Open access Research BMJ Open: first published as 10.1136/bmjopen-2018-022577 on 1 February 2019. Downloaded from Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis Jennifer R Donnan,1 Catherine A Grandy,1 Eugene Chibrikov,1 Carlo A Marra,1,2 Kris Aubrey-Bassler,3 Karissa Johnston,1 Michelle Swab,3 Jenna Hache,1 Daniel Curnew,1 Hai Nguyen,1 John-Michael Gamble1,4 To cite: Donnan JR, Grandy CA, ABSTRACT Strengths and limitations of this study Chibrikov E, et al. Comparative Objective To estimate the association between the use safety of the sodium glucose of sodium glucose co-transporter-2 (SGLT2) inhibitors ► This study provides a comprehensive systematic co-transporter 2 (SGLT2) and postmarket harms as identified by drug regulatory inhibitors: a systematic review review of potential serious adverse events related agencies. and meta-analysis. BMJ Open to use of sodium glucose co-transporter-2 (SGLT2) Design We conducted a systematic review and meta- 2019;9:e022577. doi:10.1136/ inhibitors identified by drug regulatory agencies. analysis of randomised controlled trials (RCT). Six large bmjopen-2018-022577 ► This study considered select outcomes to provide databases were searched from inception to May 2018. focused attention on the issues concerning regula- ► Prepublication history and Random effects models were used to estimate pooled tors; however, this means that additional knowledge additional material for this relative risks (RRs). paper are available online. To of the clinical benefits and harms needs to be con- Intervention SGLT2 inhibitors, compared with placebo or view these files, please visit sidered before applying the results of this study. active comparators. the journal online (http:// dx. doi. ► Several of the outcomes (eg, acute kidney injury, di- Primary outcomes Acute kidney injury (AKI), diabetic org/ 10. 1136/ bmjopen- 2018- abetic ketoacidosis, limb amputations) we evaluated ketoacidosis (DKA), urinary tract infections (UTI), bone 022577). occur infrequently and, in some cases, were not re- fractures and lower limb amputations. ported by individual studies. Received 2 March 2018 Results We screened 2418 citations of which 109 were ► Certain outcomes may have been inadequately Revised 14 June 2018 included. Most studies included one of four SGLT2 inhibitors, characterised within study reports. For example, Accepted 2 November 2018 dapagliflozin, canagliflozin, empagliflozin and ipragliflozin. while urinary tract infections were commonly re- http://bmjopen.bmj.com/ When compared with placebo, SGLT2 inhibitors were found to ported among randomised controlled trials included be significantly protective against AKI (RR=0.59; 95% CI 0.39 in this meta-analysis, data on complicated versus to 0.89; I2=0.0%), while no difference was found for DKA (RR uncomplicated infections were not. 0.66; 95% CI 0.30 to 1.45, I2=0.0%), UTI (RR 1.02; 95% CI ► Our objective is to summarise the current state of 0.95 to 1.09, I2=0.0%) or bone fracture (RR 0.87; 95% CI knowledge surrounding key postmarket safety con- 0.69 to 1.09, I2=1.3%). Three studies reported on amputation, cerns of the SGLT2 inhibitors compared with active with one finding a significant increase risk. No increased risk © Author(s) (or their and non-active comparators in patients with type 2 for either outcome was found when compared with active employer(s)) 2019. Re-use diabetes. permitted under CC BY-NC. No controls. Subgroup analysis did show an increased risk of on October 1, 2021 by guest. Protected copyright. commercial re-use. See rights UTI with dapagliflozin only (RR 1.21; 95% CI 1.02 to 1.43, and permissions. Published by I2=0.0%), but no other analysis supported an increased risk of BMJ. AKI, DKA, UTI or fracture. available for the management of type 2 1 School of Pharmacy, Memorial Conclusions Current evidence from RCTs does not suggest diabetes. Clinical guidelines recommend the University of Newfoundland, an increased risk of harm with SGLT2 inhibitors as a class St. John’s, Newfoundland and SGLT2 inhibitors as one of numerous poten- over placebo or active comparators with respect to AKI, DKA, Labrador, Canada tial pharmacological approaches for second- 2School of Pharmacy, University UTI or fracture. However, wide CIs for many comparisons line therapy following metformin failure of Otago, Dunedin, New Zealand suggest limited precision, and therefore clinically important or intolerance.1 2 Some clinical guidelines 3 adverse events cannot be ruled out. Dapagliflozin, appears Faculty of Medicine, Memorial recommend the SGLT2 inhibitors, empagli- University, St. John’s, to independently increase the risk of UTI, although the flozin or canagliflozin, or the glucagon-like Newfoundland and Labrador, mechanism for this intraclass variation in risk is unclear. Canada PROSPERO registration number CRD42016038715. peptide-1 (GLP-1) receptor agonist, liraglu- 4School of Pharmacy, Faculty of tide, as preferred second-line therapies in Science, University of Waterloo, patients with cardiovascular disease who have Waterloo, Ontario, Canada failed to achieve glycaemic control while on 1 Correspondence to INTRODUCTION monotherapy. This paradigm shift in the Dr John-Michael Gamble; The sodium glucose co-transporter 2 (SGLT2) management of type 2 diabetes is largely jm. gamble@ uwaterloo. ca inhibitors are novel glucose-lowering therapies supported by evidence from recent landmark Donnan JR, et al. BMJ Open 2019;9:e022577. doi:10.1136/bmjopen-2018-022577 1 Open access BMJ Open: first published as 10.1136/bmjopen-2018-022577 on 1 February 2019. Downloaded from clinical trials.3–6 In 2015, the Empagliflozin Outcome makers need to continue examining the potential risks Event Trial in Type 2 Diabetes Mellitus Patients–Removing to their patients. Our objective is to address the current Excess Glucose (EMPA-REG OUTCOME) trial showed knowledge gap surrounding the postmarket safety of the that the SGLT2 inhibitor, empagliflozin, significantly SGLT2 inhibitors compared with active and non-active reduced the risk for composite end point of cardiovas- comparators in patients with type 2 diabetes. We have cular death, myocardial infarction or stroke by 14% and conducted a systematic review and meta-analysis of RCTs all-cause mortality by 32%, in a population with existing to estimate the risk of AKI, DKA, UTI, bone fracture and cardiovascular disease.5 The Canagliflozin Cardiovas- lower limb amputation. cular Assessment Study (CANVAS), Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial and the Trial to Evaluate Cardio- METHODS AND ANALYSIS vascular and Other Long-term Outcomes with Semaglu- Study design tide in Subjects with Type 2 Diabetes (SUSTAIN-6) have This study has been designed in accordance with the also demonstrated similar benefits with canagliflozin, lira- Preferred Reporting Items for Systematic Reviews and 3 4 glutide and semaglutide respectively. Meta-Analyses statement on systematic reviews and Considering the relative potential harms and benefits, meta-analysis.24 This protocol has been registered clinicians and policy makers must continue to integrate (CRD42016038715) with PROSPERO (International new pharmacotherapeutic evidence to optimise health Prospective Register of Systematic Reviews).25 26 outcomes. Although the EMPA-REG trial showed that the SGLT2 inhibitor, empagliflozin, significantly reduces the Patient involvement risk of cardiovascular morbidity and mortality, regulatory Patients were not engaged in the development of this agencies including the Food and Drug Administration protocol. (FDA), the European Medicines Associations and Health Canada have issued safety warnings for several adverse Search strategy events. These include acute kidney injury (AKI), diabetic A comprehensive search strategy was developed with ketoacidosis (DKA), urinary tract infections (UTI), bone an experienced health science librarian (MS). The fractures and lower limb amputations, based primarily on search strategy for published studies was developed in case report data.7–14 the PubMed database, and comprised keywords and With respect to AKI, there is conflicting information MEDLINE controlled vocabulary or medical subject head- coming forward from clinical trials and case reports. ings. A methodological search filter was applied to iden- Despite early indication of a protective effect from SGLT2 tify RCTs26 and the search was limited to English language inhibitors,15 the FDA published in a safety communica- publications. This search strategy served as a template for tion in June 2016 that 101 cases of AKI were reported additional search strategies tailored to other databases, http://bmjopen.bmj.com/ among users of canagliflozin and dapagliflozin.12 In May including the Cochrane Library, EMBASE and Interna- 2015, the FDA published a safety update indicating an tional Pharmaceutical Abstracts. In addition, the refer- increased risk of UTI and DKA. Among patients taking ence lists of topical review articles, editorials and included SGLT2 inhibitors, they identified 19 cases of life-threat- studies were hand-searched to identify other potentially ening infections that originated as a UTI, and 73 cases relevant studies. A list of search terms is provided in of DKA. However, to date clinical trial evidence does section 1 of the online supplementary appendix. not support these potential risks. Previously published The search for unpublished studies and materials