Rationale and design of a multicenter placebo-controlled double-blind randomized trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM trial

Abstract

BackgroundType 2 diabetes mellitus (T2DM) is characterized by systemic metabolic abnormalities and the development of micro- and macrovascular complications, resulting in a shortened life expectancy. A recent cardiovascular (CV) safety trial, the EMPA-REG OUTCOME trial, showed that empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, markedly reduced CV death and all-cause mortality and hospitalization for heart failure in patients with T2DM and established CV disease (CVD). SGLT2 inhibitors are known to not only decrease plasma glucose levels, but also favorably modulate a wide range of metabolic and hemodynamic disorders related to CV pathways. Although some experimental studies revealed a beneficial effect of SGLT2 inhibitors on atherosclerosis, there is a paucity of clinical data showing that they can slow the progression of atherosclerosis in patients with T2DM. Therefore, the EMBLEM trial was designed to investigate whether empagliflozin treatment can improve endothelial function, which plays a pivotal role in the pathogenesis of atherosclerosis, in patients with T2DM and established CVD.MethodsThe EMBLEM trial is an ongoing, prospective, multicenter, placebo-controlled double-blind randomized, investigator-initiated clinical trial in Japan. A total of 110 participants with T2DM (HbA1c range 6.0–10.0%) and with established CVD will be randomized (1:1) to receive either empagliflozin 10 mg once daily or a placebo. The primary endpoint of the trial is change in the reactive hyperemia (RH)-peripheral arterial tonometry-derived RH index at 24 weeks from baseline. For comparison of treatment effects between the treatment groups, the baseline-adjusted means and their 95% confidence intervals will be estimated by analysis of covariance adjusted for the following allocation factors: HbA1c (<7.0 or ≥7.0%), age (<65 or ≥65 years), systolic blood pressure (<140 or ≥140 mmHg), and current smoking status (nonsmoker or smoker). Key secondary endpoints include the change from baseline for other vascular-related markers such as arterial stiffness, sympathetic nervous activity, and parameters of cardiac and renal function. Importantly, serious adverse effects independently on the causal relationship to the trial drugs and protocol will be also evaluated throughout the trial period.DiscussionEMBLEM is the first trial to assess the effect of empagliflozin on endothelial function in patients with T2DM and established CVD. Additionally, mechanisms associating empagliflozin-mediated actions with endothelial function and other CV markers will be evaluated. Thus, the trial is designed to elucidate potential mechanisms by which empagliflozin protects CV systems and improves CV outcomes. Trial registration Unique Trial Number, UMIN000024502 (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000028197)Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-017-0532-8) contains supplementary material, which is available to authorized users.

Effect of Canagliflozin on endothelial function in diabetic patients with suspected coronary artery disease: retrospective preliminary pilot study

“…First, this study is cross sectional retrospective single center study and the numbers of study patients are small so that the power of the study is limited. As mentioned above, in order to confirm our results and speculation, the results of currently ongoing randomized multi-center clinical 26,27) should be obtained and reviewed. Second, we performed ECF tests using simultaneous measures of FMD and RHI.…”

“…These findings are similar to our results. However, they are all preliminary study, and large scale clinical studies are now already planned 26,27) . We need to see further results of these studies to get the final answer to our hypothesis.…”

“…These results could be caused by type II errors due to the small number of study population. The conclusion on this finding should be also preserved until the results of currently ongoing randomized multi-center clinical will be obtained 26,27) . Fourth, in the previous reports 8,12) , RHI was measured by using upper arm cuff occlusion method.…”

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

“…Michio Shimabukuro, 2 Noritaka Machii, 2 Hiroki Teragawa, 3 Yosuke Okada, 4 Kosuke R. Shima, 5 Toshinari Takamura, 5 Isao Taguchi, 6 Itaru Hisauchi, 6 Shigeru Toyoda, 7 Yasushi Matsuzawa, 8 Hirofumi Tomiyama, 9 Minako Yamaoka-Tojo, 10 Hisako Yoshida, 11 Yasunori Sato, 12 Yumi Ikehara, 13 Shinichiro Ueda, 14 Yukihito Higashi, 15 and Koichi Node, 1 on behalf of the EMBLEM Investigators* Ethics approval and informed patient consent were obtained.…”

Exploring novel pharmacotherapeutic applications and repurposing potential of sodium glucose CoTransporter 2 inhibitors

“…Moreover, the use of SGLT2 inhibitors has also been proposed in the treatment of heart failure irrespective of the presence or absence of T2DM and several clinical studies are currently in progress to evaluate this prospect . A clinical trial, known as the EMBLEM trial, intending to investigate the effect of empagliflozin on endothelial function in patients with established cardiovascular disease is currently underway in Japan (Unique Trial Number: UMIN000024502) . Another clinical study investigating the effect of SGLT2 inhibitors on diabetic atherosclerosis and subsequent cardiovascular disease using intima‐media thickness as a marker of cardiovascular disease is also in progress (Unique Trial Number: UMIN000017607).…”