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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 Type 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.
PMID
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Authors

Mayor MeshTerms
Keywords

Empagliflozin

Endothelial function

Reactive hyperemia peripheral arterial tonometry (RH-PAT)

Sodium glucose cotransporter 2 (SGLT2) inhibitor

Type 2 diabetes mellitus (T2DM)

Journal Title cardiovascular diabetology
Publication Year Start




PMID- 28403850
OWN - NLM
STAT- MEDLINE
DA  - 20170413
DCOM- 20170418
LR  - 20170418
IS  - 1475-2840 (Electronic)
IS  - 1475-2840 (Linking)
VI  - 16
IP  - 1
DP  - 2017 Apr 12
TI  - Rationale and design of a multicenter placebo-controlled double-blind randomized 
      trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM
      trial.
PG  - 48
LID - 10.1186/s12933-017-0532-8 [doi]
AB  - BACKGROUND: Type 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. METHODS: The 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.
      DISCUSSION: EMBLEM 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 ).
FAU - Tanaka, Atsushi
AU  - Tanaka A
AD  - Department of Cardiovascular Medicine, Saga University, Saga, Japan.
      [email protected]
FAU - Shimabukuro, Michio
AU  - Shimabukuro M
AD  - Department of Diabetes, Endocrinology, and Metabolism, Fukushima Medical
      University, Fukushima, Japan.
FAU - Okada, Yosuke
AU  - Okada Y
AD  - The First Department of Internal Medicine, School of Medicine, University of
      Occupational and Environmental Health, Kitakyusyu, Japan.
FAU - Taguchi, Isao
AU  - Taguchi I
AD  - Department of Cardiology, Dokkyo Medical University Koshigaya Hospital,
      Koshigaya, Japan.
FAU - Yamaoka-Tojo, Minako
AU  - Yamaoka-Tojo M
AD  - Department of Cardiovascular Medicine, Kitasato University Graduate School of
      Medical Sciences, Sagamihara, Japan.
FAU - Tomiyama, Hirofumi
AU  - Tomiyama H
AD  - Department of Cardiology, Tokyo Medical University, Tokyo, Japan.
FAU - Teragawa, Hiroki
AU  - Teragawa H
AD  - Department of Cardiovascular Medicine, JR Hiroshima Hospital, Hiroshima, Japan.
FAU - Sugiyama, Seigo
AU  - Sugiyama S
AD  - Division of Cardiovascular Medicine, Diabetes Care Center, Jinnouchi Hospital,
      Kumamoto, Japan.
FAU - Yoshida, Hisako
AU  - Yoshida H
AD  - Clinical Research Center, Saga University, Saga, Japan.
FAU - Sato, Yasunori
AU  - Sato Y
AD  - Department of Global Clinical Research, Graduate School of Medicine, Chiba
      University, Chiba, Japan.
FAU - Kawaguchi, Atsushi
AU  - Kawaguchi A
AD  - Clinical Research Center, Saga University, Saga, Japan.
FAU - Ikehara, Yumi
AU  - Ikehara Y
AD  - Clinical Research and Quality Management Center, University of the Ryukyus
      Hospital, Nishihara, Japan.
FAU - Machii, Noritaka
AU  - Machii N
AD  - Department of Diabetes, Endocrinology, and Metabolism, Fukushima Medical
      University, Fukushima, Japan.
FAU - Maruhashi, Tatsuya
AU  - Maruhashi T
AD  - Department of Cardiovascular Medicine, Graduate School of Biomedical and Health
      Sciences, Hiroshima University, Hiroshima, Japan.
FAU - Shima, Kosuke R
AU  - Shima KR
AD  - Department of Endocrinology and Metabolism, Kanazawa University Graduate School
      of Medical Sciences, Kanazawa, Japan.
FAU - Takamura, Toshinari
AU  - Takamura T
AD  - Department of Endocrinology and Metabolism, Kanazawa University Graduate School
      of Medical Sciences, Kanazawa, Japan.
FAU - Matsuzawa, Yasushi
AU  - Matsuzawa Y
AD  - Division of Cardiology, Yokohama City University Medical Center, Yokohama, Japan.
FAU - Kimura, Kazuo
AU  - Kimura K
AD  - Division of Cardiology, Yokohama City University Medical Center, Yokohama, Japan.
FAU - Sakuma, Masashi
AU  - Sakuma M
AD  - Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu, Japan.
FAU - Oyama, Jun-Ichi
AU  - Oyama JI
AD  - Department of Cardiovascular Medicine, Saga University, Saga, Japan.
FAU - Inoue, Teruo
AU  - Inoue T
AD  - Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu, Japan.
FAU - Higashi, Yukihito
AU  - Higashi Y
AD  - Department of Cardiovascular Regeneration and Medicine, Research Institute for
      Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
FAU - Ueda, Shinichiro
AU  - Ueda S
AD  - Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus, 
      Nishihara, Japan.
FAU - Node, Koichi
AU  - Node K
AD  - Department of Cardiovascular Medicine, Saga University, Saga, Japan.
      [email protected]
CN  - EMBLEM Trial Investigators
LA  - eng
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
DEP - 20170412
PL  - England
TA  - Cardiovasc Diabetol
JT  - Cardiovascular diabetology
JID - 101147637
RN  - 0 (Benzhydryl Compounds)
RN  - 0 (Glucosides)
RN  - 0 (Hypoglycemic Agents)
RN  - 9100L32L2N (Metformin)
RN  - HDC1R2M35U (empagliflozin)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Atherosclerosis/drug therapy
MH  - Benzhydryl Compounds/administration & dosage/*therapeutic use
MH  - Blood Pressure/drug effects
MH  - Diabetes Mellitus, Type 2/blood/*drug therapy
MH  - Double-Blind Method
MH  - Drug Therapy, Combination/methods
MH  - Endothelial Cells/*drug effects
MH  - Glucosides/administration & dosage/*therapeutic use
MH  - Humans
MH  - Hypoglycemic Agents/*therapeutic use
MH  - Metformin/therapeutic use
MH  - Middle Aged
MH  - Prospective Studies
MH  - Treatment Outcome
MH  - Young Adult
PMC - PMC5389095
OTO - NOTNLM
OT  - *Empagliflozin
OT  - *Endothelial function
OT  - *Reactive hyperemia peripheral arterial tonometry (RH-PAT)
OT  - *Sodium glucose cotransporter 2 (SGLT2) inhibitor
OT  - *Type 2 diabetes mellitus (T2DM)
EDAT- 2017/04/14 06:00
MHDA- 2017/04/19 06:00
CRDT- 2017/04/14 06:00
PHST- 2017/02/28 [received]
PHST- 2017/04/04 [accepted]
AID - 10.1186/s12933-017-0532-8 [doi]
AID - 10.1186/s12933-017-0532-8 [pii]
PST - epublish
SO  - Cardiovasc Diabetol. 2017 Apr 12;16(1):48. doi: 10.1186/s12933-017-0532-8.

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