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Acute renal failure with sodium-glucose-cotransporter-2 inhibitors: Analysis of the FDA adverse event report system database

Published:October 17, 2017DOI:https://doi.org/10.1016/j.numecd.2017.10.011

      Highlights

      • SGLT2-inhibitors are associated with acute renal failure in the FDA adverse event reporting system.
      • Reports of acute renal failure with SGLT2-inhibitors were more likely to report concomitant diuretics and/or ACE-inhibitors.
      • Plausible biological mechanisms have been proposed for these findings.
      • The link between SGLT2-inhibitors and acute renal failure persisted when controlling for diabetes and the FDA warning.
      • SGLT2-inhibitors differed from one another in the strength of their link to acute renal failure.

      Abstract

      Background and aims

      Sodium-glucose-cotransporter-2 (SGLT2) inhibitors have recently been approved for the treatment of type II diabetes mellitus (T2DM). It has been proposed that these agents could induce acute renal failure (ARF) under certain conditions. This study aimed to evaluate the association between SGLT2-inhibitors and ARF in the FDA adverse event report system (FAERS) database.

      Methods and results

      We analyzed adverse event cases submitted to FAERS between January 2013 and September 2016. ARF cases were identified using a structured medical query. Medications were identified using both brand and generic names. During the period evaluated, 18,915 reports (out of a total of 3,832,015 registered in FAERS) involved the use of SGLT2-inhibitors. SGLT2-inhibitors were reportedly associated with ARF in 1224 of these cases (6.4%), and were defined as the “primary” or “secondary” cause of the adverse event in 96.8% of these cases. The proportion of reports with ARF among reports with SGLT2 inhibitor was almost three-fold higher compared to reports without these drugs (ROR 2.88, 95% CI 2.71–3.05, p < 0.001). The proportion of ARF reports among cases with SGLT2-inhibitors was significantly greater than the proportion of ARF among cases with T2DM without SGLT2-inhibitors (ROR 1.68, 95% CI 1.57–1.8, p < 0.001). Among the SGLT2-inhibitors, canagliflozin was associated with a higher proportion of reports of renal failure (7.3%), compared to empagliflozin and dapagliflozin (4.7% and 4.8% respectively, p < 0.001).

      Conclusion

      SGLT2-inhibitors are associated with an increase in the proportion of reports of ARF compared to other medications. SGLT2-inhibitor agents may differ from one another in their respective risk for ARF.

      Keywords

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      References

        • Zaccardi F.
        • Webb D.R.
        • Htike Z.Z.
        • Youssef D.
        • Khunti K.
        • Davies M.J.
        Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis.
        Diabetes, Obes Metab. 2016; 18: 783-794
        • Zinman B.
        • Wanner C.
        • Lachin J.M.
        • Fitchett D.
        • Bluhmki E.
        • Hantel S.
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        N Engl J Med. 2015; 373: 2117-2128
        • Wanner C.
        • Inzucchi S.E.
        • Lachin J.M.
        • 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
        • Neal B.
        • Perkovic V.
        • Mahaffey K.W.
        • 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
        • Heyman S.N.
        • Khamaisi M.
        • Rosen S.
        • Rosenberger C.
        • Abassi Z.
        Potential hypoxic renal injury in patients with diabetes on SGLT2 inhibitors: caution regarding concomitant use of NSAIDs and iodinated contrast media.
        Diabetes Care. 2017; 40: e40-e41
        • O'Neill J.
        • Fasching A.
        • Pihl L.
        • Patinha D.
        • Franzén S.
        • Palm F.
        Acute SGLT inhibition normalizes O 2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats.
        Am J Physiol - Ren Physiol. 2015; 309: F227-F234
        • Vasilakou D.
        • Karagiannis T.
        • Athanasiadou E.
        • Mainou M.
        • Liakos A.
        • Bekiari E.
        • et al.
        Sodium–Glucose cotransporter 2 inhibitors for type 2 diabetes.
        Ann Intern Med. 2013; 159: 262
        • Storgaard H.
        • Gluud L.L.
        • Bennett C.
        • Grøndahl M.F.
        • Christensen M.B.
        • Knop F.K.
        • et al.
        Benefits and harms of sodium-glucose Co-Transporter 2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis.
        PLoS One. 2016; 11e0166125
        • Tang H.
        • Li D.
        • Zhang J.
        • Li Y.
        • Wang T.
        • Zhai S.
        • et al.
        Sodium-glucose cotransporter 2 inhibitors and risk of adverse renal outcomes among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials.
        Diabetes Obes Metab. 2017;
      1. http://bioportal.bioontology.org/ontologies/MEDDRA?p=classes&conceptid=20000003.

        • Evans S.J.W.
        • Waller P.C.
        • Davis S.
        Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports.
        Pharmacoepidemiol Drug Saf. 2001; 10: 483-486
        • Harpaz R.
        • DuMouchel W.
        • LePendu P.
        • Bauer-Mehren A.
        • Ryan P.
        • Shah N.H.
        Performance of pharmacovigilance signal-detection algorithms for the FDA adverse event reporting system.
        Clin Pharmacol Ther. 2013; 93: 539-546
        • Raschi E.
        • Poluzzi E.
        • Koci A.
        • Salvo F.
        • Pariente A.
        • Biselli M.
        • et al.
        Liver injury with novel oral anticoagulants: assessing post-marketing reports in the US Food and Drug Administration adverse event reporting system.
        Br J Clin Pharmacol. 2015;
        • Sakaeda T.
        • Tamon A.
        • Kadoyama K.
        • Okuno Y.
        Data mining of the public version of the FDA adverse event reporting system.
        Int J Med Sci. 2013; 10: 796-803
        • Rothman K.J.
        • Lanes S.
        • Sacks S.T.
        The reporting odds ratio and its advantages over the proportional reporting ratio.
        Pharmacoepidemiol Drug Saf. 2004; 13: 519-523
        • Weber J.
        Epidemiology of adverse reactions to nonsteroidal antiinflammatory drugs.
        Adv Inflamm Res. 1984; 61
        • Hartnell N.R.
        • Wilson J.P.
        Replication of the Weber effect using postmarketing adverse event reports voluntarily submitted to the United States Food and Drug Administration.
        Pharmacotherapy. 2004; 24: 743-749
        • Poluzzi E.
        • Raschi E.
        • Piccinni C.D.F.
        Data mining techniques in pharmacovigilance: analysis of the publicly accessible FDA adverse event reporting system (AERS).
        in: Karahoca A. Data Min Appl Eng Med, InTech. 2012: 265-302
        • Hoffman K.B.
        • Demakas A.R.
        • Dimbil M.
        • Tatonetti N.P.
        • Erdman C.B.
        Stimulated reporting: the impact of US food and drug administration-issued alerts on the adverse event reporting system (FAERS).
        Drug Saf. 2014; 37: 971-980
        • Hoffman K.B.
        • Dimbil M.
        • Erdman C.B.
        • Tatonetti N.P.
        • Overstreet B.M.
        The weber effect and the United States food and drug Administration's adverse event reporting system (FAERS): analysis of sixty-two drugs approved from 2006 to 2010.
        Drug Saf. 2014; 37: 283-294
        • Lambers Heerspink H.J.
        • 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: 853-862
        • Heyman S.N.
        • Khamaisi M.
        • Rosenberger C.
        • Szalat A.
        • Abassi Z.
        Increased hematocrit during sodium-glucose Cotransporter-2 inhibitor therapy.
        J Clin Med Res. 2017; 9: 176-177
        • Zinman B.
        • Wanner C.
        • Lachin J.M.
        • et al.
        • Supplement to
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        N Engl J Med. 2015; 373: 2117-2128https://doi.org/10.1056/NEJMoa1504720 2015
        • Downing N.S.
        • Shah N.D.
        • Aminawung J.A.
        • Pease A.M.
        • Zeitoun J.-D.
        • Krumholz H.M.
        • et al.
        Postmarket safety events among novel therapeutics approved by the US food and drug administration between 2001 and 2010.
        JAMA. 1854; 2017: 317
        • Neal B.
        • Perkovic V.
        • Mahaffey K.W.
        • et al.
        • Protocol for
        Canagliflozin and cardiovascular and renal events in type 2 diabetes.
        N Engl J Med. 2017; 376: 644-657https://doi.org/10.1056/NEJMoa1611925 n.d
        • Mandal A.K.
        • Markert R.J.
        • Saklayen M.G.
        • Mankus R.A.
        • Yokokawa K.
        Diuretics potentiate angiotensin converting enzyme inhibitor-induced acute renal failure.
        Clin Nephrol. 1994; 42: 170-174
        • Bakris G.L.
        • Sarafidis P.A.
        • Weir M.R.
        • Dahlöf B.
        • Pitt B.
        • Jamerson K.
        • et al.
        Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial.
        Lancet (London, Engl. 2010; 375: 1173-1181
        • Knight E.L.
        • Glynn R.J.
        • McIntyre K.M.
        • Mogun H.
        • Avorn J.
        Predictors of decreased renal function in patients with heart failure during angiotensin-converting enzyme inhibitor therapy: results from the studies of left ventricular dysfunction (SOLVD).
        Am Heart J. 1999; 138: 849-855
        • Scheen A.J.
        Pharmacokinetic and pharmacodynamic profile of empagliflozin, a sodium glucose co-transporter 2 inhibitor.
        Clin Pharmacokinet. 2014; 53: 213-225
        • Baartscheer A.
        • Schumacher C.A.
        • Wüst R.C.I.
        • Fiolet J.W.T.
        • Stienen G.J.M.
        • Coronel R.
        • et al.
        Empagliflozin decreases myocardial cytoplasmic Na(+) through inhibition of the cardiac Na(+)/H(+) exchanger in rats and rabbits.
        Diabetologia. 2017; 60: 568-573