Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Mechanisms for Cardiorenal Protection of SGLT-2 Inhibitors

Author(s): Panagiotis I. Georgianos, Vasilios Vaios, Evangelia Dounousi, Marios Salmas, Theodoros Eleftheriadis and Vassilios Liakopoulos*

Volume 27, Issue 8, 2021

Published on: 19 January, 2021

Page: [1043 - 1050] Pages: 8

DOI: 10.2174/1381612827666210119102409

Price: $65

Abstract

Despite optimal treatment of diabetic kidney disease (DKD) with adequate blood pressure control and agents blocking the renin-angiotensin-system (RAS), the residual cardiorenal risk of these patients remains substantially high. There is, therefore, an unmet need for additional therapies effective to retard the progression of DKD and improve cardiovascular outcomes in this high-risk population. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors represent a novel drug class that received regulatory approval for improving glycemic control in patients with type 2 diabetes and preserved kidney function. Large outcome trials designed to test their cardiovascular safety profile showed an unexpected improvement in cardiovascular outcomes and also suggested a slower progression of DKD with SGLT-2 inhibition. The Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy (CREDENCE), a trial that was designed to specifically investigate the renoprotective properties of SGLT-2 inhibitors in patients with overt DKD already receiving guideline-based therapy with a RAS-blocker, was prematurely terminated due to an impressive benefit of canagliflozin on kidney and cardiovascular outcomes. These impressive results refine the role and the indication of SGLT-2 inhibitors as a cardioand renoprotective strategy in patients with DKD. In this article, we provide an overview of the available clinical- trial evidence and explore the mechanisms mediating the cardiorenal protection afforded by SGLT-2 inhibitors. We conclude with perspectives for a potential beneficial effect of this novel drug class in patients with non-diabetic kidney disease.

Keywords: Cardiorenal protection, clinical outcomes, diabetic kidney disease, sodium-glucose co-transporter 2 inhibitors, blood pressure, renin-angiotensin-system (RAS).

« Previous Next »
[1]
Kidney Disease Improving Global Outcomes (KDIGO) Blood PressureWork Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl 2012; 2: 337-414.
[2]
Perkovic V, Agarwal R, Fioretto P, et al. Conference Participants. Management of patients with diabetes and CKD: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int 2016; 90(6): 1175-83.
[http://dx.doi.org/10.1016/j.kint.2016.09.010] [PMID: 27884312]
[3]
Williams B, Mancia G, Spiering W, et al. Authors/Task Force Members. 2018 ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension. J Hypertens 2018; 36(10): 1953-2041.
[http://dx.doi.org/10.1097/HJH.0000000000001940] [PMID: 30234752]
[4]
Brenner BM, Cooper ME, de Zeeuw D, et al. RENAAL Study Investigators Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345(12): 861-9.
[http://dx.doi.org/10.1056/NEJMoa011161] [PMID: 11565518]
[5]
Lewis EJ, Hunsicker LG, Clarke WR, et al. Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345(12): 851-60.
[http://dx.doi.org/10.1056/NEJMoa011303] [PMID: 11565517]
[6]
Georgianos PI, Divani M, Eleftheriadis T, Mertens PR, Liakopoulos V. SGLT-2 inhibitors in Diabetic Kidney Disease: What Lies Behind their Renoprotective Properties? Curr Med Chem 2019; 26(29): 5564-78.
[http://dx.doi.org/10.2174/0929867325666180524114033] [PMID: 29792136]
[7]
Shivakumar O, Sattar N, Wheeler DC. Sodium-glucose cotransporter 2 inhibitor effects on cardiovascular outcomes in chronic kidney disease. Nephrol Dial Transplant 2020; 35(Suppl. 1): i43-7.
[http://dx.doi.org/10.1093/ndt/gfz292] [PMID: 32003831]
[8]
Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 2013; 159(4): 262-74.
[http://dx.doi.org/10.7326/0003-4819-159-4-201308200-00007] [PMID: 24026259]
[9]
Cherney DZI, Cooper ME, Tikkanen I, et al. Pooled analysis of Phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin. Kidney Int 2018; 93(1): 231-44.
[http://dx.doi.org/10.1016/j.kint.2017.06.017] [PMID: 28860019]
[10]
Cherney DZ, Kanbay M, Lovshin JA. Renal physiology of glucose handling and therapeutic implications. Nephrol Dial Transplant 2020; 35(Suppl. 1): i3-i12.
[http://dx.doi.org/10.1093/ndt/gfz230] [PMID: 32003835]
[11]
Neal B, Perkovic V, Mahaffey KW, et al. CANVAS Program Collaborative Group Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377(7): 644-57.
[http://dx.doi.org/10.1056/NEJMoa1611925] [PMID: 28605608]
[12]
Wiviott SD, Raz I, Bonaca MP, et al. DECLARE-TIMI 58 Investigators Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2019; 380(4): 347-57.
[http://dx.doi.org/10.1056/NEJMoa1812389] [PMID: 30415602]
[13]
Zinman B, Wanner C, Lachin JM, et al. EMPA-REG OUTCOME Investigators Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373(22): 2117-28.
[http://dx.doi.org/10.1056/NEJMoa1504720] [PMID: 26378978]
[14]
Cannon CP. Cardiovascular Outcomes Following Ertugliflozin Treatment In Patients with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease: the VERTIS-CV trial ADA 80th Virtual Scientific Sessions In: 13-16 June; 2020.
[15]
Perkovic V, Jardine MJ, Neal B, et al. CREDENCE Trial Investigators Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med 2019; 380(24): 2295-306.
[http://dx.doi.org/10.1056/NEJMoa1811744] [PMID: 30990260]
[16]
American Diabetes Association 11. Microvascular Complications and Foot Care: Standards of Medical Care in Diabetes-2019. Diabetes Care 2019; 42(Suppl. 1): S124-38.
[http://dx.doi.org/10.2337/dc19-S011] [PMID: 30559237]
[17]
Wanner C, Inzucchi SE, Lachin JM, et al. EMPA-REG OUTCOME Investigators Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med 2016; 375(4): 323-34.
[http://dx.doi.org/10.1056/NEJMoa1515920] [PMID: 27299675]
[18]
Inzucchi SE, Zinman B, Fitchett D, et al. How Does Empagliflozin Reduce Cardiovascular Mortality? Insights From a Mediation Analysis of the EMPA-REG OUTCOME Trial. Diabetes Care 2018; 41(2): 356-63.
[http://dx.doi.org/10.2337/dc17-1096] [PMID: 29203583]
[19]
Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019; 393(10166): 31-9.
[http://dx.doi.org/10.1016/S0140-6736(18)32590-X] [PMID: 30424892]
[20]
Cannon CP, McGuire DK, Pratley R, et al. VERTIS-CV Investigators Design and baseline characteristics of the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV). Am Heart J 2018; 206: 11-23.
[http://dx.doi.org/10.1016/j.ahj.2018.08.016] [PMID: 30290289]
[21]
Mahaffey KW, Jardine MJ, Bompoint S, et al. Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups. Circulation 2019; 140(9): 739-50.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.119.042007] [PMID: 31291786]
[22]
Debella YT, Giduma HD, Light RP, Agarwal R. Chronic kidney disease as a coronary disease equivalent-a comparison with diabetes over a decade. Clin J Am Soc Nephrol 2011; 6(6): 1385-92.
[http://dx.doi.org/10.2215/CJN.10271110] [PMID: 21393492]
[23]
Tonelli M, Muntner P, Lloyd A, et al. Alberta Kidney Disease Network. Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study. Lancet 2012; 380(9844): 807-14.
[http://dx.doi.org/10.1016/S0140-6736(12)60572-8] [PMID: 22717317]
[24]
Neuen BL, Young T, Heerspink HJL, et al. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2019; 7(11): 845-54.
[http://dx.doi.org/10.1016/S2213-8587(19)30256-6] [PMID: 31495651]
[25]
Heerspink HJ, Desai M, Jardine M, Balis D, Meininger G, Perkovic V. Canagliflozin Slows Progression of Renal Function Decline Independently of Glycemic Effects. J Am Soc Nephrol 2017; 28(1): 368-75.
[http://dx.doi.org/10.1681/ASN.2016030278] [PMID: 27539604]
[26]
Petrykiv S, Sjöström CD, Greasley PJ, Xu J, Persson F, Heerspink HJL. Differential Effects of Dapagliflozin on Cardiovascular Risk Factors at Varying Degrees of Renal Function. Clin J Am Soc Nephrol 2017; 12(5): 751-9.
[http://dx.doi.org/10.2215/CJN.10180916] [PMID: 28302903]
[27]
Dekkers CCJ, Wheeler DC, Sjöström CD, Stefansson BV, Cain V, Heerspink HJL. Effects of the sodium-glucose co-transporter 2 inhibitor dapagliflozin in patients with type 2 diabetes and Stages 3b-4 chronic kidney disease. Nephrol Dial Transplant 2018; 33(11): 2005-11.
[http://dx.doi.org/10.1093/ndt/gfx350] [PMID: 29370424]
[28]
Mazidi M, Rezaie P, Gao HK, Kengne AP. Effect of Sodium-Glucose Cotransport-2 Inhibitors on Blood Pressure in People With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of 43 Randomized Control Trials With 22 528 Patients. J Am Heart Assoc 2017; 6(6)e004007
[http://dx.doi.org/10.1161/JAHA.116.004007] [PMID: 28546454]
[29]
Baker WL, Buckley LF, Kelly MS, et al. Effects of Sodium-Glucose Cotransporter 2 Inhibitors on 24-Hour Ambulatory Blood Pressure: A Systematic Review and Meta-Analysis. J Am Heart Assoc 2017; 6(5)e005686
[http://dx.doi.org/10.1161/JAHA.117.005686] [PMID: 28522675]
[30]
Georgianos PI, Agarwal R. Ambulatory Blood Pressure Reduction With SGLT-2 Inhibitors: Dose-Response Meta-analysis and Comparative Evaluation With Low-Dose Hydrochlorothiazide. Diabetes Care 2019; 42(4): 693-700.
[http://dx.doi.org/10.2337/dc18-2207] [PMID: 30894383]
[31]
Jardine MJ, Zhou Z, Mahaffey KW, et al. CREDENCE Study Investigators Renal, Cardiovascular, and Safety Outcomes of Canagliflozin by Baseline Kidney Function: A Secondary Analysis of the CREDENCE Randomized Trial. J Am Soc Nephrol 2020; 31(5): 1128-39.
[http://dx.doi.org/10.1681/ASN.2019111168] [PMID: 32354987]
[32]
Holtkamp FA, de Zeeuw D, Thomas MC, 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.
[http://dx.doi.org/10.1038/ki.2011.79] [PMID: 21451458]
[33]
Ruggenenti P, Porrini EL, Gaspari F, et al. GFR Study Investigators Glomerular hyperfiltration and renal disease progression in type 2 diabetes. Diabetes Care 2012; 35(10): 2061-8.
[http://dx.doi.org/10.2337/dc11-2189] [PMID: 22773704]
[34]
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.
[PMID: 10589696]
[35]
Tonneijck L, Muskiet MH, Smits MM, et al. Glomerular Hyperfiltration in Diabetes: Mechanisms, Clinical Significance, and Treatment. J Am Soc Nephrol 2017; 28(4): 1023-39.
[http://dx.doi.org/10.1681/ASN.2016060666] [PMID: 28143897]
[36]
Malatiali S, Francis I, Barac-Nieto M. Phlorizin prevents glomerular hyperfiltration but not hypertrophy in diabetic rats. Exp Diabetes Res 2008; 2008305403
[http://dx.doi.org/10.1155/2008/305403] [PMID: 18769499]
[37]
Thomson SC, Rieg T, Miracle C, et al. Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol 2012; 302(1): R75-83.
[http://dx.doi.org/10.1152/ajpregu.00357.2011] [PMID: 21940401]
[38]
Vallon V, Gerasimova M, Rose MA, 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 Renal Physiol 2014; 306(2): F194-204.
[http://dx.doi.org/10.1152/ajprenal.00520.2013] [PMID: 24226524]
[39]
Kidokoro K, Cherney DZI, Bozovic A, et al. Evaluation of Glomerular Hemodynamic Function by Empagliflozin in Diabetic Mice Using in vivo Imaging. Circulation 2019; 140(4): 303-15.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.118.037418] [PMID: 30773020]
[40]
Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014; 129(5): 587-97.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.113.005081] [PMID: 24334175]
[41]
Shin SJ, Chung S, Kim SJ, et al. Effect of Sodium-Glucose Co-Transporter 2 Inhibitor, Dapagliflozin, on Renal Renin-Angiotensin System in an Animal Model of Type 2 Diabetes. PLoS One 2016; 11(11)e0165703
[http://dx.doi.org/10.1371/journal.pone.0165703] [PMID: 27802313]
[42]
Woods TC, Satou R, Miyata K, et al. Canagliflozin Prevents Intrarenal Angiotensinogen Augmentation and Mitigates Kidney Injury and Hypertension in Mouse Model of Type 2 Diabetes Mellitus. Am J Nephrol 2019; 49(4): 331-42.
[http://dx.doi.org/10.1159/000499597] [PMID: 30921791]
[43]
Hatanaka T, Ogawa D, Tachibana H, et al. Inhibition of SGLT2 alleviates diabetic nephropathy by suppressing high glucose-induced oxidative stress in type 1 diabetic mice. Pharmacol Res Perspect 2016; 4(4)e00239
[http://dx.doi.org/10.1002/prp2.239] [PMID: 28116093]
[44]
Tang L, Wu Y, Tian M, et al. Dapagliflozin slows the progression of the renal and liver fibrosis associated with type 2 diabetes. Am J Physiol Endocrinol Metab 2017; 313(5): E563-76.
[http://dx.doi.org/10.1152/ajpendo.00086.2017] [PMID: 28811292]
[45]
Chang YK, Choi H, Jeong JY, et al. Dapagliflozin, SGLT2 Inhibitor, Attenuates Renal Ischemia-Reperfusion Injury. PLoS One 2016; 11(7)e0158810
[http://dx.doi.org/10.1371/journal.pone.0158810] [PMID: 27391020]
[46]
Panchapakesan U, Pegg K, Gross S, et al. Effects of SGLT2 inhibition in human kidney proximal tubular cells-renoprotection in diabetic nephropathy? PLoS One 2013; 8(2)e54442
[http://dx.doi.org/10.1371/journal.pone.0054442] [PMID: 23390498]
[47]
Yaribeygi H, Butler AE, Atkin SL, Katsiki N, Sahebkar A. Sodium-glucose cotransporter 2 inhibitors and inflammation in chronic kidney disease: Possible molecular pathways. J Cell Physiol 2018; 234(1): 223-30.
[http://dx.doi.org/10.1002/jcp.26851] [PMID: 30076706]
[48]
Yaribeygi H, Katsiki N, Butler AE, Sahebkar A. Effects of antidiabetic drugs on NLRP3 inflammasome activity, with a focus on diabetic kidneys. Drug Discov Today 2019; 24(1): 256-62.
[http://dx.doi.org/10.1016/j.drudis.2018.08.005] [PMID: 30086405]
[49]
Dekkers CCJ, Petrykiv S, Laverman GD, Cherney DZ, Gansevoort RT, Heerspink HJL. Effects of the SGLT-2 inhibitor dapagliflozin on glomerular and tubular injury markers. Diabetes Obes Metab 2018; 20(8): 1988-93.
[http://dx.doi.org/10.1111/dom.13301] [PMID: 29573529]
[50]
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; 62(7): 1154-66.
[http://dx.doi.org/10.1007/s00125-019-4859-4] [PMID: 31001673]
[51]
Opingari E, Verma S, Connelly KA, et al. The impact of empagliflozin on kidney injury molecule-1: a subanalysis of the Effects of Empagliflozin on Cardiac Structure, Function, and Circulating Biomarkers in Patients with Type 2 Diabetes CardioLink-6 trial. Nephrol Dial Transplant 2020; 35(5): 895-7.
[http://dx.doi.org/10.1093/ndt/gfz294] [PMID: 32159783]
[52]
Dekkers CCJ, Gansevoort RT. Sodium-glucose cotransporter 2 inhibitors: extending the indication to non-diabetic kidney disease? Nephrol Dial Transplant 2020; 35(Suppl. 1): i33-42.
[http://dx.doi.org/10.1093/ndt/gfz264] [PMID: 32003836]
[53]
Bays HE, Weinstein R, Law G, Canovatchel W. Canagliflozin: effects in overweight and obese subjects without diabetes mellitus. Obesity (Silver Spring) 2014; 22(4): 1042-9.
[http://dx.doi.org/10.1002/oby.20663] [PMID: 24227660]
[54]
Rajasekeran H, Reich HN, Hladunewich MA, et al. Dapagliflozin in focal segmental glomerulosclerosis: a combined human-rodent pilot study. Am J Physiol Renal Physiol 2018; 314(3): F412-22.
[http://dx.doi.org/10.1152/ajprenal.00445.2017] [PMID: 29141939]
[55]
Cherney DZI, Dekkers CCJ, Barbour SJ, et al. DIAMOND investigators Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non-diabetic patients with chronic kidney disease (DIAMOND): a randomised, double-blind, crossover trial. Lancet Diabetes Endocrinol 2020; 8(7): 582-93.
[http://dx.doi.org/10.1016/S2213-8587(20)30162-5] [PMID: 32559474]
[56]
Heerspink HJL, Stefansson BV, Chertow GM, et al. DAPA-CKD Investigators Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial. Nephrol Dial Transplant 2020; 35(2): 274-82.
[http://dx.doi.org/10.1093/ndt/gfz290] [PMID: 32030417]

Rights & Permissions Print Cite
Article Metrics
120
1
© 2024 Bentham Science Publishers | Privacy Policy