Elsevier

Atherosclerosis

Volume 217, Issue 2, August 2011, Pages 486-491
Atherosclerosis

Ezetimibe improves postprandial hyperlipemia and its induced endothelial dysfunction

https://doi.org/10.1016/j.atherosclerosis.2011.04.019Get rights and content

Abstract

Objective

Postprandial hyperlipemia has been shown to impair endothelial function and contribute to the development of atherosclerosis. We investigated the association between postprandial lipid profiles and endothelial function, and we examined the effects of ezetimibe on postprandial hyperlipemia and lipemia-induced endothelial dysfunction.

Methods

A randomized prospective trial in which 10 mg/day of ezetimibe was administered to 10 subjects for 4 weeks and not administered to 10 subjects (control group) was performed. Lipid profiles and endothelial function, assessed by brachial artery flow-mediated dilation (FMD) during a fasting state and at 2, 4, 6 and 8 h after an oral cookie loading test, were determined before and after treatment for 4 weeks.

Results

In all subjects before treatment, the maximum reduction in postprandial %FMD was significantly correlated with the maximum increases in postprandial triglyceride (TG) (r = −0.499, P < 0.05) and apolipoprotein B-48 (apoB-48) concentrations (r = −0.551, P < 0.05). Ezetimibe treatment for 4 weeks significantly suppressed postprandial elevation in TG (area under the incremental curve, from 1419 ± 594 to 968 ± 321 mg h/dl, P < 0.05), remnant lipoprotein cholesterol (from 66.9 ± 27.6 to 38.9 ± 15.4 mg h/dl, P < 0.01) and apoB-48 (from 58.8 ± 27.5 to 36.2 ± 17.0 μg h/ml, P < 0.05) concentrations, and postprandial endothelial dysfunction assessed by %FMD (maximum reduction in %FMD, from −2.6 ± 1.1% to −1.2 ± 0.8%, P < 0.05), whereas no significant changes were observed in the control group.

Conclusion

Postprandial hyperlipemia is closely correlated with transient endothelial dysfunction. Ezetimibe improves postprandial hyperlipemia and its induced endothelial dysfunction.

Introduction

A large number of studies have demonstrated that postprandial hyperlipemia contributes to the development of atherosclerosis and coronary heart disease (CHD) [1], [2], [3]. Postprandial lipemia is a physiological phenomenon occurring several times a day after ingestion of dietary fat when the dietary sources of fat exceeded the actual needs. Disturbances of triglyceride (TG) metabolism also induce prolonged postprandial hyperlipemia. Patients with obesity, diabetes and metabolic syndrome often have postprandial hyperlipemia [4] and exaggerated postprandial hyperlipemia has been observed even in fasting normolipidemic subjects [5]. In such circumstances, TG-rich lipoproteins (TRLs), which consist of chylomicrons assembled by TG, dietary cholesterol and apolipoprotein B-48 (apoB-48), have been shown to induce endothelial dysfunction, an initial process of atherogenesis, through enhanced inflammation and oxidative stress. Norata et al. showed that postprandial TRLs upregulate the expression of pro-inflammatory cytokines, inducing the impairment of brachial artery endothelial function beyond 8 h postprandially in both hyperlipidemic and normolipidemic subjects [6]. Moreover, van Oostrom et al. demonstrated that postprandial lipemia contributes to the recruitment of neutrophils with concomitant production of pro-inflammatory cytokines and oxidative stress, resulting in endothelial dysfunction in healthy normolipidemic subjects [7]. Thus, even in healthy volunteers, postprandial lipemia has been associated with the activation of leukocytes and upregulation of pro-inflammatory cytokines on the endothelium. Actually, several studies have demonstrated that postprandial hyperlipemia caused by oral fat intake induces impairment of flow-mediated dilations (FMD) of the brachial artery in healthy volunteers [8], [9].

Ezetimibe, a novel lipid-lowering drug that selectively inhibits cholesterol absorption by inhibiting Niemann-Pick C1 like 1 (NPC1L1) protein, is commonly used for treatment of dyslipidemia. Recently, a clinical trial by Masuda et al. reported that ezetimibe improves fasting and postprandial hyperlipemia by suppression of intestinal chylomicron production in patients with type IIb hyperlipemia [10]. However, the effect of ezetimibe monotherapy on postprandial hyperlipemia-induced endothelial dysfunction was not fully evaluated.

Accordingly, the aim of the present study was to determine the association between postprandial lipid profiles and endothelial function, and to determine the effects of ezetimibe monotherapy on postprandial hyperlipemia and lipemia-induced endothelial dysfunction.

Section snippets

Study populations

Twenty volunteers, including 17 men and 3 women, were enrolled in this study. The inclusion criteria were aged of 20 years or above and not receiving lipid-lowering medications. Subjects were excluded from the study if they had undergone major surgery within 3 months prior to enrollment or if they had concomitant inflammatory diseases or malignant tumors. A randomized prospective trial in which ezetimibe (10 mg/day) was administered to 10 subjects for 4 weeks (ezetimibe group) and not

Postprandial lipid profiles and endothelial function

Postprandial changes in vital signs, lipid profile and endothelial function before treatment in all 20 subjects are shown in supplementary table (see supplementary data 1). Postprandial serum levels of TG, RLP-C and apoB-48 increased significantly and reached peak levels at the 4th hour (TG: from 115 ± 42 to 240 ± 115 mg/dl; RLP-C: from 5.1 ± 1.8 to 11.7 ± 6.1 mg/dl; apoB-48: from 4.5 ± 2.4 to 9.4 ± 3.8 μg/ml; fasting vs. at 4 h, all P < 0.0001) and returned to baseline at the 8th hour. Postprandial plasma

Discussion

In the present study, postprandial hyperlipemia induced by a conventional oral cookie loading test, a real-life situation of ingestion of dietary fat, was shown to be closely related to transient postprandial endothelial dysfunction. To the best of our knowledge, the present study is the first study showing that ezetimibe monotherapy improves postprandial hyperlipemia-induced endothelial dysfunction.

Methods for measuring apoB-48, a specific marker of intestinal lipoproteins, have recently been

Conclusions

The present study demonstrated that postprandial hyperlipemia is significantly associated with transient endothelial dysfunction and clearly showed that ezetimibe improves postprandial hyperlipemia and lipemia-induced endothelial dysfunction. Measurements of postprandial parameters may be useful and reliable for selecting patients with postprandial metabolic disturbances, and ezetimibe may be a potent agent for improving postprandial hyperlipemia.

Conflict of interest

None.

Acknowledgments

We thank Kaoru Akazawa, Miyuki Fujiwara, and Masayo Ohmori for their excellent technical assistance.

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