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 empagli...
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| Format: | Article |
| Language: | English |
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BMC
2017-04-01
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| Series: | Cardiovascular Diabetology |
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| Online Access: | http://link.springer.com/article/10.1186/s12933-017-0532-8 |
| _version_ | 1819077831044366336 |
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| author | Atsushi Tanaka Michio Shimabukuro Yosuke Okada Isao Taguchi Minako Yamaoka-Tojo Hirofumi Tomiyama Hiroki Teragawa Seigo Sugiyama Hisako Yoshida Yasunori Sato Atsushi Kawaguchi Yumi Ikehara Noritaka Machii Tatsuya Maruhashi Kosuke R. Shima Toshinari Takamura Yasushi Matsuzawa Kazuo Kimura Masashi Sakuma Jun-ichi Oyama Teruo Inoue Yukihito Higashi Shinichiro Ueda Koichi Node On Behalf of the EMBLEM Trial Investigators |
| author_facet | Atsushi Tanaka Michio Shimabukuro Yosuke Okada Isao Taguchi Minako Yamaoka-Tojo Hirofumi Tomiyama Hiroki Teragawa Seigo Sugiyama Hisako Yoshida Yasunori Sato Atsushi Kawaguchi Yumi Ikehara Noritaka Machii Tatsuya Maruhashi Kosuke R. Shima Toshinari Takamura Yasushi Matsuzawa Kazuo Kimura Masashi Sakuma Jun-ichi Oyama Teruo Inoue Yukihito Higashi Shinichiro Ueda Koichi Node On Behalf of the EMBLEM Trial Investigators |
| author_sort | Atsushi Tanaka |
| collection | DOAJ |
| description | 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. 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 ) |
| first_indexed | 2024-12-21T19:03:26Z |
| format | Article |
| id | doaj.art-03047384b5c34598bbc3090a5fe2a771 |
| institution | Directory Open Access Journal |
| issn | 1475-2840 |
| language | English |
| last_indexed | 2024-12-21T19:03:26Z |
| publishDate | 2017-04-01 |
| publisher | BMC |
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| series | Cardiovascular Diabetology |
| spelling | doaj.art-03047384b5c34598bbc3090a5fe2a7712022-12-21T18:53:24ZengBMCCardiovascular Diabetology1475-28402017-04-0116111210.1186/s12933-017-0532-8Rationale and design of a multicenter placebo-controlled double-blind randomized trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM trialAtsushi Tanaka0Michio Shimabukuro1Yosuke Okada2Isao Taguchi3Minako Yamaoka-Tojo4Hirofumi Tomiyama5Hiroki Teragawa6Seigo Sugiyama7Hisako Yoshida8Yasunori Sato9Atsushi Kawaguchi10Yumi Ikehara11Noritaka Machii12Tatsuya Maruhashi13Kosuke R. Shima14Toshinari Takamura15Yasushi Matsuzawa16Kazuo Kimura17Masashi Sakuma18Jun-ichi Oyama19Teruo Inoue20Yukihito Higashi21Shinichiro Ueda22Koichi Node23On Behalf of the EMBLEM Trial InvestigatorsDepartment of Cardiovascular Medicine, Saga UniversityDepartment of Diabetes, Endocrinology, and Metabolism, Fukushima Medical UniversityThe First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental HealthDepartment of Cardiology, Dokkyo Medical University Koshigaya HospitalDepartment of Cardiovascular Medicine, Kitasato University Graduate School of Medical SciencesDepartment of Cardiology, Tokyo Medical UniversityDepartment of Cardiovascular Medicine, JR Hiroshima HospitalDivision of Cardiovascular Medicine, Diabetes Care Center, Jinnouchi HospitalClinical Research Center, Saga UniversityDepartment of Global Clinical Research, Graduate School of Medicine, Chiba UniversityClinical Research Center, Saga UniversityClinical Research and Quality Management Center, University of the Ryukyus HospitalDepartment of Diabetes, Endocrinology, and Metabolism, Fukushima Medical UniversityDepartment of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima UniversityDepartment of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical SciencesDepartment of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical SciencesDivision of Cardiology, Yokohama City University Medical CenterDivision of Cardiology, Yokohama City University Medical CenterDepartment of Cardiovascular Medicine, Dokkyo Medical UniversityDepartment of Cardiovascular Medicine, Saga UniversityDepartment of Cardiovascular Medicine, Dokkyo Medical UniversityDepartment of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima UniversityDepartment of Clinical Pharmacology and Therapeutics, University of the RyukyusDepartment of Cardiovascular Medicine, Saga UniversityAbstract 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 )http://link.springer.com/article/10.1186/s12933-017-0532-8EmpagliflozinEndothelial functionReactive hyperemia peripheral arterial tonometry (RH-PAT)Sodium glucose cotransporter 2 (SGLT2) inhibitorType 2 diabetes mellitus (T2DM) |
| spellingShingle | Atsushi Tanaka Michio Shimabukuro Yosuke Okada Isao Taguchi Minako Yamaoka-Tojo Hirofumi Tomiyama Hiroki Teragawa Seigo Sugiyama Hisako Yoshida Yasunori Sato Atsushi Kawaguchi Yumi Ikehara Noritaka Machii Tatsuya Maruhashi Kosuke R. Shima Toshinari Takamura Yasushi Matsuzawa Kazuo Kimura Masashi Sakuma Jun-ichi Oyama Teruo Inoue Yukihito Higashi Shinichiro Ueda Koichi Node On Behalf of the EMBLEM Trial Investigators Rationale and design of a multicenter placebo-controlled double-blind randomized trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM trial Cardiovascular Diabetology Empagliflozin Endothelial function Reactive hyperemia peripheral arterial tonometry (RH-PAT) Sodium glucose cotransporter 2 (SGLT2) inhibitor Type 2 diabetes mellitus (T2DM) |
| 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 |
| title_full | Rationale and design of a multicenter placebo-controlled double-blind randomized trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM trial |
| title_fullStr | Rationale and design of a multicenter placebo-controlled double-blind randomized trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM trial |
| title_full_unstemmed | Rationale and design of a multicenter placebo-controlled double-blind randomized trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM trial |
| title_short | Rationale and design of a multicenter placebo-controlled double-blind randomized trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM trial |
| title_sort | rationale and design of a multicenter placebo controlled double blind randomized trial to evaluate the effect of empagliflozin on endothelial function the emblem trial |
| topic | Empagliflozin Endothelial function Reactive hyperemia peripheral arterial tonometry (RH-PAT) Sodium glucose cotransporter 2 (SGLT2) inhibitor Type 2 diabetes mellitus (T2DM) |
| url | http://link.springer.com/article/10.1186/s12933-017-0532-8 |
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