SGLT2 inhibitors and the risk of diabetic ketoacidosis among adults with Type 2 Diabetes: A systematic review and meta-analysis

ABSTRACT Importance The risk of diabetic ketoacidosis (DKA) with sodium-glucose cotransporter-2 (SGLT2) inhibitors is unclear. Objective To examine the risk of DKA with SGLT2 inhibitors in both observational studies and large clinical trials. Data Sources Searches of PubMed, EMBASE and CENTRAL (inception to 15 April 2019) without language restrictions; conference proceedings; and reference lists. Study Selection Randomized controlled trials and observational studies that quantified the rate of diabetic ketoacidosis with an SGLT2 inhibitor in comparison to another diabetes medication or placebo. Data Extraction and Synthesis Two independent investigators abstracted study data and assessed the quality of evidence. Data were pooled using random effects models with the Hartung-Knapp-Sidik-Jonkman method. Main Outcome and Measures Absolute event rates and hazard ratios for diabetic ketoacidosis were extracted from each study. Results Seven randomized trials encompassing 42,375 participants and five cohort studies encompassing 318,636 participants were selected. Among the 7 randomized controlled trials, the absolute rate of DKA among patients randomized to an SGLT2 inhibitor ranged from 0.6 to 2.2 events per 1000 person years. Four randomized trials were included in the meta-analysis, and compared to placebo or comparator medication, SGLT2 inhibitors had a 2.4-fold higher risk of DKA (Relative Risk⍰[RR] =⍰2.46 [95% CI, 1.16-5.21]; I2⍰=⍰0%; P⍰= 0.54). Among the 5 observational studies, the absolute rate of DKA associated with SGLT2 inhibitor use ranged from 0.6 to 4.9 per 1000 person years and a 1.7-fold higher rate of DKA compared to another diabetes medication (RR⍰=⍰1.74 [95% CI, 1.01-2.93]; I2⍰=⍰45%; P⍰= 0.12). Conclusions and Relevance In adults with type 2 diabetes, SGLT2 inhibitors increase the risk of DKA in both observational studies and large randomized clinical trials. Registration CRD42019146855 Funding Source None KEY MESSAGES ‐ Case reports and observational studies have suggested that SGLT2 inhibitors may be associated with an increased risk of DKA, but this finding has not been reproduced in older meta-analyses of randomized controlled trials. ‐ In this systematic review and meta-analysis of randomized trials and observational studies including over 350,000 patients, SGLT2 inhibitors were found to be associated with twice the risk of diabetic ketoacidosis versus placebo or a comparator medication. ‐ Patients receiving an SGLT2 inhibitors should be counselled on this risk and provided with appropriate sick-day medication management.