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

Tanaka, Atsushi; Shimabukuro, Michio; Machii, Noritaka; Teragawa, Hiroki; Okada, Yosuke; Shima, Kosuke R.; Takamura, Toshinari; Tanaka, Isao; Hisauchi, Itaru; Toyoda, Shigeru; Matsuzawa, Yasushi; Tomiyama, Hirofumi; Yamaoka‐Tojo, Minako; Yoshida, Haruhiko; Sato, Yasunori; Ikehara, Yumi; Ueda, Shinichiro; Higashi, Yukihito; Node, Koichi

doi:10.2337/dc19-1177

Cited by 46 publications

(40 citation statements)

References 5 publications

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“…As reported previously 8 , the absolute change in RHI from baseline to 24 weeks was -0.006 -0.478 (empagliflozin) and - 0.025 -0.454 (placebo), with no significant intergroup difference observed (-0.020, 95% CI -0.199 to 0.158, P = 0.821).…”

Section: Detailed Effect Of Empagliflozin On Endothelial Functionsupporting

confidence: 81%

“…In this regard, whether a longer period of SGLT2 inhibitor treatment has clinically apparent benefits on vascular function and atherosclerosis needs to be examined in greater detail. The present study had several limitations in addition to those reported for the EMBLEM trial 8 . First, this secondary analysis might have been influenced by the post-randomization nature of the post-hoc analyses and the smaller number of participants.…”

Section: And Other Physiologicalmentioning

confidence: 65%

“…The current secondary study was an exploratory post-hoc analysis of data obtained from that trial 8 . The original rationale and protocol of the trial have been reported previously 9 , and the full list of inclusion criteria and exclusion criteria is described in Data S1.…”

Section: Trial Design and Patientsmentioning

confidence: 99%

“…The recent effect of empagliflozin on endothelial function in cardiovascular high risk diabetes mellitus: Multi‐center placebo‐controlled double‐blind randomized (EMBLEM) trial investigated whether empagliflozin added to standard therapy improved peripheral endothelial function in patients with type 2 diabetes and established CVDs, and showed that 24 weeks of treatment did not affect endothelial function compared with placebo 8 . However, the study did not include a detailed evaluation of responders and non‐responders to empagliflozin therapy.…”

Section: Introductionmentioning

confidence: 99%

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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

Tanaka

Shimabukuro

Machii

et al. 2020

J of Diabetes Invest

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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.

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Section: Detailed Effect Of Empagliflozin On Endothelial Functionsupporting

confidence: 81%

Section: And Other Physiologicalmentioning

confidence: 65%

Section: Trial Design and Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

Tanaka

Shimabukuro

Machii

et al. 2020

J of Diabetes Invest

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“…The effects of SGLT2 inhibitors on endothelial function, which is an arteriosclerosis-related change that occurs on a shorter timescale than IMT hyperplasia [41], were evaluated in earlier reports. In the double-blind RCT EMBLEM, the effect of empagliflozin on the reactive hyperemia peripheral arterial tonometry index, an indicator of endothelial function, was estimated; however, the change was not significant [42]. Similarly, in another study, dapagliflozin did not significantly affect the flow-mediated dilation, another indicator of endothelial function [10].…”

Section: Effects Of Tofogliflozin On Atherosclerosismentioning

confidence: 99%

Tofogliflozin does not delay progression of carotid atherosclerosis in patients with type 2 diabetes: a prospective, randomized, open-label, parallel-group comparative study

Katakami

Mita

Yoshii

et al. 2020

Cardiovasc Diabetol

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Background: This study aimed to investigate the preventive effects of tofogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, on atherosclerosis progression in type 2 diabetes (T2DM) patients without apparent cardiovascular disease (CVD) by monitoring carotid intima-media thickness (IMT). Methods: This prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group, comparative study included 340 subjects with T2DM and no history of apparent CVD recruited at 24 clinical units. Subjects were randomly allocated to either the tofogliflozin treatment group (n = 169) or conventional treatment group using drugs other than SGLT2 inhibitors (n = 171). Primary outcomes were changes in mean and maximum common carotid IMT measured by echography during a 104-week treatment period. Results: In a mixed-effects model for repeated measures, the mean IMT of the common carotid artery (mean-IMT-CCA), along with the right and left maximum IMT of the CCA (max-IMT-CCA), significantly declined in both the tofogliflozin (− 0.132 mm, SE 0.007; − 0.163 mm, SE 0.013; − 0.170 mm, SE 0.020, respectively) and the control group (− 0.140 mm, SE 0.006; − 0.190 mm, SE 0.012; − 0.190 mm, SE 0.020, respectively). Furthermore, the tofogliflozin and the conventional treatment group did not significantly differ in the progression of the mean-IMT-CCA (mean change (95% CI) 0.008 (− 0.009, 0.025) mm, P = 0.34), along with the right (mean change (95% CI) 0.027 (− 0.005, 0.059) mm, P = 0.10) and the left max-IMT-CCA (mean change (95% CI) 0.020 (− 0.030, 0.070), P = 0.43). Similar findings were obtained even after adjusting for traditional CV risk factors and/or administration of drugs at baseline. Relative to the control treatment effects, tofogliflozin significantly reduced the HbA1c, blood glucose level, body weight/body mass index, abdominal circumference, and systolic blood pressure, and significantly increased the HDL-C. The total and serious adverse events incidences did not significantly vary between the treatment groups.

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Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis

Kanie

Mizuno

Takaoka

et al. 2021

Cochrane Database of Systematic Reviews

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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

Cited by 46 publications

References 5 publications

Tofogliflozin does not delay progression of carotid atherosclerosis in patients with type 2 diabetes: a prospective, randomized, open-label, parallel-group comparative study

Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis

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