An Appraisal of a Systematic Review and Meta-Analysis of Randomized Clinical Trials on the Efficacy and Safety of Sodium-Glucose Cotransporter-2 Inhibitors as an Adjunct to Insulin Therapy in Type 1 Diabetes Patients

Dear Editor, I am writing to share a critique about a highly cited recently published (2018) paper on the efficacy and safety of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in type 1 diabetes patients [1]. In contemporary medicine, when the knowledge in this milieu is not parallelly apparent as in type 2 diabetes mellitus patients, the paper proves vital in addressing the evidence gap [1]. I thank the authors [1] for their substantial effort to address the context. I start here with some of the discrepancies between the protocol and the published paper [1, 2]. First, it is unclear if searching of the “Web of Science” database occurred as per the protocol [1, 2]. Second, in contrast to the published paper (and its supplement), the aim of testing the safety and efficacy of weekly administered SGLT2is was not prespecified [1, 2]. Lastly, as per the protocol and the title of the study, the review intended to study the safety and efficacy of SGLT2is only (as an adjunct to insulin therapy) in type 1 diabetes patients; however, data pooled from seven trials contradict this (six tested a combination of sodium-glucose cotransporter-1 inhibitor and SGLT2i [sotagliflozin] and the remaining tested the aggregate of liraglutide, dapagliflozin, and insulin). Next, while the study aimed to test the weekly administration of SGLT2is, it primarily included trials where participants received the test drug daily. Then, the incorporation of the four conference-abstract-based data in the main (quantitative) analysis is not agreeable. While the authors assumed an unclear risk of bias in these abstracts [1], it is plausibly better to avoid a risk of bias assessment when a full manuscript is unavailable. In reality, if the risk of bias is high, the summary statistic is less likely to be of any worth. A supplementary analysis may be appropriate in such a scenario. Finally, the pooled data in the metaanalysis also do not appear conceivable. For instance, regarding side effects, data was chiefly pooled for particular doses of the respective study drugs (while the paper’s aim was not dose-specific). Another illustration: in one trial, although severe hypoglycemia occurred in one of the participants in the intervention group, a placebo recipient was also accounted for the event while pooling data [3]. In light of the pitfalls discussed above, the findings of the paper necessitate a cautious interpretation and authors may consider a revision. Disclosure Statement