Skip to main content
SpringerLink
Log in

Acute Renal Failure, Ketoacidosis, and Urogenital Tract Infections with SGLT2 Inhibitors: Signal Detection Using a Japanese Spontaneous Reporting Database

  • Original Research Article
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

Background

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a class of oral anti-hyperglycemic agents that have been available on the market in Japan since 2014. Although safety information has accumulated alongside the clinical use, the warnings issued by each country based on adverse events associated with the drug are different and examination of the safety of the drug is insufficient.

Objective

This study examined the safety of SGLT2 inhibitors by using a Japanese spontaneous reporting database and focusing on the cautions issued in each country and the disparities within existing research into the occurrence of the adverse events of acute renal failure (ARF), ketoacidosis, and urogenital tract infections (UTIs).

Patients and Methods

We analyzed data recorded on the Japanese Adverse Drug Event Report database (JADER) between April 2014 and February 2019. We calculated the reporting odds ratio (ROR) and 95% confidence interval (CI) with sex and age as adjustment factors.

Results

JADER contained 366,501 cases with the adverse events of interest; 4322 involved SGLT2 inhibitors. The ROR for SGLT2 inhibitors was calculated as 1.0 (95% CI 0.9–1.2) for ARF, 72.2 (95% CI 59.3–87.8) for ketoacidosis, and 14.0 (95% CI 11.0–17.8) for UTIs. Analysis of only subjects receiving treatment for diabetes showed a similar trend.

Conclusion

The results suggested a correlation between SGLT2 inhibitors and the onset of ketoacidosis and UTIs, but not between SGLT2 inhibitors and ARF. Further verification of the safety of SGLT2 inhibitors, through continued risk assessments and large-scale clinical studies, are necessary.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. FDA. FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. 15 May 2015. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about. Accessed 19 Dec 2019.

  2. FDA. FDA Drug Safety Communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). 14 Jun 2016. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-strengthens-kidney-warnings-diabetes-medicines-canagliflozin. Accessed 19 Dec 2019.

  3. PMDA. PMDA revises labels of ipragliflozin, luseogliflozin and tofogliflozin. 15 Sep 2015. (In Japanese). https://www.info.pmda.go.jp/kaiteip/20150915A001/02.pdf. Accessed 19 Dec 2019.

  4. PMDA. PMDA revises labels dapagliflozin, canagliflozin and empagliflozin. 15 Sep 2015. (In Japanese). https://www.info.pmda.go.jp/kaiteip/20150915A001/03.pdf. Accessed 19 Dec 2019.

  5. PMDA. PMDA revises labels ipragliflozin, dapagliflozin, luseogliflozin, canagliflozin, and empagliflozin. 9 Jan 2015. (In Japanese). https://www.info.pmda.go.jp/kaiteip/20150109A002/02.pdf. Accessed 19 Dec 2019.

  6. PMDA. PMDA revises a label tofogliflozin. 9 Jan 2015. (In Japanese). https://www.info.pmda.go.jp/kaiteip/20150109A002/03.pdf. Accessed 19 Dec 2019.

  7. Committee on the Proper Use of SGLT2 Inhibitors. Recommendations on the proper use of SGLT2 inhibitors. Diabetol Int. 2019;11(1):1–5.

    Article  Google Scholar 

  8. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–288.

    Article  CAS  Google Scholar 

  9. Donnan JR, Grandy CA, Chibrikov E, et al. Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis. BMJ Open. 2019;9:e022577.

    Article  Google Scholar 

  10. Li D, Wang T, Shen S, Fang Z, Dong Y, Tang H. Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors: a meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2017;19(3):348–55.

    Article  CAS  Google Scholar 

  11. EMA. EudraVigilance. https://www.ema.europa.eu/en/human-regulatory/research-development/pharmacovigilance/eudravigilance. Accessed 19 Dec 2019.

  12. Government of Canada. Adverse Reaction Database. https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/adverse-reaction-database/medeffect-canada-caveat-privacy-statement-interpretation-data-search-canada-vigilance-adverse-reaction-online-database.html. Accessed 19 Dec 2019.

  13. Uppsala Monitoring Centre. VigiBase. https://www.who-umc.org/vigibase/vigibase/. Accessed 19 Dec 2019.

  14. PMDA. JADER. (In Japanese). https://www.pmda.go.jp/safety/info-services/drugs/adr-info/suspected-adr/0004.html. Accessed 17 Jun 2019.

  15. FDA. FDA Adverse Event Reporting System (FAERS): Latest Quarterly Data Files. https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-latest-quarterly-data-files. Accessed 19 Dec 2019.

  16. Narukawa M. Expectations for pharmacoepidemiology studies on drug risk management. Regul Sci Med Prod. 2016;6:335–43 (in Japanese).

    Google Scholar 

  17. 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;27:1108–13.

    Article  CAS  Google Scholar 

  18. Fadini GP, Bonora BM, Avogaro A. SGLT2 inhibitors and diabetic ketoacidosis: data from the FDA Adverse Event Reporting System. Diabetologia. 2017;60:1385–9.

    Article  CAS  Google Scholar 

  19. Shen J, Yang J, Zhao B. A Survey of the FDA’s Adverse Event Reporting system database concerning urogenital tract infections and sodium glucose cotransporter-2 inhibitor use. Diabetes Ther. 2019;10:1043–50.

    Article  CAS  Google Scholar 

  20. Fujita T. Signal detection of adverse drug reactions. Japan J Pharmacoepidemiol/Yakuzai ekigaku. 2009;14:27–36.

    Article  Google Scholar 

  21. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57.

    Article  CAS  Google Scholar 

  22. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323–34.

    Article  CAS  Google Scholar 

  23. Kadowaki T, Nangaku M, Hantel S, Okamura T, von Eynatten M, Wanner C, et al. Empagliflozin and kidney outcomes in Asian patients with type 2 diabetes and established cardiovascular disease: Results from the EMPA-REG OUTCOME(®) trial. J Diabetes Investig. 2019;10(3):760–70.

    Article  CAS  Google Scholar 

  24. Chan JC, Wat NM, So WY, Lam KS, Chua CT, Wong KS, et al. Renin angiotensin aldosterone system blockade and renal disease in patients with type 2 diabetes. An Asian perspective from the RENAAL Study. Diabetes Care. 2004;27(4):874–9.

    Article  CAS  Google Scholar 

  25. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving H-H, et al. 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.

    Article  CAS  Google Scholar 

  26. Ado Moumouni AN, Robin P, Hillaire-Buys D, Faillie JL. SGLT-2 inhibitors and ketoacidosis: a disproportionality analysis in the World Health Organization's adverse drug reactions database. Fundam Clin Pharmacol. 2018;32:216–26.

    Article  CAS  Google Scholar 

  27. Taylor SI, Blau JE, Rother KI. SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab. 2015;100:2849–52.

    Article  CAS  Google Scholar 

  28. McGill JB, Subramanian S. Safety of sodium-glucose co-transporter 2 inhibitors. Am J Cardiol. 2019;124:S45–S52.

    Article  CAS  Google Scholar 

  29. Yang Y, Chen S, Pan H, Zou Y, Wang B, Wang G, et al. Safety and efficiency of SGLT2 inhibitor combining with insulin in subjects with diabetes: systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore). 2017;96(21):e6944.

    Article  CAS  Google Scholar 

  30. Puckrin R, Saltiel MP, Reynier P, Azoulay L, Yu OHY, Filion KB. SGLT-2 inhibitors and the risk of infections: a systematic review and meta-analysis of randomized controlled trials. Acta Diabetol. 2018;55(5):503–14.

    Article  CAS  Google Scholar 

  31. Cai X, Gao X, Yang W, Chen Y, Zhang S, Zhou L, et al. No disparity of the efficacy and all-cause mortality between Asian and non-Asian type 2 diabetes patients with sodium-glucose cotransporter 2 inhibitors treatment: a meta-analysis. J Diabetes Investig. 2018;9(4):850–61.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. International University of Health and Welfare Graduate School Graduate School of Health and Welfare Sciences, 4-1-26 Akasaka, Minato-city, Tokyo, 107-8402, Japan

    Yukari Katsuhara & Toshio Ogawa

Authors
  1. Yukari Katsuhara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshio Ogawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yukari Katsuhara.

Ethics declarations

Funding

The authors received no specific funding for this study.

Conflict of interest

The authors declare no conflicts of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 463 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Katsuhara, Y., Ogawa, T. Acute Renal Failure, Ketoacidosis, and Urogenital Tract Infections with SGLT2 Inhibitors: Signal Detection Using a Japanese Spontaneous Reporting Database. Clin Drug Investig 40, 645–652 (2020). https://doi.org/10.1007/s40261-020-00925-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40261-020-00925-3

Search

Navigation