TY - JOUR
T1 - Rationale and design of a multicenter randomized controlled study to evaluate the preventive effect of ipragliflozin on carotid atherosclerosis
T2 - The PROTECT study
AU - Tanaka, Atsushi
AU - Murohara, Toyoaki
AU - Taguchi, Isao
AU - Eguchi, Kazuo
AU - Suzuki, Makoto
AU - Kitakaze, Masafumi
AU - Sato, Yasunori
AU - Ishizu, Tomoko
AU - Higashi, Yukihito
AU - Yamada, Hirotsugu
AU - Nanasato, Mamoru
AU - Shimabukuro, Michio
AU - Teragawa, Hiroki
AU - Ueda, Shinichiro
AU - Kodera, Satoshi
AU - Matsuhisa, Munehide
AU - Kadokami, Toshiaki
AU - Kario, Kazuomi
AU - Nishio, Yoshihiko
AU - Inoue, Teruo
AU - Maemura, Koji
AU - Oyama, Jun ichi
AU - Ohishi, Mitsuru
AU - Sata, Masataka
AU - Tomiyama, Hirofumi
AU - Node, Koichi
N1 - Funding Information:
To conduct this study, an outsourcing agreement was signed between Saga University and Astellas Pharma Inc., Tokyo, Japan. The study was funded by Astellas Pharma Inc.
Funding Information:
AT declared no competing interests. TM received honorariums from Bayer, Daiichi Sankyo, Sumitomo Dainippon, Kowa, MSD, Mitsubishi Tanabe, Boehringer Ingelheim, Pfizer, Takeda, Sanofi, and Astellas; research grants from Astellas, Daiichi Sankyo, Sumitomo Dainippon, Kowa, MSD, Mitsubi‑ shi Tanabe, Boehringer Ingelheim, Novartis, Otsuka, Pfizer, Sanofi, Takeda, and Teijin Pharma. IT has received honorariums from Mitsubishi Tanabe, AstraZeneca, Bristol‑Myers Squibb, Bayer, Takeda, Daiichi Sankyo, Otsuka, MSD, Shionogi, Kowa, Sumitomo Dainippon, and Goodman; research grants from Eisai, Chugai, AstraZeneca, Bristol‑Myers Squibb, Bayer, Takeda, Daiichi Sankyo, Otsuka, MSD, Boehringer Ingelheim, Teijin Pharma, Ono, Shionogi, Mitsubishi Tanabe, Kowa, Mochida, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon, and Goodman. KE received honorariums from Takeda, Sumitomo Dainippon, Mitsubishi Tanabe, Omron Healthcare, Astellas, Boehringer Ingelheim, Otsuka, Sanwa Kagaku Kenkyusho, and MSD. MSu has received consulting honoraria from Fukuda Denshi. MK has received research grants from Japanese government, Japan Heart Foundation, Japan Cardiovascular Research Foundation, and Pfizer. YS has received honoraria from Japanese Association for the Diabetes Education and Care. TIs declared no competing interest. YH has received honorariums from Astellas, MSD, Boehringer Ingelheim, Teijin Pharma, and Mitsubishi Tanabe; research grant from Kao. HY received honorariums from MSD, Takeda, Sumitomo Dainip‑ pon, Actelion, Pfizer, GlaxoSmithKline, Novartis, Nippon Shinyaku, Bayer, Toshiba Medical Systems, and GE Healthcare; research grants from Ono and MSD. MN declared no competing interest. MSh operates a Donated Fund Laboratory from Boehringer Ingelheim, and is receiving a Research funding from AstraZeneca. HTe declared no competing interest. SU has received honorariums from MSD, Mitsubishi Tanabe, Pfizer, Boehringer Ingelheim, Bayer, Sumitomo Dainippon, AstraZeneca, and Astellas; research grants from Bayer, Kowa, Bristol‑Myers Squibb, MSD, Pfizer, Takeda, and Astellas. SK declared no competing interest. MM has received honorariums from Sanofi and Mitsubishi Tanabe. TK declared no competing interest. KK has received honorariums from Mochida, Takeda, Daiichi Sankyo, and Sumitomo Dainip‑ pon; research grants from Fukuda Denshi, Omron Health Care, Bayer, MSD, Mochida, Novartis, Sumitomo Dainippon, Boehringer Ingelheim, Daiichi Sankyo, Takeda, Astellas, Teijin Pharma, Bristol‑Myers Squibb, and Shionogi. YN has received honorariums from Astellas, Mitsubishi Tanabe, MSD, Takeda, and Sanofi; research grants from. Astellas, Mitsubishi Tanabe, MSD, and Ono. TIn received honorariums from Daiichi Sankyo, Otsuka, Bayer, MSD, Takeda, Shionogi, Astellas, Pfizer, Boehringer Ingelheim, Mochida, AstraZeneca, Kowa, Teijin Pharma, Medtronic, Abbott Vascular Japan, and Fukuda Denshi; research grants from Bayer, Nippon Shinyaku, Abbott Vascular Japan, Daiichi Sankyo, Otsuka, Bayer, MSD, Takeda, Shionogi, Astellas, Pfizer, Boehringer Ingelheim, Mochida, AstraZeneca, Kowa, and Teijin Pharma. KM has received honoraria from MSD. JO has belonged to the research program faculty (chair course) sponsored by Fukuda Denshi. MO has received honorariums from Daiichi Sankyo, Boehringer Ingelheim, Takeda, MSD, Pfizer, and Astellas; research grants from Daiichi Sankyo, Boehringer Ingelheim, Takeda, MSD, Kyowa Hakko Kirin, Kowa, Teijin Home Healthcare, Mitsubishi Tanabe, Pfizer, Bristol‑Myers Squibb, Sumitomo Dainippon, Mochida, Actelion, Otsuka, Teijin Pharma, and Genzyme. MSa has received honorariums from MSD, Takeda, Boehringer Ingelheim, Bayer, Mochida, Astellas, Mitsubishi Tanabe, Daiichi Sankyo, Novartis, AstraZeneca, and Pfizer; research grants from Ono, MSD, Bayer, Daiichi Sankyo, Boehringer Ingelheim, Novartis, Takeda, Mitsubi‑ shi, Tanabe, and Astellas; belongs to the research program sponsored by Boehringer Ingelheim. HTo has received honorarium from Omron Health Care. KN has received honorariums from Boehringer Ingelheim, Daiichi Sankyo, Astellas, MSD, Takeda, Mitsubishi Tanabe, and Sanofi; research grants from Sanwa Kagaku Kenkyusho, Astellas, Takeda, Boehringer Ingelheim, Bayer, Teijin Pharma, and Mitsubishi Tanabe.
Publisher Copyright:
© 2016 The Author(s).
PY - 2016/9/13
Y1 - 2016/9/13
N2 - Background: Type 2 diabetes mellitus is associated strongly with an increased risk of micro- and macro-vascular complications, leading to impaired quality of life and shortened life expectancy. In addition to appropriate glycemic control, multi-factorial intervention for a wide range of risk factors, such as hypertension and dyslipidemia, is crucial for management of diabetes. A recent cardiovascular outcome trial in diabetes patients with higher cardiovascular risk demonstrated that a SGLT2 inhibitor markedly reduced mortality, but not macro-vascular events. However, to date there is no clinical evidence regarding the therapeutic effects of SGLT2 inhibitors on arteriosclerosis. The ongoing PROTECT trial was designed to assess whether the SGLT2 inhibitors, ipragliflozin, prevented progression of carotid intima-media thickness in Japanese patients with type 2 diabetes mellitus. Methods: A total of 480 participants with type 2 diabetes mellitus with a HbA1c between 6 and 10 % despite receiving diet/exercise therapy and/or standard anti-diabetic agents for at least 3 months, will be randomized systematically (1:1) into either ipragliflozin or control (continuation of conventional therapy) groups. After randomization, ipragliflozin (50-100 mg once daily) will be added on to the background therapy in participants assigned to the ipragliflozin group. The primary endpoint of the study is the change in mean intima-media thickness of the common carotid artery from baseline to 24 months. Images of carotid intima-media thickness will be analyzed at a central core laboratory in a blinded manner. The key secondary endpoints include the change from baseline in other parameters of carotid intima-media thickness, various metabolic parameters, and renal function. Other cardiovascular functional tests are also planned for several sub-studies. Discussion: The PROTECT study is the first to assess the preventive effect of ipragliflozin on progression of carotid atherosclerosis using carotid intima-media thickness as a surrogate marker. The study has potential to clarify the protective effects of ipragliflozin on atherosclerosis. Trial registration Unique Trial Number, UMIN000018440 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021348 )
AB - Background: Type 2 diabetes mellitus is associated strongly with an increased risk of micro- and macro-vascular complications, leading to impaired quality of life and shortened life expectancy. In addition to appropriate glycemic control, multi-factorial intervention for a wide range of risk factors, such as hypertension and dyslipidemia, is crucial for management of diabetes. A recent cardiovascular outcome trial in diabetes patients with higher cardiovascular risk demonstrated that a SGLT2 inhibitor markedly reduced mortality, but not macro-vascular events. However, to date there is no clinical evidence regarding the therapeutic effects of SGLT2 inhibitors on arteriosclerosis. The ongoing PROTECT trial was designed to assess whether the SGLT2 inhibitors, ipragliflozin, prevented progression of carotid intima-media thickness in Japanese patients with type 2 diabetes mellitus. Methods: A total of 480 participants with type 2 diabetes mellitus with a HbA1c between 6 and 10 % despite receiving diet/exercise therapy and/or standard anti-diabetic agents for at least 3 months, will be randomized systematically (1:1) into either ipragliflozin or control (continuation of conventional therapy) groups. After randomization, ipragliflozin (50-100 mg once daily) will be added on to the background therapy in participants assigned to the ipragliflozin group. The primary endpoint of the study is the change in mean intima-media thickness of the common carotid artery from baseline to 24 months. Images of carotid intima-media thickness will be analyzed at a central core laboratory in a blinded manner. The key secondary endpoints include the change from baseline in other parameters of carotid intima-media thickness, various metabolic parameters, and renal function. Other cardiovascular functional tests are also planned for several sub-studies. Discussion: The PROTECT study is the first to assess the preventive effect of ipragliflozin on progression of carotid atherosclerosis using carotid intima-media thickness as a surrogate marker. The study has potential to clarify the protective effects of ipragliflozin on atherosclerosis. Trial registration Unique Trial Number, UMIN000018440 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021348 )
KW - Atherosclerosis
KW - Intima-media thickness (IMT)
KW - Ipragliflozin
KW - SGLT2 inhibitor
KW - Type 2 diabetes mellitus
UR - http://www.scopus.com/inward/record.url?scp=84987668892&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84987668892&partnerID=8YFLogxK
U2 - 10.1186/s12933-016-0449-7
DO - 10.1186/s12933-016-0449-7
M3 - Article
C2 - 27619983
AN - SCOPUS:84987668892
VL - 15
JO - Cardiovascular Diabetology
JF - Cardiovascular Diabetology
SN - 1475-2840
IS - 1
M1 - 133
ER -