Rationale and design of a multicenter randomized controlled study to evaluate the preventive effect of ipragliflozin on carotid atherosclerosis: the PROTECT study.
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.



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.



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, JPRN/UMIN000018440 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021348 ).
Department of Cardiovascular Medicine, Saga University, Saga, Japan.
Atsushi
A
Tanaka
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Toyoaki
T
Murohara
Department of Cardiology, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Japan.
Isao
I
Taguchi
Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University, Shimotsuke, Japan.
Kazuo
K
Eguchi
Cardiology Department, Kameda Medical Center, Kamogawa, Japan.
Makoto
M
Suzuki
Department of Clinical Medicine and Development, National Cerebral and Cardiovascular Center, Osaka, Japan.
Masafumi
M
Kitakaze
Department of Global Clinical Research, Graduate School of Medicine, Chiba University, Chiba, Japan.
Yasunori
Y
Sato
Department of Clinical Laboratory Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Tomoko
T
Ishizu
Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
Yukihito
Y
Higashi
Department of Cardiovascular Medicine, Tokushima University Hospital, Tokushima, Japan.
Hirotsugu
H
Yamada
Cardiovascular Center, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan.
Mamoru
M
Nanasato
Department of Cardio-Diabetes Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Kuramoto, Japan.
Michio
M
Shimabukuro
Department of Cardiovascular Medicine, JR Hiroshima Hospital, Hiroshima, Japan.
Hiroki
H
Teragawa
Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus, Nishihara, Japan.
Shinichiro
S
Ueda
Department of Cardiology, Asahi General Hospital, Chiba, Japan.
Satoshi
S
Kodera
Diabetes Therapeutics and Research Center, Tokushima University, Tokushima, Japan.
Munehide
M
Matsuhisa
Department of Cardiovascular Medicine, Saiseikai Futsukaichi Hospital, Chikushino, Japan.
Toshiaki
T
Kadokami
Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University, Shimotsuke, Japan.
Kazuomi
K
Kario
Department of Diabetes and Endocrine Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Yoshihiko
Y
Nishio
Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu, Japan.
Teruo
T
Inoue
Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Koji
K
Maemura
Department of Cardiovascular Medicine, Saga University, Saga, Japan.
Jun-Ichi
J
Oyama
Department of Cardiovascular Medicine and Hypertension, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Mitsuru
M
Ohishi
Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Masataka
M
Sata
Department of Cardiology, Tokyo Medical University, Tokyo, Japan.
Hirofumi
H
Tomiyama
Department of Cardiovascular Medicine, Saga University, Saga, Japan. node@cc.saga-u.ac.jp.
Koichi
K
Node
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D002340:Carotid Artery Diseases / Q000000981:diagnostic imaging / Q000209:etiology / Q000517:prevention & control*; D017536:Carotid Artery, Common / Q000000981:diagnostic imaging / Q000187:drug effects*; D059168:Carotid Intima-Media Thickness; D002985:Clinical Protocols; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*; D003925:Diabetic Angiopathies / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*; D004359:Drug Therapy, Combination; D005260:Female; D005960:Glucosides / Q000009:adverse effects / Q000627:therapeutic use*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007564:Japan; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012107:Research Design; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
D015415:Biomarkers; D005960:Glucosides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; C089180:SLC5A2 protein, human; C517652:hemoglobin A1c protein, human; C572941:ipragliflozin
Atherosclerosis; Intima-media thickness (IMT); Ipragliflozin; SGLT2 inhibitor; Type 2 diabetes mellitus