Effect of Empagliflozin on Endothelial Function in Patients With Type 2 Diabetes and Cardiovascular Disease: Results from the Multicenter, Randomized, Placebo-Controlled, Double-Blind EMBLEM Trial.

Abstract

Recent large trials on sodium–glucose cotransporter 2 (SGLT2) inhibitors showed that these agents improved cardiovascular outcomes in patients with type 2 diabetes (T2D) with a high risk of cardiovascular events (1). However, the underlying mechanisms of these clinical benefits and vascular effect of SGLT2 inhibitors in that patient group remain uncertain. Endothelial dysfunction is exacerbated by metabolic disorders, such as diabetes, and involved in the pathophysiology of diabetes-related cardiovascular complications (2,3). We therefore investigated whether empagliflozin added to standard therapy, compared with placebo, affected endothelial function in patients with T2D and established cardiovascular disease (CVD). This was a prospective, multicenter, randomized, placebo-controlled, double-blind clinical trial undertaken in 16 centers in Japan (clinical trial reg. no. UMI24502, www.umin.ac.jp/ctr/index.htm) (4). A total of 117 adults with T2D and established CVD were randomized (1:1) to receive either empagliflozin 10 mg daily or placebo for 24 weeks. Randomization was performed by using the web-based minimization dynamic allocation method stratified according to HbA1c, age, systolic blood pressure (BP), and smoking status. The placebo was indistinguishable from empagliflozin, and both study drugs were sequentially numbered and concealed. The participants and investigators remained masked to group assignments until the database lock (an action taken to prevent further changes to a clinical trial database). The effects of treatment on endothelial function were assessed by the reactive hyperemia peripheral arterial tonometry index (RHI) (5), with the primary efficacy end point being the change in RHI from baseline to 24 weeks. Ethics approval and informed patient consent were obtained. Of the 117 patients, 105 were included in the full analysis set. Ten patients dropped out prior to initiation of the study drug, and two patients in the placebo group were excluded due to a serious protocol deviation (lack of data …