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Acta Diabetologica

, Volume 55, Issue 5, pp 503–514 | Cite as

SGLT-2 inhibitors and the risk of infections: a systematic review and meta-analysis of randomized controlled trials

  • Robert Puckrin
  • Marie-Philippe Saltiel
  • Pauline Reynier
  • Laurent Azoulay
  • Oriana H. Y. Yu
  • Kristian B. Filion
Original Article

Abstract

Aims

There is concern about the infection-related safety profile of sodium–glucose co-transporter 2 (SGLT-2) inhibitors. We aimed to determine the effect of SGLT-2 inhibitors on genitourinary and other infections via systematic review and meta-analysis of randomized controlled trials (RCTs).

Methods

We conducted a systematic search of Medline, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov to identify double-blinded RCTs enrolling ≥ 50 patients with type 2 diabetes which compared an SGLT-2 inhibitor to placebo or active comparator. Two independent reviewers extracted data and appraised study quality. Data were pooled using random-effects models.

Results

Eighty-six RCTs enrolling 50,880 patients were included. SGLT-2 inhibitors increased the risk of genital infections compared to placebo (relative risk [RR] 3.37, 95% CI 2.89–3.93, I2 0%) and active comparator (RR 3.89, 95% CI 3.14–4.82, I2 0.3%). The risk of urinary tract infection (UTI) was not increased with SGLT-2 inhibitors compared to placebo (RR 1.03, 95% CI 0.96–1.11, I2 0%) or active comparator (RR 1.08, 95% CI 0.93–1.25, I2 22%). In drug-specific analyses, only dapagliflozin 10 mg daily was associated with a significantly increased risk of UTI compared to placebo (RR 1.33, 95% CI 1.10–1.61, I2 0%). SGLT-2 inhibitors were associated with a reduced risk of gastroenteritis (RR 0.38, 95% CI 0.20–0.72, I2 0%) but did not affect the risk of respiratory tract infections.

Conclusions/interpretation

SGLT-2 inhibitors are associated with an increased risk of genital tract infections. Although there is no association overall between SGLT-2 inhibitors and UTI, higher doses of dapagliflozin are associated with an increased risk.

Keywords

Sodium–glucose co-transporter 2 (SGLT-2) inhibitors Type 2 diabetes mellitus Infections Adverse events Systematic review and meta-analysis 

Notes

Acknowledgements

We wish to thank Mrs. Angella Lambrou, Liaison Librarian at the Life Sciences Library of McGill University, for her assistance in developing the database search strategies.

Authors contribution

RP and MS conducted the literature search, performed data extraction, and assessed study quality. PR conducted the statistical analyses. RP wrote the manuscript. All authors interpreted data and revised the manuscript for important intellectual content. RP and KBF designed the study. KBF conceived of the study idea, supervised the study, and is the guarantor.

Funding

Drs. Filion and Azoulay are supported by Fonds de Recherche du Québec—Santé (FRQS) Junior II awards.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to declare.

Ethical standard

This study used published, aggregate data and did not involve human participants or animals. Consequently, research ethics board review was not required.

Informed consent

Not applicable

Supplementary material

592_2018_1116_MOESM1_ESM.docx (8.2 mb)
Supplementary material 1 (DOCX 8421 kb)

References

  1. 1.
    Monami M, Nardini C, Mannucci E (2014) Efficacy and safety of sodium glucose co-transport 2 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 16(5):457–466CrossRefPubMedGoogle Scholar
  2. 2.
    Clar C, Gill J, Court R et al (2012) Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open 2(5):e001007CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Musso G, Gambino R, Cassader M et al (2012) A novel approach to control hyperglycemia in type 2 diabetes: sodium glucose co-transport (SGLT) inhibitors: systematic review and meta-analysis of randomized trials. Ann Med 44(4):375–393CrossRefPubMedGoogle Scholar
  4. 4.
    Vasilakou D, Karagiannis T, Athanasiadou E et al (2013) Sodium–glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 159(4):262–274CrossRefPubMedGoogle Scholar
  5. 5.
    Berhan A, Barker A (2013) Sodium glucose co-transport 2 inhibitors in the treatment of type 2 diabetes mellitus: a meta-analysis of randomized double-blind controlled trials. BMC Endocr Disord 13:58CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Liu X, Zhang N, Chen R et al (2015) Efficacy and safety of sodium–glucose cotransporter 2 inhibitors in type 2 diabetes: a meta-analysis of randomized controlled trials for 1 to 2 years. J Diabetes Complicat 29(8):1295–1303CrossRefPubMedGoogle Scholar
  7. 7.
    Johnsson K, Ptaszynska A, Schmitz B et al (2013) Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin. J Diabetes Complicat 27(5):479–484CrossRefPubMedGoogle Scholar
  8. 8.
    Food and Drug Administration (2015) 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. http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm. Accessed 12 Jan 2016
  9. 9.
    Food and Drug Administration (2016) FDA drug safety communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). http://www.fda.gov/Drugs/DrugSafety/ucm505860.htm. Accessed 6 Aug 2016
  10. 10.
    Yu S, Fu A, Qiu Y et al (2014) Disease burden of urinary tract infections among type 2 diabetes mellitus patients in the U.S. J Diabetes Complicat 28(5):621–626CrossRefPubMedGoogle Scholar
  11. 11.
    Mnif M, Kamoun N, Kacem F et al (2013) Complicated urinary tract infections associated with diabetes mellitus: pathogenesis, diagnosis and management. Indian J Endocrinol Metab 17(3):442–445CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 62:1006–1012CrossRefPubMedGoogle Scholar
  13. 13.
    Health Information Research Unit (2004) Hedges. http://hiru.mcmaster.ca/hiru/HIRU_Hedges_home.aspx. Accessed 15 Mar 2015
  14. 14.
    Higgins J, Green S (2008) Cochrane handbook for systematic reviews of interventions, version 5.0.0. The Cochrane collaboration. www.cochrane-handbook.org. Accessed 18 Aug 2016
  15. 15.
    Lundh A, Sismondo S, Lexchin J et al (2012) Industry sponsorship and research outcome. Cochrane Database Syst Rev 12:MR000033PubMedGoogle Scholar
  16. 16.
    Tahara A, Takasu T, Yokono M et al (2016) Characterization and comparison of sodium–glucose cotransporter 2 inhibitors in pharmacokinetics, pharmacodynamics, and pharmacologic effects. J Pharmacol Sci 130(3):159–169CrossRefPubMedGoogle Scholar
  17. 17.
    Geerlings S, Fonseca V, Castro-Diaz D et al (2014) Genital and urinary tract infections in diabetes: impact of pharmacologically-induced glucosuria. Diabetes Res Clin Pract 10(3):373–381CrossRefGoogle Scholar
  18. 18.
    Rosenstock J, Ferrannini E (2015) Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 38(9):1638–1642CrossRefPubMedGoogle Scholar
  19. 19.
    Food and Drug Administration (2016) FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm531517.htm. Accessed 17 Jun 2017
  20. 20.
    Zinman B, Wanner C, Lachin J et al (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373(22):2117–2128CrossRefPubMedGoogle Scholar
  21. 21.
    Monami M, Dicembrini I, Mannucci E (2017) Effects of SGLT-2 inhibitors on mortality and cardiovascular events: a comprehensive meta-analysis of randomized controlled trials. Acta Diabetol 54(1):19–36CrossRefPubMedGoogle Scholar
  22. 22.
    Zaccardi F, Webb D, Htike Z et al (2016) Efficacy and safety of sodium–glucose cotransporter 2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes Metab 18(8):783–794CrossRefPubMedGoogle Scholar
  23. 23.
    Wu J, Foote C, Blomster J et al (2016) Effects of sodium–glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 4(5):411–419CrossRefPubMedGoogle Scholar
  24. 24.
    Shyangdan D, Uthman O, Waugh N (2016) SGLT-2 receptor inhibitors for treating patients with type 2 diabetes mellitus: a systematic review and network meta-analysis. BMJ Open 6(2):e009417CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Li D, Wang T, Shen S et al (2017) 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 19(3):348–355CrossRefPubMedGoogle Scholar
  26. 26.
    Saad M, Mahmoud A, Elgendy I et al (2017) Cardiovascular outcomes with sodium–glucose cotransporter-2 inhibitors in patients with type II diabetes mellitus: a meta-analysis of placebo-controlled randomized trials. Int J Cardiol 228:352–358CrossRefPubMedGoogle Scholar
  27. 27.
    Storgaard H, Gluud L, Bennett C et al (2016) Benefits and harms of sodium–glucose co-transporter 2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis. PLoS ONE 11(11):e0166125CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Tang H, Fang Z, Wang T et al (2016) Meta-analysis of effects of sodium–glucose cotransporter 2 inhibitors on cardiovascular outcomes and all-cause mortality among patients with type 2 diabetes mellitus. Am J Cardiol 118(11):1774–1780CrossRefPubMedGoogle Scholar
  29. 29.
    Sutton A, Cooper N, Lambert P et al (2002) Meta-analysis of rare and adverse event data. Expert Rev Pharmacoecon Outcomes Res 2(4):367–379CrossRefPubMedGoogle Scholar
  30. 30.
    Walker E, Hernandez A, Kattan M (2008) Meta-analysis: its strengths and limitations. Cleve Clin J Med 75(6):431–439CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of MedicineUniversity of TorontoTorontoCanada
  2. 2.Deparment of MedicineMcGill UniversityMontrealCanada
  3. 3.Centre for Clinical EpidemiologyLady Davis InstituteMontrealCanada
  4. 4.Gerald Bronfman Department of OncologyMcGill UniversityMontrealCanada
  5. 5.Department of Epidemiology, Biostatistics, and Occupational HealthMcGill UniversityMontrealCanada
  6. 6.Division of EndocrinologyJewish General HospitalMontrealCanada

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