Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

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

Systematic Review Article

Renal Protection and Safety of Sodium-glucose Cotransporter-2 Inhibitors in Chronic Kidney Disease

Author(s): Tianbiao Zhou*, Kaijin Yao, Yina Xie, Yongda Lin, Jiali Wang and Xiutian Chen

Volume 29, Issue 21, 2023

Published on: 09 August, 2023

Page: [1659 - 1670] Pages: 12

DOI: 10.2174/1381612829666230804103643

Price: $65

conference banner
Abstract

Introduction: Chronic kidney disease (CKD) has a clinical characteristic of progressive loss of kidney function and becomes a serious health and social concern. SGLT2i (sodium-glucose cotransporter 2 inhibitors), a class of anti-diabetic medications, are shown to reduce cardiovascular and renal events. This systematic review and meta-analysis aimed to assess whether SGLT2i could become a new treatment strategy for CKD for its renal protection and safety.

Methods: Based on predetermined criteria, a bibliographical search was performed on May 31, 2022, by searching the following databases: ISI Web of Science, Embase, PubMed, and the Cochrane Library. Statistical analysis was conducted to assess renal protection and safety of SGLT2i by using Cochrane Review Manager Version 5.3.

Results: Thirty randomised controlled trials fulfilled the inclusion criteria and were eligible for this meta-analysis. Our study found that the SGLT2i can sustainably reduce the urine albumin/creatinine ratio (UACR) at different time points and prevent the progression to macroalbuminuria. Before 24 weeks, SGLT2i can decrease the estimated glomerular filtration rate (eGFR) compared to the control group. Interestingly, after 24 weeks, SGLT2i can continuously maintain the increase in eGFR when compared with the control group. Furthermore, SGLT2i can reduce the event rates of incident or worsening nephropathy, a decline in estimated eGFR of ≥ 50%, doubling of serum creatinine level, acute renal failure and renal failure. Interestingly, the renoprotective effects of SGLT2i are independent of its glycemic effects. SGLT2i can reduce the morbidity rate of any related adverse events, any related severe adverse events and SGLT2i have not increased the event rates of urinary tract infection, bone fractures, amputation, and acute pancreatitis when compared with the control group.

Conclusion: SGLT2i can protect renal function and are safe drug for CKD. SGLT2i are promising therapeutic agents for CKD patients.

Keywords: Chronic kidney disease (CKD), sodium-glucose cotransporter 2 inhibitors (SGLT2i), renal protection, loss of kidney function, anti- diabetic medications, estimated glomerular filtration rate (eGFR).

[1]
Barrera-Chimal J, Jaisser F, Anders HJ. The mineralocorticoid receptor in chronic kidney disease. Br J Pharmacol 2022; 179(13): 3152-64.
[http://dx.doi.org/10.1111/bph.15734] [PMID: 34786690]
[2]
Głuch E, Halicki P, Śliwińska WL, Niemczyk S. Selected aspects of genetic disorders in chronic kidney disease. Pol Merkuriusz Lek 2022; 50(297): 202-6.
[PMID: 35801606]
[3]
Patel N, Yaqoob MM, Aksentijevic D. Cardiac metabolic remodelling in chronic kidney disease. Nat Rev Nephrol 2022; 18(8): 524-37.
[http://dx.doi.org/10.1038/s41581-022-00576-x] [PMID: 35637381]
[4]
Yan J, Wang J, He JC, Zhong Y. Sirtuin 1 in chronic kidney disease and therapeutic potential of targeting sirtuin 1. Front Endocrinol 2022; 13: 917773.
[http://dx.doi.org/10.3389/fendo.2022.917773] [PMID: 35795148]
[5]
Xu D, Chandler O, Wee C, et al. Sodium-glucose cotransporter-2 inhibitor (SGLT2i) as a primary preventative agent in the healthy individual: A need of a future randomised clinical trial? Front Med 2021; 8: 712671.
[http://dx.doi.org/10.3389/fmed.2021.712671] [PMID: 34497814]
[6]
Ma Y, Lin C, Cai X, et al. The association between the use of sodium glucose cotransporter 2 inhibitor and the risk of diabetic retinopathy and other eye disorders: A systematic review and meta-analysis. Expert Rev Clin Pharmacol 2022; 15(7): 877-86.
[http://dx.doi.org/10.1080/17512433.2022.2102973] [PMID: 35839519]
[7]
Ishibashi F, Kosaka A, Tavakoli M. Sodium glucose cotransporter-2 inhibitor protects against diabetic neuropathy and nephropathy in modestly controlled type 2 diabetes: Follow-up study. Front Endocrinol 2022; 13: 864332.
[http://dx.doi.org/10.3389/fendo.2022.864332] [PMID: 35784562]
[8]
Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 clinical practice guideline for the management of glomerular diseases. Kidney Int 2021; 100(4S): S1-S276.
[PMID: 34556256]
[9]
Kohan DE, Fioretto P, Johnsson K, Parikh S, Ptaszynska A, Ying L. The effect of dapagliflozin on renal function in patients with type 2 diabetes. J Nephrol 2016; 29(3): 391-400.
[http://dx.doi.org/10.1007/s40620-016-0261-1] [PMID: 26894924]
[10]
Wanner C, Inzucchi SE, Lachin JM, et al. 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]
[11]
Heerspink HJL, 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]
[12]
Fioretto P, Del Prato S, Buse JB, et al. Efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment (chronic kidney disease stage 3A): The DERIVE Study. Diabetes Obes Metab 2018; 20(11): 2532-40.
[http://dx.doi.org/10.1111/dom.13413] [PMID: 29888547]
[13]
Takashima H, Yoshida Y, Nagura C, et al. Renoprotective effects of canagliflozin, a sodium glucose cotransporter 2 inhibitor, in type 2 diabetes patients with chronic kidney disease: A randomized open-label prospective trial. Diab Vasc Dis Res 2018; 15(5): 469-72.
[http://dx.doi.org/10.1177/1479164118782872] [PMID: 29923427]
[14]
Wanner C, Heerspink HJL, Zinman B, et al. Empagliflozin and kidney function decline in patients with type 2 diabetes: A slope analysis from the EMPA-REG outcome trial. J Am Soc Nephrol 2018; 29(11): 2755-69.
[http://dx.doi.org/10.1681/ASN.2018010103] [PMID: 30314978]
[15]
de Jong MA, Petrykiv SI, Laverman GD, et al. Effects of dapagliflozin on circulating markers of phosphate homeostasis. Clin J Am Soc Nephrol 2019; 14(1): 66-73.
[http://dx.doi.org/10.2215/CJN.04530418] [PMID: 30559106]
[16]
Halden TAS, Kvitne KE, Midtvedt K, et al. Efficacy and safety of empagliflozin in renal transplant recipients with posttransplant diabetes mellitus. Diabetes Care 2019; 42(6): 1067-74.
[http://dx.doi.org/10.2337/dc19-0093] [PMID: 30862658]
[17]
Perkovic V, Jardine MJ, Neal B, et al. 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]
[18]
Allegretti AS, Zhang W, Zhou W, et al. Safety and effectiveness of bexagliflozin in patients with type 2 diabetes mellitus and stage 3a/3b CKD. Am J Kidney Dis 2019; 74(3): 328-37.
[http://dx.doi.org/10.1053/j.ajkd.2019.03.417] [PMID: 31101403]
[19]
Pollock C, Stefánsson B, Reyner D, et al. Albuminuria-lowering effect of dapagliflozin alone and in combination with saxagliptin and effect of dapagliflozin and saxagliptin on glycaemic control in patients with type 2 diabetes and chronic kidney disease (DELIGHT): A randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2019; 7(6): 429-41.
[http://dx.doi.org/10.1016/S2213-8587(19)30086-5] [PMID: 30992195]
[20]
Bakris G, Oshima M, Mahaffey KW, et al. Effects of canagliflozin in patients with baseline eGFR <30 ml/min per 1.73 m2. Clin J Am Soc Nephrol 2020; 15(12): 1705-14.
[http://dx.doi.org/10.2215/CJN.10140620] [PMID: 33214158]
[21]
Chertow GM, Vart P, Jongs N, et al. Effects of dapagliflozin in stage 4 chronic kidney disease. J Am Soc Nephrol 2021; 32(9): 2352-61.
[http://dx.doi.org/10.1681/ASN.2021020167] [PMID: 34272327]
[22]
Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020; 383(15): 1436-46.
[http://dx.doi.org/10.1056/NEJMoa2024816] [PMID: 32970396]
[23]
Kroonen MYAM, Koomen JV, Petrykiv SI, Laverman GD, Heerspink HJL, Stevens J. Exposure-response relationships for the sodium-glucose co-transporter-2 inhibitor dapagliflozin with regard to renal risk markers. Diabetes Obes Metab 2020; 22(6): 916-21.
[http://dx.doi.org/10.1111/dom.13976] [PMID: 31984620]
[24]
Levin A, Perkovic V, Wheeler DC, et al. Empagliflozin and cardiovascular and kidney outcomes across KDIGO risk categories. Clin J Am Soc Nephrol 2020; 15(10): 1433-44.
[http://dx.doi.org/10.2215/CJN.14901219] [PMID: 32994159]
[25]
Oshima M, Neuen BL, Li J, et al. Early change in albuminuria with canagliflozin predicts kidney and cardiovascular outcomes: A Post Hoc analysis from the CREDENCE trial. J Am Soc Nephrol 2020; 31(12): 2925-36.
[http://dx.doi.org/10.1681/ASN.2020050723] [PMID: 32998938]
[26]
Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med 2021; 384(2): 129-39.
[http://dx.doi.org/10.1056/NEJMoa2030186] [PMID: 33200891]
[27]
Cherney DZI, Ferrannini E, Umpierrez GE, et al. Efficacy and safety of sotagliflozin in patients with type 2 diabetes and severe renal impairment. Diabetes Obes Metab 2021; 23(12): 2632-42.
[http://dx.doi.org/10.1111/dom.14513] [PMID: 34338408]
[28]
Dagogo-Jack S, Pratley RE, Cherney DZI, et al. Glycemic efficacy and safety of the SGLT2 inhibitor ertugliflozin in patients with type 2 diabetes and stage 3 chronic kidney disease: An analysis from the VERTIS CV randomized trial. BMJ Open Diabetes Res Care 2021; 9(1): e002484.
[http://dx.doi.org/10.1136/bmjdrc-2021-002484] [PMID: 34620621]
[29]
Jongs N, Greene T, Chertow GM, et al. Effect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes: A prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol 2021; 9(11): 755-66.
[http://dx.doi.org/10.1016/S2213-8587(21)00243-6] [PMID: 34619106]
[30]
McMurray JJV, Wheeler DC, Stefánsson BV, et al. Effect of dapagliflozin on clinical outcomes in patients with chronic kidney disease, with and without cardiovascular disease. Circulation 2021; 143(5): 438-48.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051675] [PMID: 33186054]
[31]
Oshima M, Jardine MJ, Agarwal R, et al. Insights from CREDENCE trial indicate an acute drop in estimated glomerular filtration rate during treatment with canagliflozin with implications for clinical practice. Kidney Int 2021; 99(4): 999-1009.
[http://dx.doi.org/10.1016/j.kint.2020.10.042] [PMID: 33316282]
[32]
Wheeler DC, Stefánsson BV, Jongs N, et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: A prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol 2021; 9(1): 22-31.
[http://dx.doi.org/10.1016/S2213-8587(20)30369-7] [PMID: 33338413]
[33]
Wheeler DC, Toto RD, Stefánsson BV, et al. A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int 2021; 100(1): 215-24.
[http://dx.doi.org/10.1016/j.kint.2021.03.033] [PMID: 33878338]
[34]
Chertow GM, Vart P, Jongs N, et al. Quételet (body mass) index and effects of dapagliflozin in chronic kidney disease. Diabetes Obes Metab 2022; 24(5): 827-37.
[http://dx.doi.org/10.1111/dom.14641] [PMID: 34984791]
[35]
Heerspink HJL, Oshima M, Zhang H, et al. Canagliflozin and kidney-related adverse events in type 2 diabetes and CKD: Findings from the randomized CREDENCE trial. Am J Kidney Dis 2022; 79(2): 244-256.e1.
[http://dx.doi.org/10.1053/j.ajkd.2021.05.005] [PMID: 34029680]
[36]
Heerspink HJL, Cherney D, Postmus D, et al. A pre-specified analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial on the incidence of abrupt declines in kidney function. Kidney Int 2022; 101(1): 174-84.
[http://dx.doi.org/10.1016/j.kint.2021.09.005] [PMID: 34560136]
[37]
Tuttle KR, Levin A, Nangaku M, et al. Safety of empagliflozin in patients with type 2 diabetes and chronic kidney disease: Pooled analysis of placebo-controlled clinical trials. Diabetes Care 2022; 45(6): 1445-52.
[http://dx.doi.org/10.2337/dc21-2034] [PMID: 35472672]
[38]
Wada T, Mori-Anai K, Kawaguchi Y, et al. Renal, cardiovascular and safety outcomes of canagliflozin in patients with type 2 diabetes and nephropathy in east and south-east asian countries: Results from the canagliflozin and renal events in diabetes with established nephropathy clinical evaluation trial. J Diabetes Investig 2022; 13(1): 54-64.
[http://dx.doi.org/10.1111/jdi.13624] [PMID: 34212533]
[39]
Fioretto P, Stefansson BV, Johnsson E, Cain VA, Sjöström CD. Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment. Diabetologia 2016; 59(9): 2036-9.
[http://dx.doi.org/10.1007/s00125-016-4017-1] [PMID: 27306615]
[40]
Jardine M, Zhou Z, Lambers Heerspink HJ, et al. Kidney, cardiovascular, and safety outcomes of canagliflozin according to baseline albuminuria. Clin J Am Soc Nephrol 2021; 16(3): 384-95.
[http://dx.doi.org/10.2215/CJN.15260920] [PMID: 33619120]
[41]
Shikata K, Ito S, Kashihara N, et al. Reduction in the magnitude of serum potassium elevation in combination therapy with esaxerenone (CS-3150) and sodium-glucose cotransporter 2 inhibitor in patients with diabetic kidney disease: Subanalysis of two phase III studies. J Diabetes Investig 2022; 13(7): 1190-202.
[http://dx.doi.org/10.1111/jdi.13778] [PMID: 35199478]
[42]
Heerspink HJL, Perkins BA, Fitchett DH, Husain M, Cherney DZI. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus. Circulation 2016; 134(10): 752-72.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.116.021887] [PMID: 27470878]
[43]
Nagasu H, Yano Y, Kanegae H, et al. Kidney outcomes associated with SGLT2 inhibitors versus other glucose-lowering drugs in real-world clinical practice: The japan chronic kidney disease database. Diabetes Care 2021; 44(11): 2542-51.
[http://dx.doi.org/10.2337/dc21-1081] [PMID: 34593566]
[44]
Maeda S, Matsui T, Takeuchi M, Yamagishi S. Sodium-glucose cotransporter 2-mediated oxidative stress augments advanced glycation end products-induced tubular cell apoptosis. Diabetes Metab Res Rev 2013; 29(5): 406-12.
[http://dx.doi.org/10.1002/dmrr.2407] [PMID: 23508966]
[45]
Ojima A, Matsui T, Nishino Y, Nakamura N, Yamagishi S. Empagliflozin, an inhibitor of sodium-glucose cotransporter 2 exerts anti-inflammatory and antifibrotic effects on experimental diabetic nephropathy partly by suppressing AGEs-receptor axis. Horm Metab Res 2015; 47(9): 686-92.
[http://dx.doi.org/10.1055/s-0034-1395609] [PMID: 25611208]
[46]
Ishibashi Y, Matsui T, Yamagishi S. Tofogliflozin, a selective inhibitor of sodium-glucose cotransporter 2, suppresses renal damage in KKAy/Ta mice, obese and type 2 diabetic animals. Diab Vasc Dis Res 2016; 13(6): 438-41.
[http://dx.doi.org/10.1177/1479164116657304] [PMID: 27407083]
[47]
Sato S, Takayanagi K, Shimizu T, Kanozawa K, Iwashita T, Hasegawa H. Correlation between albuminuria and interstitial injury marker reductions associated with SGLT2 inhibitor treatment in diabetic patients with renal dysfunction. Eur J Med Res 2022; 27(1): 140.
[http://dx.doi.org/10.1186/s40001-022-00737-5] [PMID: 35933386]
[48]
Nespoux J, Vallon V. SGLT2 inhibition and kidney protection. Clin Sci 2018; 132(12): 1329-39.
[http://dx.doi.org/10.1042/CS20171298] [PMID: 29954951]
[49]
Xie Y, Bowe B, Gibson AK, et al. Comparative effectiveness of the sodium-glucose cotransporter 2 inhibitor empagliflozin versus other antihyperglycemics on risk of major adverse kidney events. Diabetes Care 2020; 43(11): 2785-95.
[http://dx.doi.org/10.2337/dc20-1231] [PMID: 32912850]
[50]
Xie Y, Bowe B, Gibson AK, McGill JB, Maddukuri G, Al-Aly Z. Clinical implications of estimated glomerular filtration rate dip following sodium-glucose cotransporter-2 inhibitor initiation on cardiovascular and kidney outcomes. J Am Heart Assoc 2021; 10(11): e020237.
[http://dx.doi.org/10.1161/JAHA.120.020237] [PMID: 34013739]
[51]
Mayer GJ, Wanner C, Weir MR, et al. Analysis from the EMPA-REG OUTCOME® trial indicates empagliflozin may assist in preventing the progression of chronic kidney disease in patients with type 2 diabetes irrespective of medications that alter intrarenal hemodynamics. Kidney Int 2019; 96(2): 489-504.
[http://dx.doi.org/10.1016/j.kint.2019.02.033] [PMID: 31142441]
[52]
Cherney DZI, Cosentino F, Dagogo-Jack S, et al. Ertugliflozin and slope of chronic eGFR. Clin J Am Soc Nephrol 2021; 16(9): 1345-54.
[http://dx.doi.org/10.2215/CJN.01130121] [PMID: 34497110]
[53]
Heerspink HJL, Jongs N, Chertow GM, et al. Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: A prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol 2021; 9(11): 743-54.
[http://dx.doi.org/10.1016/S2213-8587(21)00242-4] [PMID: 34619108]
[54]
De Nicola L, Gabbai FB, Garofalo C, Conte G, Minutolo R. Nephroprotection by SGLT2 inhibition: Back to the future? J Clin Med 2020; 9(7): 2243.
[http://dx.doi.org/10.3390/jcm9072243] [PMID: 32679744]
[55]
Miyata KN, Lo CS, Zhao S, et al. Angiotensin II up-regulates sodium-glucose co-transporter 2 expression and SGLT2 inhibitor attenuates Ang II-induced hypertensive renal injury in mice. Clin Sci 2021; 135(7): 943-61.
[http://dx.doi.org/10.1042/CS20210094] [PMID: 33822013]
[56]
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]
[57]
Vallon V, Thomson SC. The tubular hypothesis of nephron filtration and diabetic kidney disease. Nat Rev Nephrol 2020; 16(6): 317-36.
[http://dx.doi.org/10.1038/s41581-020-0256-y] [PMID: 32152499]
[58]
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]
[59]
Toyama T, Neuen BL, Jun M, et al. Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: A systematic review and meta-analysis. Diabetes Obes Metab 2019; 21(5): 1237-50.
[http://dx.doi.org/10.1111/dom.13648] [PMID: 30697905]
[60]
McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes. JAMA Cardiol 2021; 6(2): 148-58.
[http://dx.doi.org/10.1001/jamacardio.2020.4511] [PMID: 33031522]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy