title: 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: 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.
  
  
  CONCLUSIONS
  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 ).
authors.affiliation: Department of Cardiovascular Medicine, Saga University, Saga, Japan. tanakaa2@cc.saga-u.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: Department of Diabetes, Endocrinology, and Metabolism, Fukushima Medical University, Fukushima, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Shimabukuro
authors.affiliation: The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyusyu, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Department of Cardiology, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Taguchi
authors.affiliation: Department of Cardiovascular Medicine, Kitasato University Graduate School of Medical Sciences, Sagamihara, Japan.
authors.forename: Minako
authors.initials: M
authors.lastname: Yamaoka-Tojo
authors.affiliation: Department of Cardiology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Tomiyama
authors.affiliation: Department of Cardiovascular Medicine, JR Hiroshima Hospital, Hiroshima, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Teragawa
authors.affiliation: Division of Cardiovascular Medicine, Diabetes Care Center, Jinnouchi Hospital, Kumamoto, Japan.
authors.forename: Seigo
authors.initials: S
authors.lastname: Sugiyama
authors.affiliation: Clinical Research Center, Saga University, Saga, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Department of Global Clinical Research, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Clinical Research Center, Saga University, Saga, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kawaguchi
authors.affiliation: Clinical Research and Quality Management Center, University of the Ryukyus Hospital, Nishihara, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Ikehara
authors.affiliation: Department of Diabetes, Endocrinology, and Metabolism, Fukushima Medical University, Fukushima, Japan.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Machii
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Maruhashi
authors.affiliation: Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
authors.forename: Kosuke R
authors.initials: KR
authors.lastname: Shima
authors.affiliation: Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
authors.forename: Toshinari
authors.initials: T
authors.lastname: Takamura
authors.affiliation: Division of Cardiology, Yokohama City University Medical Center, Yokohama, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsuzawa
authors.affiliation: Division of Cardiology, Yokohama City University Medical Center, Yokohama, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kimura
authors.affiliation: Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Sakuma
authors.affiliation: Department of Cardiovascular Medicine, Saga University, Saga, Japan.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Oyama
authors.affiliation: Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu, Japan.
authors.forename: Teruo
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Yukihito
authors.initials: Y
authors.lastname: Higashi
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus, Nishihara, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Ueda
authors.affiliation: Department of Cardiovascular Medicine, Saga University, Saga, Japan. node@cc.saga-u.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Node
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050197:Atherosclerosis / Q000188:drug therapy; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000379:methods; D042783:Endothelial Cells / Q000187:drug effects*; D005960:Glucosides / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D011446:Prospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001559:Benzhydryl Compounds; D005960:Glucosides; D007004:Hypoglycemic Agents; D008687:Metformin; C570240:empagliflozin
keywords: Empagliflozin; Endothelial function; Reactive hyperemia peripheral arterial tonometry (RH-PAT); Sodium glucose cotransporter 2 (SGLT2) inhibitor; Type 2 diabetes mellitus (T2DM)