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

Abstract

Background: Sodium–glucose cotransporter-2 (SGLT2) inhibitors have proven to be effective in improving glycemic control in patients with type 2 diabetes mellitus (T2DM). However, the risk of diabetic ketoacidosis (DKA) in patients remains unclear. The purpose of this study is to conduct this systematic review and network meta-analysis for the risk of DKA of SGLT2 inhibitors in patients with T2DM.Methods: We searched for randomized controlled trials (RCTs) concerning SGLT2 inhibitors in patients with T2DM in PubMed, EMBASE (Ovid SP), Cochrane Central Register of Controlled Trials (Ovid SP), and ClinicalTrials.gov from inception to January 2022. The primary outcomes were the risk of DKA. We assessed the sparse network with a fixed-effect model and consistency model in a frequentist framework with a graph-theoretical method by the netmeta package in R. We assessed the evidence quality of evidence of outcomes according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE).Results: In total, 36 studies involving 52,264 patients were included. The network showed that there was no significant difference observed among SGLT2 inhibitors, other active antidiabetic drugs, and placebo in the risk of DKA. There was no significant difference in the DKA risk between different doses of SGLT2 inhibitors. The certainty of the evidence ranged from very low to moderate. The probabilities of rankings and P-score showed that compared to placebo, SGLT2 inhibitors might increase the risk of DKA (P-score = 0.5298). Canagliflozin might have a higher DKA risk than other SGLT2 inhibitors (P-score = 0.7388).Conclusion: Neither SGLT2 inhibitors nor other active antidiabetic drugs were associated with an increased risk of DKA compared to placebo, and the risk of DKA with SGLT2 inhibitors was not found to be dose-dependent. In addition, the use of canagliflozin was less advisable than other SGLT2 inhibitors according to the rankings and P-score.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/, identifier PROSPERO, CRD42021297081.

Comparative efficacy of sodium glucose cotransporter-2 inhibitors in the management of type 2 diabetes mellitus: A real-world experience

“…Canagliflozin also possesses some inhibitory effect on SGLT-1 receptors which would have potentially helped to improve albuminuria in this cohort as suggested by a recent study[ 32 ]. Although ketoacidosis related to SGLT-2i therapy was found to be highest with canagliflozin use compared to other drugs in this class in a recent study[ 33 ], we found a lower risk compared to dapagliflozin use in our cohort. Data from more real-world studies might shed light on to the reason for this interesting new observation.…”

Risk of Diabetic Ketoacidosis Associated with Sodium Glucose Cotransporter-2 Inhibitors: A Network Meta-Analysis and Meta-Regression

“…A recent network meta-analysis, which included 36 clinical trials with 52,264 participants [ 22 ], has been the only network meta-analysis published recently on this topic. However, it focused exclusively on patients with T2D, and the overall analysis revealed no significant risk of DKA with SGLT2i.…”