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The effect of sodium-glucose cotransporter 2 inhibitors in patients with chronic kidney disease with or without type 2 diabetes mellitus on cardiovascular and renal outcomes: a systematic review and meta-analysis

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Reyes-Farias, Carlos Ignacio, Reategui-Diaz, Marcelo, Romani-Romani, Franco, Prokop, Larry·2023·PLOS ONE
DOI 10.1371/journal.pone.0295059PMC PMC10686459
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Abstract

Background: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have shown a favorable effect on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus (T2DM). However, their efficacy in patients with chronic kidney disease (CKD) with or without T2DM has not yet been analyzed. Objective: To assess the cardiovascular and renal effects of SGLT-2 inhibitors in patients with CKD with and without T2DM, including all CKD patients in the current literature. Methods: We searched MEDLINE, EMBASE, CENTRAL and Scopus for randomized controlled trials of SGLT-2 inhibitors that evaluated cardiovascular and kidney outcomes in patients with CKD, or trials in which these patients were a subgroup. We defined 2 primary outcomes: a composite of cardiovascular death or hospitalization for heart failure, and a composite renal outcome. For each outcome, we obtained overall hazard ratios with 95% confidence intervals by using a random effects model. Results: We included 14 randomized controlled trials. SGLT-2 inhibitors decreased the hazard for the primary cardiovascular outcome (HR 0.76; [95% CI 0.72–0.79]) and the primary renal outcome (HR 0.69; [95% CI 0.61–0.79]) in patients with CKD with or without T2DM. We did not find significant differences in the subgroup analyses according to diabetes status, baseline eGFR values or the type of SGLT-2 inhibitor used. Conclusion: In patients with CKD, treatment with SGLT-2 inhibitors in addition to standard therapy conferred protection against cardiovascular and renal outcomes. Further research on patients with non-diabetic CKD should be done to confirm the utility of these medications in this population. (PROSPERO ID: CRD42021275012).

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  • Dedicated kidney outcomes trials in people with CKD and type 2 diabetes have shown that the SGLT2 inhibitors empagliflozin, canagliflozin, and dapagliflozin have beneficial effects on slowing progression of CKD and CV outcomes in this population.

    “Dedicated kidney outcomes trials in people with CKD and type 2 diabetes have shown that the SGLT2 inhibitors empagliflozin, canagliflozin, and dapagliflozin have beneficial effects on slowing progression of CKD and CV outcomes in this population (139-141).”

    From 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025 (2025) · cites this paper as [140]

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  1. [1]Vos T, Lim SS, Abbafati C, Abbas KM, Abbasi M, Abbasifard M, et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020; 396: 1204– 1222. doi: 10.1016/S0140-6736(20)30925-9 33069326 PMC7567026 · DOI · Paper page
  2. [2]Willis K, Cheung M, Slifer S. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney International Supplements. 2013; 3: 163. Available from: https://kdigo.org/guidelines/ckd-evaluation-and-management/. 23989362
  3. [4]American Diabetes Association. Professional Practice Committee: Standards of Medical Care in Diabetes—2022. Diabetes Care. 2021; 45: S3. doi: 10.2337/dc22-Sppc 33298410 · DOI
  4. [5]Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: The Task Force for diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD). Eur Heart J. 2020; 41: 255– 323. doi: 10.1093/eurheartj/ehz486 31497854 · DOI · Paper page
  5. [6]Onishi A, Fu Y, Patel R, Darshi M, Crespo-Masip M, Huang W, et al. A role for tubular Na+/H+ exchanger NHE3 in the natriuretic effect of the SGLT2 inhibitor empagliflozin. Am J Physiol Renal Physiol. 2020; 319: F712– F728. doi: 10.1152/ajprenal.00264.2020 32893663 PMC7642886 · DOI · Paper page
  6. [7]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: 686– 692. doi: 10.1055/s-0034-1395609 25611208 · DOI · Paper page
  7. [8]Castoldi G, Carletti R, Ippolito S, Colzani M, Barzaghi F, Stella A, et al. Renal Anti-Fibrotic Effect of Sodium Glucose Cotransporter 2 Inhibition in Angiotensin II-Dependent Hypertension. Am J Nephrol. 2020; 51: 119– 129. doi: 10.1159/000505144 31910407 · DOI
  8. [9]Gembardt F, Bartaun C, Jarzebska N, Mayoux E, Todorov VT, Hohenstein B, et al. The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension. Am J Physiol Renal Physiol. 2014; 307: F317– F325. doi: 10.1152/ajprenal.00145.2014 24944269 · DOI
  9. [14]McGuire DK, Shih WJ, Cosentino F, Charbonnel B, Cherney DZI, Dagogo-Jack S, et al. Association of SGLT2 Inhibitors With Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes. JAMA Cardiol. 2021; 6: 1– 11. doi: 10.1001/jamacardio.2020.4511 33031522 PMC7542529 · DOI · Paper page
  10. [15]Arnott C, Li Q, Kang A, Neuen BL, Bompoint S, Lam CSP, et al. Sodium‐Glucose Cotransporter 2 Inhibition for the Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta‐Analysis. J Am Heart Assoc. 2020. doi: 10.1161/JAHA.119.014908 31992158 PMC7033896 · DOI · Paper page
  11. [21]Schünemann H H, Brożek J, Guyatt G, Oxman A. Chapter 5: Quality of evidence. In: GRADE handbook for grading quality of evidence and strength of recommendations. The GRADE Working Group; 2013. Available from: guidelinedevelopment.org/handbook.
  12. [23]Paule RC, Mandel J. Consensus Values and Weighting Factors. J Res Natl Bur Stand. 1982; 87: 377. doi: 10.6028/jres.087.022 34566088 PMC6768160 · DOI
  13. [25]Deeks JJ, Higgins JPT, Altman D. Chapter 10: Analysing data and undertaking meta-analyses. In: Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane; 2022. Available from: www.training.cochrane.org/handbook.
  14. [26]Borenstein M, Hedges LV, Higgins J, Rothstein HR. Introduction to meta-analysis. Second edition. Hoboken: Wiley; 2021.
  15. [27]Altman DG. Statistics Notes: Interaction revisited: the difference between two estimates. BMJ. 2003; 326: 219– 219. doi: 10.1136/bmj.326.7382.219 12543843 PMC1125071 · DOI · Paper page
  16. [28]Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315: 629– 634. doi: 10.1136/bmj.315.7109.629 9310563 PMC2127453 · DOI · Paper page
  17. [32]Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020; 383: 1413– 1424. doi: 10.1056/NEJMoa2022190 32865377 · DOI · Paper page
  18. [33]Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. N Engl J Med. 2021; 384: 129– 139. doi: 10.1056/NEJMoa2030186 33200891 · DOI · Paper page
  19. [35]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: 323– 334. doi: 10.1056/NEJMoa1515920 27299675 · DOI · Paper page
  20. [36]Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019; 380: 347– 357. doi: 10.1056/NEJMoa1812389 30415602 · DOI · Paper page
  21. [37]Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, et al. Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes. N Engl J Med. 2020; 383: 1425– 1435. doi: 10.1056/NEJMoa2004967 32966714 · DOI · Paper page
  22. [38]McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019; 381: 1995– 2008. doi: 10.1056/NEJMoa1911303 31535829 · DOI · Paper page
  23. [39]Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017; 377: 644– 657. doi: 10.1056/NEJMoa1611925 28605608 · DOI · Paper page
  24. [42]Cherney DZI, Charbonnel B, Cosentino F, Dagogo-Jack S, McGuire DK, Pratley R, et al. Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: an analysis from the randomised VERTIS CV trial. Diabetologia. 2021; 64: 1256– 1267. doi: 10.1007/s00125-021-05407-5 33665685 PMC8099851 · DOI
  25. [43]Zannad F, Ferreira JP, Pocock SJ, Zeller C, Anker SD, Butler J, et al. Cardiac and Kidney Benefits of Empagliflozin in Heart Failure Across the Spectrum of Kidney Function: Insights From EMPEROR-Reduced. Circulation. 2021; 143: 310– 321. doi: 10.1161/CIRCULATIONAHA.120.051685 33095032 PMC7834910 · DOI
  26. [46]Jardine MJ, Zhou Z, Mahaffey KW, Oshima M, Agarwal R, Bakris G, et al. 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: 1128– 1139. doi: 10.1681/ASN.2019111168 32354987 PMC7217416 · DOI
  27. [47]Neuen BL, Ohkuma T, Neal B, Matthews DR, de Zeeuw D, Mahaffey KW, et al. Relative and Absolute Risk Reductions in Cardiovascular and Kidney Outcomes With Canagliflozin Across KDIGO Risk Categories: Findings From the CANVAS Program. Am J Kidney Dis. 2021; 77: 23– 34.e1. doi: 10.1053/j.ajkd.2020.06.018 32971190 · DOI · Paper page
  28. [48]Mosenzon O, Wiviott SD, Cahn A, Rozenberg A, Yanuv I, Goodrich EL, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. Lancet Diabetes Endocrinol. 2019; 7: 606– 617. doi: 10.1016/S2213-8587(19)30180-9 31196815 · DOI · Paper page
  29. [49]Neuen BL, Ohkuma T, Neal B, Matthews DR, de Zeeuw D, Mahaffey KW, et al. Cardiovascular and Renal Outcomes With Canagliflozin According to Baseline Kidney Function. Circulation. 2018; 138: 1537– 1550. doi: 10.1161/CIRCULATIONAHA.118.035901 29941478 PMC6181277 · DOI · Paper page
  30. [50]Wanner C, Lachin JM, Inzucchi SE, Fitchett D, Mattheus M, George J, et al. Empagliflozin and Clinical Outcomes in Patients With Type 2 Diabetes Mellitus, Established Cardiovascular Disease, and Chronic Kidney Disease. Circulation. 2018; 137: 119– 129. doi: 10.1161/CIRCULATIONAHA.117.028268 28904068 · DOI · Paper page
  31. [51]Mc Causland FR, Claggett BL, Vaduganathan M, Desai AS, Jhund P, de Boer RA, et al. Dapagliflozin and Kidney Outcomes in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Analysis of the DELIVER Randomized Clinical Trial. JAMA Cardiol. 2023; 8(1): 56– 65. doi: 10.1001/jamacardio.2022.4210 36326604 PMC9634592 · DOI
  32. [52]Wada T, Mori‐Anai K, Takahashi A, Matsui T, Inagaki M, Iida M, et al. Effect of canagliflozin on the decline of estimated glomerular filtration rate in chronic kidney disease patients with type 2 diabetes mellitus: A multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, phase III study in Japan. J Diabetes Investig. 2022; 13: 1981– 1989. doi: 10.1111/jdi.13888 35861630 PMC9720226 · DOI
  33. [53]Heerspink HJL, Sjöström CD, Jongs N, Chertow GM, Kosiborod M, Hou FF, et al. Effects of dapagliflozin on mortality in patients with chronic kidney disease: a pre-specified analysis from the DAPA-CKD randomized controlled trial. Eur Heart J. 2021; 42: 1216– 1227. doi: 10.1093/eurheartj/ehab094 33792669 PMC8244648 · DOI
  34. [55]Levin A, Perkovic V, Wheeler DC, Hantel S, George JT, von Eynatten M, et al. Empagliflozin and Cardiovascular and Kidney Outcomes across KDIGO Risk Categories: Post Hoc Analysis of a Randomized, Double-Blind, Placebo-Controlled, Multinational Trial. Clin J Am Soc Nephrol. 2020; 15: 1433– 1444. doi: 10.2215/CJN.14901219 32994159 PMC7536760 · DOI
  35. [57]Waijer SW, Vart P, Cherney DZI, Chertow GM, Jongs N, Langkilde AM, et al. Effect of dapagliflozin on kidney and cardiovascular outcomes by baseline KDIGO risk categories: a post hoc analysis of the DAPA-CKD trial. Diabetologia. 2022; 65: 1085– 1097. doi: 10.1007/s00125-022-05694-6 35445820 PMC9174107 · DOI
  36. [58]Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021; 385: 1451– 1461. doi: 10.1056/NEJMoa2107038 34449189 · DOI · Paper page
  37. [60]Li N, Zhou G, Zheng Y, Lv D, Zhu X, Wei P, et al. Effects of SGLT2 inhibitors on cardiovascular outcomes in patients with stage 3/4 CKD: A meta-analysis. PLoS One. 2022; 17: e0261986. doi: 10.1371/journal.pone.0261986 35020750 PMC8754287 · DOI
  38. [61]Rådholm K, Figtree G, Perkovic V, Solomon SD, Mahaffey KW, de Zeeuw D, et al. Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus. Circulation. 2018; 138: 458– 468. doi: 10.1161/CIRCULATIONAHA.118.034222 29526832 PMC6075881 · DOI · Paper page
  39. [62]Cherney DZI, McGuire DK, Charbonnel B, Cosentino F, Pratley R, Dagogo-Jack S, et al. Gradient of Risk and Associations With Cardiovascular Efficacy of Ertugliflozin by Measures of Kidney Function. Circulation. 2021; 143: 602– 605. doi: 10.1161/CIRCULATIONAHA.120.051901 33186063 · DOI
  40. [63]Tsai W-C, Hsu S-P, Chiu Y-L, Yang J-Y, Pai M-F, Ko M-J, et al. Cardiovascular and renal efficacy and safety of sodium-glucose cotransporter-2 inhibitors in patients without diabetes: a systematic review and meta-analysis of randomised placebo-controlled trials. BMJ Open. 2022; 12: e060655. doi: 10.1136/bmjopen-2021-060655 36241355 PMC9577928 · DOI · Paper page
  41. [64]Salah HM, Al’Aref SJ, Khan MS, Al-Hawwas M, Vallurupalli S, Mehta JL, et al. Effect of sodium-glucose cotransporter 2 inhibitors on cardiovascular and kidney outcomes-Systematic review and meta-analysis of randomized placebo-controlled trials. Am Heart J. 2021; 232: 10– 22. doi: 10.1016/j.ahj.2020.10.064 33214130 · DOI
  42. [65]Chen H-B, Yang Y-L, Yu T-H, Li Y-H. SGLT2 inhibitors for the composite of cardiorenal outcome in patients with chronic kidney disease: A systematic review and meta-analysis of randomized controlled trials. Eur J Pharmacol. 2022; 936: 175354. doi: 10.1016/j.ejphar.2022.175354 36306924 · DOI
  43. [66]Bikbov B, Purcell CA, Levey AS, Smith M, Abdoli A, Abebe M, et al. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020; 395: 709– 733. doi: 10.1016/S0140-6736(20)30045-3 32061315 PMC7049905 · DOI
  44. [67]Jackson D, Law M, Rücker G, Schwarzer G. The Hartung‐Knapp modification for random‐effects meta‐analysis: A useful refinement but are there any residual concerns? Stat Med. 2017; 36: 3923– 3934. doi: 10.1002/sim.7411 28748567 PMC5628734 · DOI
  45. [68]Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, 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: e895– e1032. doi: 10.1161/CIR.0000000000001063 35363499 · DOI · Paper page
  46. [69]UK Kidney Association. Clinical Practice Guideline: Sodium-Glucose Co-transporter-2 (SGLT-2) Inhibition in Adults with Kidney Disease. 2021. Available from: https://ukkidney.org/sites/renal.org/files/UKKA%20guideline_SGLT2i%20in%20adults%20with%20kidney%20disease%20v1%2020.10.21.pdf. PMC10598949 37880609

Cited by

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Authors
Reyes-Farias, C. I., Reategui-Diaz, M., Romani-Romani, F., & Prokop, L.
Affiliations
  • University of Piura (PE)
  • Mayo Clinic (US)
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2023-11-29
Volume
18
Issue
11
Pages
e0295059
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0295059
PMC
PMC10686459
OpenAlex
W4389128518
Cited by
20
References
17
Citations by year
2026: 6 · 2025: 9 · 2024: 5
FWCI
0.72
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
Keywords
SGLT2 inhibitors, chronic kidney disease, type 2 diabetes, cardiovascular outcomes, renal outcomes, heart failure hospitalization, cardiovascular mortality, non-diabetic chronic kidney disease, EGFR
MeSH terms
Sodium-Glucose Transporter 2 Inhibitors, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Glucose, Heart Failure, Humans, Hypoglycemic Agents, Kidney, Sodium, Randomized Controlled Trials as Topic, Renal Insufficiency, Chronic

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