OBJECTIVES

To assess the effects of Sodium glucose co-transporter-2 (SGLT2) inhibitors on diabetic ketoacidosis (DKA) in patients with type 2 diabetes.

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 risk of bias and extracted data. Peto's method was used as 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 generalized linear mixed model were conducted. Six pre-planned subgroup analyses were conducted to explore heterogeneity. The 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: 23/25211 (0.09%), Peto odds ratio (OR) 2.13, 95% confidence interval (CI) 1.38 to 3.27, I2=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), length of follow up (interaction p=0.03) showed larger relative effect among older patients (60 years or over) and those with longer use of SGLT2 inhibitors (over 52 weeks).

CONCLUSIONS

High-quality evidence suggests that SGLT2 inhibitors may increase risk of DKA in patients with type 2 diabetes. The apparent differences in treatment effects among patients with different age or follow up were likely, suggesting the advisability of caution in patients with long-term use of SGLT2 inhibitors or older patients.