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

Q: What is the clinical evidence from this study?

Study design: RCT. Population: Type 2 diabetes and established cardiovascular disease (n=105). Intervention: Empagliflozin vs. Placebo. Primary outcome: Absolute change from baseline to 24 weeks in the reactive hyperemia index (RHI) measured by reactive hyperemia-peripheral arterial tonometry (RH-PAT) (MD -0.020, 95% CI -0.199 to 0.158, p=0.821).

Q: What does this research mean for the field?

Empagliflozin treatment for 24 weeks does not improve peripheral endothelial function measured by reactive hyperemia peripheral arterial tonometry in patients with type 2 diabetes and cardiovascular disease. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

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

doi:10.1111/jdi.13289

June 14, 2020Journal of Diabetes InvestigationOpen Access

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

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Key result

Empagliflozin for 24 weeks did not change reactive hyperemia index compared to placebo in T2D patients with CVD.

Figures

Graphical abstract published by Journal of Diabetes Investigation — Graphical abstract · Published by Journal of Diabetes Investigation · CC BY-NC-ND

Why the study?

The underlying effects of sodium-glucose cotransporter 2 inhibitors on endothelial function in patients with type 2 diabetes at high cardiovascular risk remained unclear, and clinical characteristics of treatment responders needed to be elucidated.

Does empagliflozin improve peripheral endothelial function (measured by reactive hyperemia index) at 24 weeks compared to placebo in Japanese patients with type 2 diabetes and established cardiovascular disease?

Key Points

To evaluate the effects of empagliflozin on peripheral endothelial function and identify characteristics of responders in patients with type 2 diabetes and established cardiovascular disease.
Secondary post-hoc analysis of the EMBLEM trial (UMIN000024502), a multicenter, double-blind, randomized, placebo-controlled trial across 16 centers in Japan with 105 patients in the full analysis set (52 empagliflozin, 53 placebo).
Participants received empagliflozin or placebo for 24 weeks, and peripheral endothelial function was assessed by measuring the reactive hyperemia index (RHI) via reactive hyperemia peripheral arterial tonometry.
In the empagliflozin group, 21 of 47 patients (44.7%) showed an increase in RHI after 24 weeks, with no apparent difference in clinical characteristics compared with non-responders.
The proportion of patients achieving a clinically meaningful change (≥15%) in log-transformed RHI showed no obvious difference between the empagliflozin and placebo groups.
No correlation was found between changes in RHI and clinical variables, including blood pressure, body mass index, or glycemic measures.

Study Design

Type

RCT (n=105)

Blinding

Double-blind

Randomization

1:1 Web-based minimization dynamic allocation stratified by HbA1c, age, systolic blood pressure, and current smoking habit

Multicenter

Yes

Structured PICO

Does empagliflozin improve peripheral endothelial function (measured by reactive hyperemia index) at 24 weeks compared to placebo in Japanese patients with type 2 diabetes and established cardiovascular disease?

P

Population

105 Japanese adults with type 2 diabetes (HbA1c 6.0-10.0%) and established cardiovascular disease (mean age 64.9 years, 31.4% female) followed for 24 weeks.

I

Intervention

Empagliflozin added to standard glucose-lowering and cardiovascular therapy for 24 weeks

C

Comparator

Matching placebo added to standard glucose-lowering and cardiovascular therapy for 24 weeks

O

Outcome

Change from baseline to 24 weeks in reactive hyperemia index (RHI) measured by reactive hyperemia-peripheral arterial tonometry (RH-PAT), along with post-hoc responder analyses of RHI increase (>0) and clinically meaningful change in log-transformed RHI (>=15%) at 24 weekssurrogate

Main Result

Mean Difference: -0.02 (95% CI -0.199–0.158)

Absolute Event Rate: -0.006% vs -0.025%

p-value: p=0.821

Twenty-four weeks of empagliflozin did not improve peripheral endothelial function in patients with type 2 diabetes and established CVD despite reducing plasma volume and improving glycemic and metabolic parameters, suggesting early cardiovascular benefits of SGLT2 inhibitors are driven by hemodynamic rather than direct endothelial effects.

Limitations

Post-randomization nature of the exploratory post-hoc analyses and small sample size
Lower baseline BMI, HbA1c, and atherosclerotic CVD prevalence compared to the EMPA-REG OUTCOME trial, and exclusive enrollment of Japanese patients
RH-PAT was measured only at 24 weeks, leaving shorter-term and long-term effects on peripheral endothelial function unclear
RH-PAT measurements can be partly affected by individual conditions, intravascular volume, and test room surroundings
Exploratory post-hoc secondary analysis with a relatively small sample size
Study population had lower baseline BMI and HbA1c and lower prevalence of atherosclerotic CVD compared with EMPA-REG OUTCOME, and included only Japanese patients
RH-PAT was only assessed at 24 weeks, so acute/shorter-term and longer-term effects on endothelial function were not evaluated
RH-PAT measurements may be influenced by individual physiological conditions, intravascular volume, and room environment

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Implication

No improvement in endothelial function with empagliflozin; challenges direct endothelial effects as mechanism for early SGLT2 inhibitor cardiovascular benefits.

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.

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Cite This Study

Tanaka et al. (2020) conducted an RCT in Type 2 diabetes and established cardiovascular disease (n=105). Empagliflozin vs. Placebo was evaluated on Absolute change from baseline to 24 weeks in the reactive hyperemia index (RHI) measured by reactive hyperemia-peripheral arterial tonometry (RH-PAT) (MD -0.020, 95% CI -0.199 to 0.158, p=0.821). Empagliflozin for 24 weeks did not change reactive hyperemia index compared to placebo in T2D patients with CVD.

synapsesocial.com/papers/6a8fa2c11403187eefcb415c https://doi.org/10.1111/jdi.13289

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Key Points

Study Design

Structured PICO

Main Result

Limitations

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Implication

Abstract

Discussion

Cite This Study

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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