Korean Circ J.  2016 Mar;46(2):135-144. 10.4070/kcj.2016.46.2.135.

Hypertriglyceridemia and Cardiovascular Diseases: Revisited

  • 1Department of Cardiology, Gachon University Gil Medical Center, Incheon, Korea. kwangk@gilhospital.com
  • 2Department of Cardiology, South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia.
  • 3Department of Cardiovascular Medinine, Hokko Memorial Clinic, Sapporo, Japan.
  • 4Department of Epidemiology, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing An Zhen Hospital, Capital Medical University, Beijing, China.


Residual cardiovascular risk and failure of high density lipoprotein cholesterol raising treatment have refocused interest on targeting hypertriglyceridemia. Hypertriglyceridemia, triglyceride-rich lipoproteins, and remnant cholesterol have demonstrated to be important risk factors for cardiovascular disease; this has been demonstrated in experimental, genetic, and epidemiological studies. Fibrates can reduce cardiovascular event rates with or without statins. High dose omega-3 fatty acids continue to be evaluated and new specialized targeting treatment modulating triglyceride pathways, such as inhibition of apolipoprotein C-III and angiopoietin-like proteins, are being tested with regard to their effects on lipid profiles and cardiovascular outcomes. In this review, we will discuss the role of hypertriglyceridemia, triglyceride-rich lipoproteins and remnant cholesterol on cardiovascular disease, and the potential implications for treatment stargeting hypertriglyceridemia.


Residual cardiovascular risk; Hypertriglyceridemia; Treatment; Cardiovascular disease

MeSH Terms

Apolipoprotein C-III
Cardiovascular Diseases*
Cholesterol, HDL
Epidemiologic Studies
Fatty Acids, Omega-3
Fibric Acids
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Risk Factors
Apolipoprotein C-III
Cholesterol, HDL
Fatty Acids, Omega-3
Fibric Acids


  • Fig The production of TRLs, remnant cholesterol which induces the formation of atherosclerosis. TRLs include chylomicrons, VLDL and IDL. Their major protein component is apolipoprotein B. In the fasting state, only VLDL and IDL are present in plasma, whereas chylomicrons, VLDL and their remnants circulate under non-fasting conditions. TRLs undergoes intravascular hydrolysis by lipoprotein lipase in muscle, adipose tissue, heart and other tissues, where they provide free fatty acids for energy or storage. Upon lipolysis, chylomicrons and VLDL are depleted of TG and enriched in cholesterol, resulting in the formation of chylomicron remnants and VLDL remnants. CETP mediates major lipid transfer and exchange between HDL and TRLs. During this process, cholesteryl esters are transferred from HDL to TRLs and TG move from TRLs to HDL. In addition, the plasma HDL pool involves hydrolysis of TG in VLDL, IDL, and chylomicrons. In this process, which is catalyzed by LPL, phospholipids as well as several apolipoproteins (such as apoCI, CII, CIII) are transferred to HDL. Since most cells can degrade TG, and there are not any cells that can degrade cholesterol, the cholesterol content of TRLs is more likely to be the cause of atherosclerosis and cardiovascular disease rather than raised TG per se. Indeed, cholesterol, rather than TG accumulates in intimal foam cells and in atherosclerotic plaques, and remnant lipoproteins like LDL can enter the arterial intima. In contrast, chylomicrons are too large to enter. LPL activity at the surface of remnant particles, either at the surface of vascular endothelium or within the intima, leads to liberation of free fatty acids, monoacylglycerols, and other molecules, each of which could cause local injury and inflammation. Although other possible mechanisms have been suggested, perhaps the simplest chain of events is that high triglyceride concentrations are a marker for raised remnants rich in cholesterol, which, upon entrance into the intima, leads to low-grade inflammation, foam cell formation, atherosclerotic plaques, and ultimately cardiovascular disease and increased mortality.11) TRLs: triglyceride rich lipoproteins, VLDL: very large density lipoprotein, IDL: intermediate density lipoprotein, TG: triglyceride, LDL: low density lipoprotein, CETP: cholesteryl ester transfer protein, HDL: high density lipoprotein, LPL: lipoprotein lipase, CE: cholesterol ester.


1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. J Am Coll Cardiol. 2014; 63(25 Pt B):2889–2934.
2. Mora S, Wenger NK, DeMicco DA, et al. Determinants of residual risk in secondary prevention patients treated with high- versus low-dose statin therapy: the treating to new targets (TNT) study. Circulation. 2012; 125:1979–1987.
3. Lim S, Park YM, Sakuma I, Koh KK. How to control residual cardiovascular risk despite statin treatment: Focusing on HDL–cholesterol. Int J Cardiol. 2013; 166:8–14.
4. Koh KK. How to control residual risk during statin era? J Am Coll Cardiol. 2015; 66:1848.
5. Mora S, Caulfield MP, Wohlgemuth J, et al. Atherogenic lipoprotein subfractions determined by ion mobility and first cardiovascular events after random allocation to high-intensity statin or placebo: the JUPITER trial. Circulation. 2015; 132:2220–2229.
6. Lee MH, Kim HC, Ahn SV, et al. Prevalence of dyslipidemia among Korean adults: Korea National Health and Nutrition Survey 1998-2005. Diabetes Metab J. 2012; 36:43–55.
7. Kim K. Distribution of blood cholesterol profile in untreated Korean population. Korean Circ J. 2015; 45:108–109.
8. Park JH, Lee MH, Shim JS, et al. Effects of age, sex, and menopausal status on blood cholesterol profile in the Korean population. Korean Circ J. 2015; 45:141–148.
9. Ren J, Grundy SM, Liu J, et al. Long-term coronary heart disease risk associated with very-low-density lipoprotein cholesterol in Chinese: the results of a 15-Year Chinese Multi-Provincial Cohort Study (CMCS). Atherosclerosis. 2010; 211:327–332.
10. Lim S, Shin H, Song JH, et al. Increasing prevalence of metabolic syndrome in Korea: the Korean National Health and Nutrition Examination Survey for 1998-2007. Diabetes Care. 2011; 34:1323–1328.
11. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet. 2014; 384:626–635.
12. Nordestgaard BG, Wootton R, Lewis B. Selective retention of VLDL, IDL, and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo. Molecular size as a determinant of fractional loss from the intima-inner media. Arterioscler Thromb Vasc Biol. 1995; 15:534–542.
13. Goldberg IJ, Eckel RH, McPherson R. Triglycerides and heart disease: still a hypothesis? Arterioscler Thromb Vasc Biol. 2011; 31:1716–1725.
14. Proctor SD, Vine DF, Mamo JC. Arterial retention of apolipoprotein B(48)- and B(100)-containing lipoproteins in atherogenesis. Curr Opin Lipidol. 2002; 13:461–470.
15. Chapman MJ, Ginsberg HN, Amarenco P, et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J. 2011; 32:1345–1361.
16. Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol. 2013; 61:427–436.
17. Hegele RA, Ginsberg HN, Chapman MJ, et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol. 2014; 2:655–666.
18. Rapp JH, Lespine A, Hamilton RL, et al. Triglyceride-rich lipoproteins isolated by selected-affinity anti-apolipoprotein B immunosorption from human atherosclerotic plaque. Arterioscler Thromb. 1994; 14:1767–1774.
19. Alaupovic P, Mack WJ, Knight-Gibson C, Hodis HN. The role of triglyceride-rich lipoprotein families in the progression of atherosclerotic lesions as determined by sequential coronary angiography from a controlled clinical trial. Arterioscler Thromb Vasc Biol. 1997; 17:715–722.
20. Zheng XY, Liu L. Remnant-like lipoprotein particles impair endothelial function: direct and indirect effects on nitric oxide synthase. J Lipid Res. 2007; 48:1673–1680.
21. Alipour A, van Oostrom AJ, Izraeljan A, et al. Leukocyte activation by triglyceride-rich lipoproteins. Arterioscler Thromb Vasc Biol. 2008; 28:792–797.
22. Wang L, Gill R, Pedersen TL, Higgins LJ, Newman JW, Rutledge JC. Triglyceride-rich lipoprotein lipolysis releases neutral and oxidized FFAs that induce endothelial cell inflammation. J Lipid Res. 2009; 50:204–213.
23. Moyer MP, Tracy RP, Tracy PB, van't Veer Cvt, Sparks CE, Mann KG. Plasma lipoproteins support prothrombinase and other procoagulant enzymatic complexes. Arterioscler Thromb Vasc Biol. 1998; 18:458–465.
24. Kohler HP, Grant PJ. Plasminogen-activator inhibitor type 1 and coronary artery disease. N Engl J Med. 2000; 342:1792–1801.
25. Patel A, Barzi F, Jamrozik K, et al. Serum triglycerides as a risk factor for cardiovascular diseases in the Asia-Pacific Region. Circulation. 2004; 110:2678–2686.
26. 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; 115:450–458.
27. 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.
28. Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA. 2007; 298:309–316.
29. Langsted A, Freiberg J, Tybjærg-Hansen A, Schnohr P, Jensen GB, Nordestgaard B. Nonfasting cholesterol and triglycerides and association with risk of myocardial infarction and total mortality: the Copenhagen City Heart Study with 31 years of follow-up. J Intern Med. 2011; 270:65–75.
30. Jørgensen AB, Frikke-Schmidt R, West AS, Grande P, Nordestgaard BG, Tybjærg-Hansen A. Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. Eur Heart J. 2013; 34:1826–1833.
31. Emerging Risk Factors Collaboration. Di Angelantoni E, Sarwar N, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009; 302:1993–2000.
32. Rosenson RS, Davidson MH, Hirsh BJ, Kathiresan S, Gaudet D. Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease. J Am Coll Cardiol. 2014; 64:2525–2540.
33. Schwartz GG, Abt M, Bao W, et al. Fasting triglycerides predict recurrent ischemic events in patients with acute coronary syndrome treated with statins. J Am Coll Cardiol. 2015; 65:2267–2275.
34. Jackson KG, Poppitt SD, Minihane AM. Postprandial lipemia and cardiovascular disease risk: interrelationships between dietary, physiological and genetic determinants. Atherosclerosis. 2012; 220:22–33.
35. Rip J, Nierman MC, Ross CJ, et al. Lipoprotein lipase S447X a naturally occurring gain-of-function mutation. Arterioscler Thromb Vasc Biol. 2006; 26:1236–1245.
36. Humphries SE, Nicaud V, Margalef J, Tiret L, Talmud PJ. Lipoprotein lipase gene variation is associated with a paternal history of premature coronary artery disease and fasting and postprandial plasma triglycerides: the European Atherosclerosis Research Study (EARS). Arterioscler Thromb Vasc Biol. 1998; 18:526–534.
37. Wittrup HH, Tybjærg-Hansen A, Nordestgaard BG. Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis. Circulation. 1999; 99:2901–2907.
38. Henderson HE, Kastelein JJ, Zwinderman AH, et al. Lipoprotein lipase activity is decreased in a large cohort of patients with coronary artery disease and is associated with changes in lipids and lipoproteins. J Lipid Res. 1999; 40:735–743.
39. Lettre G, Palmer CD, Young T, et al. Genome-wide association study of coronary heart disease and its risk factors in 8,090 African Americans: the NHLBI CARe project. PLoS Genet. 2011; 7:e1001300.
40. Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010; 466:707–713.
41. Waterworth DM, Ricketts SL, Song K, et al. Genetic variants influencing circulating lipid levels and risk of coronary artery disease. Arterioscler Thromb Vasc Biol. 2010; 30:2264–2276.
42. Do R, Willer CJ, Schmidt EM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013; 45:1345–1352.
43. Khetarpal SA, Rader DJ. Triglyceride-rich lipoproteins and coronary artery disease risk: new insights from human genetics. Arterioscler Thromb Vasc Biol. 2015; 35:e3–e9.
44. Ooi EM, Barrett PH, Chan DC, Watts GF. Apolipoprotein C-III: understanding an emerging cardiovascular risk factor. Clin Sci (Lond). 2008; 114:611–624.
45. Gaudet D, Alexander VJ, Baker BF, et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med. 2015; 373:438–447.
46. Kawakami A, Osaka M, Tani M, et al. Apolipoprotein CIII links hyperlipidemia with vascular endothelial cell dysfunction. Circulation. 2008; 118:731–742.
47. Abe Y, Kawakami A, Osaka M, et al. Apolipoprotein CIII induces monocyte chemoattractant protein-1 and interleukin 6 expression via Toll-like receptor 2 pathway in mouse adipocytes. Arterioscler Thromb Vasc Biol. 2010; 30:2242–2248.
48. Qamar A, Khetarpal SA, Khera AV, Qasim A, Rader DJ, Reilly MP. Plasma apolipoprotein C-III levels, triglycerides, and coronary artery calcification in type 2 diabetics. Arterioscler Thromb Vasc Biol. 2015; 35:1880–1888.
49. TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. Crosby J, Peloso GM, et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014; 371:22–31.
50. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 2014; 371:32–41.
51. Pennacchio LA, Olivier M, Hubacek JA, et al. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science. 2001; 294:169–173.
52. Tang Y, Sun P, Guo D, et al. A genetic variant c.553G > T in the apolipoprotein A5 gene is associated with an increased risk of coronary artery disease and altered triglyceride levels in a Chinese population. Atherosclerosis. 2006; 185:433–437.
53. Johansen CT, Wang J, Lanktree MB, et al. Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia. Nat Genet. 2010; 42:684–687.
54. Soufi M, Sattler AM, Kurt B, Schaefer JR. Mutation screening of the APOA5 gene in subjects with coronary artery disease. J Investig Med. 2012; 60:1015–1019.
55. Do R, Stitziel NO, Won HH, et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature. 2015; 518:102–106.
56. Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors collaboration. Sarwar N, Sandhu MS, et al. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet. 2010; 375:1634–1639.
57. Han SH, Quon MJ, Koh KK. Beneficial vascular and metabolic effects of peroxisome proliferator-activated receptor-alpha activators. Hypertension. 2005; 46:1086–1092.
58. Han SH, Oh PC, Lim S, Eckel RH, Koh KK. Comparative cardiometabolic effects of fibrates and omega-3 fatty acids. Int J Cardiol. 2013; 167:2404–2411.
59. Koh KK, Ahn JY, Han SH, et al. Effects of fenofibrate on lipoproteins, vasomotor function, and serological markers of inflammation, plaque stabilization, and hemostasis. Atherosclerosis. 2004; 174:379–383.
60. Koh KK, Han SH, Quon MJ, Ahn JY, Shin EK. Beneficial effects of fenofibrate to improve endothelial dysfunction and raise adiponectin levels in patients with primary hypertriglyceridemia. Diabetes Care. 2005; 28:1419–1424.
61. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet. 2010; 375:1875–1884.
62. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med. 2010; 363:692–694. author reply 694-5.
63. Taher TH, Dzavik V, Reteff EM, Pearson GJ, Woloschuk BL, Francis GA. Tolerability of statin-fibrate and statin-niacin combination therapy in dyslipidemic patients at high risk for cardiovascular events. Am J Cardiol. 2002; 89:390–394.
64. Koh KK, Quon MJ, Han SH, et al. Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of combined hyperlipidemia. J Am Coll Cardiol. 2005; 45:1649–1653.
65. ACCORD Study Group. Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010; 362:1563–1574.
66. Koh KK, Quon MJ, Shin KC, et al. Significant differential effects of omega-3 fatty acids and fenofibrate in patients with hypertriglyceridemia. Atherosclerosis. 2012; 220:537–544.
67. Kromhout D, Giltay EJ, Geleijnse JM. Alpha Omega Trial Group. n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. 2010; 363:2015–2026.
68. Kwak SM, Myung SK, Lee YJ, Seo HG. Korean Meta-analysis Study Group. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med. 2012; 172:686–694.
69. Kaushik M, Mozaffarian D, Spiegelman D, Manson JE, Willett WC, Hu FB. Long-chain omega-3 fatty acids, fish intake, and the risk of type 2 diabetes mellitus. Am J Clin Nutr. 2009; 90:613–620.
70. Djoussé L, Gaziano JM, Buring JE, Lee IM. Dietary omega-3 fatty acids and fish consumption and risk of type 2 diabetes. Am J Clin Nutr. 2011; 93:143–150.
71. Oh PC, Koh KK, Sakuma I, et al. Omega-3 fatty acid therapy dose-dependently and significantly decreased triglycerides and improved flow-mediated dilation, however, did not significantly improve insulin sensitivity in patients with hypertriglyceridemia. Int J Cardiol. 2014; 176:696–702.
72. Rischio and Prevenzione Investigators. Efficacy of n-3 polyunsaturated fatty acids and feasibility of optimizing preventive strategies in patients at high cardiovascular risk: rationale, design and baseline characteristics of the Rischio and Prevenzione study, a large randomised trial in general practice. Trials. 2010; 11:68.
73. Manson JE, Bassuk SS, Lee IM, et al. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials. 2012; 33:159–171.
74. Chapman MJ, Redfern JS, McGovern ME, Giral P. Niacin and fibrates in atherogenic dyslipidemia: pharmacotherapy to reduce cardiovascular risk. Pharmacol Ther. 2010; 126:314–345.
75. Clofibrate and niacin in coronary heart disease. JAMA. 1975; 231:360–381.
76. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986; 8:1245–1255.
77. HPS2-THRIVE Collaborative Group. Landray MJ, Haynes R, et al. Effects of extended-release niacin with laropiprant in high risk patients. N Engl J Med. 2014; 371:203–212.
78. Crouse JR 3rd. Hypertriglyceridemia: a contraindication to the use of bile acid binding resins. Am J Med. 1987; 83:243–248.
79. 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.
80. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007; 357:2109–2122.
81. Schwartz GC, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. New Engl J Med. 2012; 367:2089–2099.
82. Nicholls SJ, Lincoff AM, Barter PJ, et al. Assessment of the clinical effects of cholesteryl ester transfer protein inhibition with evacetrapib in patients at high-risk for vascular outcomes: rationale and design of the ACCELERATE trial. Am Heart J. 2015; 170:1061–1069.
83. Korstanje R, Eriksson P, Samnegård A, et al. Locating Ath8, a locus for murine atherosclerosis susceptibility and testing several of its candidate genes in mice and humans. Atherosclerosis. 2004; 177:443–450.
84. Hatsuda S, Shoji T, Shinohara K, et al. Association between plasma angiopoietin-like protein 3 and arterial wall thickness in healthy subjects. J Vasc Res. 2007; 44:61–66.
85. Talmud PJ, Smart M, Presswood E, et al. ANGPTL4 E40K and T266M: effects on plasma triglyceride and HDL levels, postprandial responses, and CHD risk. Arterioscler Thromb Vasc Biol. 2008; 28:2319–2325.
86. Sacks FM, Stanesa M, Hegele RA. Severe hypertriglyceridemia with pancreatitis: thirteen years' treatment with lomitapide. JAMA Intern Med. 2014; 174:443–447.
Full Text Links
  • KCJ
export Copy
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr