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Archives of cardiovascular diseases
Volume 103, n° 1
pages 26-32 (janvier 2010)
Doi : 10.1016/j.acvd.2009.10.003
Received : 4 August 2009 ;  accepted : 16 October 2009
Efficacy of simvastatin or ezetimibe on tissue factor, von Willebrand’s factor and C-reactive protein in patients with hypercholesterolaemia
L’efficacité de simvastatin ou d’ezetimibe sur facteur du tissu, von Willebrand et protéine C-réactive aux malades avec hypercholesterolémie
 

Peggy Kostakou a, Genovefa Kolovou a, , Katherine Anagnostopoulou a, Theodor Theodoridis b, Vassiliki Galea b, Constantinos Mihas c, Vassiliki Christopoulou-Cokkinou b, Dennis V. Cokkinos a
a 1st Cardiology Department, Onassis Cardiac Surgery Centre, 356, Sygrou Ave, 17674 Athens, Greece 
b Haematology Department, Evagelismos Hospital, Athens, Greece 
c Internal Medicine Department, General Hospital of Kimi, Kimi, Greece 

Corresponding author. Fax: +30 210 9493336.
Summary
Background

Statins have favourable effects on lipid profiles, decrease total mortality and have many pleiotropic effects.

Aims

To determine and compare the pleiotropic effects of simvastatin and ezetimibe in dyslipidaemic patients.

Methods

Forty-four patients (20 postmenopausal women) with low-density lipoprotein cholesterol >130mg/dL (or >100mg/dL in patients with coronary artery disease or its equivalent) were treated with simvastatin 10mg daily (n =21) or ezetimibe 10mg daily (n =23). In blood samples taken before and three months after treatment, we measured the concentration of total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein A, apolipoprotein B, lipoprotein(a), homocysteine, tissue factor, von Willebrand’s factor and C-reactive protein.

Results

Baseline lipid profiles and haematological variables were similar in both groups. Simvastatin and ezetimibe decreased the concentrations of total cholesterol (262 to 189mg/dL, p <0.001, and 268 to 220mg/dL, p =0.001, respectively), low-density lipoprotein cholesterol (177 to 114mg/dL, p <0.001 and 196 to 146mg/dL, p <0.001, respectively) and C-reactive protein (1.2 to 0.3mg/dL, p =0.001 and 2.8 to 0.8mg/dL, p =0.005, respectively). Simvastatin also reduced the concentration of apolipoprotein B (125 to 93mg/dL, p <0.001).

Conclusion

Both drugs improved lipid profiles and C-reactive protein concentration. However, no influence was found on tissue factor or von Willebrand’s factor. Our results suggest that C-reactive protein lowering may occur in conjunction with low-density-lipoprotein cholesterol lowering and not through a specific statin pleiotropic anti-inflammatory effect.

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Résumé
Contexte

Les statines ont un effet favorable sur le profil lipidémique, diminuent la mortalité totale et présentent aussi plusieurs actions pléiotropiques. Le but de cette étude était de déterminer et comparer les effets pléiotropiques de simvastatin et d’ezetimibe aux malades dyslipidémiques.

Méthodes

Quarante-quatre malades (20 femmes postmenopausales) avec basse densité lipoprotéine de cholestérol supérieure à 130mg/dL ou basse densité lipoprotéine de cholestérol supérieure à 100mg/dL (personnes avec maladie d’artère coronaire ou ses équivalents), ont été traités avec simvastatin (n =21) ou ezetimibe (n =23), 10mg par jour. Dans tous les échantillons (avant et trois mois après le traitement), on a mesuré les niveaux de cholestérol total, triglycérides, grande densité lipoprotéine de cholestérol, basse densité lipoprotéine de cholestérol, apolipoprotéine A, apolipoprotéine B, lipoprotéine(a), homocystéine, facteur du tissu, von Willebrand et protéine C-réactive.

Résultats

Les prix premiers des lipides et des paramètres hématologiques ont été pareils dans les deux groupes. Simvastatin et ezetimibe ont diminué cholestérol total (262 à 189mg/dL ; p <0,001 et 268 à 220mg/dL ; p =0,001, respectivement), basse densité lipoprotéine de cholestérol (177 à 114mg/dL ; p <0,001 et 196 à 146mg/dL ; p <0,001, respectivement) et protéine C-réactive (1,15 à 0,3mg/dL ; p =0,001 et 2,8 à 0,8mg/dL ; p =0,005, respectivement). En plus, simvastatin a diminué apolipoprotéine B (125 à 93mg/dL ; p <0,001).

Conclusions

Les deux médicaments ont amélioré le profil lipidémique des malades et les niveaux de protéine C-réactive. Pourtant, aucune influence sur facteur du tissu ni sur von Willebrand n’a été trouvé.

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Keywords : Simvastatin, Ezetimibe, Tissue factor, Von Willebrand, C-reactive protein, Lipid

Mots clés : Simvastatin, Ezetimibe, Facteur du tissu, Von Willebrand, Protéine C-réactive, Niveaux des lipides

Abbreviations : CRP, ELIZA, HDL, LDL, TF, vWf


Background

Simvastatin, like all other statins, is an inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA reductase [1] – a key enzyme in the cholesterol-synthesis pathway. Statins have proven to be especially effective in reducing the concentration of low-density lipoprotein (LDL) cholesterol and, to a lesser extent, that of triglycerides [2]. Furthermore, when administered in either primary or secondary prevention of coronary heart disease, statins reduce coronary morbidity and mortality effectively [3]. Until recently, it was believed that the beneficial effects of statins were due solely to their lipid-lowering actions [4, 5, 6, 7, 8]. Several studies [9, 10] have reported that besides their beneficial influence on lipid profiles, statins have additional, or pleiotropic , effects [11]. These studies examined a variety of disorders, and showed various benefits, ranging from an improvement in bone mineral density [12] to a reduction in the incidence of Alzheimer’s disease [13]. Furthermore, the Scandinavian Simvastatin Survival Study [14] and the Heart Protection Study [15] demonstrated that simvastatin therapy improves endothelial function, which is a strong and an independent predictor of cardiovascular events [16].

Ezetimibe is an intestinal cholesterol absorption inhibitor. Actually, in contrast to statins, ezetimibe reduces feeding cholesterol concentration without any effect on the absorption of triglycerides, fat acids, cholic acids and fat-soluble vitamins [17]. Concerning pleiotropic effects, ezetimibe therapy does not improve endothelium-dependent vasodilation, despite the reduction in LDL cholesterol serum concentration [18].

Tissue factor (TF), formerly known as thromboplastin, is a cell surface glycoprotein, synthesized and expressed by a wide variety of cells [19, 20]. Accumulating evidence presents TF as a multifaceted transmembrane signalling receptor involved in the regulation of angiogenesis, tumour growth, metastasis and inflammation [21]. Elevated concentrations of TF are observed in patients with hypertension, diabetes mellitus or dyslipidaemia, in smokers, and in those with acute coronary syndromes [22].

Von Willebrand’s factor (vWf) is a protein that ensures prothrombotic factor VIII binding and transport, and regulates platelet adhesion (to the appropriate receptors), platelet accumulation and thrombus formation [23]. Plasma vWf is increased in patients with major risk factors for atherosclerosis and in documented cardiovascular disease [24, 25].

C-reactive protein (CRP) is a circulating inflammatory marker that promotes thrombosis and may also promote arterial and tissue damage by several mechanisms [26]. CRP may contribute not only to the prognosis of coronary syndromes and acute stroke, but also to the prediction of cardiovascular events in the general population [27].

The objective of the present study was to assess the effect of simvastatin or ezetimibe therapy on the concentration of TF, vWf and CRP, after similar reductions in LDL cholesterol concentration by both drugs.

Methods
Subjects

Forty-four patients with mild hypercholesterolaemia (total cholesterol265mg/dL) were selected to ensure similar reductions in LDL cholesterol concentration after the administration of simvastatin or ezetimibe. All patients were from the Lipid Clinic of the Onassis Cardiac Surgery Centre, Athens, Greece. The centre’s Institutional Review Board approved the study. The diagnosis for mild hypercholesterolaemia was based on the following criteria: total cholesterol >240mg/dL and LDL cholesterol >130mg/dL; or LDL cholesterol >100mg/dL in patients with coronary artery disease or its equivalent; or LDL cholesterol >70mg/dL in patients with coronary artery disease and diabetes mellitus or metabolic syndrome or restenosis or multiple risk factors or who were smokers [28]. Smokers were defined as current or ex-smokers; non-smokers were defined as those who had never smoked. Women were defined as postmenopausal when they reported their last menses to have been at least 12 months earlier; they were not on hormone replacement therapy. Heavy drinking, liver and renal disease, obesity and diabetes mellitus, hypothyroidism and professional sport activity were exclusion criteria.

The subjects were divided into two groups: 23 patients (11 men and 12 postmenopausal women) were treated with ezetimibe 10mg daily while 21 patients (13 men and eight postmenopausal women) were treated with simvastatin 10mg daily. Blood samples were drawn before and 3 months after the treatment. In both samples we measured the concentration of total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, LDL cholesterol, apolipoprotein A, apolipoprotein B, lipoprotein(a), homocysteine, TF, vWf and CRP. Patients were selected randomly and were matched for age, sex, body mass index, lipid profile and haematological variables.

Determination of blood lipids

Plasma total cholesterol, triglycerides and HDL cholesterol concentrations were measured using enzymatic colorimetric methods on a Roche Integra Biochemical analyser, with commercially available kits (Roche Diagnostics Gmbh, Mannheim, Germany). Serum LDL cholesterol concentration was calculated using the Friedewald’s formula [29] in patients with a triglyceride concentration <400mg/dL. Apolipoprotein A, apolipoprotein B and lipoprotein(a) concentrations were measured by nephelometry (Nephelometer: BN-100, Behring, Germany). Blood glucose concentration was measured by the hexokinase method with a Dade Behring reagent on a Dimension instrument (Dade Behring, Liederbach, Germany). Homocysteine concentration was calculated using the Axsym Abbott method, vWf plasma concentration was defined by the congealed method and TF concentration by an enzyme-linked immunosorbent assay (ELIZA), and CRP concentration was measured by immunonephelometry.

Statistical analysis

Post-hoc power analysis showed that the differences found in total cholesterol in both subgroups and the sample size of the study produced a statistical power of 61.02% at a significance level of p <0.05. Owing to the non-normal distribution of continuous variables, non-parametric statistics were used. The aforementioned variables are presented as medians and interquartile ranges, while categorical variables are shown as absolute and relative frequencies (percentages). In order to assess any differences at baseline or after 3 months, the Mann-Whitney statistic was used. Any differences in the distribution of continuous variables between the start and the end of the study were evaluated using the Wilcoxon sign-rank test for both treatment groups. The potential association between categorical variables and treatment was tested using Pearson’s Chi2 statistic. In order to adjust for the inflation of type I error due to the large number of multiple comparisons, we used the Bonferroni correction, setting a new level of p -value, which was considered to be significant if <0.001 for each two-sided test. Data were analysed using STATA™ (Version 9.0, Stata Corporation, College Station, TX, USA).

Results
Baseline characteristics

The clinical and biochemical characteristics of the two groups are shown in Table 1. As expected, given the study design, there were no significant differences between the two patient groups in terms of age, body mass index (calculated as weight divided by height squared and expressed in kg/m2), waist circumference or baseline lipid and haematological variables. There were no significant differences between the two groups in terms of sex, number of smokers or frequency of diabetes mellitus or coronary heart disease.

Changes in lipid, CRP and haematological concentrations after simvastatin treatment

There were significant reductions in the concentrations of total cholesterol, LDL cholesterol, apolipoprotein B and CRP (Table 2). There were no significant differences in the concentrations of lipoprotein(a), homocysteine, vWf or TF after treatment with simvastatin (Table 2).

Changes in lipid, CRP and haematological concentrations after ezetimibe treatment

There were significant reductions in the concentrations of total cholesterol, LDL cholesterol and CRP (Table 3). There were no significant differences in the concentrations of lipoprotein(a), homocysteine, vWf or TF after treatment with ezetimibe (Table 3).

Drug comparison in terms of lipid, CRP and haematological changes

Simvastatin treatment provides greater lipid-lowering efficacy compared with ezetimibe treatment, leading to greater reductions in the concentrations of total cholesterol (28% vs 18% respectively, p =0.001), LDL cholesterol (36% vs 25.5%, respectively, p <0.001) and CRP (74% vs 71%, respectively, p =0.001). After simvastatin administration, but not ezetimibe administration, there was a significant reduction in the concentration of apolipoprotein B (26%, p <0.001; Figure 1).



Figure 1


Figure 1. 

Comparison of the effects of ezetimibe and simvastatin on lipids and C-reactive protein, in terms of percentage change in concentration. apoB: apolipoprotein B, p <0.001; CRP: C-reactive protein, p =0.001; LDL: low-density lipoprotein cholesterol, p <0.001; TC: total cholesterol, p =0.001.

Zoom

Discussion

Both drugs improved lipid profiles, lowering total cholesterol and LDL cholesterol concentrations and improving CRP concentration. Furthermore, simvastatin treatment reduced apolipoprotein B concentration. However, neither drug had an influence on TF or vWf.

CRP may contribute, not only to the prognosis of coronary syndromes and acute stroke, but also to the prediction of cardiovascular events in the general population [27]. This study and others before [30] have demonstrated that both simvastatin and ezetimibe can reduce CRP concentration. Ridker [31] identified the effect of statins on CRP concentration and suggested that it could be used as an indicator to evaluate the effectiveness of statin treatment in patients with elevated LDL cholesterol concentration, and also in those with very high CRP concentration. In particular, the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study [32] suggests that increased high-sensitivity CRP concentration may be useful in making decisions about the initiation of statin therapy for the primary prevention of vascular disease.

The importance of TF is due to its potential role in the coagulation pathway [33]. TF expression abnormalities may lead to the pathogenesis of intravascular thrombosis, and increased TF concentration and activity have been found in atherectomy specimens from patients with unstable angina or myocardial infarction compared with patients with stable angina [34]. In the future, it is possible that an elevated TF concentration may ‘predict’ coronary events in patients with unstable angina [35]. On the other hand, vWf is important not only in haemostasis but also in thrombus formation, especially in small vessels under conditions of high shear stress [36]. Increased vWf concentrations are found in patients with high atheromatosis risk and known cardiovascular disease, and are associated with poor prognosis for these patients [25, 37]. Statin administration reduces TF expression in endothelial and vascular smooth muscle cells [38]. Bea et al. demonstrated that simvastatin inhibits TF expression in advanced atherosclerotic lesions in apolipoprotein E-deficient mice, independently of lipid blood concentrations [39]. Also, there are studies indicating some pleiotropic effects after ezetimibe administration [40, 41]. The fact that the present study did not demonstrate any significant reduction in TF or vWf concentration may be due to the small number of patients, although there have been studies with smaller patient numbers that have shown statins to have pleiotropic effects [19].

One explanation could be that studies indicating statin pleiotropic effects involve patients with coronary heart disease [42]. In our study, only 11% of patients presented with coronary heart disease. Also, it is possible that the mild hypercholesterolaemia that these patients presented with and the mild reduction in LDL cholesterol after drug administration (LDL cholesterol decrease must be >30% [19]) are responsible for the lack of effect on TF and vWf concentrations after drug treatment. On the other hand, it is not possible to give ezetimibe in a dose >10mg/dL, which therefore restricted the simvastatin dose to 10mg/dL. Moreover, the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study [43] demonstrated that the addition of ezetimibe to simvastatin treatment did not improve the pleiotropic effects of ezetimibe. Also, a greater reduction in the vWf concentration was probably not possible in the present study, because vWf fasting concentrations were almost normal [44] in both patient groups.

There are some limitations to this study. One reason for the small number of patients was that the subjects had to be matched in both groups, with similar baseline lipid profiles and haematological variables, which led to a small number of patients being selected. The same problem (relatively small sample size) was an important factor that contributed to the low (61.02%) statistical power of the study, leading to limited conclusions. The methods used for the measurement of haematological variables (vWf plasma concentration was defined by the congealed method, TF by ELIZA) probably influenced the final results. ELIZA has been used for TF measurement in other studies [45, 46], while Chan et al. [47] used sodium dodecyl sulphate polyacrylamide gel electrophoresis for TF determination and Lee et al. [44] used ELIZA for vWf determination. Also, the maximum dose of ezetimibe that can be given is 10mg/dL, which restricted the dose of simvastatin to 10mg/dL to ensure that similar reductions in LDL cholesterol concentration were achieved; this may explain the lack of pleiotropic effects (i.e., changes in TF or vWf concentrations). Although there was not the same reduction in LDL cholesterol concentration in the two groups, both drugs reduced CRP concentration significantly (ezetimibe by 71% and simvastatin by 74%).

Conclusions

The lipid profile of both groups was improved after drug administration, with better results achieved after simvastatin treatment. Both drugs also reduced CRP concentration. However, neither simvastatin nor ezetimibe affected the concentration of TF or vWf. Our results suggest that CRP lowering may occur in conjunction with LDL cholesterol lowering and not through a specific statin pleiotropic anti-inflammatory effect.

Conflict of interest

None.

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