Secondary analyses to assess the profound effects of empagliflozin on endothelial function in patients with type 2 diabetes and established cardiovascular diseases: The placebo‐controlled double‐blind randomized effect of empagliflozin on endothelial function in cardiovascular high risk diabetes mellitus: Multi‐center placebo‐controlled double‐blind randomized trial

Abstract

Aims/Introduction Recent clinical trials on sodium–glucose cotransporter 2 inhibitors showed improved outcomes in patients with type 2 diabetes at a high risk of cardiovascular events. However, the underlying effects on endothelial function remain unclear. Materials and Methods The effect of empagliflozin on endothelial function in cardiovascular high risk diabetes mellitus: Multi‐center placebo‐controlled double‐blind randomized (EMBLEM) trial in patients with type 2 diabetes and cardiovascular disease showed empagliflozin treatment for 24 weeks had no effect on peripheral endothelial function measured by reactive hyperemia peripheral arterial tonometry. This post‐hoc analysis of the EMBLEM trial included a detailed evaluation of the effects of empagliflozin on peripheral endothelial function in order to elucidate the clinical characteristics of responders or non‐responders to treatment. Results Of the 47 patients randomized into the empagliflozin group, 21 (44.7%) showed an increase in the reactive hyperemia index (RHI) after 24 weeks of intervention, with no apparent difference in the clinical characteristics between patients whose RHI either increased (at least >0) or did not increase. There was also no obvious difference between the treatment groups in the proportion of patients who had a clinically meaningful change (≥15%) in log‐transformed RHI. No correlation was found between changes in RHI and clinical variables, such as vital signs and laboratory parameters. Conclusions Treatment with empagliflozin for 24 weeks in patients with type 2 diabetes and cardiovascular disease did not affect peripheral endothelial function, and was not related to changes in clinical variables, including glycemic parameters. These findings suggest that the actions of sodium–glucose cotransporter 2 inhibitors other than direct improvement in peripheral endothelial function were responsible, at least in the early phase, for the clinical benefits found in recent cardiovascular outcome trials.

Reduction of estimated fluid volumes following initiation of empagliflozin in patients with type 2 diabetes and cardiovascular disease: a secondary analysis of the placebo-controlled, randomized EMBLEM trial

“…Accordingly, 105 patients were primarily analyzed (empagliflozin n = 52, placebo n = 53). Detailed baseline characteristics have been reported [ 16 , 17 ], and were balanced between the treatment groups (Table 1 ). Briefly, the majority of the subjects were male and had a history of multiple cardiovascular risk factors.…”

“…Detailed changes in clinical parameters, including body weight, hematocrit, and hemoglobin, from baseline to weeks 4, 12, and 24 are shown in Additional file 1 , while changes in other clinical data from baseline to week 24 have been reported previously [ 16 , 17 ]. There were weak correlations between changes from baseline to week 24 in ePV and glycohemoglobin and estimated glomerular filtration rate, and the change in eEV was correlated with changes in systolic blood pressure and BMI (Table 3 ).…”

“…In the initial results of the EMBLEM trial, 24 weeks of empagliflozin did not affect endothelial function as assessed by RHI in patients with type 2 diabetes and CVD [ 16 , 17 ], suggesting that improvement of vascular function was unlikely to have been responsible for the early clinical benefits observed in the CVOTs with SGLT2 inhibitors. In contrast, the present analysis demonstrated reductions of the estimated fluid volumes at week 4 following initiation of empagliflozin that were maintained until 24 weeks.…”

“…In the EMBLEM (Effect of Empagliflozin on Endothelial Function in Cardiovascular High Risk Diabetes Mellitus: Multi-Center Placebo-Controlled Double-Blind Randomized) trial, 24 weeks of empagliflozin treatment did not affect endothelial function in patients with type 2 diabetes and established cardiovascular disease ( CVD ) [ 16 ]. Meanwhile, the erythropoietic parameters increased, and a parameter of estimated plasma volume ( ePV ) decreased 24 weeks after initiation of empagliflozin, relative to placebo [ 17 ]. To extend this initial observation regarding the plasma volume effect of empagliflozin, in the present post-hoc analysis of the EMBLEM trial we sought to further examine the serial changes in estimated fluid volume and their correlations with other clinical variables.…”

Association of estimated plasma volume and weight loss after long‐term administration and subsequent discontinuation of the sodium‐glucose cotransporter‐2 inhibitor tofogliflozin

“…4 However, the validity of using ePV as an index of PV changes due to SGLT2 inhibitors (especially short-term changes) was not fully established, 4 but there is no other PV index that can be easily calculated in routine clinical practice. Since previous studies related to SGLT2 inhibitors used ePV, 5,6 we used ePV in the present study.…”