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Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis
  1. Jennifer R Donnan1,
  2. Catherine A Grandy1,
  3. Eugene Chibrikov1,
  4. Carlo A Marra1,2,
  5. Kris Aubrey-Bassler3,
  6. Karissa Johnston1,
  7. Michelle Swab3,
  8. Jenna Hache1,
  9. Daniel Curnew1,
  10. Hai Nguyen1,
  11. John-Michael Gamble1,4
  1. 1 School of Pharmacy, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
  2. 2 School of Pharmacy, University of Otago, Dunedin, New Zealand
  3. 3 Faculty of Medicine, Memorial University, St. John’s, Newfoundland and Labrador, Canada
  4. 4 School of Pharmacy, Faculty of Science, University of Waterloo, Waterloo, Ontario, Canada
  1. Correspondence to Dr John-Michael Gamble; jm.gamble{at}uwaterloo.ca

Abstract

Objective To estimate the association between the use of sodium glucose co-transporter-2 (SGLT2) inhibitors and postmarket harms as identified by drug regulatory agencies.

Design We conducted a systematic review and meta-analysis of randomised controlled trials (RCT). Six large databases were searched from inception to May 2018. Random effects models were used to estimate pooled relative risks (RRs).

Intervention SGLT2 inhibitors, compared with placebo or active comparators.

Primary outcomes Acute kidney injury (AKI), diabetic ketoacidosis (DKA), urinary tract infections (UTI), bone fractures and lower limb amputations.

Results We screened 2418 citations of which 109 were included. Most studies included one of four SGLT2 inhibitors, dapagliflozin, canagliflozin, empagliflozin and ipragliflozin. When compared with placebo, SGLT2 inhibitors were found to be significantly protective against AKI (RR=0.59; 95% CI 0.39 to 0.89; I2=0.0%), while no difference was found for DKA (RR 0.66; 95% CI 0.30 to 1.45, I2=0.0%), UTI (RR 1.02; 95% CI 0.95 to 1.09, I2=0.0%) or bone fracture (RR 0.87; 95% CI 0.69 to 1.09, I2=1.3%). Three studies reported on amputation, with one finding a significant increase risk. No increased risk for either outcome was found when compared with active controls. Subgroup analysis did show an increased risk of UTI with dapagliflozin only (RR 1.21; 95% CI 1.02 to 1.43, I2=0.0%), but no other analysis supported an increased risk of AKI, DKA, UTI or fracture.

Conclusions Current evidence from RCTs does not suggest an increased risk of harm with SGLT2 inhibitors as a class over placebo or active comparators with respect to AKI, DKA, UTI or fracture. However, wide CIs for many comparisons suggest limited precision, and therefore clinically important adverse events cannot be ruled out. Dapagliflozin, appears to independently increase the risk of UTI, although the mechanism for this intraclass variation in risk is unclear.

PROSPERO registration number CRD42016038715.

  • epidemiology
  • therapeutics
  • adverse events

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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Footnotes

  • Contributors JRD led the review and was involved at every stage, including protocol development, search strategy design, screening, data extraction, quality appraisal, analysis and manuscript preparation. CG was involved in screening, data extraction, quality appraisal and manuscript revisions and final approval. EC was involved in data cleaning and analysis, manuscript revisions and final approval. CAM was involved in project conception, protocol development and manuscript revisions and final approval. KAB was involved in project conception, protocol development and manuscript revisions and final approval. KJ was involved in project conception, protocol development and manuscript revisions and final approval. MS was involved in search strategy design, literature search and manuscript revisions and final approval. JH was involved in screening, data extraction, quality appraisal and manuscript revisions and final approval. DC was involved in screening, data extraction, quality appraisal and manuscript revisions and final approval. HN was involved in interpretation of study results, manuscript revisions and final approval. JMG supervised this research and was involved in protocol development, consensus on disagreements in data extraction, data analysis, interpretation of results, manuscript revisions and final approval.

  • Funding This work was partially supported by the Newfoundland and Labrador Centre for Applied Health Research.

  • Competing interests None declared.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All data used in this systematic review and meta-analysis are available through previously published articles and/or through clinical trials.gov. Section 2 of the supplementary appendix includes a complete list of data extraction variables that were collected. Access to the data can be granted by contacting the corresponding author.

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