Effects of ezetimibe on atherogenic lipoproteins and glucose metabolism in patients with diabetes and glucose intolerance

diabetes research and clinical practice 100 (2013) 46–52

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Diabetes Research and Clinical Practice jou rnal hom ep ag e: w ww.e l s e v i er . c om/ loca te / d i ab r es

Effects of ezetimibe on atherogenic lipoproteins and glucose metabolism in patients with diabetes and glucose intolerance Tetsuji Tsunoda a,1,*, Tsuyoshi Nozue b,1, Masayo Yamada a, Ichiro Mizuguchi b, Mayuko Sasaki a, Ichiro Michishita b a

Division of Metabolism and Endocrinology, Department of Internal Medicine, Yokohama Sakae Kyosai Hospital, Federation of National Public Service Personnel Mutual Associations, Yokohama, Japan b Division of Cardiology, Department of Internal Medicine, Yokohama Sakae Kyosai Hospital, Federation of National Public Service Personnel Mutual Associations, Yokohama, Japan

article info

abstract

Article history:

Aim: To evaluate the effects of ezetimibe on atherogenic lipoproteins and glucose metabo-

Received 8 March 2012

lism in patients with diabetes and glucose intolerance.

Received in revised form

Methods: Seventy-six patients with diabetes and glucose intolerance were enrolled in this

8 November 2012

study. At baseline and 12 weeks after treatment with ezetimibe 10 mg/day, we measured the

Accepted 20 December 2012

levels of lipid and glucose parameters.

Published on line 28 January 2013

Results: Ezetimibe reduced the mean levels of low-density lipoprotein cholesterol (LDL-C)

Keywords:

( 19%, P < 0.001), apolipoprotein B-48 ( 2%, P < 0.01), malondialdehyde modified-LDL

( 20%, P < 0.001), remnant-like particle cholesterol ( 22%, P < 0.001), small dense-LDL Diabetes mellitus

( 15%, P < 0.001), and serum immunoreactive insulin (IRI) ( 4%, P < 0.01). In the insulin

Ezetimibe

resistance subgroup, ezetimibe reduced the abdominal circumference ( 1%, P < 0.05) and

Insulin resistance

mean levels of fasting plasma glucose ( 7%, P < 0.05), IRI ( 36%, P < 0.01), s-CPR ( 27%,

Lipoprotein

P < 0.01), HOMA-IR ( 39%, P < 0.01) and HbA1c tended to decrease ( 2%, P = 0.06). Conclusions: Ezetimibe reduced atherogenic lipoproteins in patients with diabetes and glucose intolerance; besides, it improved glucose metabolism in patients with insulin resistance. # 2012 Elsevier Ireland Ltd. All rights reserved.

1.

Introduction

Patients with diabetes are at a high risk of cardiovascular events [1]. Diabetic patients often have dyslipidemia, in particular elevated triglycerides (TG) and low level of highdensity lipoprotein cholesterol (HDL-C) [2]. Furthermore, low-density lipoprotein cholesterol (LDL-C) level is similar to that in the general population, the LDL particles are smaller and denser [3,4], and the level of remnant-like

particle cholesterol (RLP-C) is increased in these patients [5,6]. We have already reported that ezetimibe decreases the level of RLP-C [7], and another study has shown that ezetimibe decreases that of small dense-LDL (sd-LDL) [8]. Ezetimibe inhibits cholesterol-absorption from the small intestine [9], and it has also shown to improve insulin resistance in an animal model [10]. However, the impact of ezetimibe on atherogenic lipoproteins and glucose metabolism has not been well evaluated in patients with diabetes and glucose intolerance.

* Corresponding author at: Division of Metabolism and Endocrinology, Department of Internal Medicine, Yokohama Sakae Kyosai Hospital, Federation of National Public Service Personnel Mutual Associations, 132 Katsura-cho, Sakae-ku, Yokohama 247-8581, Japan. Tel.: +81 45 891 2171; fax: +81 45 895 8352. E-mail address: [email protected] (T. Tsunoda). 1 The first two authors contributed equally to this work. 0168-8227/$ – see front matter # 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.diabres.2012.12.026

diabetes research and clinical practice 100 (2013) 46–52

In this study, we examined the effects of ezetimibe on atherogenic lipoproteins and glucose metabolism in patients with diabetes and glucose intolerance.

b-cell function (HOMA-b) according to the following formula: HOMA-b = 360  fasting IRI (mU/mL)/[FPG (mg/dL) 63].

3.2.

2.

Subjects

Between December 2009 and September 2010, patients with diabetes and glucose intolerance who were being treated at our hospital were enrolled into this study if they had not achieved the target lipid levels recommended by the Japan Atherosclerosis Society Guidelines [11]. Diabetes and glucose intolerance were defined if patients met one of the following criteria: (1) fasting plasma glucose (FPG) level  110 mg/dL, (2) random plasma glucose level  140 mg/dL, (3) HbA1c  5.8% (JDS), and (4) the patient was under treatment with antidiabetic agents. Exclusion criteria were as follows: (1) HbA1c was 8.0%, (2) being treated with insulin, a-glucosidase inhibitors, or cholestyramine, (3) the patient was under 20 years old, (4) had suffered myocardial or cerebral infarction within the previous 3 months, or (5) the patient had liver or renal failure. All patients were treated with 10 mg/day of ezetimibe for 12 weeks. Medication for diabetes, hypertension, and dyslipidemia was not changed during at least 4 weeks before the start of treatment with ezetimibe. We measured height, body weight, abdominal circumference, blood pressure and laboratory parameters at baseline and at the end of the administration. During the study period, there were no lifestyle changes, the use of anti-dyslipidemic agents was prohibited, and the antidiabetic and anti-hypertensive therapy used at enrollment was continued without modifications of the dose. This study was approved by the ethics committee of our hospital and written informed consent was obtained from each patient enrolled into this study (UMIN ID: 000003165).

3.

Materials and methods

3.1.

Measurements

Blood samples were obtained after an overnight fast. HbA1c was measured by HPLC (Adams Alc HA-8160; Arkray Inc., Kyoto, Japan) and plasma glucose was measured using the glucose oxidation method (chemical reagent and Glucose AUTO, and STAT GA-1160 analyzer; Arkray Inc.). Serum total cholesterol (TC), LDL-C, HDL-C, and TG were measured by standard enzymatic methods (Kyowa Medex, Tokyo, Japan). Serum RLP-C, sd-LDL, malondialdehyde modified-LDL (MDALDL), apolipoprotein B-48 (apo B-48), adiponectin, and highsensitivity C-reactive protein (hs-CRP) were measured by SRL Central Laboratory Testing for Clinical Trials (SRL, Inc., Tokyo). The modified homeostatic model of assessment of insulin resistance (HOMA-IR) was calculated according to the following formula [12]: HOMA-IR = fasting immunoreactive insulin (IRI) (mU/mL)  FPG (mg/dL)/405. We defined insulin resistance as HOMA-IR  2.5. We excluded the patients with an FPG > 140 mg/dL for calculating the HOMA-IR. b-Cell function was calculated using the homeostatic model assessment of

47

Statistical analysis

Statistical analyses were performed using SPSS version 11.0.1 J (SPSS Inc., Armonk, NY). Results are the mean  SD. Differences in continuous variables within each group were compared using the paired t-test when the variable showed a normal distribution, or using the Wilcoxon signed-rank test when it did not. Differences in continuous variables between the 2 groups were compared using the unpaired t-test when the variable showed a normal distribution, or using the Mann– Whitney’s U-test when it did not. Categorical variables were compared between the 2 groups using the chi-square test. The relations between changes in atherogenic lipoproteins and those in several parameters were evaluated using Pearson’s rank correlation when the variable showed a normal distribution, or using Spearman’s rank correlation when it did not. The level of statistical significance was set at P < 0.05.

4.

Results

Baseline characteristics and the effects of ezetimibe on lipid and glucose parameters are shown in Tables 1 and 2. Seventysix subjects were enrolled and 72 patients completed the study protocol. Two patients did not attend hospital for the final evaluation because of abdominal symptoms, one patient had renal cell carcinoma, and another patient suffered from fever of unknown origin. Twenty subjects were treated with antidiabetic agents, 42 with anti-hypertensive agents, and 17 with anti-dyslipidemic agents. No significant changes were observed in body mass index (BMI), abdominal circumference, and blood pressure. Ezetimibe significantly reduced the mean levels of TC (from 221  35 to 192  33 mg/dL, 13%; P < 0.001), LDL-C (from 152  30 to 121  29 mg/dL, 20%; P < 0.001), TG (from 159  100 to 139  70 mg/dL, 13%; P < 0.05), RLP-C (from 8.4  10.2 to 4.8  2.6 mg/dL, 22%; P < 0.001), sd-LDL (from 43.8  16.3 to 34.2  13.1 mg/dL, 19%; P < 0.001), MDALDL (from 141  49 to 114  37 U/L, 15%; P < 0.001), and apo B48 (from 7.3  6.3 to 5.5  4.6 mg/mL, 2%; P < 0.01) at 12 weeks. Neither serum HDL-C nor FPG, HbA1c, serum C-peptide immunoreactivity (s-CPR), or adiponectin changed after treatment with ezetimibe, while serum IRI decreased significantly (from 9  10 to 7  4 mU/mL, 4%; P < 0.01). The correlations between changes in atherogenic lipoproteins and those in biochemical parameters are shown in Table 3. The change in RLP-C was strongly correlated with that in TG (r = 0.83, P < 0.001) and showed a moderate correlation with the change in apo B-48 (r = 0.46, P < 0.001). The changes in sd-LDL and MDA-LDL correlated with the change in LDL-C (r = 0.76, P < 0.001; r = 0.41, P < 0.001; respectively). In particular, the changes in RLP-C and apo B-48 were weak, but significantly correlated with those in HbA1c (r = 0.26, P < 0.05; r = 0.39, P < 0.01; respectively), IRI (r = 0.28, P < 0.05; r = 0.39, P < 0.01; respectively), s-CPR (r = 0.26, P < 0.05; r = 0.43, P < 0.001; respectively), and HOMA-IR (r = 0.29, P < 0.05, each other). When we compared the patients with and without hyperTG (TG  150 mg/dL versus TG < 150 mg/dL), the mean percent

48

diabetes research and clinical practice 100 (2013) 46–52

Table 1 – Baseline characteristics and effects of ezetimibe on lipid and glucose parameters.

Age (years) Gender (male/female) Height (cm) Body weight (kg) BMI (kg/m2) Abdominal circumference (cm) Medications Anti-diabetes (%) Sulfonylureas (%) Biguanides (%) Thiazolidines (%) DPP-IV inhibitors (%) Anti-hypertension (%) ARBs (%) CCBs (%) Diuretics (%) b-Blockers (%) Anti-dyslipidemia (%) Statins (%) Fibrates (%) Ethyl icosapentate (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) TC (mg/dL) % change (%) LDL-C (mg/dL) % change (%) HDL-C (mg/dL) % change (%) LDL-C/HDL-C % change (%) TG (mg/dL) % change (%) Non-HDL-C (mg/dL) % change (%) RLP-C (mg/dL) % change (%) Sd-LDL (mg/dL) % change (%) MDA-LDL (U/L) % change (%) ApoB-48 (mg/mL) % change (%) HbA1c (%) % change (%) FPG (mg/dL) % change (%) IRI (mU/mL) % change (%) s-CPR (ng/mL) % change (%) HOMA-IR % change HOMA-b (%) % change (%) Adiponectin (mg/mL) Hs-CRP (ng/mL)

Baseline

12 weeks

P value

67  10 45/27 161  9 63.9  11.0 24.4  3.0 90.5  7.9

63.7  11.1 24.3  3.1 90.2  7.6

NS NS NS

134  23 78  11 192  33 13  11 121  29 20  15 59  14 2  13 2.2  0.7 21  15 139  70 13  41 133  28 18  13 4.8  2.6 22  41 34.2  13.1 19  26 114  37 15  27 5.5  4.6 2  88 6.1  0.4 04 111  16 2  12 74 4  44 1.99  0.85 2  34 1.8  1.2 0  50 1.2  0.9 1  48 10.1  5.8 1689  3381

NS NS <0.001

20 (28) 4 (6) 13 (18) 7 (10) 2 (3) 42 (58) 23 (32) 26 (36) 4 (6) 14 (19) 17 (24) 14 (19) 2 (3) 1 (1) 139  24 79  13 221  35 152  30 58  14 2.8  0.8 159  100 163  30 8.4  10.2 43.8  16.3 141  49 7.3  6.3 6.1  0.4 114  17 9  10 2.36  1.54 2.4  2.8 1.6  1.6 10.1  6.3 1124  1297

<0.001 NS <0.001 <0.05 <0.001 <0.001 <0.001 <0.001 <0.01 NS NS <0.01 NS NS NS NS NS

Data are expressed as the mean  SD or number (%). BMI, body mass index; DPP-IV, dipeptidyl peptidase-IV; ARBs, angiotensin II receptor blockers; CCBs, calcium channel blockers; TC, total cholesterol; TG, triglycerides; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; RLP-C, remnant-like particle cholesterol; sd-LDL, small dense-LDL; MDA-LDL, malondialdehyde modified-LDL; apoB-48, apolipoprotein B-48; FPG, fasting plasma glucose; IRI, immunoreactive insulin; s-CPR, serum C-peptide immunoreactivity; HOMA-IR, homeostatic model of assessment of insulin resistance; HOMA-b, homeostatic model assessment of b-cell function; hs-CRP, high-sensitivity C-reactive protein.

diabetes research and clinical practice 100 (2013) 46–52

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Table 2 – Baseline characteristics and effects of ezetimibe on lipid and glucose parameters in patients not receiving anti-diabetic and anti-dyslipidemic medications.

Age (years) Gender (male/female) Height (cm) Body weight (kg) BMI (kg/m2) Abdominal circumference (cm) Medications Anti-hypertension (%) ARBs (%) CCBs (%) Diuretics (%) b-Blockers (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) TC (mg/dL) % change (%) LDL-C (mg/dL) % change (%) HDL-C (mg/dL) % change (%) LDL-C/HDL-C % change (%) TG (mg/dL) % change (%) Non-HDL-C (mg/dL) % change (%) RLP-C (mg/dL) % change (%) Sd-LDL (mg/dL) % change (%) MDA-LDL (U/L) % change (%) ApoB-48 (mg/mL) % change (%) HbA1c (%) % change (%) FPG (mg/dL) % change (%) IRI (mU/mL) % change (%) s-CPR (ng/mL) % change (%) HOMA-IR % change (%) HOMA-b % change (%) Adiponectin (mg/mL) Hs-CRP (ng/mL)

Baseline

12 weeks

P value

67  10 26/14 162  10 63.7  11.9 24.1  3.2 89.1  8.3

63.3  11.9 24.0  3.3 88.8  7.7

P < 0.05 P < 0.05 NS

22 (55) 14 (35) 15 (38) 4 (10) 9 (23) 139  24

130  22

P < 0.05

81  14

77  10

P < 0.05

230  33

200  33 12  11 129  27 20  14 60  13 3  15 2.2  0.7 21  13 136  61 5  26 140  26 18  13 4.9  2.7 28  26 37.6  14.4 18  21 117  37 18  27 5.0  3.5 5  60 6.1  0.4 03 111  16 0  11 63 3  45 1.87  0.81 3  31 1.6  0.9 0  48 47  27 1  49 10.9  5.7 1619  3739

P < 0.001

161  28 59  14 2.9  0.8 155  86 170  28 9.4  12.4 46.9  17.0 150  49 7.1  6.8 6.1  0.4 112  15 9  10 2.22  1.52 2.2  3.1 64  62 10.9  6.2 1072  1196

P < 0.001 NS P < 0.001 NS P < 0.001

Fig. 1 – Mean percent changes in triglycerides (TG), lowdensity lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), small dense-LDL (sdLDL), and remnant-like particle cholesterol (RLP-C) after 12 weeks of treatment with ezetimibe. There were significant differences in mean percent changes of TG, LDL-C, nonHDL-C and sd-LDL between the subgroups with and without hyper-TG.

P < 0.05 P < 0.001

P < 0.05

We distributed the patients into those with a HOMA-IR value of 2.5 (insulin resistance) and those with a value of <2.5 (non-insulin resistance). The effects of ezetimibe on lipid and glucose metabolism in these two subgroups are shown in Table 4. In the insulin resistance subgroup, ezetimibe significantly reduced the mean abdominal circumference (from 95.3  7.8 to 94.3  7.5 cm; P < 0.05), FPG (from 118  16 to 109  11 mg/dL; P < 0.05), IRI (from 18  12 to 10  6 mU/mL; P < 0.01), and HOMA-IR (from 5.3  3.9 to 2.7  1.5; P < 0.01); besides HbA1c tended to decrease (from 6.2  0.4 to 6.1  0.4%; P = 0.06). There were significant differences in the mean percent changes of FPG ( 7% vs. 1%, P < 0.05), IRI ( 36% vs. 15%, P < 0.001), and HOMA-IR ( 39% vs. 17%, P < 0.001) between the two subgroups.

NS NS

5.

P < 0.001 P < 0.05 NS NS P < 0.05 P < 0.05 NS

Data are expressed as the mean  SD or number (%). Abbreviations see in Table 1.

changes in TG ( 16% vs. 9%; P < 0.001), LDL-C ( 24% vs. 17%; P < 0.05), non-HDL-C ( 22% vs. 14%; P < 0.05), and sd-LDL 13%; P < 0.01) in the hyper-TG group were ( 30% vs. significantly higher than those in the group without hyperTG; and the mean percent change in RLP-C ( 31% vs. 15%; P = 0.13) tended to be higher in the hyper-TG group (Fig. 1).

Discussion

The main findings of this study were that ezetimibe reduced not only LDL-C but also atherogenic lipoproteins such as sdLDL, RLP-C, and MDA-LDL in patients with diabetes and glucose intolerance; that the mean percent changes in TG, LDL-C, non-HDL-C, and sd-LDL in the hyper-TG group were significantly higher than those in the group without hyper-TG; and that ezetimibe improved glucose metabolism in patients with insulin resistance. Cholesterol in food and bile is absorbed by Niemann–Pick C1 like 1 (NPC1L1) protein in the small intestine and becomes

50

diabetes research and clinical practice 100 (2013) 46–52

Table 3 – Correlations between percent changes in atherogenic lipoproteins and those in biochemical parameters. % change in RLP-C r TC TG HDL-C LDL-C Non-HDL RLP-C Sd-LDL MDA-LDL Apo B-48 Hs-CRP Adiponectin FPG HbA1c IRI s-CPR HOMA-IR HOMA-B

0.14 0.83 0.00 0.00 0.16 – 0.36 0.43 0.46 0.18 0.10 0.13 0.26 0.28 0.26 0.29 0.31

P value NS <0.001 NS NS NS – <0.05 NS <0.001 NS NS NS <0.05 <0.05 <0.05 <0.05 <0.05

b

% change in Sd-LDL P value

0.67

<0.001

0.09

NS

0.26

<0.05

0.00 0.88 0.12 0.95 0.12

NS NS NS NS NS

r 0.79 0.35 0.39 0.76 0.77 0.36 – 0.42 0.20 0.17 0.21 0.11 0.04 0.17 0.12 0.22 0.05

% change in MDA-LDL r TC TG HDL-C LDL-C Non-HDL RLP-C Sd-LDL MDA-LDL Apo B-48 Hs-CRP Adiponectin FPG HbA1c IRI s-CPR HOMA-IR HOMA-B

0.40 0.03 0.19 0.41 0.39 0.04 0.42 – 0.07 0.13 0.03 0.08 0.16 0.04 0.01 0.06 0.05

P value

b

P value

<0.001 <0.01 <0.01 <0.001 <0.001 <0.01 – <0.001 NS NS NS NS NS NS NS NS NS

0.42 0.22 0.09 0.74 0.47 0.19 – 0.11

NS NS NS <0.01 NS NS – NS

% change in apo B-48

P value

b

P value

<0.001 NS NS <0.001 <0.01 NS <0.001 – NS NS NS NS NS NS NS NS NS

0.10

NS

0.21 0.10

NS NS

0.25

NS

r 0.19 0.66 0.13 0.29 0.14 0.67 0.05 0.14 – 0.02 0.22 0.08 0.39 0.39 0.43 0.29 0.50

P value NS <0.001 NS <0.05 NS <0.001 NS NS – NS NS NS <0.01 <0.01 <0.001 <0.05 <0.001

b

P value

0.31

0.050

0.25

<0.01

0.30

0.052

0.16 0.19 0.33 0.01 0.18

NS NS <0.05 NS NS

Abbreviations see in Table 1.

chylomicrons [9]. RLP-C and apo B-48 were significantly decreased by ezetimibe and the changes strongly correlated with each other. Sandoval et al. reported that ezetimibe downregulated mRNA expression of apo B-48 and fatty acid transporters in the small intestine, and decreased the level of circulating chylomicrons [13]. Thus, the decrease in RLP-C may be explained by a reduction of chylomicrons. In addition, changes in apo B-48 and RLP-C positively correlated with those in HbA1c, FPG, IRI, and HOMA-IR. These findings suggested that glucose metabolism may improve if the level of chylomicrons decreases. Hydrolysis of chylomicrons results in increasing levels of chylomicron remnants and free fatty acids (FFA), and in turn, the increase in FFA causes insulin resistance in the liver and muscle [14] which further increases the level of FFA [15]. Furthermore, Bajaj et al. reported that a decrease in FFA correlated with the improvement of insulin resistance [16]. Previous studies reported that ezetimibe reduced FFA in animal models and in humans [13,17]. The reduction of FFA and chylomicrons by ezetimibe [13] may lead to an improvement of insulin resistance.

Insulin resistance is known to lead to a fatty liver [18], which is also caused by oxidant stress [19]. NPC1L1 protein is expressed in the small intestine and liver [9]. Ezetimibe reduces cholesterol by inhibiting the expression of NPC1L1 in the liver and in the small intestine [20]. It seems possible that these effects of ezetimibe alleviate hepatic steatosis leading to an improvement of insulin resistance [10]. Nomura et al. reported that ezetimibe improved insulin sensitivity in steatotic hepatocytes in vitro by reducing the generation of hepatic reactive oxygen species, c-jun N-terminal kinase activation and endoplasmic reticulum stress [21]. Muraoka et al. reported that ezetimibe up-regulated hepatic sterol regulatory element-binding protein (SREBP)-2 and downregulated hepatic SREBP-1 resulting in an improvement of hepatic insulin resistance [22]. Ezetimibe significantly decreased IRI, FPG, and HOMA-IR, in the insulin resistance subgroup, and also lowered somewhat the level of HbA1c in this subgroup. Improvement of insulin resistance in the liver is another reason for the improvement of glucose metabolism by ezetimibe. Interestingly, a significant reduction of the

51

diabetes research and clinical practice 100 (2013) 46–52

Table 4 – Effects of ezetimibe on lipid and glucose metabolism in patients with and without insulin resistance. HOMA-IR  2.5 (n = 18) Baseline Gender (M/F) BMI (kg/m2) AC (cm) % change (%) TC (mg/dL) % change (%) LDL-C (mg/dL) % change (%) HDL-C (mg/dL) % change (%) TG (mg/dL) % change (%) non-HDL-C (mg/dL) % change (%) RLP-C (mg/dL) % change (%) Sd-LDL (mg/dL) % change (%) Apo-B48 (mg/mL) % change (%) MDA-LDL (U/L) % change (%) HbA1c (%) % change (%) FPG (mg/dL) % change (%) IRI (mU/mL) % change (%) s-CPR (ng/dL) % change (%) HOMA-IR % change (%) HOMA-b % change (%)

12/6 26.5  3.3 95.3  7.8 220  37 152  28 53  15 199  115 167  32 10.5  9.5 47  17 8.3  4.6 145  52 6.2  0.4 118  16 18  12 3.7  1.3 5.3  3.9 121  70

HOMA-IR < 2.5 (n = 42)

12 weeks

P value

Baseline

26.4  3.3 94.3  7.5 12 189  31 13  10 122  27 19  13 52  15 09 161  59 8  31 137  25 13  10 5.1  2.2 32  30 34  14 25  18 5.5  4.1 27  48 109  32 19  27 6.1  0.4 24 109  11 7  11 10  6 36  26 2.6  1.0 27  25 2.7  1.5 39  28 89  75 24  33

NS <0.05

25/17 23.6  2.5 88.7  7.2

<0.001

226  32

<0.001

157  28

NS

61  12

NS

139  88

<0.001

165  28

<0.05

7.4  11.0

<0.001

43  14

<0.05

6.4  7.1

<0.01

148  47

0.06

6.1  0.4

<0.05

108  13

<0.01

52

<0.01

1.6  0.9

<0.01

1.2  0.4

<0.05

42  28

Inter group P value

12 weeks

P value

Baseline

23.6  2.6 88.6  7.0 03 197  33 13  9 125  29 20  14 62  12 1  10 129  75 1  44 136  29 18  13 4.7  2.9 16  45 34  12 19  24 5.5  5.1 14  102 119  41 17  24 6.1  0.4 14 108  14 1  10 52 15  42 1.7  0.7 12  30 1.4  0.7 17  48 43  19 17  48

NS NS

NS <0.001 <0.01

<0.001

NS

<0.001

NS

NS

<0.05

NS

<0.05

<0.001

NS

<0.001

<0.05

<0.001

NS

NS

<0.05

<0.001

NS

NS

NS

NS

NS

NS

<0.001

NS

<0.001

NS

<0.001

NS

<0.001

12 weeks <0.05 <0.01 NS NS NS NS NS <0.05 NS <0.05 NS NS NS NS NS NS NS NS <0.05 NS NS NS <0.05 NS <0.05 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

Data are expressed as the mean  SD or number. AC, abdominal circumference. Other abbreviations see in Table 1.

abdominal circumference was observed only in the insulin resistance subgroup. Park et al. reported that ezetimibe reduced visceral fat area in Japanese patients with insulin resistance [23]. In this study, the reduction of abdominal circumference in the insulin resistance subgroup may have been due to a reduction of the amount of visceral fat. Although statins are widely used in primary and secondary prevention of cardiovascular events, these agents involve the risk of developing diabetes according to the results of randomized placebo-controlled trials [24,25] and a metaanalysis [26]. Thus, ezetimibe may be an option to treat dyslipidemia in patients with diabetes or glucose intolerance. Increases in sd-LDL and MDA-LDL are risk factors for cardiovascular events [2,27]. Sd-LDL is likely to be oxidized [28] and MDA-LDL is the main oxidized LDL modified by malondialdehyde [29]. In this study ezetimibe reduced both sdLDL and MDA-LDL levels and the changes correlated positively with the change in LDL-C. The reduction of sd-LDL and MDALDL may result in the reduction of LDL. There are several limitations in this study. First, we evaluated a small number of patients and did not compare them with a placebo-controlled group. Thus, there may be some bias in this study. Second, we did not measure serum

FFA level and did not evaluate fatty liver using an imaging modality or liver biopsy. We could not ascertain whether ezetimibe reduced the level of FFA or that the reduction of FFA resulted in an improvement of fatty liver. Finally, we did not perform a glucose tolerance test in all patients. In conclusion, ezetimibe reduced not only LDL-C but also atherogenic lipoproteins such as RLP-C, sd-LDL and MDA-LDL in patients with diabetes and glucose intolerance, suggesting it might reduce the risk of cardiovascular events. Furthermore, ezetimibe improved glucose metabolism in patients with insulin resistance.

Conflict of interest There are no conflicts of interest.

references

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