SGLT2 inhibitors and diabetic ketoacidosis in patients with type 2 diabetes: systematic review and meta-analysis of randomized controlled trials

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Liu J1
1Chinese Evidence-Based Medicine Center, West China Hospital, Sichuan University

Background: The concern continues as to whether Sodium glucose co-transporter-2 (SGLT2) inhibitors can increase the risk of diabetic ketoacidosis (DKA). There is a clear and urgent need for a rigorous evaluation of the risk of DKA.

Objectives: To assess the effects of SGLT2 inhibitors on 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) (Figure 1). Sensitivity analyses showed similar results (Table 1). 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) (Table 2).

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.

Patient or healthcare consumer involvement: Patients and healthcare consumer were not involved in setting the research question or the outcome measures, nor were they involved in developing plans for design or implementation of the study. No patients were asked to advise on interpretation or writing up of results. Where possible, results of this meta-analysis will be disseminated to the patient community or individual patients and families through the investigators of this meta-analysis.