Current Treatment Options in Cardiovascular Medicine

, Volume 15, Issue 1, pp 104–117

What should we do about Hypertriglyceridemia in Coronary Artery Disease Patients?

  • Amita Singh
  • Arthur Schwartzbard
  • Eugenia Gianos
  • Jeffrey S. Berger
  • Howard Weintraub
Coronary Artery Disease (PG Steg, Section Editor)

Opinion statement

Triglycerides are routinely obtained with standard lipid testing, but their role in cardiovascular risk is controversial. An excess of triglycerides is commonly encountered in patients with the metabolic syndrome or diabetes, and represents an excess burden of small, dense low-density lipoproteins (LDLs), which confers additive risk for cardiovascular disease. Current guidelines prioritize LDL targets first, but treatment of triglycerides once LDL targets are achieved bears consideration. Beyond lifestyle modification, potential pharmacologic therapies include statins, fibrates, niacin, omega-3 fatty acids and antidiabetic drugs. There are few trials to date comparing these agents directly in the management of hypertriglyceridemia, but available data seems to demonstrate that the greatest benefit of triglyceride lowering is experienced in a subgroup of patients with an atherogenic lipid profile (elevated triglycerides, low high-density lipoprotein (HDL), elevated small, dense LDL particles). Here, we discuss the current understanding of how triglyceride elevations impart cardiovascular risk, current therapies and the data supporting their use, and ongoing studies to elucidate the degree to which treatment of triglycerides modifies risk of future cardiovascular events.

Keywords

Triglycerides Cardiovascular disease Fibrates Omega-3 fish oil Niacin 

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Mahley RW, Ji ZS. Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E. J Lipid Res. 1999;40:1–16.PubMedGoogle Scholar
  2. 2.
    Labossiere R, Goldberg I. Management of Hypertriglyceridemia. In: Davidson M, editor. In: Therapeutic Lipidology. Totowa: Humana Press; 2007. p. 201–20.Google Scholar
  3. 3.
    Hanak V, Munoz J, Teague J, et al. Accuracy of the triglycerides to high-density lipoprotein cholesterol ratio for prediction of the low-density lipoprotein phenotype B. Am J Cardiol. 2004;94:219–22.PubMedCrossRefGoogle Scholar
  4. 4.
    Austin MA. Plasma triglyceride and coronary heart disease. Arterioscler Throm. 1991;11:2–14.CrossRefGoogle Scholar
  5. 5.
    Nordestgaard BG, Benn M, Schnohr P, Tybjærg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298:299–308.PubMedCrossRefGoogle Scholar
  6. 6.
    Castelli WP, Anderson K, Wilson PW, Levy D. Lipids and Risk of Coronary Heart Disease: The Framingham Study. Ann Epidemiol. 1992;2:23–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Assmann G, Cullen P, Schulte H. The Munster Heart Study (PROCAM)—results of follow-up at 8 years. Eur Heart J. 1998;19:A2–A11.PubMedGoogle Scholar
  8. 8.
    Jeppesen J, Hein HO, Suadicani P, Gyntelberg F. Triglyceride concentration and ischemic heart disease—an eight-year follow-up in the Copenhagen Male Study. Circulation. 1998;97:1029–36.PubMedCrossRefGoogle Scholar
  9. 9.
    Bansal S, Buring JE, Rifai N, Mora S, et al. Fasting Compared With Nonfasting Triglycerides and Risk of Cardiovascular Events in Women. JAMA. 2007;298(3):309–16.PubMedCrossRefGoogle Scholar
  10. 10.
    Austin MA, Hokanson JE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol. 1998;81:7B–12B.PubMedCrossRefGoogle Scholar
  11. 11.
    Patel A, Barzi F, Jamrozik K, et al. Serum Triglycerides as a Risk Factor for Cardiovascular Diseases in the Asia-Pacific Region Asia. Circulation. 2004;110:2678–86.PubMedCrossRefGoogle Scholar
  12. 12.
    Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. 2007;115:450–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Emerging Risk Factor’s Collaboration. Major Lipids, Apolipoproteins and Risk of Vascular Disease JAMA 2009;302: 1993–2000.Google Scholar
  14. 14.
    Miller M, Cannon CP, Murphy SA, et al. Impact of Triglyceride Levels Beyond Low-Density Lipoprotein Cholesterol After Acute Coronary Syndrome in the PROVE IT-TIMI 22 Trial. J Am Coll Cardiol. 2008;51:724–30.PubMedCrossRefGoogle Scholar
  15. 15.
    Faergeman O, Holme I, Fayya R, et al. Plasma Triglycerides and Cardiovascular Events in the Treating to New Targets and Incremental Decrease in End-Points Through Aggressive Lipid Lowering Trials of Statins in Patients With Coronary Artery Disease. Am J Cardiol. 2009;104:459–63.PubMedCrossRefGoogle Scholar
  16. 16.
    National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 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.Google Scholar
  17. 17.
    Standards of Medical Care in Diabetes—2011. Diab Care 2011;34:S11-S61.Google Scholar
  18. 18.
    Dattilo AM, Kris-Etherton PM. Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr. 1992;56:320–8.PubMedGoogle Scholar
  19. 19.
    Haskell WL, Lee IM, Pate RR, et al. Physical activity and public health: updated recommendations for adults from the American College of Sports Medicine and the America Heart Association. Circulation. 2007;116:1081.PubMedCrossRefGoogle Scholar
  20. 20.
    Kraus WE, Houmart JA, Duscha BD, et al. Effects of the amount and intensity of exercise on plasma lipoproteins. NEJM. 2002;347:1483.PubMedCrossRefGoogle Scholar
  21. 21.
    Pieke B, von Eckardstein A, Gülbahçe E, et al. Treatment of hypertriglyceridemia by two diets rich either in unsaturated fatty acids or in carbohydrates: effects on lipoprotein subclasses, lipolytic enzymes, lipid transfer proteins, insulin and leptin. Int J Obes Relat Metab Disord. 2000;24:1286–96.PubMedCrossRefGoogle Scholar
  22. 22.
    Sacks FM, Katan M. Randomized clinical trials on the effects of dietary fat and carbohydrate on plasma lipoproteins and cardiovascular disease. Am J Med. 2002;113:13S–24S.PubMedCrossRefGoogle Scholar
  23. 23.
    Brinton EA. Effects of ethanol intake on lipoproteins and atherosclerosis. Curr Opin Lipidol. 2010;21:346–51.PubMedCrossRefGoogle Scholar
  24. 24.
    LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. NEJM. 2005;352:1425–35.PubMedCrossRefGoogle Scholar
  25. 25.
    The Stroke Prevention by Aggressive Reductioni n Cholesterol Levels (SPARCL) Investigators. High-Dose Atorvastatin after Stroke or Transient Ischemic Attack. NEJM 2006;355:549–559.Google Scholar
  26. 26.
    Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22.Google Scholar
  27. 27.
    Ridker PM, Danielson E, Francisco AH, et al. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. NEJM. 2008;359:2195–207.PubMedCrossRefGoogle Scholar
  28. 28.
    Stein EA, Lane M, Laskarzewski P, et al. Comparison of Statins in Hypertriglyceridemia. Am J Cardiol. 1998;81:6609.CrossRefGoogle Scholar
  29. 29.
    Bakker-Arkema RG, Davidson MH, Goldstein RJ. Efficacy and Safety of a New HMG-CoA Reductase Inhibitor, Atorvastatin, in Patients With Hypertriglyceridemia. JAMA. 1996;275:128–33.PubMedCrossRefGoogle Scholar
  30. 30.
    Staels B, Dallongeville J, Auwerx J, et al. Mechanism of Action of Fibrates on Lipid and Lipoprotein Metabolism. Circulation. 1998;98:2088–93.PubMedCrossRefGoogle Scholar
  31. 31.
    Arakawa R, Tamehiro N, Nishimaki-Mogami T, Ueda K, Yokoyama S. Fenofibric acid, an active form of fenofibrate, increases apoAI–mediated HDL biogenesis by enhancing transcription of ABCA1 gene in an LXR-dependent manner. Arterioscler Thromb Vasc Biol. 2005;25:1193–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Dachet C, Cavalerro E, Martin C, Girardot G, Jacotot B. Effect of gemfibrozil on the concentration and composition of very low density and low density lipoprotein subfractions in hypertriglyceridemic patients. Atherosclerosis. 1995;113:1–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Rubens HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. NEJM. 1999;341:410–8.CrossRefGoogle Scholar
  34. 34.
    Otvos JD, Collins D, Freedman DS, et al. Low Density Lipoprotein and High-Density Lipoprotein Particle Subclasses Predict Coronary Events And Are Favorably Changed by Gemfibrozil Therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation. 2006;113:1556–63.PubMedCrossRefGoogle Scholar
  35. 35.
    BIP Study Group. Secondary Prevention by Raising HDL Cholesterol and Reducing Triglycerides in Patients with Coronary Artery Disease: the Bezafibrate Infarction Prevention Study. Circulation. 2000;102:21–7.CrossRefGoogle Scholar
  36. 36.
    Franssen R, Vergeer M, Stroes ES, Kastelein JJ. Combination statin-fibrate therapy: safety aspects. Diabetes Obes Metab. 2009;11:89–94.PubMedCrossRefGoogle Scholar
  37. 37.
    The FIELD Study Investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849–61.CrossRefGoogle Scholar
  38. 38.
    The ACCORD Study Group. Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus. NEJM. 2010;362:1563–74.CrossRefGoogle Scholar
  39. 39.
    Scott R, O’Brien R, Fulcher G. Effects of Fenofibrate Treatment on Cardiovascular Disease Risk in 9,795 Individuals With Type 2 Diabetes and Various Components of the Metabolic Syndrome: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care. 2009;32:493–8.PubMedCrossRefGoogle Scholar
  40. 40.•
    Otvos, J. The surprising AIM-HIGH results are not surprising when viewed through a particle lens. J Clin Lipid 2011;5: 368–70.Google Scholar
  41. 41.
    Vaijinath SK, Kashyap L. Mechanism of Action of Niacin. Am J Card. 2008;101:S20–6.Google Scholar
  42. 42.
    McKenney J. New Perspectives on the Use of Niacin in the Treatment of Lipid Disorders. Arch Intern Med. 2004;164:697–705.PubMedCrossRefGoogle Scholar
  43. 43.
    The Coronary Drug Project Research Group. Clofibrate and Niacin in Coronary Heart Disease. JAMA. 1975;231:360–81.CrossRefGoogle Scholar
  44. 44.
    Canner PL, Berrge KG, Wenger NK, et al. Fifteen year Mortality in Coronary Drug Project Patients: long-term benefit with niacin. JACC 1986;1245.Google Scholar
  45. 45.•
    The AIM-HIGH investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. NEJM 2011;365:2255–2267. Widely publicized clinical trial of niacin versus placebo to raise low HDL in patients with established cardiovascular disease, which was stopped early due to lack of efficacy.Google Scholar
  46. 46.
    HPS2-THRIVE: A Randomized Trial of the Long-term Clinical Effects of Raising HDL Cholesterol With Extended Release Niacin/Laropiprant. http://clinicaltrials.gov/ct2/show/NCT00461630. Accessed August 2012.
  47. 47.
    Armitage, Jane. HPS2-THRIVE: Treatment of HDL to Reduce the Incidence of Vascular Events. Presented at the European Society of Cardiology 2012 Congress. Munich, Germany. August 25–29, 2012.Google Scholar
  48. 48.
    Grundy DM, Vega GL, McGovern ME, et al. Diabetes Multicenter Research Group: Efficacy, safety and tolerability of once daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial. Arch Intern Med. 2002;162:1568.PubMedCrossRefGoogle Scholar
  49. 49.
    Elam MB, Hunninghake DB, Davis KB, et al. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease. The ADMIT study: a randomized trial. JAMA. 2000;284:1263.PubMedCrossRefGoogle Scholar
  50. 50.
    Stone NJ. Fish Consumption, Fish Oil, Lipids and Coronary Heart Disease. Circulation. 1996;94:2337–40.PubMedCrossRefGoogle Scholar
  51. 51.
    Jacobson TA, Glickstein SB, Rowe JD, Soni P. Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: A review. C Clin Lipid. 2012;6:5–18.CrossRefGoogle Scholar
  52. 52.
    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.Google Scholar
  53. 53.
    Yokoyama M, Origasa H, Masunori M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090–8.PubMedCrossRefGoogle Scholar
  54. 54.
    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;29:1354–67.PubMedCrossRefGoogle Scholar
  55. 55.•
    Bays HE, Ballantyne CM, Kastelein JJ, et al. Eicosapentaenoic Acid Ethyl Ester (AMR101) Therapy in Patients With Very High Triglyceride Levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] Trial). Am J Card. 2011;108:682–90. Initial published results of AMR101 (now Vascepa), a new purified EPA-only omega 3 fish oil for use in moderate to severe hypertriglyceridemia.PubMedCrossRefGoogle Scholar
  56. 56.•
    Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and Safety of Eicosapentaenoic Acid Ethyl Ester (AMR101) Therapy in Statin Treated Patients with Persistent High Triglycerides (from the ANCHOR Study). Am J Card. Epub July 23, 2012. Followup study of Vascepa, with results demonstrating greater triglyceride-lowering with high potency statins as well as potential reductions in LDL.Google Scholar
  57. 57.
    A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients With Hypertriglyceridemia and on Statin. The Primary Objective is to Evaluate the Effect of 4 g/Day AMR101 for Preventing the Occurrence of a First Major Cardiovascular Event. (REDUCE-IT) (http://clinicaltrials.gov/ct2/show/NCT01492361. Accessed August 2012.
  58. 58.
    Zhou G, Myers R, Li Y. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108:1167–74.PubMedGoogle Scholar
  59. 59.
    Stumvoll M, Nurjhan N, Perriello G. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. NEJM. 1995;333:550–4.PubMedCrossRefGoogle Scholar
  60. 60.
    DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. NEJM. 1995;333:541–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Wuffeele MG, Kooy A, de Zeeuw D, et al. The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review. J Int Med. 2004;256:1–14.CrossRefGoogle Scholar
  62. 62.
    Gurnell M, Savage DB, Chatterjee KK. The Metabolic Syndrome: Peroxisome Proliferator-Activated Receptor γ and Its Therapeutic Modulation. J of Clin Endo& Met. 2003;88:2412–21.CrossRefGoogle Scholar
  63. 63.
    Ginsberg HN, Plutzky J, Sobel BE. A review of metabolic and cardiovascular effects of oral antidiabetic agents: Beyond glucose lowering. J Cardiovasc Risk. 1999;6:337–47.PubMedGoogle Scholar
  64. 64.
    Van Wijk JP, de Koning EJ, Martens EP, Rabelink TJ. Thiazolidinediones and blood lipids in type 2 diabetes. Arterioscler Thromb Vasc Biol. 2003;23:1744–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Goldberg RB, Kendall DM, Deeg MA. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2005;28:1547.PubMedCrossRefGoogle Scholar
  66. 66.
    Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279–89.PubMedCrossRefGoogle Scholar
  67. 67.
    Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. NEJM. 1987;317:1237–45.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Amita Singh
    • 1
  • Arthur Schwartzbard
    • 1
  • Eugenia Gianos
    • 1
  • Jeffrey S. Berger
    • 1
  • Howard Weintraub
    • 1
  1. 1.Division of CardiologyNYU Langone Medical CenterNew YorkUnited States
  2. 2.NY Harbor Health Care SystemVeteran Affairs HospitalNew YorkUnited States

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