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The effect of ezetimibe monotheraphy on mean platelet volume in patients with hyperlipidaemia: a retrospective study of 45 patients.

Byline: Yasar Sertbas, Meltem Sertbas, Ugur Ersoy, Bulent Bilir, Seracettin Gunaydin and Ali Ozdemir

Abstract

Objective: To investigate the effect of ezetimibe on platelet functions as a drug which increases mevalonate levels.

Methods: This retrospective study was conducted in Istanbul, Turkey, and comprised record of normolipidaemic and hyperlipidaemic patients taken from the outpatient clinic from October 2004 to February 2015,. The results were taken from the baseline and third-month data of ezetimibe treatment. SPSS 22 was used for statistical analysis.

Results: Of the total, there were 50(53%) normolipidaemic patients and 45(47%) hyperlipidaemic ones. Pre- and post-treatment values of mean platelet volume were significantly higher in the hyperlipidaemic group than controls (p0.05).

Conclusion: The use of ezetimibe alone should not be the first choice in hyperlipidaemia treatment.

Keywords: Ezetimibe, Mean platelet volume, Platelet activation. (JPMA 66: 1559; 2016)

Introduction

Hyperlipidaemia is an important risk factor for the cardiovascular diseases (CVD).1,2 Ezetimibe is a lipid-lowering drug, which acts by inhibiting the absorption of cholesterol from the jejunum.3 In many studies showing the pleitrophic effects of statins, another lipid-lowering drug, ezetimibe have been used as a placebo to decrease the serum cholesterol levels. In these studies ezetimibe decreased the low-density lipoprotein (LDL) levels, but unlike statins it also increased the mevalonate levels.4,5 Although statins have some pleitrophic effects, such as improvement of endothelial function, an increase in nitric oxide (NO) levels, anti-oxidant and anti-thrombotic functions, ezetimibe is not known to have any pleitrophic effect.6-9

Platelet activity plays a role in the development and progression of atherosclerosis, and reduction of platelet activity is another pleitrophic effect of statins.10,11 There are many methods to show the platelet activation but they are expensive and time-consuming with the requirement of special experience.12-14 Mean platelet volume (MPV) is a simple marker for the platelet activity that is determined with routine automated haemograms as a part of the whole blood count (WBC).15 The current study was planned to investigate the effect of ezetimibe on platelet activity as a drug which increases mevalonate levels.

Patients and Methods

This retrospective study was conducted in Istanbul, Turkey, and comprised data of hyperlipidaemic patients from October 2004 to February 2015 that was compared with gender- and age-matched normolipidemic subjects. Data was collected from the internal medicine outpatient clinical records of Fatih Sultan Mehmet Education and Research Hospital. Patients who had been treated only with ezetimibe were included. Moreover, as we usually control the lipid parameters at the third month of treatment for the hyperlipidaemic patients, we preferred to include patients examined in outpatient clinics for at least 3 months period with full laboratory parameters of lipid profiles and whole blood counts.

Patients who had any infection, thrombotic or haematologic disorders, any medication effecting platelet function, haemoglobin (Hb) < 12.5 g/dl in men and <11.5 g/dl in women were excluded. Lipid parameters and MPV values at baseline and 3 months after ezetimibe treatment were used for statistical analysis. Approval for this study was obtained from the ethical committee of the Fatih Sultan Mehmet Education and Research Hospital.

SPSS 22 was used for statistical analysis. Data was expressed as mean standard deviation (SD). One-sample Kolmogorov-Smirnov test was performed to assess the distribution of data. Numerical variables in different subjects were compared by t-test or Mann-Whitney U test. Variables calculated before and after the treatment were compared by paired t-test or Wilcoxon test. Bivariate correlation analyses were made by Pearson's correlation test. Probability values were two-tailed, and a p0.005). There was no statistically significant difference for age in hyperlipidaemic patients and the controls (53.40 9.35 vs. 49.44 10.07 years; p>0.05). LDL cholesterol levels were significantly higher in the hyperlipidaemic group than the controls (190.16+-39.91 vs.116.46+-26.43 mg/d;, p<0.001). Among the cases, the mean LDL cholesterol level decreased from 190.16+-39.91 before ezetimibe treatment to 148.21+-30.10 mg/dL after the treatment (p<0.001), whereas the mean total cholesterol levels fell from 271.28+-48.83 to 219.26 36.18 mg/dL (p<0.001).

Among controls, the mean LDL was 116.46+-26.43 while total cholesterol was 190.58+-34.6 mg/dL, both before and after the treatment (Table-1)

Table-1: Baseline and post-treatment cholesterol values of case and control groups.

###Case group###Control group###P value

Tot.chol.before treatment###271.28+-48.83###190.58+-34.6###<0.001

Tot.chol.after treatment###219.26 36.18###190.58+-34.6###<0.001

p value btw. case groups###<0.001

HDL chol.before treatment###48.80+-14.74###44.70+-10.91###0.178

HDL chol. after treatment###44.33+-13.15###44.70+-10.91###0.883

p value btw. case groups###0.013

Triglyceride before treatment###148.00+-64.68###145.60+-65.35###0.884

Triglyceride after treatment###132.32+-53.49###145.60+-65.35###0.292

p value btw. case groups###0.841

LDL chol.before treatment###190.16+-39.91###116.46+-26.43###<0.001

LDL chol. after treatment###148.21+-30.10###116.46+-26.23###<0.001

p value btw. case groups###<0.001

Although there was no significant difference between WBC, haemoglobin and platelet levels, the MPV values were significantly higher in the hyperlipidaemic patients than the controls (8.96+-0.93 and 7.56+-0.69 pre-treatment and 8.92+-0.84 and 7.56+-0.69 post-treatment; p 0.05) (Table-2)

Table-2: Baseline and post-treatment haematological values of case and control groups.

###Case group###Control group###P value

WBC before treatment###6957.55+-1553.24###7055.60+-1354.84###0.740

WBC after treatment###6298.19 2510.88###7055.60+-1354.84###0.07

p value btw. case groups###0.095

Hb. before treatment###14.27+-1.30###13.95+-0.72###0.141

Hb.after treatment###14.02+-1.28###13.95+-0.72###0.748

p value btw. case groups###0.168

Plt. before treatment###277.68+-71.06###256.08+-52.91###0.096

Plt. after treatment###261.73+-68.61###256.08+-52.91###0.658

p value btw. case groups###0.017

MPV before treatment###8.96+-0.93###7.56+-0.69###<0.001

MPV after treatment###8.92+-0.84###7.56+-0.69###<0.001

p value btw. case groups###0.616

Discussion

The results of this study show that ezetimibe treatment does not affect the platelet activity, which plays an important role in development and progression of atherosclerosis.

Besides their lipid lowering effects, statins being major anti-hyerlipidaemic agents have some pleitrophic effects, such as improving endothelial function, decreasing oxidative stress and inflammation, improving the stability of atherosclerotic plaques, and decreasing thrombotic activity. Pleitrophic effects of ezetimibe, if any, are not as prominent as statins. Grioge et al. and Maki-Petaja et al. reported that both statins and ezetimibe themselves improve endothelial functions.6,16 Another study has shown that neither ezetimibe alone nor ezetimibe /simvastatin combination has any effect on endothelial function while high-dose atorvastatin improves these functions.17

Superoxide dismutase and high-sensitivity C-reactive protein (hs-CRP) are the commonly used inflammatory markers among these studies. For inflammatory markers, studies have shown contradictory results for both ezetimibe and statins. In some of these studies, both simvastatin and ezetimibe decreased the CRP levels.16,18 Landmesser et al.reported that ezetimibe had no effect on flow dependent dilatation and superoxide dismutases, while simvastatin treatment improved endothelial function and increased superoxide dismutase activity.19 Sager et al. demonstrated that ezetimibe co-administration with simvastatin provides incremental decreases in hs-CRP, compared with simvastatin monotheraphy.20 Piorkowski et al. reportedthat statins were more effective in decreasing platelet functions than ezetimibe.

Most pleiotropic effects of statins are thought to be related to inhibition of the mevalonate-dependent isoprenylation of small guanosine triphosphate (GTP)-binding proteins, such as Rho, Ras, and Rac 1. The inhibition of RhoA and Rac 1 may cause a decrease of plasminogen activator inhibitor-1 (PAI-1), endothelin-1 (ET-1), oxidative stress and vascular smooth muscle proliferation with an increase of endothelial nitric oxide synthase (eNOS) and tissue plasminogen activator (t-PA).21

The opposite effect on the mevalonate of statins and ezetimibe may be a mechanism behind different pleitrophic effects. Hyperlipidaemia, particularly high LDL-cholesterol, is an important risk factor in atherogenesis. In our study, although ezetimibe treatment provided a 20% decrease in LDL cholesterol levels, post-treatment LDL-cholesterol levels were significantly higher than the controls. This insufficient reduction of LDL-cholesterol with ezetimibe treatment may be another mechanism behind no altered platelet activity. There is a need to verify these results with prospective, randomised, large-scale studies.

Conclusion

In order to provide a beneficial effect on platelet activity during hyperlipidaemia treatment, the use of ezetimibe alone should not be the first choice of treatment. If there is low or no risk of myopathy, it may be better to use high doses of statins or combination treatment, suhc as ezetimibe plus statins.

Disclaimer: None.

Conflict of Interest: None.

Source of Funding: None.

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Publication:Journal of Pakistan Medical Association
Date:Dec 31, 2016
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