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Comparative Effectiveness of Sodium- Glucose Co-Transporter 2 Inhibitors

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Comparative Effectiveness of Sodium- Glucose Co-Transporter 2 Inhibitors Open Access Protocol BMJ Open: first published as 10.1136/bmjopen-2015-010252 on 29 January 2016. Downloaded from Comparative effectiveness of sodium- glucose co-transporter 2 inhibitors for controlling hyperglycaemia in patients with type 2 diabetes: protocol for a systematic review and network meta-analysis Min Chen,1 Chun-Guang Xie,1 Hong Gao,1 Hui Zheng,2 Qin Chen,3 Jian-Qiao Fang3 To cite: Chen M, Xie C-G, ABSTRACT et al Strengths and limitations of this study Gao H, . Comparative Introduction: As a new class of glucose-lowering effectiveness of sodium- drugs, sodium-glucose co-transporter 2 (SGLT2) ▪ glucose co-transporter 2 We will include recently published studies that inhibitors are effective for controlling hyperglycaemia, inhibitors for controlling assessed incidence of cardiovascular disease, hyperglycaemia in patients however, the relative effectiveness and safety of 6 ketoacidosis and cancer caused by SGLT2 inhibi- with type 2 diabetes: protocol recently available SGLT2 inhibitors have rarely been tors, which will add knowledge to the safety of for a systematic review and studied. Therefore, we aim to perform pairwise SGLT2 inhibitors. network meta-analysis. BMJ comparisons of the 6 SGLT2 inhibitors. ▪ The result of this meta-analysis will help patients Open 2016;6:e010252. Methods and analysis: A systematic review and with type 2 diabetes, clinicians and policymakers doi:10.1136/bmjopen-2015- network meta-analysis will be conducted. Clinical in selecting a SGLT2 inhibitor for controlling 010252 studies that examine effectiveness and safety of either hyperglycaemia. canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, ▪ A possible limitation is that we may not have ▸ Prepublication history for tofogliflozin or luseogliflozin will be included. These enough data to perform pairwise comparisons this paper is available online. studies will be systematically retrieved in MEDLINE, between the SGLT2 inhibitors, since these inhibi- http://bmjopen.bmj.com/ To view these files please EMBASE and the Cochrane Library, from inception to tors will be compared in four situations: mono- visit the journal online November 2015. Two reviewers will independently therapy, dual therapy, triple or quadruple therapy (http://dx.doi.org/10.1136/ screen for eligible studies and then extract data bmjopen-2015-010252). and in combination with insulin. from the studies as well as assess risk of bias. Discrepancies in screening and data extraction will be arbitrated by a third reviewer. A traditional meta- INTRODUCTION MC and C-GX contributed analysis will be performed to combine the effect sizes Hyperglycaemia is a major manifestation of equally to this work. calculated from head-to-head comparisons with a diabetes mellitus. The most important bio- on September 25, 2021 by guest. Protected copyright. random effect model. The effect sizes computed from Received 13 October 2015 indirect comparisons will be further combined in a marker of hyperglycaemia is glycated haemo- Revised 7 December 2015 network meta-analysis. Heterogeneity will be tested globin (HbA1c). Including HbA1c to the Accepted 29 December 2015 with the Cochrane’s Q statistic, and publication bias diagnostic criteria accounts for a 75% will be assessed using a funnel plot and the Egger’s increase of individuals with diabetes mellitus test. across all age-groups.1 Patients with elevated Ethics and dissemination: Relative effectiveness HbA1c level are at high risk for developing and harms of the 6 SGLT2 inhibitors will be diabetic retinopathy and cardiovascular – demonstrated through this systematic review and disease.2 4 Lowering HbA1c to <7.0% signifi- network meta-analysis. The result of the review will cantly reduces the risk of microvascular com- – be disseminated through a peer-review journal and plications in patients with type 2 diabetes.5 7 conference presentations. Patients, clinicians and Given that type 2 diabetes is, globally, a For numbered affiliations see policymakers will benefit from this review in selecting end of article. major public health problem (affecting 347 a SGLT2 inhibitor for glucose control in patients 8 with type 2 diabetes. million individuals in the year 2008), strin- Correspondence to Trial registration number: PROSPERO gent control for hyperglycaemia is needed. Professor Jian-Qiao Fang; CRD42015025981. As a new class of drugs, sodium-glucose [email protected] co-transporter 2 (SGLT2) inhibitors are Chen M, et al. BMJ Open 2016;6:e010252. doi:10.1136/bmjopen-2015-010252 1 Open Access BMJ Open: first published as 10.1136/bmjopen-2015-010252 on 29 January 2016. Downloaded from recommended in a report on hyperglycaemia manage- canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, ment released by the American Diabetes Association tofogliflozin and luseogliflozin. After evaluating the eligi- (ADA) and the European Association for the Study of bility of potential studies, we will collect data from them Diabetes (EASD).9 SGLT2 inhibitors activate at the prox- and assess risk of bias. In the network meta-analysis, we imal nephron to decrease glucose absorption, so they are will combine both—direct and indirect comparisons— independent of insulin and therefore can be used in any using a statistical package of ‘netmeta’ which has been stage of type 2 diabetes. Several systematic reviews have designed for pairwise comparisons in a frequentist shown that SGLT2 inhibitors are effective for controlling framework. This study has been registered at – HbA1c.10 17 In these reviews, when different doses of a PROSPERO (http://www.crd.york.ac.uk/PROSPERO) SGLT2 inhibitor are tested in a trial, only the highest with registration number CRD42015025981. dose of this SGLT2 is chosen to include for meta-analysis. In addition, some reviews summarise canagliflozin, dapa- gliflozin and empagliflozin in the same category, and DATA SOURCE assess them as one treatment, ignoring heterogeneity in We will search for studies that examined effectiveness 13 14 18 their treatment effects. Rosenstock et al found that and adverse events of the 6 SGLT 2 inhibitors in the fol- 50 mg canagliflozin worked better than 200 mg canagli- lowing electronic databases: MEDLINE (via Ovid), flozin in lowering HbA1c. A similar finding of EMBASE ( http://www.embase.com) and the Cochrane dose-ranging effect of dapagliflozin was discovered in a library, from inception to November 2015. Table 1 shows 12 systematic review. Therefore, we hypothesise that the a search strategy developed with comprehensive use of treatment effects of canagliflozin, dapagliflozin and medical subject headings and keywords. Besides the empagliflozin are different, especially when administered electronic search, we will also perform a manual search in different doses. Recently, three new SGLT2 inhibiting for conference abstracts or e-posters in the areas of drugs (ipragliflozin, tofogliflozin and luseogliflozin) were introduced to clinical practice and tested by rando- Table 1 Search strategy for MEDLINE (via OVID) 19–21 mised controlled trials, but they were not included No. Search terms in previous systematic reviews. A systematic review proto- col was recently published to evaluate the efficacy of 1 randomized controlled trial.pt. SGLT2 inhibitors by comparing them to placebo.22 2 controlled clinical trial.pt. 3 randomized.ab. However, this systematic review did not assess the efficacy fl fl fl 4 randomised.ab. of ipragli ozin, tofogli ozin and luseogli ozin, nor did it 5 placebo.ab. assess their relative effectiveness. Additionally, adverse 6 randomly.ab. events of the 6 SGLT2 inhibitors have not been fully eval- 7 trial.ab. uated in previous reviews, especially for events such as 8 groups.ab. http://bmjopen.bmj.com/ cardiovascular diseases, ketoacidosis and cancer. 9 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 Methods of network meta-analysis (NMA) have been 10 exp hyperglycemia/ developed as alternative treatment options for disease con- 11 exp Diabetes Mellitus, Type 2 / ditions, however, increased and comparative effectiveness 12 hyperglycemia. ti, ab. research is needed. NMA can be carried out using frequen- 13 Type 2 diabetes. ti, ab. tist or Bayesian statistics.23 Lumley developed a package, 14 10 or 11 or 12 or 13 15 sodium glucose co-transporter. ti, ab. ‘NLME’, for conducting NMA in a frequentist framework,24 16 SGLT2. ti, ab. on September 25, 2021 by guest. Protected copyright. with a major advantage of addressing inconsistency in the 17 Canagliflozin. sh, ti, ab. network to assess the uncertainty in treatment estimates. 18 Dapagliflozin. sh,ti, ab. However, the ‘NLME’ package could not handle a trial with 19 Empagliflozin. sh, ti, ab. threeormorearms.AsthetechniquesofNMAdevelop, 20 ipragliflozin. sh, ti, ab. Rucker has proposed a new NMA statistical solution to deal 21 tofogliflozin. sh, ti, ab. with trials that have three or more arms,25 with the advan- 22 luseogliflozin. sh, ti, ab. tage of addressing inconsistency within and between trials as 23 A10BX11. sh, ti, ab. well as adjusting treatment estimates in trials with multiple 24 A10BX09. sh, ti, ab. arms. Therefore, we aim to test the relative effectiveness and 25 A10BX12. sh, ti, ab. safety of canagliflozin, dapagliflozin, empagliflozin, ipragli- 26 ASP1941. sh, ti, ab. 27 CSG452. sh, ti, ab. flozin, tofogliflozin and luseogliflozin, using a systematic 28 TS-071. sh, ti, ab. review and NMA in a frequentist framework. 29 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 30 9 and 14 and 29 METHODS SGLT2, sodium-glucose co-transporter 2 inhibitor. A10BX11, A systematic review and network meta-analysis will be A10BX09, A10BX12, ASP1941, CSG452 and TS-071 are the performed. In the systematic review, we will retrieve clin- codenames for canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, tofogliflozin and luseogliflozin, respectively. ical studies that tested the effectiveness and safety of 2 Chen M, et al. BMJ Open 2016;6:e010252. doi:10.1136/bmjopen-2015-010252 Open Access BMJ Open: first published as 10.1136/bmjopen-2015-010252 on 29 January 2016. Downloaded from diabetes, in the ADA, EASD, Canadian Diabetes monotherapy, dual therapy, triple or quadruple therapy Association (CDA) and International Diabetes and in combination with insulin.
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