Acute kidney injury and adverse renal events in patients receiving SGLT2-inhibitors: A systematic review and meta-analysis

English version

Autoři: Jan Menne ^aff001; Eva Dumann ^aff001; Hermann Haller ^aff001; Bernhard M. W. Schmidt ^aff001
Působiště autorů: Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany ^aff001
Vyšlo v časopise: Acute kidney injury and adverse renal events in patients receiving SGLT2-inhibitors: A systematic review and meta-analysis. PLoS Med 16(12): e1002983. doi:10.1371/journal.pmed.1002983
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pmed.1002983

Souhrn

Background

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) represent a new class of oral hypoglycemic agents used in the treatment of type 2 diabetes mellitus. They have a positive effect on the progression of chronic kidney disease, but there is a concern that they might cause acute kidney injury (AKI).

Methods and findings

We conducted a systematic review and meta-analysis of the effect of SGLT2is on renal adverse events (AEs) in randomized controlled trials and controlled observational studies. PubMed, EMBASE, Cochrane library, and ClinicalTrials.gov were searched without date restriction until 27 September 2019. Data extraction was performed using a standardized data form, and any discrepancies were resolved by consensus. One hundred and twelve randomized trials (n = 96,722) and 4 observational studies with 5 cohorts (n = 83,934) with a minimum follow-up of 12 weeks that provided information on at least 1 adverse renal outcome (AKI, combined renal AE, or hypovolemia-related events) were included. In 30 trials, 410 serious AEs due to AKI were reported. SGLT2is reduced the odds of suffering AKI by 36% (odds ratio [OR] 0.64 [95% confidence interval (CI) 0.53–0.78], p < 0.001). A total of 1,089 AKI events of any severity (AEs and serious AEs [SAEs]) were published in 41 trials (OR 0.75 [95% CI 0.66–0.84], p < 0.001). Empagliflozin, dapagliflozin, and canagliflozin had a comparable benefit on the SAE and AE rate. AEs related to hypovolemia were more commonly reported in SGLT2i-treated patients (OR 1.20 [95% CI 1.10–1.31], p < 0.001). In the observational studies, 777 AKI events were reported. The odds of suffering AKI were reduced in patients receiving SGLT2is (OR 0.40 [95% CI 0.33–0.48], p < 0.001). Limitations of this study are the reliance on nonadjudicated safety endpoints, discrepant inclusion criteria and baseline hypoglycemic therapy between studies, inconsistent definitions of renal AEs and hypovolemia, varying follow-up times in different studies, and a lack of information on the severity of AKI (stages I–III).

Conclusions

SGLT2is reduced the odds of suffering AKI with and without hospitalization in randomized trials and the real-world setting, despite the fact that more AEs related to hypovolemia are reported.

Klíčová slova:

Adverse events – Systematic reviews – Kidneys – Hypoglycemics – Randomized controlled trials – Acute renal failure

Zdroje

1. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, 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):31–39. Epub 2018 Nov 10. doi: 10.1016/S0140-6736(18)32590-X 30424892.

2. 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):2117–2128. doi: 10.1056/NEJMoa1504720 26378978.

3. 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):323–334. doi: 10.1056/NEJMoa1515920 27299675.

4. Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669–2701. doi: 10.2337/dci18-0033 30291106; PubMed Central PMCID: PMC6245208.

5. Hahn K, Ejaz AA, Kanbay M, Lanaspa MA, Johnson RJ. Acute kidney injury from SGLT2 inhibitors: potential mechanisms. Nat Rev Nephrol. 2016;12(12):711–2. doi: 10.1038/nrneph.2016.159 27847389.

6. FDA. 6-14-2016; FDA Drug Safety Communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). 2016 [cited 2019 Feb 15]. Available from: https://www.fda.gov/Drugs/DrugSafety/ucm505860.htm.

7. Perlman A, Heyman SN, Matok I, Stokar J, Muszkat M, Szalat A. Acute renal failure with sodium-glucose-cotransporter-2 inhibitors: Analysis of the FDA adverse event report system database. Nutr Metab Cardiovasc Dis. 2017;27(12):1108–1113. doi: 10.1016/j.numecd.2017.10.011 29174031.

8. Tang H, Li D, Zhang J, Li Y, Wang T, Zhai S, et al. Sodium-glucose co-transporter-2 inhibitors and risk of adverse renal outcomes among patients with type 2 diabetes: A network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2017;19(8):1106–1115. doi: 10.1111/dom.12917 28240446.

9. Cahn A, Melzer-Cohen C, Pollack R, Chodick G, Shalev V. Acute renal outcomes with sodium-glucose co-transporter-2 inhibitors: Real-world data analysis. Diabetes Obes Metab. 2019;21(2):340–348. Epub 2018 Oct 15. doi: 10.1111/dom.13532 30207040.

10. Szalat A, Perlman A, Muszkat M, Khamaisi M, Abassi Z, Heyman SN. Can SGLT2 Inhibitors Cause Acute Renal Failure? Plausible Role for Altered Glomerular Hemodynamics and Medullary Hypoxia. Drug Saf. 2018;41(3):239–252. Epub 2017 Sept 26. doi: 10.1007/s40264-017-0602-6 28952138.

11. Doyle JF, Forni LG. Acute kidney injury: short-term and long-term effects. Crit Care. 2016;20(1):188. doi: 10.1186/s13054-016-1353-y 27373891; PubMed Central PMCID: PMC4931701.

12. Fortrie G, de Geus HRH, Betjes MGH. The aftermath of acute kidney injury: a narrative review of long-term mortality and renal function. Crit Care. 2019;23(1):24. doi: 10.1186/s13054-019-2314-z 30678696; PubMed Central PMCID: PMC6346585.

13. See EJ, Jayasinghe K, Glassford N, Bailey M, Johnson DW, Polkinghorne KR, et al. Long-term risk of adverse outcomes after acute kidney injury: a systematic review and meta-analysis of cohort studies using consensus definitions of exposure. Kidney Int. 2019;95(1):160–172. Epub 2018 Nov 23. doi: 10.1016/j.kint.2018.08.036 30473140.

14. Susantitaphong P, Cruz DN, Cerda J, Abulfaraj M, Alqahtani F, Koulouridis I, et al. World incidence of AKI: a meta-analysis. Clin J Am Soc Nephrol. 2013;8(9):1482–93. doi: 10.2215/CJN.00710113 23744003; PubMed Central PMCID: PMC3805065.

15. Hodgson LE, Sarnowski A, Roderick PJ, Dimitrov BD, Venn RM, Forni LG. Systematic review of prognostic prediction models for acute kidney injury (AKI) in general hospital populations. BMJ Open. 2017;7(9):e016591. doi: 10.1136/bmjopen-2017-016591 28963291; PubMed Central PMCID: PMC5623486.

16. Zhang Y, Nakano D, Guan Y, Hitomi H, Uemura A, Masaki T, et al. A sodium-glucose cotransporter 2 inhibitor attenuates renal capillary injury and fibrosis by a vascular endothelial growth factor-dependent pathway after renal injury in mice. Kidney Int. 2018;94(3):524–535. doi: 10.1016/j.kint.2018.05.002 30045814.

17. Chang YK, Choi H, Jeong JY, Na KR, Lee KW, Lim BJ, et al. Dapagliflozin, SGLT2 Inhibitor, Attenuates Renal Ischemia-Reperfusion Injury. PLoS ONE. 2016;11(7):e0158810. doi: 10.1371/journal.pone.0158810 27391020; PubMed Central PMCID: PMC4938401.

18. Ito M, Tanaka T. The Anticipated Renoprotective Effects of Sodium-glucose Cotransporter 2 Inhibitors. Intern Med. 2018;57(15):2105–2114. doi: 10.2169/internalmedicine.9842-17 29491318; PubMed Central PMCID: PMC6120824.

19. 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):1988–1993. doi: 10.1111/dom.13301 29573529; PubMed Central PMCID: PMC6055757.

20. Mayer GJ, Wanner C, Weir MR, Inzucchi SE, Koitka-Weber A, Hantel S, et al. Analysis from the EMPA-REG OUTCOME((R)) 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. doi: 10.1016/j.kint.2019.02.033 31142441.