Sodium‐glucose co‐transporter‐2 inhibitors and the risk of diabetic ketoacidosis in patients with type 2 diabetes: A systematic review and meta‐analysis of randomized controlled trials

Abstract Aim To assess the effects of sodium‐glucoseco‐transporter‐2 (SGLT2) inhibitors on diabetic ketoacidosis (DKA) in patients with type 2 diabetes. Materials and Methods We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov from inception to 13 June 2019 for randomized controlled trials (RCTs) that compared SGLT2 inhibitors with control in patients with type 2 diabetes. Paired reviewers independently screened citations, assessed the risk of bias and extracted data. Peto's method was used as the primary approach to pool the effect of SGLT2 inhibitors on DKA. Sensitivity analyses with the alternative effect measure (risk ratio) or pooling method (Mantel–Haenszel), the use of continuity correction of 0.5 for zero‐event trials or a generalized linear mixed model were conducted. Six preplanned subgroup analyses were performed to explore heterogeneity. The grading of recommendations assessment, development and evaluation (GRADE) approach was used to rate the quality of evidence. Results A total of 39 RCTs were included, involving 60 580 patients and 85 DKA events. SGLT2 inhibitors were statistically associated with an increased risk of DKA versus control (SGLT2 inhibitors: 62/34 961 0.18% vs. control: 23/25 211 0.09%, Peto odds ratio OR 2.13, 95% confidence interval CI 1.38 to 3.27, I 2 = 8%; RD 1.7 more events, 95% CI 0.6 more to 3.4 more events per 1000 over 5 years; high‐quality evidence). Sensitivity analyses showed similar results. The subgroup analyses by mean age (interaction P = 0 .02) and length of follow‐up (interaction P = 0 .03) showed a larger relative effect among older patients (aged ≥60 years) and those with longer use of SGLT2 inhibitors (>52 weeks). Conclusions High‐quality evidence suggests that SGLT2 inhibitors may increase the risk of DKA in patients with type 2 diabetes. The apparent differences in treatment effects among patients of a different age or follow‐up were probable, suggesting the advisability of caution in patients with long‐term use of SGLT2 inhibitors or in older patients.