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Comparison of the Effects of Combination Atorvastatin (40 mg) ؉
Ezetimibe (10 mg) Versus Atorvastatin (40 mg) Alone on Secretory
Phospholipase A2 Activity in Patients With Stable Coronary Artery
Disease or Coronary Artery Disease Equivalent
Mireille Azar, MDa, Emmanuel Valentin, PhDb, Georges Badaoui, MDa, Roland Kassab, MDa, Antoine Sarkis, MDa, and Rabih R. Azar, MDa,* Secretory phospholipase A2 (sPLA2) is an enzyme that plays an important role in the
pathogenesis of atherosclerosis and of adverse cardiovascular events. It is currently the
target of emerging therapeutic agents. Our study was designed to investigate the effect of
aggressive lowering of low-density lipoprotein (LDL) cholesterol with ezetimibe and ator-
vastatin on sPLA2 activity. We randomized 100 patients with stable coronary artery disease
(CAD) or CAD equivalent (diabetes, stroke, or peripheral vascular disease) to receive
ezetimibe 10 mg/day in association with atorvastatin 40 mg/day (combination therapy
group) versus atorvastatin 40 mg/day and placebo (monotherapy group). Patients on statin
therapy before inclusion were allowed to enter the study as long as the potency of the statin
was lower than atorvastatin 40 mg/day. Lipid profile, high-sensitivity C-reactive protein
(hs-CRP), and sPLA activity were measured at baseline and after 8 weeks of therapy. The
decrease in LDL cholesterol was more significant in the combination therapy group, but the
decrease in hs-CRP was similar. sPLA2 activity significantly decreased in the ezetimibe/
atorvastatin group from 29 U/ml (interquartile range 23 to 35) to 26 U/ml (23 to 29, p ؍
0.001) but remained similar in the placebo/atorvastatin group (23 U/ml, 19 to 32, vs 22
U/ml, 19 to 28, p ؍ NS). In a multivariate stepwise linear regression model, change in
sPLA2 correlated with change in hs-CRP (p <0.001), baseline LDL cholesterol level (p ؍
0.001), body mass index (p ؍ 0.003), diabetes mellitus (p ؍ 0.04) and combination therapy
with ezetimibe/atorvastatin (p ؍ 0.05). In conclusion, this study demonstrates that coad-
ministration of ezetimibe and atorvastatin decreases sPLA2 activity.
2011 Elsevier Inc.
All rights reserved. (Am J Cardiol 2011;107:1571–1574)
Secretory phospholipase A2 (sPLA2) is an enzyme as- using ezetimibe in coadministration with high-dose atorva- sociated with incident coronary atherosclerosis in healthy statin versus high-dose atorvastatin alone on sPLA2 activity men and women and with recurrent adverse cardiovascular in patients with stable coronary artery disease (CAD) or Ezetimibe is a cholesterol absorption inhibitor that is fre-quently added to statins in patients with lower than optimal levels of low-density lipoprotein (LDL) cholesterol. Al-though ezetimibe is very effective in providing additional This was a prospective, randomized, double-blind, pla- lowering of LDL cholesterol when coadministered with cebo-controlled trial. The objective was to investigate the statins, the effects of ezetimibe/statin coadministration “be- effect of ezetimibe 10 mg/day coadministered with atorva- yond” LDL lowering such as the effect on sPLA2 remain statin 40 mg/day on sPLA2 activity compared to coadmin- unknown. Given the more potent LDL decrease obtained istration of placebo and atorvastatin 40 mg/day in patients with coadministration of statins and ezetimibe, it is likely with CAD or CAD equivalent. The protocol was approved that this regimen will result in better lowering of athero- by the Hotel Dieu de France Hospital ethics committee and genic markers such as sPLA2. Our study was designed to written informed consent was obtained from all patients.
test the effect of a very aggressive LDL-lowering approach Patients were included in the study if they had stable CAD or CAD equivalent. Stable CAD was defined by his-tory of myocardial infarction, history of coronary revascu-larization, or documented coronary artery stenosis Ն50% aDivision of Cardiology, Hotel Dieu de France Hospital and Saint on coronary angiogram. CAD equivalent was defined by Joseph University School of Medicine, Beirut, Lebanon; bAterovax, Paris, presence of diabetes mellitus requiring medications, history France. Manuscript received November 7, 2010; revised manuscript re- of ischemic stroke, or history of peripheral vascular disease.
ceived and accepted January 20, 2011.
Lipid levels were not entry criteria. Patients who were This work was supported by a research grant to Dr. R. Azar from receiving statins were allowed to enter the study as long as *Corresponding author: Tel: 00961-3-590-999; fax: 00961-4-917-775.
the potency of the statin used was atorvastatin Յ20 mg/day.
This meant that patients who were statin naive or patients 0002-9149/11/$ – see front matter 2011 Elsevier Inc. All rights reserved.
The American Journal of Cardiology (www.ajconline.org) Values of lipid parameters, high-sensitivity C-reactive protein, andsecretory phospholipase A2 at baseline and at end of therapy None of the differences is statistically significant between the 2 groups.
Note that the number of inclusion criteria is Ͼ100% because each patient may have Ͼ1 criterion that defines coronary artery disease.
Baseline demographics, clinical characteristics, and concomitant Data are summarized as mean Ϯ SD or median (interquartile range).
Patients were initially seen in the fasting state for mea- surement of total cholesterol, LDL cholesterol, very LDL cholesterol, high-density lipoprotein cholesterol, sPLA2 ac- tivity, high-sensitivity C-reactive protein (hs-CRP), and cre- * Low-density lipoprotein cholesterol Ն130 mg/dl before initiation of atine phosphokinase and aspartate aminotransferase. Pa- tients were then equally randomized to receive atorvastatin † Blood pressure Ն140/90 mm Hg before initiation of antihypertensive 40 mg/day plus ezetimibe 10 mg/day (combination therapy group) or atorvastatin 40 mg/day plus placebo (mono- p ϭ 0.023; p ϭ NS for all other comparisons between the 2 groups.
therapy group). Patients who were receiving statin therapybefore randomization had their initial statin stopped andreplaced by atorvastatin 40 mg/day, as mentioned previ- who were taking atorvastatin 10 to 20 mg/day, simvastatin ously. Duration of treatment was 8 weeks, at the end of 10 to 40 mg/day, pravastatin 10 to 40 mg/day, or fluvastatin which patients had the same blood tests performed.
80 mg/day could be enrolled in the study. All patients Serum sPLA2 activity was measured using a new fluo- receiving atorvastatin Ն40 mg/day and those receiving any rimetric method (Aterovax, Paris, France) on serum samples dose of rosuvastatin were excluded. Also excluded were that were stored at Ϫ80°C and that were thawed only 1 patients Ͼ80 years of age, those who received ezetimibe or time. All samples were tested in duplicate and serum activ- niacin or fibrate within the previous 3 months, patients with ity was expressed as units per milliliter. The minimum a history of acute coronary syndromes or coronary revas- detectable activity was 10 U/ml and the intra- and interassay cularization within the previous 3 months, patients with an coefficients of variation were Ͻ13%.
ejection fraction Ͻ35% or history of severe heart failure For statistical analysis, categorical variables were ex- (New York Heart Association class ϾII), and patients with pressed as absolute values and percentages and were com- a creatinine clearance Ͻ30 ml/min or creatine phosphoki- pared using chi-square test. Continuous variables were rep- nase or aspartate aminotransferase Ͼ2 times the upper nor- resented as mean Ϯ SD. Hs-CRP and sPLA2 were not normally distributed and were expressed as median and Coronary Artery Disease/Effect of Ezetimibe/Atorvastatin on sPLA2 interquartile ranges. Pre- and post-treatment levels of these markers were compared in each group using nonparametric Variables independently associated with change in secretory Wilcoxon signed-rank test and were compared between the phospholipase A2 in linear regression model 2 groups using nonparametric Mann–Whitney test. Corre- lations between changes in marker levels were performed using Pearson correlation. A forward stepwise linear regres- sion model was used to test the correlation of change in sPLA2 with baseline clinical and biological variables. All tests were 2-tailed and p values Յ0.05 were considered statistically significant. SPSS 15.0 (SPSS, Inc., Chicago, Illinois) was used for statistical analysis.
Variables that were tested in the model and that were not independent predictors of change in secretory phospholipase A2 were age, gender, One hundred patients were included in the trial (50 in inclusion criteria, statin therapy versus statin naive before randomization, each group). Inclusion criteria are listed in Of note, strength of statin before randomization, smoking status, hyperlipidemia 90% of patients were receiving statins before randomiza- (defined as low-density lipoprotein cholesterol level Ͼ130 mg/dl before tion. Simvastatin was most commonly used (53 patients), initiation of lipid-lowering therapy), hypertension (defined as blood pres- followed by atorvastatin (30 patients). Types and doses of sure Ն140/90 mm Hg before initiation of antihypertensive therapy), base- statins used were similar between the 2 groups. Baseline line high-sensitivity C-reactive protein level, and change in low-density demographics, clinical characteristics, and concomitant lipoprotein cholesterol level at the end of the study.
medical therapy are listed in All patients took theirinvestigational treatment according to the protocol for a a good and statistically significant correlation between period of 8 weeks. None of the patients had an increase of creatine phosphokinase or aspartate aminotransferase Ͼ2 (r ϭ 0.39, p ϭ 0.005) and between changes in hs-CRP and sPLA2 activity (r ϭ 0.38, p ϭ 0.007). In the placebo/ Values of different lipid parameters are listed in atorvastatin group, the only significant correlation was be- Patients were well treated with statins before inclusion in tween hs-CRP and sPLA2 activity (r ϭ 0.63, p Ͻ0.001).
the study, as attested by mean baseline LDL cholesterol Changes in LDL cholesterol and sPLA2 activity did not levels of 102 mg/dl in the combined therapy group and 99 correlate together in that group (r ϭ 0.13, p ϭ NS). There mg/dl in the monotherapy group (p ϭ NS). Coadministra- was no correlation in either group between change in LDL tion of ezetimibe with atorvastatin resulted in a more im- portant decrease in total LDL cholesterol compared to ator- To determine the most important factors associated with vastatin alone (average decrease 20% vs 10%, p ϭ 0.01).
decrease in sPLA2, we performed in the entire group of 100 Hs-CRP levels were similar at baseline and decreased patients a forward stepwise linear regression analysis where equally in the 2 groups after treatment.
change in sPLA2 was the dependent variable and patients’ At randomization, sPLA2 activity levels were 29 U/ml clinical and demographic characteristics (risk factors, inclu- (23 to 35) in the ezetimibe/atorvastatin group and 23 U/ml sion criteria, and baseline lipid and hs-CRP values) and (19 to 32) in the placebo/atorvastatin group (p ϭ 0.02; changes of hs-CRP and LDL cholesterol during the study sPLA2 activity at baseline was higher in women than in were the predictors. This model demonstrated that change in men (33 U/ml, 27 to 44, vs 25 U/ml, 20 to 32, p ϭ 0.015) hs-CRP, baseline level of LDL cholesterol, body mass in- and tended to be higher in patients who had hyperlipidemia dex, presence of diabetes mellitus, and randomization to (27 U/ml, 21 to 34, vs 20 U/ml, 16 to 27, p ϭ 0.05) and in combination therapy were independently correlated with those who were statin naive before inclusion (35 U/ml, 26 to 37, vs 26 U/ml, 20 to 33, p ϭ 0.06). sPLA2 activity at Discussion
baseline correlated significantly with total cholesterol (r ϭ0.3, p ϭ 0.002), LDL cholesterol (r ϭ 0.3, p ϭ 0.002), and This study demonstrates that coadministration of hs-CRP (r ϭ 0.46, p Ͻ0.001). sPLA2 activity at baseline ezetimibe with atorvastatin leads to a significant decrease in was not associated with any of the other clinical or demo- sPLA2 activity after 8 weeks of therapy in patients who graphic characteristics and concomitant medications.
were already on statins and who had optimal baseline LDL After 8 weeks of therapy, sPLA2 activity significantly levels. This was associated with an important decrease in decreased in the ezetimibe/atorvastatin group but did not LDL cholesterol and in inflammation. Increasing solely the significantly change in the placebo/atorvastatin group potency of statin in the atorvastatin monotherapy group did At the end of treatment, activity of sPLA2 remained not significantly decrease sPLA2 activity despite a signifi- higher in the combination therapy group compared to the cant decrease in hs-CRP, most likely because the decrease monotherapy group because of the much higher activity at in LDL cholesterol was minor. To the best of our knowl- edge, this trial is the first to document the effect of aggres- To investigate the relation among LDL cholesterol, hs- sive lipid lowering with atorvastatin/ezetimibe combination CRP, and sPLA2, we performed a correlation analysis be- tween the changes in LDL cholesterol, hs-CRP, and sPLA2 The nonsignificant change in sPLA2 activity in the pla- in each group. In the ezetimibe/atorvastatin group, there was cebo/atorvastatin group does not mean that statins do not The American Journal of Cardiology (www.ajconline.org) affect sPLA2. To the contrary, our results suggest that sPLA2 activity in the monotherapy group. However, it does statins decrease sPLA2 because it decreases LDL choles- not limit the validity of our conclusion that combination terol and inflammation. This is supported by findings that therapy decreases sPLA2. Third, we have demonstrated that patients who were statin naive before inclusion tended to the combination of ezetimibe/atorvastatin lowers sPLA2 have higher baseline sPLA2 activity compared to those who activity. The effect of ezetimibe monotherapy on sPLA2 were already treated with statins. Because 90% of our pa- tients were pretreated with statins (albeit at a lower dose)before randomization, the decrease in LDL cholesterol ob- 1. Mallat Z, Simon T, Benessiano J, Ederhy S, Sebella-Arguelles C, tained when shifted to atorvastatin 40 mg and placebo was Cohen A, Huart V, Wareham NJ, Luben R, Khaw KT, Tedgui A, minor (10%). We may thus hypothesize that if the LDL Boekholdt SM. Circulating secretory phospholipase A2 activity and cholesterol decrease was more potent, the decrease in risk of incident coronary events in healthy men and women: theEPIC-Norfolk study. Arterioscler Thromb Vasc Biol 2007;27:1177– sPLA2 activity might have been significant.
Our findings may have important clinical implications.
2. Mallat Z, Steg G, Benessiano J, Tanguy ML, Fox KA, Collet JP, The sPLA2 enzymatic system hydrolyzes the ester bond of Dabbous OH, Henry P, Carruthers KF, Dauphin A, Arguelles CS, phospholipid molecules at the sn-2 position and produces Masliah J, Hugel B, Montalescot G, Freyssinet JM, Asselain B, Tedgui bioactive lipids such as arachidonic acid and lysophospho- A. Circulating secretory phospholipase A2 activity predicts recurrentevents in patients with severe acute coronary syndromes. J Am Coll This leads to modification of LDL particles resulting Cardiol 2005;46:1249 –1257.
in a decrease in their binding affinity to LDL receptors and 3. Lambeau G, Gelb MH. Biochemistry and physiology of mammalian in a longer “residence time” in the sPLA2 secreted phospholipases A2. Annu Rev Biochem 2008;77:495–520.
also potentiates oxidation of LDL cholesterol and increases 4. Flood C, Gustafsson M, Pitas RE, Arnaboldi L, Walzem RL, Boren J.
binding of LDL molecules to proteoglycans of human arte- Molecular mechanism for changes in proteoglycan binding on com-positional changes of the core and the surface of low-density lipopro- rial cells, leading to foam cell formation and an increase of tein-containing human apolipoprotein B100. Arterioscler Thromb Vasc Biol 2004;24:564 –570.
associated with increased risk of incident coronary heart 5. Kleinman Y, Krul ES, Burnes M, Aronson W, Pfleger B, Schonfeld G.
disease events in apparently healthy men and women and in Lipolysis of LDL with phospholipase A2 alters the expression of patients with stable CAD or with acute coronary syn- selected apoB-100 epitopes and the interaction of LDL with cells. J Lowering sPLA2 activity with specific inhibitors Lipid Res 1988;29:729 –743.
6. Wooton-Kee CR, Boyanovsky BB, Nasser MS, de Villiers WS, Webb resulted in significant improvement in atherosclerosis in NR. Group V sPLA2 hydrolysis of low-density lipoprotein results in animal A specific sPLA2 inhibitor was recently spontaneous particle aggregation and promotes macrophage foam cell tested in a phase II clinical study on humans and was shown formation. Arterioscler Thromb Vasc Biol 2004;24:762–767.
to dramatically decrease sPLA2 concentration and LDL 7. Hakala JK, Oorni K, Pentikainen MO, Hurt-Camejo E, Kovanen PT.
cholesterol and LDL particle However, the ef- Lipolysis of LDL by human secretory phospholipase A(2) inducesparticle fusion and enhances the retention of LDL to human aortic ficacy of specific sPLA2 inhibitors on clinical end points proteoglycans. Arterioscler Thromb Vasc Biol 2001;21:1053–1058.
8. Shaposhnik Z, Wang X, Trias J, Fraser H, Lusis AJ. The synergistic In contrast, the benefit of lipid-lowering therapy with inhibition of atherogenesis in ApoEϪ/Ϫ mice between pravastatin and statins on adverse cardiovascular end points is clearly es- the sPLA2 inhibitor varespladib (A-002). J Lipid Res 2009;50:623– tablished. Use of ezetimibe remains and is 9. Fraser H, Hislop C, Christie RM, Rick HL, Reidy CA, Chouinard ML, currently recommended for patients who do not reach their Eacho PL, Gould KE, Trias J. Varespladib (A-002), a secretory phos- LDL goal with a maximal dose of statin or for patients who pholipase A2 inhibitor, reduces atherosclerosis and aneurysm forma- are statin intolerant. Our study demonstrates that the com- tion in ApoEϪ/Ϫ mice. J Cardiovasc Pharmacol 2009;53:60 – 65.
bination of ezetimibe/atorvastatin results in a synergistic 10. Rosenson RS, Hislop C, McConnell D, Elliott M, Stasiv Y, Wang N, effect that leads to a decrease in sPLA2 activity, in addition Waters DD, for the PLASMA Investigators. Effects of 1-H-indole-3-glyoxamide (A-002) on concentration of secretory phospholipase A2 to improvement of standard lipid parameters. This may (PLASMA study): a phase II double-blind, randomised, placebo-con- translate to a better event-free survival. Our findings should trolled trial. Lancet 2009;373:649 – 658.
be tested in prospective clinical studies and will be useful in 11. Kastelein JJP, Akdim F, Stroes ESG, Zwinderman AH, Bots ML, the interpretation of the Improved Reduction of Outcomes: Stalenhoef AFH, Visseren FLJ, Sijbrands EJG, Trip MD, Stein EA, Vytorin Efficacy International Trial (IMPROVE-IT), an on- Gaudet D, Duivenvoorden R, Veltri EP, Marais AD, de Groot E, for going clinical trial measuring the efficacy of ezetimibe on the ENHANCE Investigators. Simvastatin with or without ezetimibe infamilial hypercholesterolemia. N Engl J Med 2008;358:1431–1443.
12. Fleg JL, Mete M, Howard BV, Umans JG, Roman MJ, Ratner RE, Silverman A, Galloway JM, Henderson JA, Weir MR, Wilson C, Our study has a few limitations. First, baseline sPLA2 Stylianou M, Howard WJ. Effect of statins alone versus statins plus activity was not similar between the 2 groups. Despite ezetimibe on carotid atherosclerosis in type 2 diabetes: the SANDS randomization, some confounding variables not investi- (Stop Atherosclerosis in Native Diabetics Study) Trial. J Am CollCardiol 2008;52:2198 –2205.
gated in this study may have been more prevalent in the 13. Fichtlscherer S, Schmidt-Lucke C, Bojunga S, Rossig L, Heeschen C, combination therapy group, resulting in higher baseline Dimmeler S, Zeiher AM. Differential effects of short-term lipid low- sPLA2 activity compared to the monotherapy group. How- ering with ezetimibe and statins on endothelial function in patient with ever, this does not affect our finding that coadministration of CAD: clinical evidence for “pleiotropic” functions of statin therapy.
ezetimibe and atorvastatin decreases sPLA2 activity. Sec- Eur Heart J 2006;27:1182–1190.
14. Settergren M, Böhm F, Rydén L, Pernow J. Cholesterol lowering is ond, 90% of our patients were treated with statins before more important than pleiotropic effects of statins for endothelial func- randomization. This may explain why increasing the po- tion in patients with dysglycaemia and coronary artery disease. Eur tency of the statin did not result in a significant decrease in

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