Effect of sarpogrelate, a selective 5-HT2A receptor antagonist, on characteristics of coronary artery disease in patients with type 2 diabetes

Accepted Manuscript Effect of sarpogrelate, a selective 5-HT2A receptor antagonist, on characteristics of coronary artery disease in patients with type 2 diabetes Dong-Hwa Lee, Eun Ju Chun, Jee Hye Hur, Se Hee Min, Jie-Eun Lee, Tae Jung Oh, Kyoung Min Kim, Hak Chul Jang, Seung Jin Han, Doo Kyoung Kang, Hae Jin Kim, Soo Lim PII:

S0021-9150(16)31532-5

DOI:

10.1016/j.atherosclerosis.2016.12.011

Reference:

ATH 14902

To appear in:

Atherosclerosis

Received Date: 19 May 2016 Revised Date:

16 November 2016

Accepted Date: 9 December 2016

Please cite this article as: Lee D-H, Chun EJ, Hur JH, Min SH, Lee J-E, Oh TJ, Kim KM, Jang HC, Han SJ, Kang DK, Kim HJ, Lim S, Effect of sarpogrelate, a selective 5-HT2A receptor antagonist, on characteristics of coronary artery disease in patients with type 2 diabetes, Atherosclerosis (2017), doi: 10.1016/j.atherosclerosis.2016.12.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Effect of sarpogrelate, a selective 5-HT2A receptor antagonist, on

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characteristics of coronary artery disease in patients with type 2 diabetes

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Dong-Hwa Leea, Eun Ju Chunb, Jee Hye Hurb, Se Hee Mina, Jie-Eun Leea, Tae Jung Oha,

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Kyoung Min Kima, Hak Chul Janga, Seung Jin Hanc, Doo Kyoung Kangd, Hae Jin Kimc,*

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Soo Lima*

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National University Bundang Hospital, Seongnam, South Korea

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Department of Internal Medicine, Seoul National University College of Medicine and Seoul

Department of Radiology, Seoul National University College of Medicine and Seoul

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National University Bundang Hospital, Seongnam, South Korea

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Department of Internal Medicine, Ajou University School of Medicine, Suwon, South Korea Department of Radiology, Ajou University School of Medicine, Suwon, South Korea

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*Corresponding authors: Department of Internal Medicine, Seoul National University

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College of Medicine and Seoul National University Bundang Hospital, 173-82 Gumi-ro,

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Bundang-gu, Seongnam, South Korea 463-707 (S. Lim); Department of Internal Medicine,

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Ajou University School of Medicine, 164 Word Cup-ro, Yeongtong-gu, Suwon, South

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Korea 443-380 (H.

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[email protected] (H. J. Kim)

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J. Kim). E-mail addresses: [email protected] (S.

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Lim);

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Abstract

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Background and aims: Sarpogrelate, a 5-hydroxytryptamine type 2A antagonist, is a potential

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antiplatelet agent. We performed a randomized study to evaluate the effect of sarpogrelate on

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vascular health in Korean patients with diabetes.

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Methods: Forty diabetic patients aged 58.6±6.8 years with 10–75% coronary artery stenosis,

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as assessed by coronary computed tomography angiography, were randomly assigned to

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sarpogrelate 300 mg/day plus aspirin 100 mg/day (SPG+ASA group) or aspirin 100 mg/day

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alone (ASA group) for 6 months. The primary endpoint of this study was the change in

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coronary artery disease including the calcium score (CACS), maximal stenosis, and plaque

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volume (calcified vs. noncalcified). The secondary endpoints were changes in biochemical

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parameters related to glucose and lipid metabolism, and in subclinical atherosclerosis

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assessed by ankle–brachial index and pulse wave velocity.

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Results: After 6-month treatment, there was no significant difference in the changes in CACS,

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coronary stenosis, ankle–brachial index, and pulse wave velocity, between groups. The total

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plaque volume decreased from 82.4±14.5 mm3 to 74.6±14.4 mm3 in the SPG+ASA group,

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but increased from 64.9±16.0 mm3 to 68.6±16.3 mm3 in the ASA group (p<0.05), mainly

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driven by changes in the noncalcified component (SPG+ASA group 15.6±4.6 mm3 to

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11.2±3.7 mm3 vs. ASA group 21.2±6.2 mm3 to 22.8±6.6 mm3, p<0.01). Serum C-reactive

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protein levels and homeostasis model assessment of insulin resistance tended to decrease in

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the SPG+ASA group, but they were not altered in the ASA group.

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Conclusions: The present study demonstrated that sarpogrelate treatment may decrease

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coronary artery plaque volume, particularly the noncalcified portion, in patients with diabetes.

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Keywords

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Coronary artery disease, Coronary plaque, Sarpogrelate, Diabetes mellitus

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ACCEPTED MANUSCRIPT 1. Introduction

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Serotonin (5-hydroxytryptamine, 5-HT) is a naturally occurring vasoactive substance that is

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released from activated platelets [1]. 5-HT is known to be associated with vasoconstriction,

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activation of other platelets, and vascular inflammation leading to atherosclerosis [2, 3].

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Serum 5-HT levels are elevated in several conditions, including type 2 diabetes mellitus

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(T2DM), hypertension, myocardial infarction, and stroke [4]. Sarpogrelate, a selective 5-

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HT2A receptor antagonist, was introduced as an antiplatelet agent for the prevention of

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atherosclerosis. Previous studies have reported that sarpogrelate administration suppresses

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platelet aggregation, thrombus formation, endothelial dysfunction, vasoconstriction, and

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vascular smooth muscle cell proliferation, which are mediated by 5-HT2A receptors [1, 5]. The prevalence of cardiovascular disease (CVD) is increasing worldwide and it is the most

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common cause of morbidity and mortality [6]. The risk for CVD, including coronary artery

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disease (CAD) and cerebrovascular disease, in patients with DM is 2- to 4-fold higher than in

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patients without DM [7]. However, patients with DM are often asymptomatic, even though

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they have severe CAD. Therefore, considering the high morbidity and mortality in this

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population, identification of CVD and its appropriate management has important implications.

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Coronary angiography is considered the gold standard for assessing CAD, but its

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invasiveness limits its use in asymptomatic patients. Recently, computed tomography (CT)

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has emerged as a robust noninvasive tool for diagnosis of CAD. The development of

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coronary CT angiography (CCTA) provides the opportunity to assess comprehensively the

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presence and severity of CAD [8]. Many studies have shown a strong correlation between

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CCTA and invasive coronary angiography in the assessment of CAD [9]. Furthermore, recent

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studies have demonstrated that CCTA can also evaluate the characteristics of plaque

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composition in coronary arteries [10, 11]. Several clinical studies have confirmed that sarpogrelate treatment has beneficial effects on

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atherosclerosis [12-15]. However, most studies have been performed in patients with

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peripheral artery disease [12-14] or cerebrovascular disease [15]. The effect of sarpogrelate

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on CAD has not been elucidated fully, particularly in patients with DM. Therefore, we

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investigated the effect of sarpogrelate plus aspirin compared with aspirin alone in Korean

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patients with T2DM and mild-to-moderate coronary artery stenosis.

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2. Materials and methods

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2.1. Subjects

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This study was performed in two university hospitals in South Korea. Patients 40 to 70 years

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of age with T2DM were screened at Seoul National University Bundang Hospital (SNUBH)

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(Seongnam, South Korea) and Ajou University Hospital (Suwon, South Korea). Inclusion

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criteria were T2DM, no history of previous myocardial infarction or stroke, and 10–75%

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coronary artery stenosis on CCTA. We excluded patients who had a history of

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hypersensitivity to salicylic acid or cilostazol, acute bleeding, or severe kidney or liver

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dysfunction.

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Eligible patients were randomly assigned in a 1:1 ratio to receive sarpogrelate 300

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mg/day plus aspirin 100 mg/day (SPG+ASA group) or aspirin 100 mg/day alone (ASA group)

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for 6 months. All subjects volunteered to participate in the study and provided written

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informed consent. The study protocol was approved by each hospital’s Institutional Review 5

ACCEPTED MANUSCRIPT Board (SNUBH IRB#B-1111/139-007 and AJ IRB#MED-CT4-11-352). This study was

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registered at ClinicalTrials.gov: NCT02607436.

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2.2. Measurement of anthropometric and biochemical parameters

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Height (in centimeters) and body weight (in kilograms) were measured by standard methods.

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Body mass index (BMI) was calculated by dividing body weight (in kilograms) by the square

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of the height (m2). Waist circumference was measured to the nearest 0.1 cm at the midpoint

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between the lateral iliac crest and the lowest rib at the end of expiration in standing position.

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Blood pressure was measured using an automatic blood pressure measurement device (Easy

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X 800, Jawon, Seoul, South Korea) after the subjects had been in a resting state for at least 5

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minutes. After a 10-hour overnight fast, blood samples were obtained in the morning. The

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glycated hemoglobin (HbA1c) level was measured by affinity chromatography (Bio-Rad

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Laboratories, Hercules, CA, USA). A complete blood cell count analysis was performed

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using a Sysmex XE-2100 (Sysmex, Mundelein, IL, USA). Fasting plasma concentrations of

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glucose, total cholesterol, triglycerides, high-density lipoprotein (HDL)-cholesterol, low-

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density lipoprotein (LDL)-cholesterol, blood urea nitrogen, and serum creatinine were

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measured on a Hitachi 747 chemistry analyzer (Hitachi, Tokyo, Japan). Serum aspartate

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aminotransferase (AST) and alanine aminotransferase (ALT) were measured with an

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autoanalyzer (TBA-200FR; Toshiba, Tokyo). Serum levels of apolipoprotein (Apo) A1 and B

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were measured using an AU5800 (Beckman Coulter, La Brea, CA, USA). Serum high-

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sensitivity C-reactive protein (hsCRP) level was measured with a high-sensitivity automated

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immunoturbidimetric method (CRP II Latex 3 2; Denka Seiken, Tokyo). Creatine kinase-

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myoglobin (CK-MB) and cardiac troponin-I levels were measured by a chemiluminescence

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method using an automated chemistry analyzer (Dimension Vista 1500; Siemens, Berlin,

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ACCEPTED MANUSCRIPT Germany). The homeostasis assessment of insulin resistance (HOMA-IR) and β-cell function

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(HOMA-β) were calculated using fasting insulin and glucose levels as previously described

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[16].

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2.3. CCTA data acquisition

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In all patients, CCTA was performed with a 256-multidetector CT (Brilliance iCT; Philips

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Healthcare, Cleveland, OH, USA) with 128 × 0.625 mm detector collimation and a gantry

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rotation time of 270 msec. Before performing the CCTA, esmolol (Brevibloc; Jeil

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Pharmaceutical, Seoul) at a dose of 10–30 mg was administered intravenously to subjects

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with a heart rate higher than 70 beats per min. Prior to contrast-enhanced CCTA, the coronary

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artery calcium score (CACS) was obtained by the Agatston method [17]. Prospective

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electrocardiogram (ECG)-gated calcium scoring scans were performed using 55-mAs tube

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current and rotation time product and reconstructed using a 2.5-mm slice thickness. After

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CACS measurement, CCTA was performed immediately following the administration of

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sublingual nitroglycerin for those patients who did not have contraindications. Iomeprol

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(Iomeron 370; Bracco, Milan, Italy) at a bolus dose of 80 mL was injected intravenously at a

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rate of 4 mL/s and followed by a 50 mL saline chaser. To minimize the radiation dose, the

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CCTA technique was configured based on the BMI. The tube potential was applied as follows:

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120 kVp for patients with BMI ≥25, 100 kVp for patients with BMI <25.

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2.4. CT image analysis for coronary stenosis, CACS, and plaque characteristics

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All scans were analyzed independently by two experienced radiologists (E.J.C., 9 years and

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J.H.H., 2 years) who were blinded to the treatment group, using a three-dimensional

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ACCEPTED MANUSCRIPT workstation (Brilliance; Philips Medical Systems, Best, The Netherlands). Each lesion was

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assessed using a multiplanar reconstruction technique and maximum-intensity projection in

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short-axis, two-chamber, and four-chamber views. The CACS was calculated using the

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Agatston score and the threshold was 130 Hounsfield units (HU) on precontrast images [17].

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The degree of coronary artery stenosis was evaluated by tracing the contrast material-

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enhanced portion of the coronary lumen in a semiautomatic fashion at the site of maximal

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stenosis and comparing it with the mean value for the proximal and distal reference sites. The

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plaque characteristics were analyzed on a per-segment basis according to the modified

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American Heart Association classification [18]. Plaque was classified into calcified or

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noncalcified based on the proportion of the lesion that was calcified [19].

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2.5. Plaque volume measurement

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All reconstructed datasets were transferred to an offline workstation for quantitative coronary

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atheroma volume analysis using a semiautomated software system (Cardiac Viewer and

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Comprehensive Cardiac Analysis, Extended Brilliance Workspace V4.5; Philips Healthcare,

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Best, The Netherlands). One experienced radiologist who was blinded to all clinical data and

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the allocated treatment groups evaluated all the scans. Plaque analysis was performed by

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multiple serial steps as described previously [20]. The coronary tree was extracted

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automatically and the contour of luminal and vessel walls was visualized. Semiautomatic

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plaque analysis included interactive lesion identification (single user click within a visually

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identified lesion), automatic lesion segmentation and characterization (software-identified

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lesion voxels and their classification), and quantification (software-calculated cross-sectional

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and volumetric lesion measurements). These processes are outlined in Supplementary Fig. 1.

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Corrections to vessel centerlines, contours, and lesion segmentation were made as necessary

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based on the expert’s experience. For our study, plaques with attenuation ≥130 HU were highlighted in light orange on the

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volume image and labeled as ‘‘high-attenuation voxels” or calcified plaque. Plaques with

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attenuation <130 HU were labeled as “low-attenuation voxels’’ and are shown in purple.

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These low-attenuation portions of plaque were classified as noncalcified plaques.

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2.6. Study endpoints

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The primary endpoint of the study was change of CAD assessed by CCTA after treatment.

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CAD indicates CACS, maximal stenosis, and plaque volume (calcified vs. noncalcified). The

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secondary endpoints were changes in risk factors of atherosclerosis such as glucose and lipid

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parameters. Changes in ankle–brachial index and pulse wave velocity which were conducted

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for assessing subclinical atherosclerosis were also the secondary endpoints.

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2.7. Statistical analysis

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Data are presented as the mean ± standard deviation (SD), and p <0.05 was considered

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significant. The baseline characteristics were compared using Student's t-test or Chi-square

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test. To evaluate changes between baseline and after treatment, paired t-test was used. All

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statistical analyses were performed using SPSS for Windows 22.0 (IBM Corp., Armonk, NY,

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USA).

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For the power calculation, we referred to a study that compared the efficacy of sarpogrelate

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and aspirin for the improvement of intermittent claudication in patients with arteriosclerosis

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obliterans [21], because no studies have used sarpogrelate specifically for primary prevention

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of CAD. The incidence of patients with intermittent claudication decreased significantly in 9

ACCEPTED MANUSCRIPT the sarpogrelate group (from 54.3% to 28.3%, p <0.001), whereas no significant change was

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observed in the aspirin group (from 51.2% to 48.8%, p >0.05). Based on this study, we

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defined an α-cutoff of 5% and a β-cutoff of 10% for a superiority design. The dropout rate

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was determined to be 15%. In consequence, the recommended number of study subjects was

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40 (20 in each group) (90% power, significance level p <0.05).

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3. Results

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3.1. Subject allocation and baseline characteristics

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Fifty-three patients were enrolled at the SNUBH (n = 25) and Ajou University Hospital (n =

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28). Of these, 13 were excluded for the reasons detailed in Fig. 1. The remaining 40 patients

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were randomly allocated to either the SPG+ASA group (n = 20) or the ASA group (n = 20).

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The demographic and clinical characteristics of the study population are presented in Table 1.

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The two groups were well matched with respect to baseline characteristics such as age, male–

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female ratio, anthropometric parameters, and laboratory findings at randomization. The mean

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± SD of the age and BMI of the study population were 60.3 ± 5.9 years and 26.2 ± 4.7 kg/m2

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for the SPG+ASA group, and 56.9 ± 7.3 years and 25.0 ± 3.1 kg/m2 for the ASA group. There

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were no significant differences in fasting plasma glucose (FPG) concentrations, HbA1c levels,

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and lipid profiles between the groups (p = NS for all). Sixty percent of participants in each

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group had hypertension at baseline.

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During the 6-month treatment, three patients discontinued the intervention and were lost to

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follow-up. Finally, 37 patients (n = 19 in the SPG+ASA group and n = 18 in the ASA group)

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were included in the analysis (Fig. 1). 10

ACCEPTED MANUSCRIPT 3.2. Changes in anthropometric and laboratory parameters after treatment

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Table 2 shows the changes in various parameters after treatment. There were no significant

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changes in BMI and blood pressure of either group after 6-month treatment. Slight decreases

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in FPG (from 153.6 ± 39.5 to 133.0 ± 27.9 mg/dL) of borderline significance (p = 0.05) were

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observed in the SPG+ASA group. The HOMA-IR tended to decrease in the SPG+ASA group

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and to increase in the ASA group, resulting in borderline significance of the delta changes (–

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0.71 ± 0.31 vs. 0.52 ± 0.21, p = 0.09). A significant increase in HOMA-β was observed in the

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SPG+ASA group (from 55.4 ± 53.6 to 79.3 ± 94.2, p = 0.04), whereas there was no

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significant change in the ASA group (from 50.6 ± 34.4 to 49.0 ± 22.6, p = 0.85). After the 6-

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month treatment, no significant differences were observed between groups in the changes in

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lipid profiles, including total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol,

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Apo A1, Apo B and cardiac enzymes such as CK-MB and troponin-I. Serum hsCRP levels in

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the SPG+ASA group decreased from 0.19 ± 0.14 mg/dL to 0.16 ± 0.13 mg/dL (p = 0.06), but

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increased in the ASA group from 0.13 ± 0.13 mg/dL to 0.31 ± 0.52 mg/dL (p = 0.13) (p for

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delta changes between groups = 0.04).

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3.3. Changes in CCTA findings after treatment

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Table 3 summarizes the changes after treatment in coronary atherosclerosis assessed by

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CCTA. The CACS decreased from 197.2 ± 53.1 to 188.7 ± 45.2 in the SPG+ASA group

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whereas it increased from 96.1 ± 35.9 to 99.1 ± 34.7 in the ASA group, but the differences

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were not significant. The degree of maximal stenosis of the coronary artery decreased from

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34.6 ± 4.5% to 33.3 ± 3.8% in the SPG+ASA group and from 30.9 ± 3.9% to 28.4 ± 3.2% in

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the ASA group, but these were also not significant. However, the total plaque volume

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decreased significantly from 82.4 ± 14.5 mm3 to 74.6 ± 14.4 mm3 in the SPG+ASA group (p

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<0.01), but increased from 64.9 ± 16.0 mm3 to 68.6 ± 16.3 mm3 in the ASA group (p = 0.03)

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(Table 3 and Fig. 2A). We further analyzed the changes in plaque composition. In the SPG+ASA group, the

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volume of noncalcified plaque decreased significantly by 28.2% (from 15.6 ± 4.6 mm3 to 11.2

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± 3.7 mm3, p <0.01), and the volume of calcified plaque decreased by only 5.1% (from 66.7 ±

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13.5 mm3 to 63.3 ± 13.2 mm3, p = 0.13) (Table 3 and Fig. 2B and C). In the ASA group, there

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was a trend to a slight increase in the volume of both calcified and noncalcified plaque

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(+4.8%, p = 0.09; +7.5%, p = 0.10, respectively) (Table 3 and Fig. 2B and C). Representative

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examples of changes in noncalcified plaque that were measured using semiautomated plaque

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analysis software are presented in Supplementary Fig. 2.

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3.4. Changes in pulse wave velocity and ankle–brachial index after treatment

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There were no significant changes in either group in the carotid–femoral pulse wave velocity

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after 6 months treatment (both p >0.05) (Table 3). There were also no significant changes in

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the ankle–brachial index in either group (Table 3).

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4. Discussion

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In this study, administration of SPG+ASA or ASA alone for 6 months did not change

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coronary artery stenosis or CACS significantly in DM patients with mild-to-moderate

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coronary atherosclerosis. However, the SPG+ASA treatment decreased the total plaque 12

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volume in the coronary artery, mainly because of a decrease in the noncalcified component

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(28.2% relative volume reduction). Although a small number of studies have investigated the effect of sarpogrelate treatment

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on development of CVD, most have evaluated the role of sarpogrelate in prevention of

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secondary CVD. In a study comparing sarpogrelate and placebo in patients with stable angina,

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the restenosis rate after coronary stenting in the sarpogrelate group was 4.3%, which was

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significantly lower than the 28.6% in the placebo group [22]. In another study of patients

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with acute coronary syndrome, the restenosis rate after percutaneous balloon angioplasty was

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37% in the sarpogrelate-treated group, which was significantly lower than the 57% in the

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aspirin-treated group [23]. Thus, sarpogrelate treatment was effective in reducing restenosis

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in patients with acute coronary syndrome. However, to the best of our knowledge, no clinical

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studies have evaluated the efficacy of sarpogrelate in primary CVD prevention.

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In our study, the combined treatment with sarpogrelate and aspirin significantly reduced

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the noncalcified component of total atheroma plaque in coronary arteries. Several possible

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mechanisms can be postulated for this effect. Sarpogrelate is known to reduce platelet

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aggregation and thrombus formation, which is a major component of noncalcified plaque [5,

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24]. Sarpogrelate is also known to inhibit vascular smooth muscle contraction and cell

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proliferation via the 5-HT2A receptor [25], which potentiates the platelet response to

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thrombogenic factors such as collagen and thromboxane A2 [26]. Treatment with sarpogrelate

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inhibited expression of acyl-coenzyme A:cholesterol acyltransferase-1, which plays a crucial

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role in the accumulation of lipid droplets within macrophages in early atherosclerotic lesions

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[27]. Vascular smooth muscle proliferation and lipid accumulation also contribute to

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development of the noncalcified portion of atheromatous plaque.

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ACCEPTED MANUSCRIPT Sarpogrelate also has anti-inflammatory and insulin-sensitizing effects. In a previous

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study, 3 months treatment with sarpogrelate decreased serum hsCRP levels in patients with

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arteriosclerosis obliterans [28]. In the present study, 6 months treatment with sarpogrelate

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plus aspirin showed a tendency to decrease serum hsCRP levels, but treatment with aspirin

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alone did not affect hsCRP levels: comparison of the delta changes between the two groups

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showed that this difference was significant.

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In a previous experimental study, treatment with sarpogrelate produced glucose-lowering

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effects [29]. In that study, sarpogrelate attenuated the decrease in expression of glucose

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transporter-1 that is seen in DM. Another study showed that sarpogrelate treatment decreased

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the serum glucose level in diabetic rats [30]. It was shown that the plasma concentration of

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serotonin was elevated in impaired glucose metabolism, and this elevation of serotonin led to

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insulin resistance and a consequent increase in blood glucose levels [31]. Therefore, the

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beneficial effects of sarpogrelate may be related to its ability to block 5-HT2A receptors in

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different organs. This beneficial effect of sarpogrelate might have indirectly contributed to the

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reduction in plaque volume, particularly in the noncalcified component, seen in this study.

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In the present study, combined treatment with sarpogrelate and aspirin decreased serum

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glucose concentrations compared with aspirin treatment alone. Furthermore, insulin

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resistance estimated by HOMA-IR showed a tendency to decrease in the SPG+ASA group

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but was not altered in the ASA group: comparison of the delta changes showed borderline

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significance. Moreover, HOMA-β significantly increased in the SPG+ASA group while it did

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not change in the ASA group. These data suggest that the anti-inflammatory effect and

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alleviation of insulin resistance by sarpogrelate may possibly contribute to a reduction in

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plaque volume as well as an improvement in β-cell function.

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ACCEPTED MANUSCRIPT Although we did not measure adiponectin levels, sarpogrelate treatment for 3 months

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increased circulating adiponectin levels in patients with arteriosclerosis obliterans [28].

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Adiponectin has anti-inflammatory and insulin-sensitizing effects [32, 33]. In another study,

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sarpogrelate treatment of patients with diabetes and arteriosclerosis reduced Interleukin (IL)-

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18 concentrations [12]. Plasma levels of IL-18 increased in patients with restenosis after

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percutaneous coronary intervention [34]. These data suggest that sarpogrelate might be able

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to modulate various pathways of platelet activation, lipid deposition, and plaque formation

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and progression, leading to a reduction in the noncalcified component of plaque.

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CCTA has emerged as an attractive noninvasive tool for the assessment of coronary

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atherosclerosis. A number of studies have demonstrated the role of CCTA in assessing

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cardiovascular morbidity [35, 36]. One study demonstrated that higher CACS as assessed by

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CCTA was associated with higher cardiovascular mortality in patients with DM [36]. Another

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study showed that adding CACS to the Framingham risk score significantly improved the

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prediction of cardiovascular mortality [37]. In terms of plaque burden, a meta-analysis

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demonstrated that CT had excellent diagnostic accuracy for the detection of plaques

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compared with intravascular ultrasound [38]. Furthermore, CCTA has emerged as a tool with

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potential for the assessment of plaque characteristics [10, 39]. In a recent meta-analysis,

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patients with high-risk plaque assessed by CCTA features such as low attenuation, spotty

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calcification, napkin-ring sign, and positive remodeling, had more cardiovascular events than

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those without [40]. A few studies have demonstrated that positive remodeling, noncalcified

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plaque, and spotty calcification were more frequent in patients with acute coronary syndrome

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than in those with stable angina [41, 42]. However, plaque size and volume were not assessed

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in those studies.

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ACCEPTED MANUSCRIPT CCTA has several issues including the degree of radiation exposure and the possibility of

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false-negative and -positive results, especially because of motion artifacts and calcified

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plaque [43]. However, with recent technological advances, detailed low-radiation dose

4

analysis of CAD, including plaque composition, is possible. In our study, coronary vascular

5

health was comprehensively investigated using multislice CCTA and sophisticated software.

6

Thus, the information about plaque characteristics obtained from CCTA will become more

7

frequently utilized in the prediction of plaque instability and possibly in the evaluation of the

8

effects of drugs on CAD.

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This study has several strengths. We performed a comprehensive evaluation of coronary

10

arteries using CCTA, including CACS, degree of coronary stenosis, plaque volume and, most

11

importantly, plaque composition. Various parameters of atherosclerosis such as pulse wave

12

velocity and ankle–brachial index as well as relevant biochemical parameters reflecting

13

insulin resistance, inflammation, and myocardial damage were evaluated in the analysis.

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Our study also has some limitations. First, the number of subjects was relatively small.

15

Second, the duration of treatment was short. These factors might be possible reasons that why

16

other typical parameters related to atherosclerosis did not alter significantly.

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14

In conclusion, the combined treatment with sarpogrelate and aspirin for 6 months

18

decreased plaque volume in patients with T2DM and mild-to-moderate coronary

19

atherosclerosis, mainly because of a reduction in the noncalcified component. These

20

beneficial effects are attributable to the pleiotropic properties of sarpogrelate including its

21

anti-inflammatory and insulin-sensitizing properties. The present study suggests that

22

sarpogrelate is a potential treatment option for preventing the development and progression of

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ACCEPTED MANUSCRIPT 1

coronary atherosclerosis in patients with T2DM. Longer-term large-scale studies are needed

2

to validate these findings.

3

Conflict of interest

5

The authors declared they do not have anything to disclose regarding conflict of interest with

6

respect to this manuscript.

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Financial support

9

This research was funded by Yuhan Pharma Corporation (Seoul, South Korea) through a

10

subcontract with SNUBH (Seongnam, South Korea) (06-2012-046). The funding agency had

11

no role in the study design, data collection and analysis, decision to publish, or preparation of

12

the manuscript.

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Acknowledgements

15

We are grateful to Taehyun Nam and Soon Ahn Kwon who were CT-technicians from the

16

department of radiology for their help regarding data acquisition.

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Appendix A. Supplementary data

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ACCEPTED MANUSCRIPT

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ACCEPTED MANUSCRIPT References

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ACCEPTED MANUSCRIPT computed tomographic characteristics of coronary lesions in acute coronary syndromes.

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ACCEPTED MANUSCRIPT 1

Tables and Figures

2

Table 1. Baseline characteristics of the study populations. p

60.3 ± 5.9

56.9 ± 7.3

NS

12/8

14/6

NS

163.7 ± 8.1

164.5 ± 8.2

NS

Weight (kg)

70.2 ± 13.1

67.8 ± 10.2

NS

BMI (kg/m2)

26.2 ± 4.7

25.0 ± 3.1

NS

WC (cm)

91.2 ± 9.8

87.5 ± 7.2

NS

126.2 ± 13.3

NS

126.8 ± 11.7

DBP (mmHg)

72.9 ± 8.1

74.4 ± 10.5

NS

7.23 ± 1.90

6.50 ± 2.23

NS

13.7 ± 1.2

14.0 ± 1.7

NS

252.5 ± 57.4

235.3 ± 63.6

NS

7.5 ± 1.2

7.3 ± 1.0

NS

156.1 ± 40.1

148.4 ± 37.0

NS

11.9 ± 9.5

9.8 ± 3.7

NS

4.5 ± 3.4

3.5 ± 1.5

NS

53.4 ± 52.9

51.2 ± 33.5

NS

15.5 ± 5.6

14.9 ± 3.5

NS

Creatinine (mg/dL)

0.87 ± 0.20

0.94 ± 0.25

NS

AST (IU/L)

30.5 ± 16.4

28.5 ± 12.2

NS

ALT (IU/L)

33.7 ± 21.5

29.1 ± 15.0

NS

Total cholesterol (mg/dL)

166.9 ± 35.4

162.2 ± 36.5

NS

Triglycerides (mg/dL)

189.3 ± 136.1

168.7 ± 170.6

NS

HDL-cholesterol (mg/dL)

49.8 ± 14.9

51.2 ± 9.4

NS

LDL-cholesterol (mg/dL)

87.4 ± 34.8

84.8 ± 26.7

NS

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SBP (mmHg)

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Height (cm)

SC

Gender (male/female)

ASA (n = 20)

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Age (years)

SPG+ASA (n = 20)

Laboratory findings WBC (103/µL) Hemoglobin (g/dL)

HbA1c (%) FPG (mg/dL) Insulin (µIU/mL)

HOMA-β

EP

HOMA-IR

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Platelet (103/µL)

BUN (mg/dL)

26

ACCEPTED MANUSCRIPT 139.6 ± 26.4

146.8 ± 26.2

NS

Apo B (mg/dL)

93.6 ± 30.8

85.3 ± 22.0

NS

CK-MB (ng/mL)

1.75 ± 1.58

1.46 ± 1.85

NS

1.920 ± 1.436

2.415 ± 1.416

NS

0.18 ± 0.14

0.14 ± 0.14

NS

Smoking, non/ex-/current

12(60)/4(20)/4(20)

11(55)/4(20)/5(25)

NS

Alcohol, non/light/moderate

11(55)/5(25)/4(20)

7(35)/5(25)/8(40)

NS

Hypertension

12 (60)

12 (60)

NS

Dyslipidemia

20 (100)

20 (100)

NS

hsCRP (mg/dL) Lifestyles, n (%)

Comorbidity, n (%)

SC

Troponin I (ng/mL)

RI PT

Apo A1 (mg/dL)

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Data are expressed as the mean ± SD. BMI, body mass index; WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; WBC, white blood cell; FPG, fasting plasma glucose; BUN, blood urea nitrogen; AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDL, low-density lipoprotein; HDL, high-density lipoprotein; Apo, apolipoprotein; CK-MB, creatine kinase-MB; NS, not significant. p values were calculated by

3 4

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Student’s t-test for continuous data and Chi-square test for categorical data.

27

ACCEPTED MANUSCRIPT

Table 2. Changes of various parameters after treatment. SPG+ASA (n = 19)

ASA (n = 18)

BMI (kg/m2)

26.6 ± 4.6

26.6 ± 4.7

0.71

WC (cm)

91.5 ± 9.9

93.2 ± 10.7

0.16

SBP (mmHg)

127.1 ± 12.0

129.7 ± 13.5

0.32

DBP (mmHg)

73.1 ± 8.3

73.8 ± 9.3

0.75

WBC (103/µL)

7.29 ± 1.94

7.50 ± 2.71

0.61

Hemoglobin (g/dL)

13.7 ± 1.2

13.8 ± 0.9

253.9 ± 58.6

HbA1c (%) FPG (mg/dL)

After treatment

p

24.9 ± 3.1

25.0 ± 3.1

0.52

0.97

86.1 ± 5.6

86.5 ± 5.0

0.29

0.46

127.6 ± 13.3

124.1 ± 8.7

0.29

0.14

76.0 ± 9.8

76.5 ± 8.3

0.85

0.95

6.64 ± 2.31

6.45 ± 2.07

0.44

0.40

0.67

14.2 ± 1.6

14.3 ± 1.4

0.36

0.61

263.5 ± 54.9

0.21

235.6 ± 65.8

227.1 ± 41.9

0.51

0.19

7.4 ± 1.0

7.1 ± 0.7

0.28

7.1 ± 0.8

7.3 ± 1.1

0.47

0.19

153.6 ± 39.5

133.0 ± 27.9

0.05

149.6 ± 38.4

146.1 ± 28.7

0.64

0.18

12.2 ± 9.2

0.98

9.8 ± 3.8

10.9 ± 5.9

0.47

0.52

3.9 ± 2.8

0.18

3.6 ± 1.5

4.1 ± 2.6

0.30

0.09

79.3 ± 94.2

0.04

50.6 ± 34.4

49.0 ± 22.6

0.85

0.07

14.7 ± 3.4

0.86

14.4 ± 3.4

14.8 ± 3.9

0.64

0.70

0.88 ± 0.20

0.61

0.89 ± 0.16

0.86 ± 0.17

0.24

0.25

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Platelet (103/µL)

*

Baseline

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p

SC

After treatment

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Baseline

p

12.2 ± 9.7

HOMA-IR

4.6 ± 3.5

HOMA-β

55.4 ± 53.6

BUN (mg/dL)

15.0 ± 5.2

Creatinine (mg/dL)

0.88 ± 0.19

AST (IU/L)

27.8 ± 11.6

29.1 ± 13.3

0.51

28.6 ± 12.9

29.2 ± 10.1

0.82

0.84

ALT (IU/L)

30.0 ± 14.2

30.7 ± 13.1

0.79

29.4 ± 15.8

36.4 ± 20.1

0.03

0.12

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Fasting insulin (µIU/mL)

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ACCEPTED MANUSCRIPT

166.0 ± 36.2

170.5 ± 30.7

0.53

165.4 ± 36.0

159.9 ± 27.0

0.52

0.36

Triglycerides (mg/dL)

177.9 ± 129.9

167.4 ± 91.2

0.68

173.8 ± 179.4

157.1 ± 103.7

0.57

0.87

HDL-cholesterol (mg/dL)

51.3 ± 13.8

49.8 ± 10.4

0.60

52.1 ± 9.5

51.6 ± 11.9

0.86

0.81

LDL-cholesterol (mg/dL)

86.6 ± 35.6

91.2 ± 27.1

0.38

86.1 ± 27.2

83.9 ± 21.1

0.73

0.40

Apo A1 (mg/dL)

142.8 ± 22.7

145.8 ± 20.0

0.30

150.1 ± 25.4

147.0 ± 25.8

0.60

0.33

Apo B (mg/dL)

93.1 ± 31.6

95.8 ± 23.1

0.70

88.3 ± 21.1

86.8 ± 21.9

0.87

0.65

CK-MB (ng/mL)

1.81 ± 1.60

1.55 ± 1.29

0.69

1.51 ± 1.95

1.24 ± 0.96

0.40

0.60

Troponin I (ng/mL)

1.86 ± 1.45

1.73 ± 1.46

0.33

2.29 ± 1.44

2.16 ± 1.47

0.16

0.66

hsCRP (mg/dL)†

0.19 ± 0.14

0.16 ± 0.13

0.06

0.13 ± 0.13

0.31 ± 0.52

0.13

0.04

M AN U

SC

RI PT

Total cholesterol (mg/dL)

Data are expressed as the mean ± SD. p values were calculated by paired t test between baseline and after treatment. *p values were calculated by Student t-

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test for delta changes between both groups. †Log-transformed values were used for comparison.

29

ACCEPTED MANUSCRIPT

Table 3. Changes of coronary atherosclerosis parameters, PWV, and ABI after treatment. ASA (n = 18)

After treatment

p

197.2 ± 53.1

188.7 ± 45.2

0.14

Maximal stenosis (%)

34.6 ± 4.5

33.3 ± 3.8

0.41

Total plaque volume (mm3)

82.4 ± 14.5

74.6 ± 14.4

<0.01

66.7 ± 13.5

63.3 ± 13.3

0.13

15.6 ± 4.6

11.2 ± 3.7

1970.6 ± 76.9 1.16 ± 0.03

Calcified plaque volume (mm3) 3

Noncalcified plaque volume (mm ) PWV (m/s) ABI

After treatment

p

96.1 ± 35.9

99.1 ± 34.7

0.48

0.29

30.9 ± 3.9

28.4 ± 3.2

0.28

0.65

64.9 ± 16.0

68.6 ± 16.3

0.03

<0.01

43.7 ± 14.0

45.8 ± 14.3

0.09

0.03

<0.01

21.2 ± 6.2

22.8 ± 6.6

0.10

<0.01

1979.8 ± 81.1

0.88

1839.2 ± 65.3

1904.7 ± 83.1

0.29

0.52

1.18 ± 0.03

0.44

1.15 ± 0.02

1.18 ± 0.01

0.20

0.87

M AN U

CACS†

*

Baseline

SC

Baseline

RI PT

SPG+ASA (n = 19)

p

Data are expressed as the mean ± SE. CACS, coronary artery calcium score; PWV, carotid-femoral pulse wave velocity; ABI, ankle-brachial

TE D

index. p values were calculated by paired t test between baseline and after treatment. *p values were calculated by Student t-test for delta

AC C

EP

changes between both groups. †Log-transformed values were used for comparison.

30

ACCEPTED MANUSCRIPT Figure legends

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Fig. 1. Disposition of patients and reasons for patient exclusion.

Fig. 2. Changes in total, calcified, and noncalcified plaque volumes by CCTA. *p <0.05 by paired t test between before and after treatment. †p <0.05 by Student’s t test for delta

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changes between both groups.

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Fig. 1.

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SPG+ASA ASA †

120

*

100

*

80

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3

Total plaque volume (mm )

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60 40 20

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0 Before After

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Calcified plaque volume (mm )

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Before After

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Noncalcified plaque volume (mm )

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Highlights

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Sarpogrelate, a selective 5-HT2A receptor antagonist, reduced coronary artery plaque volume significantly in patients with type 2 diabetes mellitus

Regression of atheroma was more prominent in noncalcified plaque than in calcified

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plaque.

These beneficial effects are attributable to the pleiotropic properties of sarpogrelate

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including its anti-inflammatory and insulin-sensitizing properties.

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ATHEROSCLEROSIS International Journal for Research and Investigation on Atherosclerosis and Related Diseases

MANUSCRIPT REFERENCE NUMBER:

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FIRST AUTHOR: Dong-Hwa Lee

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Conflict of Interest

TITLE: Effect of Sarpogrelate, a Selective 5-HT2A Receptor Antagonist, on

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Characteristics of Coronary Artery Disease in Patients with Type 2 Diabetes

There are no conflicts of interest associated with this publication.

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Signature of Corresponding Author

Name: Soo Lim MD, PhD

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Date: May 18, 2016