Effects of prescription omega-3-acid ethyl esters,coadministered with atorvastatin,on circulating levels of lipoprotein particles,apolipoprotein CIII,andlipoprotein-associated phospholipase A 2mass in men and women with mixed dyslipidemiaKevin C.Maki,PhD *,Harold E.Bays,MD,Mary R.Dicklin,PhD,Susan L.Johnson,MD,MS,Mayadah Shabbout,MSProvident Clinical Research,Biofortis North America,489Taft Avenue,Glen Ellyn,IL 60137,USA (Drs.Maki and Dicklin);Louisville Metabolic and Atherosclerosis Research Center,Louisville,KY,USA (Dr.Bays);and GlaxoSmithKline,Research Triangle Park,NC,USA (Dr.Johnson and Shabbout)KEYWORDS:Apolipoprotein CIII;Lipoprotein-associated phospholipase A 2;Lipoprotein particles;Omega-3fatty acids;Statins;TriglyceridesBACKGROUND:Prescription omega-3-acid ethyl esters (POM3)reduce triglycerides (TG)and very low-density lipoprotein cholesterol and increase high-density lipoprotein cholesterol (HDL-C)in pa-tients with hypertriglyceridemia.OBJECTIVE:To examine the effects of POM3plus atorvastatin versus placebo plus atorvastatin on lipoprotein particle concentrations and sizes,apolipoprotein (Apo)CIII,and lipoprotein-associated phospholipase A 2mass in subjects with mixed dyslipidemia.METHODS:After a 4-week diet lead in,men and women with non-HDL-C .160mg/dL and TG 250-599mg/dL,while taking no lipid-altering drugs,received double-blind 4g/d POM3(n 5118)or placebo (n 5119)with open-label atorvastatin 10mg/d for 8weeks,followed by escalation to 20mg/d atorvastatin for 4weeks,then 40mg/d atorvastatin for 4weeks.RESULTS:Total low-density lipoprotein particle (LDL-P)concentration decreased significantly from baseline,and the reductions did not differ between the POM3and placebo groups (2659.7vs 2624.4nmol/L,P 5.181).With POM3,compared with placebo,small LDL-P concentration decreased (P 5.026),large LDL-P concentration increased (P ,.001),mean LDL-P size increased (P 5.001),a larger fraction of subjects switched from LDL subclass pattern B to A,and Apo CIII and lipoprotein-associated phospholipase A 2levels were reduced (P ,.001).The incremental effects of POM3were sim-ilar across atorvastatin doses for most variables.CONCLUSION:This analysis supports the view that LDL-P concentration is not increased by POM3plus atorvastatin,relative to atorvastatin monotherapy,and is associated with potentially favorable shifts in LDL-P subfractions,Apo CIII and lipoprotein-associated phospholipase A 2in mixed dyslipidemia.Ó2011National Lipid Association.All rights reserved.*Corresponding author.E-mail address:KMaki@Submitted June 27,2011.Accepted for publication September 8,2011.1933-2874/$-see front matter Ó2011National Lipid Association.All rights reserved.doi:10.1016/j.jacl.2011.09.001Journal of Clinical Lipidology (2011)5,483–492IntroductionElevated triglyceride(TG)concentration is an indepen-dent risk factor for coronary heart disease(CHD).1–5There is a substantial body of research supporting the consumption of long-chain polyunsaturated omega-3fatty acids,includ-ing eicosapentaenoic acid(EPA)and docosahexaenoic acid(DHA),for lowering elevated TG.6,7Administration of the prescription form of concentrated omega-3-acid ethyl esters(POM3)in combination with a3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor(statin)in patients with hypertriglyceridemia has been shown to lower the circulating TG concentration and to reduce non-high-density lipoprotein cholesterol(non-HDL-C),a measure of the cholesterol carried by all potentially atherogenic lipo-protein particles.8–13The effects of POM3plus statin therapy on lipoprotein particle sizes,concentrations,and compositions has been less well characterized.The major classes of lipoprotein particles are heterogeneous with respect to size,density, and pared with large,buoyant low-density lipoprotein particles(LDL-P),small,dense LDL-P may be more atherogenic as the result of greater ease with which they enter the subendothelial space and interact with subendothelial proteoglycans,lower binding affinity for the LDL receptor,prolonged plasma half-life,and greater susceptibility to oxidative modification.14–16Recent data suggest that some statin-treated patients may experience a decrease in LDL-P size,which may be attributable to greater affinity of larger LDL-P for hepatic LDL receptors, the expression of which is up-regulated during statin ther-apy,resulting in a greater reduction in larger than smaller LDL-P.17,18The effects of lipid-altering therapies on lipoprotein particle concentration is also of interest because analyses of data from prospective studies suggest that LDL-P concen-tration may be a better predictor of CHD risk than lipoprotein lipid concentrations.19–24Results from previous studies have suggested that the addition of POM3to statin therapy may produce a modest increase in LDL-C level but that this is not accompanied by an increase in LDL-P con-centration,but rather it is attributable to a shift toward larger,less dense LDL-P.7,11,12Apolipoprotein(Apo)CIII may be an important modu-lator of LDL-P remodeling because it acts as an inhibitor of lipoprotein lipase and of remnant uptake by the liver,thus its reduction would facilitate more rapid clearance of very-low-density lipoprotein(VLDL)-TG from the circula-tion.12,25,26Reduced Apo CIII would also tend to enhance the rate of conversion of VLDL to LDL particles and re-duce the substrate available for cholesteryl ester transfer protein,thereby decreasing the rate of exchange of VLDL-TG for cholesteryl esters from LDL-P and high-density lipoprotein particles(HDL-P).In addition,the concentration of Apo CIII carried by Apo B-containing lip-oprotein particles has been found to be an independent predictor of CHD event risk.27–30An additional element of lipoprotein composition that may have relevance for CHD risk is lipoprotein-associated phospholipase A2(Lp-PLA2).In circulation,Lp-PLA2is as-sociated mainly with LDL-P,particularly small,dense,elec-tronegative LDL-P,31–33although approximately20%is associated with HDL-P.33,34In the arterial wall,Lp-PLA2 catalyzes the hydrolysis of oxidized phospholipids on LDL particles,thus producing two highly inflammatory media-tors,lysophosphatidylcholine and oxidized fatty acid,result-ing in up-regulation of adhesion molecules,expression of cytokines,recruitment of monocytes to the intimal space, and differentiation of monocytes into macrophages.35The circulating concentration of Lp-PLA2has been shown to pre-dict risk for CHD and stroke.35–38Results from previous studies have suggested that both POM3and statin therapy lower circulating levels of Lp-PLA2,12,39,40but very limited information is available regarding the effects of these agents in combination.In the present investigation we assessed the effects of POM3or placebo,in combination with atorvastatin,on lipoprotein particle concentrations and sizes,as well as circulating levels of Apo CIII and Lp-PLA2in subjects with mixed dyslipidemia.MethodsStudy designThe results described herein are from an analysis of data from a20-week,randomized,double-blind study conducted at37clinical sites in the United States.The original study was designed to evaluate the effects of POM3on non-HDL-C levels in atorvastatin-treated individuals with elevated non-HDL-C and TG.13The study was conducted according to the guidelines of Good Clinical Practice,the Declaration of Helsinki(2000),and U.S.21Code of Federal Regula-tions.The protocol was approved by the institutional review board of each site,and signed written informed consent for the study was obtained from all subjects.Participants entered a4-week Therapeutic Lifestyle Changes diet lead-in period during which they did not use any lipid-altering agents.41After the lead-in phase,subjects were randomly assigned to receive double-blind treatment with either POM34g/d(Lovaza;GlaxoSmithKline,Research Triangle Park,NC)or matching placebo capsules(containing corn oil),each in combination with open-label atorvastatin 10mg/d,for8weeks.The primary end point of the initial study was the end of the10mg/d atorvastatin dose period. After this initial treatment phase,the dose of open-label atorvastatin was increased in both groups to20mg/d for an ad-ditional4weeks and then to40mg/d for thefinal4weeks of the treatment period(secondary end points).Subjects contin-ued to receive their randomly assigned double-blinded POM3 or placebo throughout the16-week treatment period.A full description of the methods and results for the primary analyses from this study was previously published.13484Journal of Clinical Lipidology,Vol5,No6,December2011SubjectsMen and nonpregnant,nonlactating women ages18279 years,with non-HDL-C.160mg/dL and hypertriglycer-idemia(TG$250mg/dL and,600mg/dL)after the Therapeutic Lifestyle Changes diet lead-in phase were eligible for randomization.Major exclusion criteria in-cluded a history of cardiovascular events;significant renal or pulmonary disease;cancer;poorly controlled hyperten-sion;signs of possible myopathy;known lipoprotein lipase impairment/deficiency or Apo CII deficiency;familial dysbetalipoproteinemia;body mass index.40kg/m2;gly-cosylated hemoglobin.9%;elevated serum transaminase, creatinine or creatine kinase;or a history of drug or alcohol e of nonstudy lipid-altering drugs was prohibited for the duration of the study,as was the use of systemic or high-dose topical corticosteroids,grapefruit juice(.1 quart/d),antihypertensive medications,antibiotics,antifun-gals,protease inhibitors,and weight loss drugs. Laboratory measurementsCentral laboratories were used for all tests.Blood sam-ples were collected at baseline and at the conclusion of each atorvastatin dose period for measurement of the following parameters.Lipoprotein subfractions were measured using the Nuclear Magnetic Resonance LipoProfile method (LipoScience,Inc.,Raleigh,NC).19Red blood cell EPA and DHA,as a percentage of total fatty acids,were measured at Sanford Research/OmegaQuant LLC(Sioux Falls,SD) according to previously described methods.42Medpace Ref-erence Laboratories,LLC(Cincinnati,OH)measured Lp-PLA2plasma concentrations by the use of a microtiter enzyme-linked immunosorbent assay43and Apo CIII con-centrations with an immunoturbidimetric assay.27 Statistical analysesThe analyses described here were conducted with SAS version9.2(SAS Institute,Cary NC),and all were preplanned in the original study except the LDL subclass pattern analysis,which was conducted post-hoc.Analyses were completed on the modified intent-to-treat population, which included all subjects who were randomized,took at least one dose of study drug,and provided at least one postrandomization efficacy data point.Statistical tests were performed at a two-sided significance level of.05with the exception of tests of interactions which were performed at a significance level of.10.Between-treatment group differences in changes from baseline in lipoprotein particle sizes and concentrations and Apo CIII,Lp-PLA2,EPA,and DHA levels at each dose level of atorvastatin were assessed by nonparametric analysis of covariance with a model including terms for treatment group,baseline TG stratum(2502399or4002599mg/ dL),and baseline value.Because the results for lipoprotein particle sizes and concentrations were not markedly skewed and the mean and median changes were similar in all in-stances,mean6SD values are presented for those variables. Median(interquartile range)values are presented for Apo CIII,Lp-PLA2,EPA,and DHA.Subjects were classified post-hoc as having LDL subclass pattern A(predominance of LDL-P size.20.5nm)or pattern B(predominance of LDL-P size#20.5nm)at each clinic visit at which lipopro-tein particle concentrations was measured.Chi-square tests were used to test for differences between treatment groups in the prevalence of shifts from pattern B to pattern A by each atorvastatin dose level.ResultsSubjectsA sample of245subjects was randomized to either POM3plus atorvastatin(n5123)or placebo plus atorvastatin(n5122).Participants were predominantly male(58%),non-Hispanic white(89%),and had a mean6 SD age of56.1610.2years and body mass index of 30.664.3kg/m2.13A subset of243subjects(POM3, n5122and placebo,n5121)were included in the mod-ified intent-to-treat population.As reported previously, compared with placebo plus atorvastatin,POM3plus atorvastatin at10,20,and40mg/d doses reduced median non-HDL-C from baseline by6.5%,7.9%,and4.1%,re-spectively.13Treatment differences in VLDL-C and TG changes from baseline across atorvastatin doses ranged from217.3%to218.1%and218.6%to220.5%,respec-tively;and differences in LDL-C and HDL-C changes from baseline across atorvastatin doses ranged from0.0%to 2.2%,respectively,and from2.4%to6.3%,respectively.13 Lipoprotein particle sizes and concentrations Values and responses(changes from baseline)for lipo-protein particle sizes and concentrations according to treatment with POM3or placebo in combination with atorvastatin at10mg/d(week8),20mg/d(week12),and 40mg/d(week16)doses are shown in Table1.VLDL-P size decreased from baseline with POM3and placebo at all doses of atorvastatin,but the reduction with POM3 was significantly larger compared with placebo(P,.001 for all atorvastatin doses).LDL-P size increased from base-line with atorvastatin treatment in both the POM3and pla-cebo groups,but the increase with POM3was significantly larger than with placebo(P#.001for all atorvastatin doses).HDL-P size was not affected differentially by POM3plus atorvastatin versus placebo plus atorvastatin.The concentrations of total VLDL-P,as well as large and medium VLDL-P subclasses,were reduced from baseline to a larger extent with POM3than with placebo at all doses(P,.05for all).Small VLDL-P concentration changes from baseline did not differ significantly between treatment groups.Maki et al Omega-3plus atorvastatin and lipoprotein particles485486Journal of Clinical Lipidology,Vol5,No6,December2011The reductions from baseline in total LDL-P concentra-tion with placebo and POM3during the10mg/d and40mg/d atorvastatin phases were not significantly different from one another.However,at20mg/d atorvastatin,POM3resulted in a significantly larger reduction from baseline in total LDL-P compared with placebo(2828vs2742nmol/L,P5.020). Intermediate-density lipoprotein(IDL)-P and small LDL-P concentrations were reduced from baseline significantly more with POM3versus placebo at the10mg/d and20 mg/d atorvastatin doses(P,.05for all).Although the direc-tion of the responses at40mg/d atorvastatin was similar to that at10mg/d and20mg/d doses,differences between treat-ments in IDL-P and small LDL-P concentration changes from baseline failed to reach statistical significance(P5 .060and P5.108,respectively).Large LDL-P concentration increased from baseline with POM3versus placebo at all doses of atorvastatin(P,.001for all).Total HDL-P concentration was either increased to a lesser extent or reduced from baseline with POM3vs. placebo at all atorvastatin doses(P,.05for all).POM3-treated subjects showed significant shifts from baseline in HDL subclass distribution,including a significantly greater increase from baseline versus placebo in large HDL-P con-centration(P,.001for all atorvastatin doses),and a significant reduction from baseline versus placebo in me-dium HDL-P concentration(P,.05for all atorvastatin doses).Small HDL-P concentration increased from baseline with both POM3and placebo;at the20and40mg/d atorvas-tatin doses,but not with10mg/d,the increase with placebo was greater than that with POM3(P,.01for both).LDL subclass patternA significantly(P5.024)larger fraction of subjects switched from pattern B(predominance of small LDL parti-cles)to pattern A(predominance of large LDL particles)in the POM3group(n522;18.5%)compared with the placebo group(n510;8.5%)with10mg/d of atorvastatin.These findings were maintained in POM3-treated subjects as the atorvastatin dose was escalated(25.7%vs.10.6%,P5 .003at20mg/d atorvastatin;25.7%vs10.8%,P5.004at 40mg/d atorvastatin).Apo CIII and Lp-PLA2Median(interquartile range)baseline Apo CIII concen-trations for the POM3(n5119)and placebo(n5119) treatment groups were18.0(15.0221.0)mg/dL and17.0 Maki et al Omega-3plus atorvastatin and lipoprotein particles487(14.0219.0)mg/dL,respectively.Median percent changes from baseline in Apo CIII concentrations are shown in Figure1.There was a213.4%(95%confidence interval [95%CI]218.3,29.5)difference(POM3–placebo)be-tween treatments in the median percent changes from base-line to the conclusion of the10mg/d atorvastatin dose period(P,.001),a211.8%(95%CI219.5,210.0) difference at the end of the20mg/d atorvastatin dose pe-riod(P,.001),and a213.1%(95%CI217.9,27.9)dif-ference following the40mg/d atorvastatin dose period (P,.001).Median(interquartile range)baseline Lp-PLA2concen-trations for the POM3plus atorvastatin(n5119)and pla-cebo plus atorvastatin(n5118)treatment groups were 176.0(153.0,198.0)nmol/L and172.5(155.0,191.0) nmol/L,respectively.Median percent changes from base-line in Lp-PLA2concentrations are shown in Figure1. There was a211.0%(95%CI213.4,26.6)difference (POM3–placebo)between treatments in the median per-cent changes from baseline to the conclusion of the 10mg/d atorvastatin dose period(P,.001),a27.9% (95%CI212.9,25.6)difference at the end of the20 mg/d atorvastatin dose period(P,.001),and a25.1% (95%CI28.6,21.3)difference following the40mg/d atorvastatin dose period(P5.007).EPA and DHABaseline and on-treatment values and percent changes from baseline(median[interquartile range])for red blood cell EPA and DHA concentrations for the POM3plus atorvastatin or placebo plus atorvastatin10mg/d(week8)and40mg/d(week16)treatments are presented in Table2. EPA and DHA were not measured at week12(atorvastatin 20mg/d).As anticipated,both EPA and DHA were signif-icantly elevated during treatment with POM3. DiscussionThe results of this analysis demonstrate that the combi-nation of POM3with atorvastatin lowers the concentration and average diameter for VLDL particles,increases aver-age LDL-P size without increasing LDL-P concentration, and lowers Apo CIII and Lp-PLA2from their baseline levels,compared with atorvastatin with placebo.These findings may have important implications for understanding the influence of POM3therapy on lipoprotein metabolism, although the clinical implications of the changes observed are uncertain at present.POM3is believed to lower circulating levels of TG and TG-rich lipoproteins mainly by reducing the hepatic secre-tion of VLDL-TG.44–46This effect may result in part from inhibition of diacylglycerol-acyl-transferase-2by EPA and DHA,which reduces the TG available for incorporation into VLDL-P.EPA and DHA are also ligands for the perox-isome proliferator activator receptor-a,stimulation of which increases hepatic fatty acid oxidation.47,48Treatment with POM3reduces entry of VLDL-P into the circulation and reduces the average level of TG enrichment of secreted VLDL-P.10,47,49–52These effects likely account in part for the reductions in VLDL-P concentration and size observed in the present investigation in the POM3plus atorvastatin group.Although kinetic measurements were not part of the present study,in previous kinetic studies investigators suggest that POM3reduces the hepatic circulatory release of VLDL-P and that this effect may be additive to atorvastatin’s enhancement in the removal of Apo-B-containing lipoproteins(VLDL-P and LDL-P)from the circulation.10This is supported by analyses wherein the ad-ministration offish oil reduced the production rate for VLDL Apo B and increased the rates of conversion of VLDL to LDL but did not influence the fractional catabolic rates of VLDL or LDL.Atorvastatin may not affect the rate of VLDL Apo B production but does increase the fractional catabolic rates for VLDL and LDL.The reductions in VLDL particle number and size with POM3in the present trial are consistent with thesefindings.Although non-HDL-C was reduced by POM3,Apo B and LDL-P were not significantly lowered.Because 124124POM3 + atorvastatin 10, 20, 40 mgPlacebo + atorvastatin 10, 20, 40 mgMedianPercentChangefromBaselineApo CIII*Lp-PLA2*Figure1Median percent changes from baseline in Apo CIII and Lp-PLA2concentrations among subjects receiving POM3or pla-cebo plus atorvastatin10mg/d(week8),20mg/d(week12), and40mg/d(week16).For Apo CIII,the numbers of subjects in the POM3/placebo treatment groups at atorvastatin doses10, 20,and40mg/d were119/119,115/116,and113/112,respec-tively.For Lp-PLA2,the numbers of subjects in the POM3/pla-cebo treatment groups at atorvastatin doses10,20and40mg/d were119/118,115/115,and113/111,respectively.*Percent changes from baseline in Apo CIII and Lp-PLA2were significantly different between POM3and placebo at all doses of atorvastatin (P,.001for all except Lp-PLA2at40mg/d atorvastatin,P5 .007)as assessed by nonparametric analysis of covariance with a model including terms for treatment group,baseline TG stratum (250–399or400–599mg/dL),and baseline value.488Journal of Clinical Lipidology,Vol5,No6,December2011approximately90%of circulating Apo B is associated with LDL particles,the reduction in VLDL entry was likely not sufficient to produce a significant reduction in LDL-P(or Apo B)concentration.The mean LDL-P reduction across atorvastatin doses,although not statistically significant,was 37nmol/L larger with POM3than placebo,which is consistent with a modest reduction in the total circulating number of Apo B containing particles(VLDL1LDL),as has been reported previously based on changes in Apo B and/or LDL-P concentrations.11,12,53The reduction in non-HDL-C associated with adding POM3to a statin appears to be driven by a large(w50%)reduction in VLDL-C. VLDL-C accounted for approximately one-third of the non-HDL-C concentration at baseline,whereas VLDL par-ticles accounted for only5%to10%of the VLDL plus LDL particle concentration at baseline.Thus,the change in non-HDL-C,although correlated with changes in Apo B and Apo B-containing particle concentrations,is not a perfect surrogate for the change in the number of circulat-ing Apo B-containing particles.A second mechanism through which POM3may reduce circulating TG is by enhancement of TG hydrolysis via peroxisome proliferator activator receptor-a-stimulated activation of lipoprotein lipase,45,46as well as from a reduc-tion in Apo CIII concentration.Apo CIII inhibits the effect of Apo CII to stimulate lipoprotein lipase,which would be expected to increase lipoprotein lipase activity.25,26In Apo CIII knockout mice,the rate of conversion of VLDL-P to LDL-P is increased compared with control mice.54Thus, the decrease in Apo CIII may contribute to more rapid clearance of TG from the circulation and also to the rise in LDL-C that is sometimes observed with POM3therapy,53,55although there was no significant elevation in LDL-C in the POM3group compared with the placebo group in the current trial.13Results from some studies have suggested that LDL-P size decreases with statin therapy,possibly resulting from up-regulation of hepatic LDL receptors,which may have a greater affinity for larger LDL particles.17,18Placebo plus atorvastatin treatment did not reduce LDL-P size in the pre-sent study;in fact,mean particle size increased somewhat from baseline at each atorvastatin dose.Nevertheless,the increase in LDL-P size was significantly larger in the POM3group at each atorvastatin dose.The POM3group also had a larger fraction of subjects that converted from LDL subclass pattern B to pattern A.We and others have hypothesized that LDL subclass pattern conversion is a threshold phenomenon such that when the TG concentra-tion is raised or reduced beyond a threshold for an individ-ual to switch,LDL subclass pattern conversion will occur.12,14,56,57It is notable that POM3therapy was not accompanied by a change in LDL-P concentration compared with placebo. Thisfinding is consistent with those from trials of POM3 plus simvastatin therapy,which have also shown no increase in LDL-P,but a shift in LDL subclasses(reduced IDL-P,increased large LDL-P and reduced small LDL-P), producing a net increase in mean LDL-P size.11,12In con-trast,HDL-P size was not significantly increased in the POM3group compared with the placebo group,despite a significant increase in HDL-C,as reported previously.13 Both POM3plus atorvastatin and placebo plus atorvas-tatin treatments lowered Apo CIII and Lp-PLA2and these effects showed a dose-response pattern withincreasing Maki et al Omega-3plus atorvastatin and lipoprotein particles489atorvastatin doses.For Apo CIII,the incremental effect ofPOM3was statistically significant and similar at each ator-vastatin dose(11.8%-13.4%).This was similar to the11%incremental Apo CIII reduction shown previously forPOM3plus simvastatin compared with placebo plus simva-statin12and was slightly larger than the8.2%incrementalApo CIII reduction reported for the combination of fenofi-brate plus simvastatin compared to simvastatin alone.58ForLp-PLA2,the incremental effect of POM3was statisticallysignificant for each dose,but the difference between groupsdiminished as the atorvastatin dose was increased,from 211.0%to27.9%to-5.1%at the10-,20-,and40-mg ator-vastatin doses,respectively.It is notable that the differentialbetween treatment groups for the reduction in small LDLparticles was also smaller and non-significant at the40-mg atorvastatin dose compared with the10-and20-mg doses.It is possible that the narrowing of the incre-mental effect of POM3on Lp-PLA2related to a narrowingof the circulating small LDL-P concentration.However,anexploratory analysis showed no significant correlationbetween the changes in small LDL-P or mean LDL-Psize with the change in Lp-PLA2concentration at anydose level(data not shown),which would argue againstthis explanation.Consistent with previous reports,59,60baseline levels ofEPA(w0.47%)were lower than those of DHA(w3.30%)in red blood cell membranes.POM3treatment increasedlevels of both EPA and DHA.Because the life span of ared blood cell is roughly120days,it is not surprising thatthe increase in red blood cell EPA and DHA levels did notappear to be maximal after8weeks of POM3administration,at which time the increases were72%(EPA)to79%(DHA)of those observed after16weeks of administration.In conclusion,compared with placebo plus atorvastatin,treatment with POM3plus atorvastatin lowered mean TG-rich lipoprotein particles and remnants(VLDL-P and IDL-P)and reduced mean VLDL-P size.Changes from baselinein LDL-P concentration were similar between the twotreatments,but POM3produced a shift in LDL subclassesthat resulted in larger mean particle size.POM3plusatorvastatin reduced Apo CIII and Lp-PLA2levels to agreater degree than placebo plus atorvastatin.Thus,the co-administration of POM3and atorvastatin,compared withplacebo and atorvastatin,produced multiple effects on lip-oprotein particle concentrations,sizes and compositions.These changes were generally in theoretically favorable di-rections,although their ultimate impact on cardiovasculardisease event risk remains to be demonstrated. AcknowledgmentsAll listed authors meet the criteria for authorship setforth by the International Committee for Medical JournalEditors.The authors wish to acknowledge the followingindividuals for their critical review during the developmentof this manuscript:Rosemary Schroyer,MS,and Doug Wicks,MPH,both employees of GlaxoSmithKline.Edito-rial support in the form of development of draft outline and first draft of manuscript,editorial suggestions to draft versions of this paper,assembling tables andfigures, collating author comments,copyediting,fact checking, and referencing was provided by Biofortis-Provident Clin-ical Research,and was funded by GlaxoSmithKline.We further acknowledge the following individuals for their contributions as investigators at each of the clinical sites in the United States where the original study was conducted: Neville Bittar,MD,Madison,WI;Lambert H.K.Chee,MD, Walnut Creek,CA;Sidney E.Clevinger,MD,Ocala,FL; Kenneth R.Cohen,MD,Golden,CO;Gordon T.Connor, MD,Birmingham,AL;John R.Crouse,III,MD,Winston-Salem,NC;Steven K.Elliott,MD,Evansville,IN;Cecil M. Farrington,Jr.,MD,Salisbury,NC;Alan D.Forker,MD, Kansas City,MO;Anne C.Goldberg,MD,St.Louis,MO; Colette M.Hall,MD,Atlanta,GA;Stephen W.Halpern,MD, Santa Rosa,CA;Barry S.Horowitz,MD,West Palm Beach, FL;Cynthia L.Huffman,MD,Tampa,FL;Michael J.Koren, MD,Jacksonville,FL;Wayne Larson,MD,Lakewood,WA; Andrew J.Lewin,MD,Los Angeles,CA;Thomas W. Littlejohn,III,MD,Winston-Salem,NC;Richard N.Marple, MD,Tulsa,OK;Dennis C.McCluskey,MD,Mogadore,OH; James M.McKenney,PharmD,Richmond,V A;Sam S. Miller,MD,San Antonio,TX;David J.Morin,RPh,MD, Bristol,TN;Carlos A.Petit,MD,Overland Park,KS;John Pullman,MD,Butte,MT;James M.Rhyne,MD,Statesville, NC;Sheila Rodstein,MD,Edina,MN;Eli M.Roth,MD, Cincinnati,OH;John Rubino,MD,Raleigh,NC;Mercedes B.Samson,MD,Buena Park,CA;Sherwyn L.Schwartz, MD,San Antonio,TX;Gregory T.Serfer,DO,Hollywood, FL;Evan A.Stein,MD,PhD,Cincinnati,OH;Craig Thompson,MD,Marion,OH;Philip D.Toth,MD,Indian-apolis,IN;and Mervyn U.Weerasinghe,MD,Rochester,NY. Financial disclosuresFunding for this study was provided by GlaxoSmithK-line,Research Triangle Park,NC( iden-tifier NCT00435045).Drs.Maki and Bays have received research funding and consulting/speaking fees from Glax-oSmithKline.Dr.Johnson and Ms.Shabbout are employees of GlaxoSmithKline.References1.Ginsberg HN.Hypertriglyceridemia:new insights and new approachesto pharmacologic therapy.Am J Cardiol.2001;87:1174–1180.2.Liu J,Sempos CT,Donahue RP,Dorn J,Trevisan M,Grundy SM.Non-high-density lipoprotein and very-low-density lipoprotein choles-terol and their risk predictive values in coronary heart disease.Am J Cardiol.2006;98:1363–1368.3.Sarwar N,Danesh J,Eiriksdottir G,et al.Triglycerides and the risk ofcoronary heart disease:10,158incident cases among262,525partici-pants in29Western prospective studies.Circulation.2007;115: 450–458.490Journal of Clinical Lipidology,Vol5,No6,December2011。
