Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Disclaimer
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Bhatnagar, D.
Right arrow Articles by Durrington, P.N.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Bhatnagar, D.
Right arrow Articles by Durrington, P.N.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?


Treatment of mixed hyperlipidaemia using a combination of omega-3 fatty acids and HMG CoA reductase inhibitor

D. Bhatnagar*,1,2, M.I. Mackness1 and P.N. Durrington1

1 University Department of Medicine, Manchester Royal Infirmary, UK
2 The Royal Oldham Hospital, UK

* Correspondence: Dr D. Bhatnagar, The Royal Oldham Hospital, Rochdale Road, Oldham OL1 2JH.

Abstract

Serum triglycerides tend to be particularly strong predictors of coronary risk. A meta-analysis of 17 population-based prospective studies indicates that after adjustment for highdensity lipoprotein (HDL) cholesterol, a 1 mmol . 1–1 increase in serum triglyceride level was associated with a 4% increase in risk in men and 37% in women. There is also evidence to indicate that serum triglyceride levels greater than 1·5 mmol. 1–1 are associated with the presence of the more atherogenic small and dense low-density lipoprotein (LDL) subtraction. Many patients who develop coronary heart disease (CHD) have both hypercholesterolaemia and hypertriglyceridaemia. When diet is improved hypertriglyceridaemia up to 4 mmol . 1– is often corrected, so that many of these patients can be managed on a statin alone. In some patients, however, and particularly those with genetic disorders such as familial combined hyperlipidaemia and the rarer remnant hyperlipidaemia (type III hyperlipoproteinaemia), the hyperlipidaemia responds poorly to lifestyle changes. In many patients with mixed hyperlipidaemia lipid-lowering monotherapy often produces improvement in serum cholesterol level, but not in serum triglyceride level or vice versa. One strategy is to use a combination of a statin and a fibrate in high-risk patients with mixed hyperlipidaemia. While effective, this combination increases the possibility of abnormal biochemical liver function tests and myalgia.

Concentrated omega-3 fatty acids can lower serum triglyceride levels by up to 38% in a dose-dependent manner. Serum cholesterol levels usually remain unchanged, but there is a modest increase of about 6% in HDL cholesterol. We carried out a randomized double-blind, placebo-controlled trial using a parallel group design to examine the triglyceride-lowering effects of Omacor® in patients with established CHD and type IIb hyperlipidaemia who were already on simvastatin. Our results show that, in patients with CHD and moderate hypertriglyceridaemia who were receiving simvastatin in a dose similar to that seen in the Scandinavian Simvastatin Survival Study, concentrated omega-3 fatty acids administration was effective in lowering serum triglyceride levels.

Further long-term studies are needed to see if effective triglyceride level lowering using this combination will result in a decrease in new CHD events including non-fatal myocardial infarction over and above of that seen with statin use alone.

Key Words: Hyperlipidaemia • triglycerides • cholesterol • omega 3-fatty acids • statins

References

  1. Durrington PN. Hyperlipidaemia. Diagnosis and Management. 2nd edn. London: Butterworth Heinemann; 1995.
  2. Bhatnagar D. Hypertriglyceridaemia. Chapter 42 Betteridge J, Illingworth J, Shepherd DR. Lipoproteins in Health and Disease. 2nd edn. London: Edward Arnold; 1999.
  3. Criqui MIL. Triglycerides and cardiovascular disease. A focus on clinical trials. Eur Heart J. 1998;19(Suppl A):A36–A39
  4. Durrington PN. Triglycerides are more important in atherosclerosis than epidemiology has suggested. Atherosclerosis. 1998;141(Suppl 1):S57–S62
  5. Lewis B, Chair A, Wootton LDP, et al. Frequency of risk factors for ischaemic heart disease in a British population. Lancet. 1974;i:141–144
  6. Hamsten A, Walldius G, Dahlen G, et al. Serum lipoproteins and apolipoproteins in young male survivors of myocardial infarction. Atherosclerosis. 1985;59:223–235
  7. Hamsten A. Hypertriglyceridaemia, triglyceride-rich lipoproteins and coronary heart disease. Bailliere's Clin Endocrinol Metab. 1990;4:895–922[CrossRef][Web of Science][Medline]
  8. Patsch JR, Misenbock G, Hopferweiser T, et al. Relation of triglyceride metabolism and coronary artery disease. Studies in the postprandial state. Arterioscler Thromb. 1992;12:1336–1345[Abstract/Free Full Text]
  9. Simpson HS, Williamson CM, Olivecrona T, et al. Postprandial lipaemia, fenofibrate and coronary artery disease. Atherosclerosis. 1990;85:193–202[CrossRef][Web of Science][Medline]
  10. Stampfer ML, Krauss RM, Ma J, et al. A prospective study of triglyceride level, low-density lipoprotein particle diameter and risk of myocardial infarction. J Am Med Assoc. 1996;276:882–888[Abstract/Free Full Text]
  11. Carlson LA, Bottiger LE. Ischaemic heart disease in relation to fasting values of plasma triglycerides and cholesterol. Stockholm Prospective Study. Lancet. 1972;1:865–868
  12. Kuller LH, Meilahn EN. Risk factors for cardiovascular disease in women. Curr Opin Lipidol. 1996;7:203–208[Web of Science][Medline]
  13. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of highdensity lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk. 1996;3:213–219[Medline]
  14. Caslake MJ, Packard CJ, Series JJ, et al. Plasma triglyceride and low density lipoprotein metabolism. Eur J Clin Invest. 1992;22:96–104[Web of Science][Medline]
  15. Bhatnagar D. Lipid-lowering drugs in the management of hyperlipidaemia. Pharmacol Therapeutics. 1998;79:205–230[CrossRef][Web of Science][Medline]
  16. Pasternak RC, Brown LE, Stone PH, et al. Effect of combination therapy with lipid-reducing drugs in patients with coronary heart disease and ‘normal’ cholesterol levels. A randomized, placebo-controlled trial. Ann Intern Med. 1996;125:529–540[Abstract/Free Full Text]
  17. Feher MD, Foxton J, Banks D, et al. Long-term safety of statin-fibrate combination treatment in the management of hypercholesterolaemia in patients with coronary artery disease. Br Heart J. 1995;74:14–17[Abstract/Free Full Text]
  18. Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated with lovastatin—gemfibrozil combination therapy. J Am Med Assoc. 1990;264:71–75[Abstract/Free Full Text]
  19. Shepherd J. Fibrates and statins in the treatment of hyperlipidaemia: an appraisal of their efficacy and safety. Eur Heart J. 1995;16:5–13
  20. Connor SL, Connor WE. Are fish oils beneficial in the prevention and treatment of coronary artery disease? Am J Clin Nutr. 1997;66:1020S–1031S (Suppl)[Abstract/Free Full Text]
  21. Schmidt EB, Varming K, Ernst E, et al. Dose-response studies on the effect of n-3 polyunsaturated fatty acids on lipids and haemostasis. Thromb Haemostasis. 1990;61:631–635
  22. Mackness MI, Bhatnagar D, Durrington PN, et al. Effect of a new fish oil concentrate on plasma lipids and lipoproteins in patients with hypertriglyceridaemia. Eur J Clin Nutr. 1994;48:859–865[Web of Science][Medline]
  23. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease; the Scandinavian Survival Study. Lancet. 1994;344:1383–1389[CrossRef][Web of Science][Medline]
  24. Sandset PM, Lund H, Norseth J, et al. Treatment with hydroxymethylglutaryl-coenzyme A reductase inhibitors in hypercholesterolaemia induces changes in components of the extrinsic coagulation system. Arterioscler Thromb Vase Biol. 1991;13:138–145
  25. Contacos C, Barter PL, Sullivan DR. Effect of pravastatin and omega-3 fatty acids on plasma lipids and lipoproteins in patients with combined hyperlipidemia. Arterioscler Thromb. 1993;13:1755–1762[Abstract/Free Full Text]
  26. Salvi A, Distefano O, Sleiman I, et al. Effects of fish oil on serum lipids and lipoprotein(A) levels in heterozygous familial hypercholesterolemia. Curr Therapeut Res. 1993;53:717–721[CrossRef]
  27. Nordoy A, Bonaa KH, Nilsen H, et al. Effects of simvastatin and omega-3 fatty acids on plasma lipoprotein and lipid peroxidation in patients with combined hyperlipidaemia. J Int Med. 1998;243:163–170[CrossRef][Web of Science][Medline]
  28. Nakamura N, Hamazaki T, Ohta M, et al. Joint effects of HMG-CoA reductase inhibitors and eicosapentanoic acids on serum lipid profile and fatty acid concentrations inpatients with hyperlipidaemia. Int J Clin Lab Res. 1999;29:22–25[CrossRef][Web of Science][Medline]
  29. Nordoy A, Bonaa KH, Sandset PM, et al. Effect of omega-3 fatty acids and simvastatin on hemostatic risk factors and postprandial hyperlipidaemia in patients with combined hyperlipidaemia. Arteriosclr Thromb Vase Biol. 2000;20:259–265
  30. Durrington PN, Bhatnagar D, Mackness MI, et al. The effect of an omega-3 fatty polyunsaturated acid concentrate administered for one year to simvastatin treated patients with established coronary artery disease and persisting hypertriglyceridaemia. Heart. 2001;: in press
  31. Grundy SJ, Bilheimer DW. Inhibition of 3-hydroxy-3methylglutaryl-CoA reductase by mevinolin in familial hypercholesterolaemia heterozygotes: effects on cholesterol balance. Proc Natl Acad Sci USA. 2nd edn. 1984. p. 2538–2542
  32. Feussner G. HMG-CoA reductase inhibitors. Curr Opin Lipidol. 1994;5:59–69[CrossRef][Medline]
  33. Bilheimer DW, Grundy SM, Brown MS, et al. Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolaemia heterozygotes. Proc Natl Acad Sci USA. 2nd edn. 1983. p. 4124–4128
  34. Stein EA, Lane M, Laskarzewski P. Comparisons of statins in hypertriglyceridaemia. Am J Cardiol. 1998;81:66B–69B[CrossRef][Web of Science][Medline]
  35. Rambjor GS, Walen AI, Windsor SL, Harris WS. Eicosapentanoic acid is primarily responsible for hypotriglyceridemic effect of fish oil in humans. Lipids. 1996;31:S45–S49
  36. Harris WS, Windsor SL, Caspermeyer JJ. Modification of lipid-related atherosclerosis risk factors by omega-3 fatty acid ethyl esters in hypertriglyceridemic patients. J Nutr Biochem. 1993;4:706–712[CrossRef]
  37. Dagnelie PC, Rietveld T, Swart GR, et al. Effect of dietary fish oil on blood levels of free fatty acids, ketone bodies and triacylglycerol in humans. Lipids. 1994;29:41–45[CrossRef][Web of Science][Medline]
  38. Hsu H-C, Lee Y-T, Chen M-F. Effect of n-3 fatty acids on the composition and binding properties of lipoproteins in hypertriglyceridaemic patients. Am J Clin Nutr. 2000;71:28–35[Abstract/Free Full Text]
  39. Lu GP, 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[CrossRef][Web of Science][Medline]
  40. Bordin P, Bodamer OA, Venkatesan, et al. Effects of fish oil supplementation on apolipoprotein B100 production and lipoprotein metabolism in normolipidaemic males. Eur J Clin Nutr. 1998;52:104–109[CrossRef][Web of Science][Medline]
  41. Calabresi L, Donati D, Pazzucconi F, et al. Omacor in familial combined hyperlipidaemia: effects on lipids and low density lipoprotein subclasses. Atherosclerosis. 2000;148:387–396[CrossRef][Web of Science][Medline]
  42. Kasim-Karakas SE, Herrmann R, Almario R. Effects of omega-3 fatty acids on intravascular lipolysis of very-lowdensity lipoproteins in humans. Metabolism. 1995;44:122–330
  43. Chin JPF, Gust AP, Nestel PL, Dart AM. Fish oils dosedependently inhibit vasoconstriction of forearm resistance vessels in humans. Hypertension. 1993;21:22–28[Abstract/Free Full Text]
  44. Bauman KH, Hessel F, Larass I, et al. Omega-3, omega-6 and omega-9 unsaturated fatty acids and growth factor and cytokine gene expression in unstimulated and stimulated monocytes. A randomised volunteer study. Arterioscler Thromb Vase Biol. 1999;19:59–66
  45. De Caterina R, Cybulsky MI, Clinton SK, et al. The omega3 fatty acids and endothelial leukocyte adhesion molecules. Prostaglandins Leukot Essent Fatty Acids. 1995;52:191–195[CrossRef][Web of Science][Medline]
  46. Leaf A. Omega-3 fatty acids and prevention of ventricular fibrillation. Prostaglandins Leukot Essent Fatty Acids. 1995;52:197–198[CrossRef][Web of Science][Medline]
  47. Dyerberg J, Bang HO. Haemostatic function and platelet polyunsaturated acids in Eskimos. Lancet. 1979;2:117–119
  48. Burr ML, Gilbert IF, Holliday RM, et al. Effects of changes in fat, fish and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet. 1989;2:757–761[Web of Science][Medline]
  49. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet. 1999;354:447–455[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Disclaimer
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Bhatnagar, D.
Right arrow Articles by Durrington, P.N.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Bhatnagar, D.
Right arrow Articles by Durrington, P.N.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?