Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors and The Risk of Diabetic Ketoacidosis: An Example of Complementary Evidence for Rare Adverse Events.

Evidence from observational studies may be considered complementary to that of randomized controlled trials (RCTs), particularly when assessing rare outcomes of drug therapies. The sodium glucose co-transporter-2 (SGLT-2) inhibitors are a novel class of antidiabetics that has been linked to an increased risk of diabetic ketoacidosis (DKA). In this study, we conducted a systematic review and meta-analyzed data from RCTs (n=18) and observational (n=7) studies separately, to assess the consistency of the magnitude of association between SGLT-2 inhibitors and DKA. We also illustrate the strengths and weakness of the two designs. Results from RCTs and observational studies consistently show almost a doubling in the risk of DKA in patients using an SGLT-2 inhibitor compared to placebo or active comparator. Using a random-effects model, the pooled relative risk [RR], (95% confidence interval [CI]) was 2.08, (95%CI 1.28, 3.40) from placebo-controlled RCTs and was 0.82 (95%CI 0.25, 2.68) from active-comparator RCTs. The pooled adjusted hazard ratio from observational studies was 1.74, (95%CI 1.28, 2.38). Notably, the two designs complement each other in several domains, including external and internal validity and power. This demonstrates the need for both sources for a more comprehensive evidence when assessing rare adverse events.