itach S, Ori Y, Rozen-Zvi B, et al. Effect of acetazolamide on obesity-induced glomerular hyperfiltration: a randomized controlled trial. PLoS One. 2015;10(9):e0137163.
50. Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129(5):587–97.
51. Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 2016;134(10):752–72.
52. Verbrugge FH, Dupont M, Bertrand PB, Nijst P, Penders J, Dens J, et al. Determinants and impact of the natriuretic response to diuretic therapy in heart failure with reduced ejection fraction and volume overload. Acta Cardiol. 2015;70(3):265–73.
53. Verbrugge FH, Mullens W, Tang WH. Management of cardio-renal syndrome and diuretic resistance. Curr Treat Options Cardiovasc Med. 2016;18(2):11.
54. Neubauer S. The failing heart--an engine out of fuel. N Engl J Med. 2007;356(11):1140–51.
55. Ferrannini E, Santoro D, Bonadonna R, Natali A, Parodi O, Camici PG. Metabolic and hemodynamic effects of insulin on human hearts. Am J Physiol. 1993;264(2 Pt 1):E308–15.
56. Sato K, Kashiwaya Y, Keon CA, Tsuchiya N, King MT, Radda GK, et al. Insulin, ketone bodies, and mitochondrial energy transduction. Faseb J. 1995;9(8):651–8.
57. Diamant M, Lamb HJ, Groeneveld Y, Endert EL, Smit JW, Bax JJ, et al. Diastolic dysfunction is associated with altered myocardial metabolism in asymptomatic normotensive patients with well-controlled type 2 diabetes mellitus. J Am Coll Cardiol. 2003;42(2):328–35.
58. Young ME, Guthrie PH, Razeghi P, Leighton B, Abbasi S, Patil S, et al. Impaired long-chain fatty acid oxidation and contractile dysfunction in the obese Zucker rat heart. Diabetes. 2002;51(8):2587–95.
59. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124(2):499–508.
60. Inagaki N, Kondo K, Yoshinari T, Takahashi N, Susuta Y, Kuki H. Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise: a 24-week, randomized, double-blind, placebo-controlled, Phase III study. Expert Opin Pharmacother. 2014;15(11):1501–15.
61. Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, et al. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science. 2013;339(6116):211–4.
62. Marti CN, Gheorghiade M, Kalogeropoulos AP, Georgiopoulou VV, Quyyumi AA, Butler J. Endothelial dysfunction, arterial stiffness, and heart failure. J Am Coll Cardiol. 2012;60(16):1455–69.
63. Mackenzie IS, McEniery CM, Dhakam Z, Brown MJ, Cockcroft JR, Wilkinson IB. Comparison of the effects of antihypertensive agents on central blood pressure and arterial stiffness in isolated systolic hypertension. Hypertension. 2009;54(2):409–13.
64. Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010;33(10):2217–24.
65. Lytvyn Y, Perkins BA, Cherney DZ. Uric acid as a biomarker and a therapeutic target in diabetes. Can J Diabetes. 2015;39(3):239–46.
66. • Wu JH, Foote C, Blomster J, Toyama T, Perkovic V, Sundstrom J, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2016;4(5):411–9. Recent meta-analysis comprising over 35,000 patients focusing on safety and adverse events of sodium-glucose transporter-2 inhibitors in diabetes.
67. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr., Drazner MH, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013.