Journal of Clinical Lipidology
Volume 6, Issue 1 , Pages 5-18 , January 2012

Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: A review

  • Terry A. Jacobson, MD

      Affiliations

    • Office of Health Promotion and Disease Prevention, Department of Medicine, Emory University School of Medicine, Faculty Office Building, 49 Jesse Hill Jr. Drive SE, Atlanta, GA 30303, USA
    • Corresponding Author InformationCorresponding author.
  • ,
  • Sara B. Glickstein, PhD

      Affiliations

    • Rete Biomedical Communications Corp., Wyckoff, NJ, USA
  • ,
  • Jonathan D. Rowe, PhD

      Affiliations

    • When the manuscript was drafted, Dr. Rowe was an employee of, and minor shareholder in, the study sponsor. His current affiliation is Dignity Sciences Ltd.
    • Dignity Sciences Ltd, Dublin, Ireland
  • ,
  • Paresh N. Soni, MD, PhD

      Affiliations

    • Amarin Corporation, Mystic, CT, USA

Received 4 April 2011 ,Accepted 23 October 2011.

References 

  1. Cohen JD, Cziraky MJ, Cai Q, et al. 30-year trends in serum lipids among United States adults: results from the National Health and Nutrition Examination Surveys II, III, and 1999-2006. Am J Cardiol. 2010;106:969–975
  2. Kris-Etherton PM, Harris WS, Appel LJ American Heart Association Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106:2747–2757
  3. 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
  4. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090–1098
  5. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet. 1999;354:447–455
  6. Lovaza® (omega-3-acid ethyl esters) [US full prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2009. Available at: http://us.gsk.com/products/assets/us_lovaza.pdf. Accessed March 23, 2011.
  7. Epadel® [Complete prescribing information]. Update (Version 5). Tokyo, Japan: Mochida Pharmaceutical; January 2007.
  8. Harris WS, Ginsberg HN, Arunakul N, et al. Safety and efficacy of Omacor in severe hypertriglyceridemia. J Cardiovasc Risk. 1997;4:385–391
  9. Pownall HJ, Brauchi D, Kilinç C, et al. 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
  10. Center for Drug Evaluation and Research. Approval Package for: 21-654 (Omacor/Lovaza). Statistical Review; 2004. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-654_Omacor_AdminCorres_P1.pdf. Accessed June 24, 2011.
  11. Maki KC, Dicklin MR, Davidson MH, Doyle RT, Ballantyne CM COMBination of prescription Omega-3 with Simvastatin (COMBOS) Investigators. Baseline lipoprotein lipids and low-density lipoprotein cholesterol response to prescription omega-3 acid ethyl ester added to simvastatin therapy. Am J Cardiol. 2010;105:1409–1412
  12. Davidson MH, Stein EA, Bays HE, et al. 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
  13. Bays HE, Maki KC, McKenney J, et al. Long-term up to 24-month efficacy and safety of concomitant prescription omega-3-acid ethyl esters and simvastatin in hypertriglyceridemic patients. Curr Med Res Opin. 2010;26:907–915
  14. Center for Drug Evaluation and Research. Application Number: 21-853, 21654s016, (Omacor). Statistical Review and Evaluation: Clinical Studies, Omacor (omega-3 acid ethyl ester) Capsules, 4 grams/day; 2007. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021853s000;%20021654s016_StatR.pdf. Accessed June 24, 2011.
  15. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–1278
  16. Balk EM, Lichtenstein AH, Chung M, Kupelnick B, Chew P, Lau J. Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic review. Atherosclerosis. 2006;189:19–30
  17. Hartweg J, Farmer AJ, Holman RR, Neil A. Potential impact of omega-3 treatment on cardiovascular disease in type 2 diabetes. Curr Opin Lipidol. 2009;20:30–38
  18. Lien EL. Toxicology and safety of DHA. Prostaglandins Leukot Essent Fatty Acids. 2009;81:125–132
  19. Haney EM, Huffman LH, Bougatsos C, et al. Screening for lipid disorders in children and adolescents; Systematic evidence review for the U.S. Preventive Services Task Force (evidence synthesis). No. 47. Rockville, MD: Agency for Healthcare Research and Quality, US Department of Health and Human Services; AHRQ Publication No. 07-0598-EF-1; July 2007. Available at: http://www.uspreventiveservicestaskforce.org/uspstf07/chlipid/chlipidsyn.pdf. Accessed March 23, 2011.
  20. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502
  21. Egert S, Kannenberg F, Somoza V, Erbersdobler HF, Wahrburg U. Dietary alpha-linolenic acid, EPA, and DHA have differential effects on LDL fatty acid composition but similar effects on serum lipid profiles in normolipidemic humans. J Nutr. 2009;139:861–868
  22. Grimsgaard S, Bonaa KH, Hansen JB, Nordøy A. Highly purified eicosapentaenoic acid and docosahexaenoic acid in humans have similar triacylglycerol-lowering effects but divergent effects on serum fatty acids. Am J Clin Nutr. 1997;66:649–659
  23. Mori TA, Burke V, Puddey IB, Watts GF, O’Neal DN, Best JD, et al. Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men. Am J Clin Nutr. 2000;71:1085–1094
  24. Nestel P, Shige H, Pomeroy S, Cehun M, Abbey M, Raederstorff D. The n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid increase systemic arterial compliance in humans. Am J Clin Nutr. 2002;76:326–330
  25. Park Y, Harris WS. Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance. J Lipid Res. 2003;44:455–463
  26. Woodman RJ, Mori TA, Burke V, Puddey IB, Watts GF, Beilin LJ. Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension. Am J Clin Nutr. 2002;76:1007–1015
  27. Ando M, Sanaka T, Nihei H. Eicosapentanoic acid reduces plasma levels of remnant lipoproteins and prevents in vivo peroxidation of LDL in dialysis patients. J Am Soc Nephrol. 1999;10:2177–2184
  28. Kurabayashi T, Okada M, Tanaka K. Eicosapentaenoic acid effect on hyperlipidemia in menopausal Japanese women. The Niigata Epadel Study Group. Obstet Gynecol. 2000;96:521–528
  29. Satoh N, Shimatsu A, Kotani K, et al. Purified eicosapentaenoic acid reduces small dense LDL, remnant lipoprotein particles, and C-reactive protein in metabolic syndrome. Diabetes Care. 2007;30:144–146
  30. Tanaka K, Ishikawa Y, Yokoyama M, et al. Reduction in the recurrence of stroke by eicosapentaenoic acid for hypercholesterolemic patients: subanalysis of the JELIS trial. Stroke. 2008;39:2052–2058
  31. Agren JJ, Hänninen O, Julkunen A, et al. Fish diet, fish oil and docosahexaenoic acid rich oil lower fasting and postprandial plasma lipid levels. Eur J Clin Nutr. 1996;50:765–771
  32. Conquer JA, Holub BJ. Supplementation with an algae source of docosahexaenoic acid increases (n-3) fatty acid status and alters selected risk factors for heart disease in vegetarian subjects. J Nutr. 1996;126:3032–3039
  33. Conquer JA, Holub BJ. Effect of supplementation with different doses of DHA on the levels of circulating DHA as non-esterified fatty acid in subjects of Asian Indian background. J Lipid Res. 1998;39:286–292
  34. Davidson MH, Maki KC, Kalkowski J, Schaefer EJ, Torri SA, Drennan KB. Effects of docosahexaenoic acid on serum lipoproteins in patients with combined hyperlipidemia: a randomized, double-blind, placebo-controlled trial. J Am Coll Nutr. 1997;16:236–243
  35. Engler MM, Engler MB, Malloy M, et al. Docosahexaenoic acid restores endothelial function in children with hyperlipidemia: results from the EARLY study. Int J Clin Pharmacol Ther. 2004;42:672–679
  36. Geppert J, Kraft V, Demmelmair H, Koletzko B. Microalgal docosahexaenoic acid decreases plasma triacylglycerol in normolipidaemic vegetarians: a randomised trial. Br J Nutr. 2006;95:779–786
  37. Kelley DS, Siegel D, Vemuri M, Mackey BE. Docosahexaenoic acid supplementation improves fasting and postprandial lipid profiles in hypertriglyceridemic men. Am J Clin Nutr. 2007;86:324–333
  38. Maki KC, Van Elswyk ME, McCarthy D, et al. Lipid responses to a dietary docosahexaenoic acid supplement in men and women with below average levels of high density lipoprotein cholesterol. J Am Coll Nutr. 2005;24:189–199
  39. Sanders TA, Gleason K, Griffin B, Miller GJ. Influence of an algal triacylglycerol containing docosahexaenoic acid (22:6 n-3) and docosapentaenoic acid (22:5 n-6) on cardiovascular risk factors in healthy men and women. Br J Nutr. 2006;95:525–531
  40. Stark KD, Holub BJ. Differential eicosapentaenoic acid elevations and altered cardiovascular disease risk factor responses after supplementation with docosahexaenoic acid in postmenopausal women receiving and not receiving hormone replacement therapy. Am J Clin Nutr. 2004;79:765–773
  41. Theobald HE, Chowienczyk PJ, Whittall R, Humphries SE, Sanders TA. LDL cholesterol-raising effect of low-dose docosahexaenoic acid in middle-aged men and women. Am J Clin Nutr. 2004;79:558–563
  42. Wu WH, Lu SC, Wang TF, Jou HJ, Wang TA. Effects of docosahexaenoic acid supplementation on blood lipids, estrogen metabolism, and in vivo oxidative stress in postmenopausal vegetarian women. Eur J Clin Nutr. 2006;60:386–392
  43. Robinson JG, Wang S, Smith BJ, Jacobson TA. Meta-analysis of the relationship between non-high-density lipoprotein cholesterol reduction and coronary heart risk. J Am Coll Cardiol. 2009;53:316–322
  44. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. Br Med J. 2003;326:1423–1427
  45. Gould AL, Rossown JE, Santanello NC, Heyse JF, Furberg CD. Cholesterol reduction yields clinical benefit: impact of statin trials. Circulation. 1998;97:946–952
  46. Gordon DJ, Probstfield JL, Garrison RJ, et al. High density lipoprotein cholesterol and cardiovascular disease: four prospective American studies. Circulation. 1989;79:8–15
  47. Mori TA, Woodman RJ. The independent effects of eicosapentaenoic acid and docosahexaenoic acid on cardiovascular risk factors in humans. Curr Opin Clin Nutr Metab Care. 2006;9:95–104
  48. Ryan AS, Keske MA, Hoffman JP, Nelson EB. Clinical overview of algal-docosahexaenoic acid: effects on triglyceride levels and other cardiovascular risk factors. Am J Ther. 2009;16:183–192
  49. Schaefer EJ, Asztalos IB, Gleason JA, et al. Effects of eicosapentaenoic acid, docosahexaenoic acid, and olive oil on cardiovascular disease risk factors [abstract 20007]. Circulation. 2010;122:A20007
  50. Bays HE, Tighe AP, Sadovsky R, Davidson MH. Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications. Expert Rev Cardiovasc Ther. 2008;6:391–409
  51. Lu G, Windsor SL, Harris WS. Omega-3 fatty acids alter lipoprotein subfraction distributions and the in vitro conversion of very low density lipoproteins to low density lipoproteins. J Nutr Biochem. 1999;10:151–158
  52. Berge RK, Madsen L, Vaagenes H, Tronstad KJ, Göttlicher M, Rustan AC. In contrast with docosahexaenoic acid, eicosapentaenoic acid and hypolipidaemic derivatives decrease hepatic synthesis and secretion of triacylglycerol by decreased diacylglycerol acyltransferase activity and stimulation of fatty acid oxidation. Biochem J. 1999;343(Pt 1):191–197
  53. Chapman MJ, Le Goff W, Guerin M, Kontush A. Cholesteryl ester transfer protein: at the heart of the action of lipid-modulating therapy with statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors. Eur Heart J. 2010;31:149–164
  54. Hirano R, Igarashi O, Kondo K, Itakura H, Matsumoto A. Regulation by long-chain fatty acids of the expression of cholesteryl ester transfer protein in HepG2 cells. Lipids. 2001;36:401–406
  55. Nozaki S, Matsuzawa Y, Hirano K, Sakai N, Kubo M, Tarui S. Effects of purified eicosapentaenoic acid ethyl ester on plasma lipoproteins in primary hypercholesterolemia. Int J Vitam Nutr Res. 1992;62:256–260
  56. Campos H, Moye LA, Glasser SP, Stampfer MJ, Sacks FM. Low-density lipoprotein size, pravastatin treatment, and coronary events. JAMA. 2001;286:1468–1474
  57. Mora S, Szklo M, Otvos JD, et al. LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis. 2007;192:211–217
  58. Hannah J, Kataoka S, Yamane K, Schectman G, Kaul S, Howard BV. Effect of dietary fatty acids on LDL binding. Ann N Y Acad Sci. 1993;683:178–182
  59. Lindsey S, Pronczuk A, Hayes KC. Low density lipoprotein from humans supplemented with n-3 fatty acids depresses both LDL receptor activity and LDLr mRNA abundance in HepG2 cells. J Lipid Res. 1992;33:647–658
  60. Rambjør GS, Walen AI, Windsor SL, Harris WS. Eicosapentaenoic acid is primarily responsible for hypotriglyceridemic effect of fish oil in humans. Lipids. 1996;31(Suppl):S45–S49
  61. Roach PD, Kambouris AM, Trimble RP, Topping DL, Nestel PJ. The effects of dietary fish oil on hepatic high density and low density lipoprotein receptor activities in the rat. FEBS Lett. 1987;222:159–162
  62. Schectman G, Boerboom LE, Hannah J, Howard BV, Mueller RA, Kissebah AH. Dietary fish oil decreases low-density-lipoprotein clearance in nonhuman primates. Am J Clin Nutr. 1996;64:215–221
  63. Surette ME, Whelan J, Lu GP, Broughton KS, Kinsella JE. Dependence on dietary cholesterol for n-3 polyunsaturated fatty acid-induced changes in plasma cholesterol in the Syrian hamster. J Lipid Res. 1992;33:263–271
  64. Morton RE. Specificity of lipid transfer protein for molecular species of cholesteryl ester. J Lipid Res. 1986;27:523–529
  65. Nestel PJ. Effects of N-3 fatty acids on lipid metabolism. Ann Rev Nutr. 1990;10:149–167

PII: S1933-2874(11)00745-8

doi: 10.1016/j.jacl.2011.10.018

Journal of Clinical Lipidology
Volume 6, Issue 1 , Pages 5-18 , January 2012