Sodium/Glucose Cotransporter 2 Inhibitors and the Risk of Diabetic Ketoacidosis

An Example of Complementary Evidence for Rare Adverse Events

Wajd Alkabbani; Ryan Pelletier; John-Michael Gamble


Am J Epidemiol. 2021;190(8):1572-1581. 

In This Article


We conducted a systematic review and meta-analysis. First, leveraging data from an ongoing overview of reviews on SGLT-2 inhibitor safety,[9] we conducted a systematic review of RCTs and observational studies evaluating the risk of DKA associated with 1 or more individual SGLT-2 inhibitors, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.[10] Details on inclusion criteria are provided in the Web Appendix (available online at, and the search strategy is shown in Web Table 1. Abstract and full-text screening, data extraction, and quality assessment[11] were conducted by 2 of the authors (W.A. and R.P.). Conflicts were resolved by a third author (J.M.G.).

Second, we conducted a meta-analysis using data from studies reporting at least 1 DKA event in either the SGLT-2 inhibitor group or the control group. For RCTs and cohort studies, pooled relative risks were calculated (number of events/number of persons at risk) using both fixed-effects and random-effects models. Between-study variance was estimated using restricted maximum likelihood estimation for random-effects models. Heterogeneity was assessed using the I 2 statistic, and subgroup analysis was conducted by type of comparator. Data from RCTs and observational studies were pooled separately. For studies reporting multiple relevant results, we used data from the longest reported follow-up and the broadest cohort definition. We also pooled adjusted results using reported adjusted hazard ratios and 95% confidence intervals from cohort studies.

All analyses were conducted using R software, version 4.0.1 (R Foundation for Statistical Computing, Vienna, Austria).