Evaluation of the Effectiveness of Sarpogrelate on the Surrogate

Endocrine Journal 2012, 59 (8), 709-716

Or i g i n a l Evaluation of the effectiveness of sarpogrelate on the surrogate markers for macrovascular complications in patients with type 2 diabetes So Young Park1)*, Sang Youl Rhee1), 2)*, Seungjoon Oh1), 2), Hyuk Sang Kwon3), Bong-Yun Cha3), Hyun Joo Lee4), Hyun Chul Lee4) and Young Seol Kim1), 2)

1) Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, Korea 2) Research Institute of Endocrinology, Kyung Hee University, Seoul, Korea 3) Division of Endocrinology and Metabolism, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea 4) Division of Endocrinology and Metabolism, Department of Internal Medicine,Yonsei University College of Medicine, Seoul, Korea

Abstract. Sarpogrelate, a selective 5-HT2 receptor antagonist, is known to have a significant effect on antiplatelet action. This study was a double-blinded, randomized, paralleled multicenter trial to compare the effects of sarpogrelate and aspirin on preventing macrovascular complications in patients with type 2 diabetes. The subjects were randomly assigned to either the sarpogrelate or the aspirin group. The baseline parameters for macrovascular complications, such as intima media thickness (IMT), ankle-brachial index (ABI), IL-6, serotonin, adiponectin, and hsCRP, were measured before drug administration. Changes were compared at 6 and 12 months after the administration of each drug. A total of 127 subjects (63 in the sarpogrelate group and 64 in the aspirin group) were pooled during the study period. No significant differences were found in baseline IMT or in other predictors of macrovascular complications. The mean IMT increased in both groups after 12 months, but there was no significant difference between the two groups. No significant change was found in the other predictors of macrovascular complications nor in the incidence of drug-related adverse events between the two groups. During the study period, no significant differences were found between the sarpogrelate group and aspirin group in the clinical indices or in the safety of the subjects related to macrovascular complications. This suggests that sarpogrelate may be clinically useful for the primary prevention of macrovascular complications in patients with type 2 diabetes.

Key words: Sarpogrelate, Aspirin, Type 2 diabetes mellitus, Macrovascular complications

DYSINSULINISM and insulin resistance are known diabetes mellitus (T2DM) [3]. causes of diabetes-related complications because they A recent study has reported that serotonin (5-HT2) induce hyperglycemia, hyperinsulinemia, dyslipi- is involved in peripheral circulatory disturbances [4]. demia, hypertension, and hemostatic disorder [1]. In Direct blood exposure to subendothelial collagen due particular, macrovascular complications are dangerous to endothelial damage caused by arteriosclerosis can and can be fatal. The early prevention of the incidence result in platelet adhesion, platelet aggregation, and and progression of atherosclerosis, which causes mac- serotonin discharge from platelets [5]. Serotonin binds rovascular complications, is an important therapeutic to and activates the 5-HT2 receptor on the other platelet aim in the treatment of patients with diabetes [2]. At membranes, resulting in increased platelet aggregation. present, most clinical practice guidelines recommend Moreover, serotonin binds with 5-HT2 receptors on the aspirin as the first line medication for the prevention vascular smooth muscle cell membrane at the inhibitory of macrovascular complications in patients with type 2 site to contract vascular smooth muscles. As a result, serotonin inhibits blood flow by increasing the platelet Submitted Feb. 2, 2012; Accepted Apr. 25, 2012 as EJ12-0047 thrombus inside the impaired blood vessels and by con- Released online in J-STAGE as advance publication Jun. 3, 2012 Correspondence to: Young Seol Kim, M.D., Ph.D., Department of tracting the blood vessels from the outside [5, 6]. Endocrinology and Metabolism, Kyung Hee University School of Repression of the serotonin 5-HT2 receptor func- Medicine, Seoul 130-702, Korea. E-mail: [email protected] tions would improve the symptoms of patients with * These authors equally contributed to this article. peripheral circulatory disturbances by reducing the ©The Japan Endocrine Society 710 Park et al. incidence and progression of macrovascular compli- pooled from three hospitals, Kyung Hee University cations. Such a treatment may be especially effective Hospital, Seoul St. Mary’s Hospital, and Severance in the high-risk macrovascular disease group, which Hospital, between March 2005 and June 2007. The includes patients with T2DM. However, few studies selection criteria for the subjects included T2DM diag- have been performed regarding the effects of serotonin nosis between the ages of 40 and 80 years with no his- 5-HT2 receptor blockers on macrovascular complica- tory of ketoacidosis or ketonuria, a glycosylated hae- tions in patients with T2DM [5]. There have been very moglobin (HbA1c) level of 8% or lower, an LDL few studies on the clinical effects of 5-HT2 receptor cholesterol level of 160 mg/dL or lower, and a body blockers compared to aspirin, which is the first line mass index (BMI) less than 30 kg/m2(with the refer- medication for the primary prevention of macrovascu- ence values measured within the last three months). lar complications [7, 8]. Subjects were excluded from the study if they felt it Sarpogrelate, which is a selective 5-HT2 receptor difficult to participate, had any other medical diseases antagonist, has a significant effect on antiplatelet action that could affect the results or their safety, or if they had and improves endothelial functions. It locally represses taken any other drugs which could aggravate bleed- serotonin action only inside the lesion and does not ing tendency such as warfarin, clopidogrel, ticlopi- affect the normal tissues [4, 9-14]. We performed this dine, and cilostazol (Table 1). The study protocol was study to investigate if sarpogrelate has a positive effect approved by the Institutional Review Board at Kyung on the surrogate markers for macrovascular complica- Hee University Hospital. Before participating, all sub- tions in patients with type 2 diabetes. In addition, the jects submitted written consent and received a suffi- effect is compared to that of aspirin, which is the first cient explanation from the relevant medical staff. line medication for this type of situation. Methods Materials and Methods The study was performed as a double-blinded, paralleled, randomized multicenter clinical trial. The Study subjects subjects were assigned to either the sarpogrelate This study was conducted with 146 T2DM patients group or the aspirin group by simple randomization.

Table 1 Inclusion and exclusion criteria of the study subjects Inclusion criteria Subjects diagnosed as type 2 diabetes mellitus - Age more than 40 years and less than 80 years - without any medical history of DKA or Ketonuria - HbA1c less than 8.0% - BMI less than 30 kg/m2 - LDL cholesterol less than 160 mg/dL Exclusion criteria Medical history of malignancy Hepatic dysfunction (AST or ALT > 2.5 UNL) Renal dysfunction (creatinine> 1.6 mg/dL) Medical history of angina pectoris, congestive heart failure, cerebrovascular accident Patient of uncontrolled or untreated hypertension (SBP≥180 mmHg and/or DBP≥95mmHg) Medical history of Buerger’s disease or any occlusive arteriosclerotic disease Patient of overt proteinuria (albumin ≥300 mg/day) Diabetic foot ulcer Clinically evident proliferative diabetic retinopathy or macular degeneration Medical history of hypersensitivity reaction to study medication or their metabolites Pregnant or breast feeding women Alcohol or drug addict Current medication users which could affect bleeding tendency (warfarin, clopidogrel, ticlopidine, and cilostazol) DKA, diabetic ketoacidosis; LDL, low density lipoprotein; AST, aspartate aminotransferase; ALT, alanine aminotransferase; UNL, upper normal limit; SBP, systolic blood pressure; DBP, diastolic blood pressure Effect of sarpogrelate on type 2 DM 711

The respective groups were administered 300 mg/day second endpoint was defined as the changes in CAVI, of sarpogrelate or 100 mg/day of aspirin. The base- ABI, serotonin, hsCRP, adiponectin, and IL-6. To line values of macrovascular disease predictors were assess the safety of sarpogrelate, adverse drug reactions measured before the administration of the medica- and changes in laboratory test results were monitored. tion. These factors include intima-media thickness (IMT), ankle-brachial index (ABI), cardio ankle vas- Statistical analysis cular index (CAVI), IL-6, serotonin, adiponectin, Statistical analysis and data management were car- and hsCRP. Changes at six and 12 months after drug ried out with the Statistical Package for Social Science administration and the incidence of adverse drug reac- (SPSS, version 13.0; SPSS Inc., Chicago, IL, USA). tions were compared between the groups. All statistical analyses were performed as intention to The imaging test to measure IMT was conducted by treat analysis (ITT). A Student’s t-test and Chi-square one skilled sonographer at each hospital, using a B-mode test were conducted to test the significance of the dif- high-resolution sonograph, to which a liner probe over ferences between the two groups in baseline charac- 7.5 MHz was applied. The images were transmitted teristics and changes during the follow-up period. A to a computer, and the IMT and plaque existence were repeated measures ANOVA was performed to deter- analyzed with an IntimaScope (version 1.13E, Media mine the difference in therapeutic effects between the Cross Co. Ltd., Tokyo, Japan). Both carotid arteries two groups during the follow-up period. A p-value of were divided into total carotid region, carotid opening, 0.05 or less was considered significant. and carotid branch, and the maximum measurement in each region was obtained to define the maximum Results IMT. The mean IMT was defined as the value measured at 1 cm intervals of the far wall of the boundary Patient characteristics toward the carotid ampullary region. To evaluate the A total of 146 subjects were pooled during the study ankle-brachial index (ABI) and the cardio ankle vascu- period and randomly assigned to either the sarpogre- lar index (CAVI), the VaSera VS-1000 (Fukuda Denshi late group (72 subjects) or the aspirin group (74 sub- Co. Ltd., Tokyo, Japan) was used. ABI was defined as jects) (Fig. 1). Among the subjects in the sarpogrelate the ratio of the systolic blood pressure measured at the group, 11 were eliminated for either protocol violation ankle anterior dorsalis artery or posterior tibial artery (3 subjects) or consent withdrawal (8 subjects). Two to the upper limb systolic blood pressure measured at subjects were eliminated for other reasons, resulting in the brachial artery. The mean pulse transmission rate 59 (81.9%) of 72 original subjects in the sarpogrelate- from aortic origin to the aorta, leg, and inferior horn group who completed the test. Among the subjects in region was measured. CAVI was defined as the ratio the aspirin group, 17 were eliminated, either for pro- of the distance to the transmission time. Serum sam- tocol violation (3 subjects), consent withdrawal (12 ples were immediately centrifuged, aliquoted, frozen at subjects), or incidence of abnormal reactions (2 sub- -70°C, and moved to the central laboratory (Research jects). Thus, 57 (77.0%) of 74 original subjects in the Institute of Endocrinology, Kyung Hee University, aspirin group completed the test. There was no signifi- Seoul, Korea). Serum serotonin was measured using cant difference in the ratio of subjects who dropped out ELISA assay (Labor Diagnostika Nord GmbH & Co., between the two groups (p=0.157). Nordhorm, Germany), and hsCRP was measured using The mean age of the subjects was 62 in the sarpogrelate an HS-CRP assay kit (Siemens Health care Diagnostics group and 63 in the aspirin group, with no significant dif- Inc., IL, USA). The hsCRP level was estimated in fresh ference between the two groups. There was no significant serum samples after centrifugation. The quantity of the difference in the sex ratio between the two groups. There respective CRP was calculated in micrograms per mil- was no significant difference between the two groups in liliter. Adiponectin was measured using radioimmuno- anthropometric and biochemical parameters (Table 2). assay (LINCO Research, MO, USA). IL-6 was measured using ELISA (R&D Systems, Inc., MN, USA). Changes in the IMT The primary endpoint with respect to the efficacy of At baseline, the mean IMT was 0.77±0.22 mm on the the result was defined as a change in IMT from the day left and 0.72±0.14 mm on the right. The maximum IMT of the test medication to the end of the study time. The was 0.94±0.37 mm on the left and 0.88±0.21 mm on the 712 Park et al.

Fig. 1 Summary of progression in this study ITT, intention to treat; F/U, follow up

Table 2 Baseline characteristics of the study subjects Sarpogrelate group Aspirin group Variables p Total (n=63) (n=64) Gender (M/F, n) 23 / 40 27 / 37 0.567 50 / 77 Age (years) 61.9±6.6 62.6±9.3 0.641 62.2±8.1 Height (cm) 158.7±8.4 159.0±8.1 0.821 158.9±8.2 Body weight (kg) 63.8±8.4 63.1±8.3 0.642 63.4±8.3 BMI (kg/m2) 25.2±2.0 24.9±2.3 0.456 25.0±2.2 SBP (mmHg) 129.3±14.9 129.9±15.7 0.847 129.6±15.3 DBP (mmHg) 79.7±8.8 80.3±9.0 0.727 80.0±8.9 Smoking (n, %) 16 (25.4) 22 (34.4) 0.269 38 (29.9) HbA1c (%) 6.3±1.0 6.0±1.0 0.117 6.2±1.0 FPG (mg/dL) 125.7±38.8 113.7±22.3 0.258 119.4±31.3 Total cholesterol (mg/dL) 177.4±33.8 171.3±31.8 0.513 174.4±32.6 LDL cholesterol (mg/dL) 109.3±30.0 105.3±25.2 0.614 107.3±27.6 HDL cholesterol (mg/dL) 44.3±18.9 43.6±9.9 0.884 44.0±15.0 Triglyceride (mg/dL) 138.2±86.4 122.9±66.2 0.483 130.7±76.8 IMT average (mm) Left 0.77±0.26 0.76±0.17 0.773 0.77±0.22 Right 0.71±0.14 0.73±0.14 0.533 0.72±0.14 IMT Max (mm) Left 0.96±0.48 0.92±0.22 0.587 0.94±0.37 Right 0.87±0.21 0.88±0.21 0.769 0.88±0.21 CAVI (m/s) Left 8.78±1.17 8.43±1.22 0.107 8.60±1.20 Right 8.83±1.09 8.53±1.32 0.174 8.68±1.21 ABI Left 1.11±0.10 1.10±0.10 0.546 1.10±0.10 Right 1.09±0.10 1.08±0.10 0.373 1.09±0.10 Serotonin (ng/mL) 73.17±43.11 73.07±53.89 0.990 73.1±48.6 hsCRP (mg/L) 1.14±2.28 1.82±3.32 0.186 1.48±2.86 Adiponectin (ug/mL) 5.02±3.61 7.13±7.03 0.035 6.08±5.68 IL-6 (ng/mL) 1.87±2.02 3.86±8.41 0.071 2.87±6.20 mean±S.D. IMT indicates intima media thickness; CAVI indicates cardio ankle vascular index; ABI indicates ankle-brachial index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; LDL, low density lipoprotein; HDL, high density lipoprotein; hsCRP, high sensitive C-reactive protein Effect of sarpogrelate on type 2 DM 713 right, indicating no significant difference between the in the sarpogrelate group and the aspirin group, respec- sarpogrelate group and the aspirin group (Table 2). tively, with reference to the average IMT on the right. During the study period, the IMT increased in both The differences in the ratios between the two groups the sarpogrelate group and the aspirin group. In the were not significant p( =0.775, 0.768). sarpogrelate group, the measured IMT was 0.79±0.25 mm on the left and 0.75±0.13 mm on the right after Change in the atherosclerosis markers 24 weeks and 0.80±0.26 mm on the left and 0.75±0.14 The baseline serotonin value was 73.17±43.11 ng/ mm on the right after 48 weeks. In the aspirin group, mL in the sarpogrelate group and 73.07±53.89 ng/ the measured IMT was 0.74±0.16 mm on the left mL in the aspirin group, with no significant differ- and 0.70±0.14 mm on the right after 24 weeks and ence (p=0.990, Table 2). The baseline hsCRP value 0.80±0.25 mm on the left and 0.78±0.25 mm on the was 1.14±2.28 mg/L in the sarpogrelate group and right after 48 weeks (Table 3). However, the changes 1.82±3.32 mg/L in the aspirin group, with no signif- in IMT were similar between the two groups, showing icant difference (p=0.186). The baseline IL-6 value no significant difference. was 1.87±2.02 ng/mL in the sarpogrelate group and The ratio of the subjects whose IMT value decreased 3.86±8.41 ng/mL in the aspirin group, with no signif- by more than 15% during the follow-up period was icant difference (p=0.071). Conversely, the baseline 15.9% and 14.1% in the sarpogrelate group and the adiponectin value was 5.02±3.61 ug/mL in the sar- aspirin group, respectively, with reference to the aver- pogrelate group and 7.13±7.03 ug/mL in the aspirin age IMT on the left. The values were 14.3% and 12.5% group, with a significantly higher level in the aspirin

Table 3 Changes of vascular endothelial cell function variables from baseline to 12 and 24 weeks later Variables Group Baseline 24 wks 48 wks p IMT average Sarpogrelate 0.77±0.26 0.79±0.25 0.80±0.26 0.621 Left (mm) Aspirin 0.76±0.17 0.74±0.16 0.80±0.25 IMT average Sarpogrelate 0.71±0.14 0.75±0.13 0.75±0.14 0.920 Right (mm) Aspirin 0.73±0.14 0.70±0.14 0.78±0.25 IMT max Sarpogrelate 0.96±0.48 0.99±0.49 0.97±0.46 0.520 Left (mm) Aspirin 0.92±0.22 0.90±0.23 0.67±0.33 IMT max Sarpogrelate 0.87±0.21 0.91±0.21 0.88±0.19 0.773 Right (mm) Aspirin 0.88±0.21 0.82±0.19 0.92±0.34 CAVI Sarpogrelate 8.78±1.16 8.84±1.19 8.88±1.36 0.227 Left (m/s) Aspirin 8.43±1.22 8.70±1.89 8.60±1.64 CAVI Sarpogrelate 8.83±1.09 9.05±1.53 8.78±1.07 0.147 Right (m/s) Aspirin 8.53±1.32 8.60±1.55 8.63±1.48 Sarpogrelate 1.11±0.11 1.10±0.10 1.09±0.10 ABI Left 0.492 Aspirin 1.10±0.10 1.24±1.16 1.07±0.12 Sarpogrelate 1.09±0.10 1.08±0.08 1.08±0.09 ABI Right 0.284 Aspirin 1.08±0.10 1.06±0.11 1.07±0.09 Serotonin Sarpogrelate 73.17±43.11 72.30±44.41 76.07±50.07 0.292 (ng/mL) Aspirin 73.07±53.89 79.66±51.34 87.87±51.49 hsCRP Sarpogrelate 1.14±2.28 1.08±1.27 1.06±1.70 0.051 (mg/L) Aspirin 1.82±3.32 1.93±4.53 1.19±2.03 Adiponectin Sarpogrelate 5.02±3.61 5.74±4.94 5.73±6.44 0.071 (ug/mL) Aspirin 7.13±7.03 6.28±6.62 7.16±8.47 IL-6 Sarpogrelate 1.87±2.02 1.90±2.39 1.57±1.15 0.032 (ng/mL) Aspirin 3.86±8.41 3.39±4.80 2.70±5.36 mean±S.D. IMT indicates intima media thickness; CAVI indicates cardio ankle vascular index; ABI indicatesankle-brachial index; hsCRP, high sensitive C-reactive protein 714 Park et al. group (p=0.035). sarpogrelate in preventing secondary cerebral infarc- Changes in serological markers during the study tion [8]. Weber et al. reported that combined treatment period were analyzed, but there was no significant dif- with aspirin and clopidogrel showed the greatest prom- ference in serum serotonin concentration between the ise in preventing secondary cerebral infarction [22]. two groups. The hsCRP and adiponectin levels were The current study is ahead-to-head comparison of the lower in the sarpogrelate group, though the difference effects of sarpogrelate and aspirin, the first line medi- was not significant. The IL-6 level was significantly cation for the prevention of macrovascular complica- lower in the sarpogrelate group (Table 3). tions in type 2 diabetes patients. Our results show that the IMT value (IMT average Changes in the ABI and CAVI levels left/right and IMT maximum left/right), which was the In the sarpogrelate group, the baseline CAVI value primary endpoint, did not show a significant decrease in was 8.78±1.16 m/s on the left and 8.83±1.09 m/s on the either the sarpogrelate group or the aspirin group. There right, and the baseline ABI value was 1.11±0.11 on the was no significant difference between the two groups in left and 1.09±0.10 on the right. In the aspirin group, the ratio of the subjects whose IMT value decreased by the baseline CAVI value was 8.43±1.22 m/s on the left more than 15%. No significant difference was found and 8.53±1.32 m/s on the right, and the baseline ABI in the changes of the ABI and CAVI values, which value was 1.10±0.10 on the left and 1.08±0.10 on the were the secondary endpoints. Among the serologi- right. There was no significant difference between the cal markers, the adiponectin, IL-6, and hsCRP values two groups (Table 2). Changes in CAVI and ABI dur- were more favorable in the sarpogrelate group than in ing the follow-up period did not show any significant the aspirin group. The incidence of abnormal reactions difference between the two groups (Table 3). was not significantly different between the two groups. The results suggest that sarpogrelate may play a role Safety assessment in the prevention of macrovascular diseases in patients Thirteen adverse drug reactions were found in eight with T2DM, and that additional benefits of the drug can subjects (12.5%) from the sarpogrelate group, and 13 be expected. In particular, when compared with other abnormal reactions were found in ten subjects (15.2%) studies, our study makes an objective comparison of the from the aspirin group. There was no significant differ- various risk factors of macrovascular diseases. Various ence between the two groups (p=0.662). serological markers, IMT, CAVI, and ABI are sensitive and effective predictors of cardiovascular diseases, and Discussion so were selected as the outcome variables [21-27]. The effect of aspirin on the prevention of macrovas- At present, several studies have been performed on cular diseases has been well established by many stud- the use of sarpogrelate for the prevention of diabetes- ies. The effect of sarpogrelate cannot be sufficiently related complications in T2DM patients. Sarpogrelate proven by the current study, which was conducted on has been shown to be effective in the prevention of a small scale for a short period of time. However, the diabetic neuropathy and diabetic nephropathy. It is results of this study provide useful data for the treat- also known to be effective in the recovery of insulin ment of patients who need another treatment option resistance and in the prevention of neurogenic bladder due to adverse effects related to the use of aspirin or caused by autonomic nervous system complications in other thienopyridine alternatives. These adverse effects type 2 diabetes patients [15-21]. Additionally, studies include resistance to the medication’s effect and gas- have shown that sarpogrelate is effective in prevent- trointestinal bleeding [28, 29]. Until now, cilostazol, ing peripheral circulatory disturbances. The risk of ticlopidine hydrochloride, and clopidogrel studies have cardiovascular and cerebrovascular diseases may be been conducted regarding alternatives for aspirin. The reduced in type 2 patients who take sarpogrelate [7-12]. results showed that cilostazol and ticlopidine hydro- However, few studies have compared the effects of sar- chloride were equal to aspirin in preventing macrovas- pogrelate with those of other drugs [7, 8, 22, 23]. In cular diseases, and that clopidogrel had a greater effect S-ACCESS, a comparative study of antiplatelet drugs than aspirin. Although these studies demonstrated that for the prevention of secondary cerebral infarction, aspirin alternatives have equal or superior effects to there was no significant difference between aspirin and aspirin, further studies are necessary to determine the Effect of sarpogrelate on type 2 DM 715 long-term effects. rovascular complications in patients with type 2 diabe- Our study has some limitations. First, the drop-out tescomparable to that of aspirin. In conclusion, no sig- ratio of the subjects was higher (20.5%) than expected. nificant difference was found between the two groups This might have affected the significance comparisons in the clinical indices or in the safety of sarpogrelate for the clinical indices between the two groups. In related to macrovascular complications. However, the addition, the baseline risk of cardiovascular diseases serological markers were more favorable in the sar- was not very high in the pooled subjects, and cardio- pogrelate group than in the aspirin group. This indi- vascular disease-related factors, rather than the sig- cates that sarpogrelate could be effectively used as an nificant difference in the incidence of cardiovascular aspirin alternative for the prevention of macrovascular diseases, was set as the end point. It was not suffi- complications in patients with T2DM. ciently verified if the results from the two groups had the same clinical effect on a significant incidence of Acknowledgements cardiovascular disease. Moreover, variation due to the raters could not be completely excluded, even though This study was supported by a grant of the Korea the IMT was measured by skilled raters in each of the Health care technology R&D Project, Ministry of centers. Despite these limitations, our study is signif- Health and Welfare, Republic of Korea (A102065). icant because it is the first to show that sarpogrelate The Yuhan Corporation provided financial support for may be used safely for the prevention of cardiovascu- this study. The authors have no conflicts of interest lar diseases in type 2 diabetes patients, and that it has a to disclose. We are immensely grateful to Dr. Kwang clinical significance on the surrogate markers for mac- Sik Suh for his assistance in the laboratory work.

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