- Email: [email protected]
Baseline Lipoprotein Lipids and Low-Density Lipoprotein Cholesterol Response to Prescription Omega-3 Acid Ethyl Ester Added to Simvastatin Therapy
Baseline Lipoprotein Lipids and Low-Density Lipoprotein Cholesterol Response to Prescription Omega-3 Acid Ethyl Ester Added to Simvastatin Therapy Kevin C. Maki, PhDa,*, Mary R. Dicklin, PhDa, Michael H. Davidson, MDb,e, Ralph T. Doyle, BAc, and Christie M. Ballantyne, MDd; COMBination of prescription Omega-3 with Simvastatin (COMBOS) Investigators The present post hoc analysis of data from the COMBination of prescription Omega-3 with Simvastatin (COMBOS) study investigated the predictors of the low-density lipoprotein (LDL) cholesterol response to prescription omega-3 acid ethyl ester (P-OM3) therapy in men and women with high (200 to 499 mg/dl) triglycerides during diet plus simvastatin therapy. Subjects (n ⴝ 256 randomized) received double-blind P-OM3 4 g/day or placebo for 8 weeks combined with diet and open-label simvastatin 40 mg/day. The percentage of changes from baseline (with diet plus simvastatin) in lipids was evaluated by tertiles of baseline LDL cholesterol and triglyceride concentrations. The baseline LDL cholesterol tertile was a significant predictor of the LDL cholesterol response (p ⴝ 0.022 for the treatment by baseline tertile interaction). The median LDL cholesterol response in the P-OM3 group was ⴙ9.5% (first tertile, <80.4 mg/dl), ⴚ0.9% (second tertile), and ⴚ6.4% (third tertile, >99.0 mg/dl). Non– high-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride responses did not vary significantly by baseline LDL cholesterol tertile. The reductions in very-lowdensity lipoprotein cholesterol concentrations were greater than the increases in LDL cholesterol, where present, resulting in a net decrease in the concentration of cholesterol carried by atherogenic particles (non– high-density lipoprotein cholesterol) in all baseline LDL cholesterol tertiles. In conclusion, these results suggest that the increase in LDL cholesterol that occurred with the addition of P-OM3 to simvastatin therapy in subjects with mixed dyslipidemia was confined predominantly to those with low LDL cholesterol levels while receiving simvastatin monotherapy. © 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:1409 –1412) Numerous studies have shown that the long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid are effective for lowering triglycerides (TG) and non– high-density lipoprotein (HDL) cholesterol, when used alone or as an adjunct to statin therapy, in subjects with hypertriglyceridemia or mixed dyslipidemia.1–13 However, omega-3 fatty acids can also produce an increase in low-density lipoprotein (LDL) cholesterol in some patients.1,2,9,13–17 The COMBination of prescription Omega-3 with Simvastatin (COMBOS) study was an 8-week, placebo-controlled, double-blind trial.9 In the COMBOS study, 4 g/day prescription omega-3 acid ethyl esters (P-OM3) combined with 40 mg/day simvastatin significantly lowered the concentrations of TG, very-low-
a
Provident Clinical Research, Glen Ellyn, Illinois and Bloomington, Indiana; bRadiant Research, Chicago, Illinois; cGlaxoSmithKline, Research Triangle Park, North Carolina; dCenter for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Baylor College of Medicine, Houston, Texas; and eThe University of Chicago Pritzker School of Medicine, Chicago, Illinois. Manuscript received October 20, 2009; revised manuscript received and accepted December 22, 2009. This trial was funded by grant NCT00246701 from GlaxoSmithKline, Research Triangle Park, North Carolina. *Corresponding author: Tel: (630) 858-4400; fax: (630) 858-4490. E-mail address: [email protected] (K.C. Maki). 0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.12.063
density lipoprotein (VLDL) cholesterol, and non–HDL cholesterol and increased the HDL cholesterol in patients with mixed dyslipidemia. During treatment, a trend was seen for an increase in LDL cholesterol with P-OM3 relative to placebo (⫹0.7% vs ⫺2.8%, p ⫽ 0.052).9 The present post hoc analysis of data from the COMBOS study9 was undertaken to examine the relation between the baseline concentrations of LDL cholesterol and TG and the LDL cholesterol response to P-OM3 when combined with simvastatin therapy. Methods A full description of the procedures and main results from the COMBOS study have been previously published.9 In brief, the participants were men and women 18 to 79 years old who had been receiving stable-dose statin therapy for ⱖ8 weeks at study enrollment. The subjects completed an 8-week lead-in of the National Cholesterol Education Program Therapeutic Lifestyle Changes diet plus 40 mg/day simvastatin therapy (Zocor, Merck, Whitehouse Station, New Jersey). After the lead-in phase, those who had a fasting TG concentration of 200 to 499 mg/dl and LDL cholesterol concentration of ⱕ10% above their National Cholesterol Education Program Third Adult Treatment Panel treatment goal18 were eligible to enter the doublewww.AJConline.org
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Table 1 Lipoprotein lipid responses according to baseline low-density lipoprotein (LDL) cholesterol tertile in subjects receiving simvastatin 40 mg/day plus either prescription omega-3 acid ethyl esters (P-OM3) 4 g/day or placebo for 8 weeks Lipid Parameter
LDL Cholesterol (mg/dl) ⬍80.4
Very-low-density lipoprotein cholesterol Baseline (mg/dl) Change (%) Non–high-density lipoprotein cholesterol Baseline (mg/dl) Change (%) High-density lipoprotein cholesterol Baseline (mg/dl) Change (%) Triglycerides Baseline (mg/dl) Change (%)
P-OM3 (n ⫽ 43)
Placebo (n ⫽ 41)
P-OM3 (n ⫽ 40)
52 (45, 60) ⫺27 (⫺39, ⫺15)
54 (45, 62) ⫺7 (⫺19, 1)
53 (45, 59) ⫺28 (⫺36, ⫺13)
112 (105, 127) ⫺5 (⫺14, 5)
113 (103, 126) 0 (⫺5, 6)
138 (127, 146) ⫺13 (⫺19, ⫺6)
42 (35, 48) 4 (0, 11) 282 (230, 364) ⫺27 (⫺42, ⫺16)
ⱖ99.0
80.4–⬍99.0
38 (36, 45) ⫺1 (⫺7, 5) 281 (227, 332) ⫺8 (⫺18, 2)
47 (41, 55) 2 (⫺4, 7) 268 (224, 299) ⫺32 (⫺42, ⫺18)
Placebo (n ⫽ 46) 50 (44, 60) ⫺10 (⫺16, 2) 138 (124, 148) ⫺4 (⫺11, 4) 43 (39, 50) ⫺1 (⫺9, 6) 269 (222, 347) ⫺5 (⫺18, 6)
P-OM3 (n ⫽ 39)
Placebo (n ⫽ 45)
51 (45, 58) ⫺29 (⫺41, ⫺11)
50 (46, 57) ⫺7 (⫺15, 8)
153 (141, 169) ⫺11 (⫺16, ⫺3)
159 (153, 181) ⫺2 (⫺12, 8)
49 (43, 54) 4 (⫺3, 13) 255 (220, 313) ⫺30 (⫺43, ⫺14)
47 (42, 54) ⫺1 (⫺5, 2) 261 (233, 290) ⫺6 (⫺14, 12)
Data are presented as median (interquartile limits).
blind treatment phase. During the treatment phase, the patients underwent 8 weeks of the Therapeutic Lifestyle Changes diet and received 40 mg/day simvastatin therapy combined with either 4 g/day P-OM3 (Lovaza, previously known as Omacor, GlaxoSmithKline, Philadelphia, Pennsylvania) or placebo. The prespecified primary outcome variable was the nonHDL cholesterol concentration (calculated as the difference between the total cholesterol and HDL cholesterol concentrations). Additional outcome variables included the levels of TG, VLDL cholesterol (calculated), LDL cholesterol (direct), and HDL cholesterol. The fasting serum lipoprotein lipids were analyzed by the Mayo Central Laboratory for Clinical Trials (Rochester, Minnesota), as previously described.9 Statistical analyses were generated using Statistical Analysis Systems for the personal computer, version 8.0 or greater (SAS Institute, Cary, North Carolina). The baseline lipoprotein lipid values were calculated as the average of the values collected at weeks ⫺2, ⫺1, and 0. The end-oftreatment values were defined as the average of those collected at weeks 6 and 8, with the last observation carried forward (nonbaseline values only) for the subjects with missing end-of-treatment data. Two-way analysis of variance was used to assess the relations between the baseline levels of LDL cholesterol and the TG and lipid responses. Each analysis of variance model used the percentage of change from the baseline LDL cholesterol as the dependent variable and contained terms for treatment group, baseline LDL cholesterol or TG tertile, and treatment by baseline tertile interaction as independent variables. As with the primary analysis reported in the COMBOS study,9 the analyses were based on ranks because of the significant non-normality for several variables. Results In the double-blind study, 256 subjects were randomly assigned to receive P-OM3 (n ⫽ 123) or placebo (n ⫽ 133),
Figure 1. Median percentage of changes in LDL cholesterol by treatment group and baseline LDL cholesterol tertile for subjects receiving doubleblind simvastatin 40 mg/day plus either P-OM3 4 g/day or placebo for 8 weeks. Cut point was ⬍80.4 and ⱖ99.0 mg/dl for upper and lower bound of first and third tertiles, respectively. p ⫽ 0.022 for treatment group by baseline LDL cholesterol tertile interaction.
and 254 were included in the modified intent-to-treat analyses.9 The subjects were predominantly men (57.5%) and non-Hispanic white (95.7%) and had a mean age of 59.8 years. No treatment by tertile interaction was present for the baseline tertiles of TG (data not shown). The lipoprotein lipid concentrations at baseline and the responses according to the baseline LDL cholesterol tertile are listed in Table 1. The baseline LDL cholesterol tertile had a significant interaction with treatment for the LDL cholesterol response (p ⫽ 0.022). The percentage of changes in LDL cholesterol from baseline to the end of treatment according to treatment group and baseline LDL cholesterol tertile are shown in Figure 1. The largest increase relative to placebo in the LDL cholesterol concentration occurred in the group of subjects with the lowest baseline LDL cholesterol and was offset by a larger decrease in the VLDL cholesterol concentration
Preventive Cardiology/LDL Cholesterol and P-OM3 Therapy
(Table 1), resulting in a net reduction in non-HDL cholesterol in all tertiles (Table 1). Discussion The results of the present post hoc analysis suggest that the increase in LDL cholesterol reported in the COMBOS study9 was largely attributable to subjects with a baseline (during simvastatin monotherapy) LDL cholesterol level in the lowest tertile (⬍80.4 mg/dl). Furthermore, although the LDL cholesterol concentration increases were most pronounced in those with a low baseline LDL cholesterol concentration, VLDL cholesterol was reduced to a larger extent, resulting in a net decrease in the concentration of cholesterol carried by atherogenic particles (non-HDL cholesterol) across all baseline LDL cholesterol tertiles. The principal components of non-HDL cholesterol are VLDL cholesterol and LDL cholesterol, but non-HDL cholesterol also includes cholesterol carried by other potentially atherogenic lipoproteins, including partially degraded chylomicron particles.18 Non-HDL cholesterol was identified by the National Cholesterol Education Program Third Adult Treatment Panel as a secondary target of therapy for patients with a TG concentration of ⱖ200 mg/dl, because of its ability to enhance coronary heart disease risk prediction beyond that of LDL cholesterol alone. Data from large cohort studies,19 –21 intervention trials,22 and meta-analyses23 have consistently shown that the non-HDL cholesterol concentration is a stronger predictor of cardiovascular disease event rates than LDL cholesterol in men and women. Non-HDL cholesterol has also been strongly correlated with the apolipoprotein B-100 concentration, a direct indicator of the number of circulating atherogenic particles of hepatic origin.18 Studies have shown that treatment with omega-3 fatty acids reduces the rate of entry of VLDL particles into the circulation,6,7 lowers the circulating level of apolipoprotein CIII,24 –27 and increases the rate at which VLDL particles are converted to particles in the LDL density range.6,7,27,28 More rapid conversion to LDL particles might result because P-OM3 treatment lowers the circulating levels of apolipoprotein CIII. Because apolipoprotein CIII inhibits lipoprotein lipase activity,29 reducing the level in the circulation would be expected to enhance delipidation of TG-rich lipoproteins and increase the fractional rate of VLDL conversion to LDL particles.6,7 In addition, P-OM3 treatment might shift hepatic secretion toward VLDL particles that are smaller and less rich in TG,30 thereby requiring less delipidation to convert to LDL particles. An examination of the LDL particle concentration changes in the COMBOS study indicated that the total circulating concentration of LDL particles was not altered by P-OM3 treatment27 and that the increase in LDL cholesterol was attributable to a shift toward larger, more cholesterol-rich LDL particles. These results are consistent with those reported from a similar trial that used P-OM3 combined with 20 mg/day simvastatin,11 confirming that the addition of P-OM3 to simvastatin therapy does not change the total number of circulating LDL particles but does alter their distribution across the spectrum of particle sizes. Ad-
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ditional research is necessary to assess the possible clinical implications of the changes in LDL subclasses. Subjects with the lowest levels of LDL cholesterol during the diet plus simvastatin lead-in likely had lower pretreatment LDL cholesterol levels, a greater responsiveness to simvastatin therapy, or some combination of these characteristics. Because all the subjects in the COMBOS study had been treated with statin therapy before enrollment, the pretreatment lipid levels and responsiveness to simvastatin could not be assessed in the present study. Nevertheless, our findings suggest that LDL cholesterol should be periodically monitored during P-OM3 therapy, and, where necessary, the treatment regimen should be modified to ensure that both non-HDL cholesterol and LDL cholesterol treatment goals are achieved and maintained.18 Acknowledgment: All listed authors met the criteria for authorship set forth by the International Committee for Medical Journal Editors. We acknowledge the following GlaxoSmithKline employees for their editorial contributions to the draft versions and critical review of this report: Robert Samuels, MS; Rose Snipes, MD; Amy Meadowcroft, PharmD; Rosemary Schroyer, MS. Manuscript writing and editorial support for the development of this report was provided by Kevin C. Maki, PhD, and Mary R. Dicklin, PhD, of Provident Clinical Research and was funded by GlaxoSmithKline, Whitehouse Station, New Jersey. 1. Harris WS, Ginsberg H, Arunakul N, Shachter NS, Windsor SL, Adams M, Berglund L, Osmundsen K. Safety and efficacy of Omacor in severe hypertriglyceridemia. J Cardiovasc Risk 1997;4:385–391. 2. Harris WS, Lu G, Rambjør GS, Wålen AI, Ontko JA, Cheng Q, Windsor SL. Influence of n-3 fatty acid supplementation on the endogenous activities of plasma lipases. Am J Clin Nutr 1997;66:254 – 260. 3. Nordøy A, Bønaa KH, Nilsen H, Berge RK, Hansen JB, Ingebretsen OC. Effects of simvastatin and omega-3 fatty acids on plasma lipoproteins and lipid peroxidation in patients with combined hyperlipidaemia. J Intern Med 1998;243:163–170. 4. Nordøy A, Hansen JB, Brox J, Svensson B. Effects of atorvastatin and omega-3 fatty acids on LDL subfractions and postprandial hyperlipemia in patients with combined hyperlipemia. Nutr Metab Cardiovasc Dis 2001;11:7–16. 5. Durrington PN, Bhatnagar D, Mackness MI, Morgan J, Julier K, Khan MA, France M. An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia. Heart 2001;85:544 –548. 6. Chan DC, Watts GF, Barrett PHR, Beilin LJ, Redgrave TG, Mori TA. Regulatory effects of HMG CoA reductase inhibitor and fish oils on apolipoprotein B-100 kinetics in insulin-resistant obese male subjects with dyslipidemia. Diabetes 2002;51:2377–2386. 7. Chan DC, Watts GF, Mori TA, Barrett PHR, Redgrave TG, Beilin LJ. Randomized controlled trial of the effect of n-3 fatty acid supplementation on the metabolism of apolipoprotein B-100 and chylomicron remnants in men with visceral obesity. Am J Clin Nutr 2003;77:300 – 307. 8. Ginsberg HN. Hypertriglyceridemia: new insights and new approaches to pharmacologic therapy. Am J Cardiol 2001;87:1174 –1180. 9. Davidson MH, Stein SE, Bays HE, Maki KC, Doyle RT, Shalwitz RA, Ballantyne CM, Ginsberg HN. Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study. Clin Ther 2007;29:1354 –1367.
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10. Barter P, Ginsberg HN. Effectiveness of combined statin plus omega-3 fatty acid therapy for mixed dyslipidemia. Am J Cardiol 2008;102: 1040 –1045. 11. Maki KC, McKenney JM, Reeves MS, Lubin BC, Dicklin MR. Effects of adding prescription omega-3 acid ethyl esters to simvastatin (20 mg/day) on lipids and lipoprotein particles in men and women with mixed dyslipidemia. Am J Cardiol 2008;102:429 – 433. 12. Maki KC, Lubin BC, Reeves MS, Dicklin MR, Harris WS. Prescription omega-3 acid ethyl esters plus simvastatin 20 and 80 mg: effects in mixed dyslipidemia. J Clin Lipidol 2009;3:33–38. 13. Bays H, McKenney J, Maki KC, Doyle R, Carter RN, Stein E. Effects of prescription omega-3-acid ethyl esters on non-high-density lipoprotein cholesterol when coadministered with escalating doses of atorvastatin. Mayo Clin Proc 2010;85:122–128. 14. Sullivan DR, Sanders TA, Trayner IM, Thompson GR. Paradoxical elevation of LDL apoprotein B levels in hypertriglyceridaemic patients and normal subjects ingesting fish oil. Atherosclerosis 1986;61:129 – 134. 15. Pownall HJ, Brauchi D, Kilinc C, Osmundsen K, Pao Q, Payton-Ross C, Gotto AM Jr, Ballantyne CM. Correlation of serum triglyceride and its reduction by omega-3 fatty acids with lipid transfer activity and the neutral lipid compositions of high-density and low-density lipoproteins. Atherosclerosis 1999;143:285–297. 16. Calabresi L, Donati D, Pazzucconi F, Sirtori CR, Franceschini G. Omacor in familial combined hyperlipidemia: effects on lipids and low density lipoprotein subclasses. Atherosclerosis 2000;148:387–396. 17. McKenney JM, Sica D. Role of prescription omega-3 fatty acids in the treatment of hypertriglyceridemia. Pharmacotherapy 2007;27:715– 728. 18. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143–3421. 19. Pischon T, Girman CJ, Sacks FM, Rifai N, Stampfer MJ, Rimm EB. Non-high-density lipoprotein cholesterol and apolipoprotein B in the prediction of coronary heart disease in men. Circulation 2005;112: 3375–3383. 20. Liu J, Sempos CT, Donahue RP, Dorn J, Trevisan M, Grundy SM. Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their risk predictive values in coronary heart disease. Am J Cardiol 2006;98:1363–1368.
21. Mora S, Otvos JD, Rifai N, Rosenson RS, Buring JE, Ridker PM. Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women. Circulation 2009;119:931–939. 22. Kastelein JJ, van der Steeg WA, Holme I, Gaffney M, Cater NB, Barter P, Deedwania P, Olsson AG, Boekholdt SM, Demicco DA, Szarek M, LaRosa JC, Pedersen TR, Grundy SM; TNT Study Group; IDEAL Study Group. Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment. Circulation 2008; 117:3002–3009. 23. Robinson JG, Wang S, Smith BJ, Jacobson TA. Meta-analysis of the relationship between non-high-density lipoprotein cholesterol reduction and coronary heart disease risk. J Am Coll Cardiol 2009;53:316 – 322. 24. Schoonjans K, Staels B, Auwex J. Role of peroxisome proliferatoractivated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J Lipid Res 1996;37:907–925. 25. Swahn E, von Schenck H, Olsson AG. Omega-3 ethyl ester concentrate decreases total apolipoprotein CIII and increases antithrombin III in postmyocardial infarction patients. Clin Drug Invest 1998;15:473– 482. 26. Olivieri O, Martinelli N, Sandri M, Bassi A, Guarini P, Trabetti E, Pizzolo F, Girelli D, Friso S, Pignatti PF, Corrocher R. Apolipoprotein C-III, n-3 polyunsaturated fatty acids, and “Insulin-Resistant” T-455C APOC3 gene polymorphism in heart disease patients: example of gene– diet interaction. Clin Chem 2005;51:360 –367. 27. Davidson MH, Maki KC, Bays HE, Carter R, Ballantyne CM. Effects of prescription omega-3-acid ethyl esters on lipoprotein particle concentrations, apolipoproteins AI and CIII, and lipoprotein-associated phospholipase A2 mass in statin-treated subjects with hypertriglyceridemia. J Clin Lipidol 2009;3:333–320. 28. Huff MW, Telford DE. Dietary fish oil increases conversion of very low density lipoprotein apoprotein B to low density lipoprotein. Arteriosclerosis 1989;9:58 – 66. 29. Ginsberg HN, Le N-A, Goldberg IJ, Gibson JC, Rubinstein A, WangIverson P, Norum R, Brown WV. Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo. J Clin Invest 1986;78:1287–1295. 30. Harris WS, Miller M, Tighe AP, Davidson MH, Schaefer EJ. Omega-3 fatty acids and coronary heart disease risk: clinical and mechanistic perspectives. Atherosclerosis 2008;197:12–24.
a
Provident Clinical Research, Glen Ellyn, Illinois and Bloomington, Indiana; bRadiant Research, Chicago, Illinois; cGlaxoSmithKline, Research Triangle Park, North Carolina; dCenter for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Baylor College of Medicine, Houston, Texas; and eThe University of Chicago Pritzker School of Medicine, Chicago, Illinois. Manuscript received October 20, 2009; revised manuscript received and accepted December 22, 2009. This trial was funded by grant NCT00246701 from GlaxoSmithKline, Research Triangle Park, North Carolina. *Corresponding author: Tel: (630) 858-4400; fax: (630) 858-4490. E-mail address: [email protected] (K.C. Maki). 0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.12.063
density lipoprotein (VLDL) cholesterol, and non–HDL cholesterol and increased the HDL cholesterol in patients with mixed dyslipidemia. During treatment, a trend was seen for an increase in LDL cholesterol with P-OM3 relative to placebo (⫹0.7% vs ⫺2.8%, p ⫽ 0.052).9 The present post hoc analysis of data from the COMBOS study9 was undertaken to examine the relation between the baseline concentrations of LDL cholesterol and TG and the LDL cholesterol response to P-OM3 when combined with simvastatin therapy. Methods A full description of the procedures and main results from the COMBOS study have been previously published.9 In brief, the participants were men and women 18 to 79 years old who had been receiving stable-dose statin therapy for ⱖ8 weeks at study enrollment. The subjects completed an 8-week lead-in of the National Cholesterol Education Program Therapeutic Lifestyle Changes diet plus 40 mg/day simvastatin therapy (Zocor, Merck, Whitehouse Station, New Jersey). After the lead-in phase, those who had a fasting TG concentration of 200 to 499 mg/dl and LDL cholesterol concentration of ⱕ10% above their National Cholesterol Education Program Third Adult Treatment Panel treatment goal18 were eligible to enter the doublewww.AJConline.org
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Table 1 Lipoprotein lipid responses according to baseline low-density lipoprotein (LDL) cholesterol tertile in subjects receiving simvastatin 40 mg/day plus either prescription omega-3 acid ethyl esters (P-OM3) 4 g/day or placebo for 8 weeks Lipid Parameter
LDL Cholesterol (mg/dl) ⬍80.4
Very-low-density lipoprotein cholesterol Baseline (mg/dl) Change (%) Non–high-density lipoprotein cholesterol Baseline (mg/dl) Change (%) High-density lipoprotein cholesterol Baseline (mg/dl) Change (%) Triglycerides Baseline (mg/dl) Change (%)
P-OM3 (n ⫽ 43)
Placebo (n ⫽ 41)
P-OM3 (n ⫽ 40)
52 (45, 60) ⫺27 (⫺39, ⫺15)
54 (45, 62) ⫺7 (⫺19, 1)
53 (45, 59) ⫺28 (⫺36, ⫺13)
112 (105, 127) ⫺5 (⫺14, 5)
113 (103, 126) 0 (⫺5, 6)
138 (127, 146) ⫺13 (⫺19, ⫺6)
42 (35, 48) 4 (0, 11) 282 (230, 364) ⫺27 (⫺42, ⫺16)
ⱖ99.0
80.4–⬍99.0
38 (36, 45) ⫺1 (⫺7, 5) 281 (227, 332) ⫺8 (⫺18, 2)
47 (41, 55) 2 (⫺4, 7) 268 (224, 299) ⫺32 (⫺42, ⫺18)
Placebo (n ⫽ 46) 50 (44, 60) ⫺10 (⫺16, 2) 138 (124, 148) ⫺4 (⫺11, 4) 43 (39, 50) ⫺1 (⫺9, 6) 269 (222, 347) ⫺5 (⫺18, 6)
P-OM3 (n ⫽ 39)
Placebo (n ⫽ 45)
51 (45, 58) ⫺29 (⫺41, ⫺11)
50 (46, 57) ⫺7 (⫺15, 8)
153 (141, 169) ⫺11 (⫺16, ⫺3)
159 (153, 181) ⫺2 (⫺12, 8)
49 (43, 54) 4 (⫺3, 13) 255 (220, 313) ⫺30 (⫺43, ⫺14)
47 (42, 54) ⫺1 (⫺5, 2) 261 (233, 290) ⫺6 (⫺14, 12)
Data are presented as median (interquartile limits).
blind treatment phase. During the treatment phase, the patients underwent 8 weeks of the Therapeutic Lifestyle Changes diet and received 40 mg/day simvastatin therapy combined with either 4 g/day P-OM3 (Lovaza, previously known as Omacor, GlaxoSmithKline, Philadelphia, Pennsylvania) or placebo. The prespecified primary outcome variable was the nonHDL cholesterol concentration (calculated as the difference between the total cholesterol and HDL cholesterol concentrations). Additional outcome variables included the levels of TG, VLDL cholesterol (calculated), LDL cholesterol (direct), and HDL cholesterol. The fasting serum lipoprotein lipids were analyzed by the Mayo Central Laboratory for Clinical Trials (Rochester, Minnesota), as previously described.9 Statistical analyses were generated using Statistical Analysis Systems for the personal computer, version 8.0 or greater (SAS Institute, Cary, North Carolina). The baseline lipoprotein lipid values were calculated as the average of the values collected at weeks ⫺2, ⫺1, and 0. The end-oftreatment values were defined as the average of those collected at weeks 6 and 8, with the last observation carried forward (nonbaseline values only) for the subjects with missing end-of-treatment data. Two-way analysis of variance was used to assess the relations between the baseline levels of LDL cholesterol and the TG and lipid responses. Each analysis of variance model used the percentage of change from the baseline LDL cholesterol as the dependent variable and contained terms for treatment group, baseline LDL cholesterol or TG tertile, and treatment by baseline tertile interaction as independent variables. As with the primary analysis reported in the COMBOS study,9 the analyses were based on ranks because of the significant non-normality for several variables. Results In the double-blind study, 256 subjects were randomly assigned to receive P-OM3 (n ⫽ 123) or placebo (n ⫽ 133),
Figure 1. Median percentage of changes in LDL cholesterol by treatment group and baseline LDL cholesterol tertile for subjects receiving doubleblind simvastatin 40 mg/day plus either P-OM3 4 g/day or placebo for 8 weeks. Cut point was ⬍80.4 and ⱖ99.0 mg/dl for upper and lower bound of first and third tertiles, respectively. p ⫽ 0.022 for treatment group by baseline LDL cholesterol tertile interaction.
and 254 were included in the modified intent-to-treat analyses.9 The subjects were predominantly men (57.5%) and non-Hispanic white (95.7%) and had a mean age of 59.8 years. No treatment by tertile interaction was present for the baseline tertiles of TG (data not shown). The lipoprotein lipid concentrations at baseline and the responses according to the baseline LDL cholesterol tertile are listed in Table 1. The baseline LDL cholesterol tertile had a significant interaction with treatment for the LDL cholesterol response (p ⫽ 0.022). The percentage of changes in LDL cholesterol from baseline to the end of treatment according to treatment group and baseline LDL cholesterol tertile are shown in Figure 1. The largest increase relative to placebo in the LDL cholesterol concentration occurred in the group of subjects with the lowest baseline LDL cholesterol and was offset by a larger decrease in the VLDL cholesterol concentration
Preventive Cardiology/LDL Cholesterol and P-OM3 Therapy
(Table 1), resulting in a net reduction in non-HDL cholesterol in all tertiles (Table 1). Discussion The results of the present post hoc analysis suggest that the increase in LDL cholesterol reported in the COMBOS study9 was largely attributable to subjects with a baseline (during simvastatin monotherapy) LDL cholesterol level in the lowest tertile (⬍80.4 mg/dl). Furthermore, although the LDL cholesterol concentration increases were most pronounced in those with a low baseline LDL cholesterol concentration, VLDL cholesterol was reduced to a larger extent, resulting in a net decrease in the concentration of cholesterol carried by atherogenic particles (non-HDL cholesterol) across all baseline LDL cholesterol tertiles. The principal components of non-HDL cholesterol are VLDL cholesterol and LDL cholesterol, but non-HDL cholesterol also includes cholesterol carried by other potentially atherogenic lipoproteins, including partially degraded chylomicron particles.18 Non-HDL cholesterol was identified by the National Cholesterol Education Program Third Adult Treatment Panel as a secondary target of therapy for patients with a TG concentration of ⱖ200 mg/dl, because of its ability to enhance coronary heart disease risk prediction beyond that of LDL cholesterol alone. Data from large cohort studies,19 –21 intervention trials,22 and meta-analyses23 have consistently shown that the non-HDL cholesterol concentration is a stronger predictor of cardiovascular disease event rates than LDL cholesterol in men and women. Non-HDL cholesterol has also been strongly correlated with the apolipoprotein B-100 concentration, a direct indicator of the number of circulating atherogenic particles of hepatic origin.18 Studies have shown that treatment with omega-3 fatty acids reduces the rate of entry of VLDL particles into the circulation,6,7 lowers the circulating level of apolipoprotein CIII,24 –27 and increases the rate at which VLDL particles are converted to particles in the LDL density range.6,7,27,28 More rapid conversion to LDL particles might result because P-OM3 treatment lowers the circulating levels of apolipoprotein CIII. Because apolipoprotein CIII inhibits lipoprotein lipase activity,29 reducing the level in the circulation would be expected to enhance delipidation of TG-rich lipoproteins and increase the fractional rate of VLDL conversion to LDL particles.6,7 In addition, P-OM3 treatment might shift hepatic secretion toward VLDL particles that are smaller and less rich in TG,30 thereby requiring less delipidation to convert to LDL particles. An examination of the LDL particle concentration changes in the COMBOS study indicated that the total circulating concentration of LDL particles was not altered by P-OM3 treatment27 and that the increase in LDL cholesterol was attributable to a shift toward larger, more cholesterol-rich LDL particles. These results are consistent with those reported from a similar trial that used P-OM3 combined with 20 mg/day simvastatin,11 confirming that the addition of P-OM3 to simvastatin therapy does not change the total number of circulating LDL particles but does alter their distribution across the spectrum of particle sizes. Ad-
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ditional research is necessary to assess the possible clinical implications of the changes in LDL subclasses. Subjects with the lowest levels of LDL cholesterol during the diet plus simvastatin lead-in likely had lower pretreatment LDL cholesterol levels, a greater responsiveness to simvastatin therapy, or some combination of these characteristics. Because all the subjects in the COMBOS study had been treated with statin therapy before enrollment, the pretreatment lipid levels and responsiveness to simvastatin could not be assessed in the present study. Nevertheless, our findings suggest that LDL cholesterol should be periodically monitored during P-OM3 therapy, and, where necessary, the treatment regimen should be modified to ensure that both non-HDL cholesterol and LDL cholesterol treatment goals are achieved and maintained.18 Acknowledgment: All listed authors met the criteria for authorship set forth by the International Committee for Medical Journal Editors. We acknowledge the following GlaxoSmithKline employees for their editorial contributions to the draft versions and critical review of this report: Robert Samuels, MS; Rose Snipes, MD; Amy Meadowcroft, PharmD; Rosemary Schroyer, MS. Manuscript writing and editorial support for the development of this report was provided by Kevin C. Maki, PhD, and Mary R. Dicklin, PhD, of Provident Clinical Research and was funded by GlaxoSmithKline, Whitehouse Station, New Jersey. 1. Harris WS, Ginsberg H, Arunakul N, Shachter NS, Windsor SL, Adams M, Berglund L, Osmundsen K. Safety and efficacy of Omacor in severe hypertriglyceridemia. J Cardiovasc Risk 1997;4:385–391. 2. Harris WS, Lu G, Rambjør GS, Wålen AI, Ontko JA, Cheng Q, Windsor SL. Influence of n-3 fatty acid supplementation on the endogenous activities of plasma lipases. Am J Clin Nutr 1997;66:254 – 260. 3. Nordøy A, Bønaa KH, Nilsen H, Berge RK, Hansen JB, Ingebretsen OC. Effects of simvastatin and omega-3 fatty acids on plasma lipoproteins and lipid peroxidation in patients with combined hyperlipidaemia. J Intern Med 1998;243:163–170. 4. Nordøy A, Hansen JB, Brox J, Svensson B. Effects of atorvastatin and omega-3 fatty acids on LDL subfractions and postprandial hyperlipemia in patients with combined hyperlipemia. Nutr Metab Cardiovasc Dis 2001;11:7–16. 5. Durrington PN, Bhatnagar D, Mackness MI, Morgan J, Julier K, Khan MA, France M. An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia. Heart 2001;85:544 –548. 6. Chan DC, Watts GF, Barrett PHR, Beilin LJ, Redgrave TG, Mori TA. Regulatory effects of HMG CoA reductase inhibitor and fish oils on apolipoprotein B-100 kinetics in insulin-resistant obese male subjects with dyslipidemia. Diabetes 2002;51:2377–2386. 7. Chan DC, Watts GF, Mori TA, Barrett PHR, Redgrave TG, Beilin LJ. Randomized controlled trial of the effect of n-3 fatty acid supplementation on the metabolism of apolipoprotein B-100 and chylomicron remnants in men with visceral obesity. Am J Clin Nutr 2003;77:300 – 307. 8. Ginsberg HN. Hypertriglyceridemia: new insights and new approaches to pharmacologic therapy. Am J Cardiol 2001;87:1174 –1180. 9. Davidson MH, Stein SE, Bays HE, Maki KC, Doyle RT, Shalwitz RA, Ballantyne CM, Ginsberg HN. Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study. Clin Ther 2007;29:1354 –1367.
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