Elevated LDL-C is an established risk factor for atherosclerotic cardiovascular disease (ASCVD) and a primary target for prevention of major adverse cardiovascular events.^1,2

However, in light of emerging evidence, particularly the REDUCE-IT trial, renewed attention has been placed on the role of triglycerides (TG), remnant cholesterol (RC) and triglyceride-rich lipoproteins (TGRL) in the development of ASCVD.^3,4 In fact, persistently elevated TGs are recognized as a risk enhancer according to the 2018 ACC/American Heart Association (AHA) Guidelines on the Management of Blood Cholesterol.⁵

Background

Circulating TGRL are derived from the diet (chylomicrons and their remnants) and the liver (very-low density lipoprotein cholesterol [VLDL] and their remnants). Lipoprotein lipase (LPL) lines the luminal surface of capillaries and hydrolyzes the TG within the core of these TGRL to free fatty acids (FFA) and glycerol.⁶

As FFA are liberated, the TGRL particles are remodeled physically (become smaller by losing TG and surface phospholipids) and chemically (become relatively cholesterol enriched).⁷ These partially lipolyzed TGRL are known as remnant particles. In the setting of altered metabolism, postprandial remnant particles may accumulate and contribute to atherogenesis.⁸ Clinically, plasma TG concentrations serve as a surrogate measure of TGRL/remnants.⁹

Pathophysiology

There are several hypothesized mechanisms by which TGs, RC and TGRLs contribute to ASCVD. TGRL and their remnants can readily penetrate the arterial wall and are susceptible to retention within the connective tissue matrix similar with LDL. However, once trapped in the subendothelial space, TGRL may be taken up directly by arterial wall macrophages without the need for further modification (in contrast to the oxidative modification required by arterial macrophages to take up LDL).¹⁰

Additionally, elevated concentrations of TGRL have been linked to markers of endothelial dysfunction, which often precedes ASCVD. Measures of endothelial function, including coronary vasomotor function and brachial artery flow-mediated dilation, have been shown to be impaired in individuals with high TGRL remnants.^11,12 The exact mechanisms by which TGRL contribute to endothelial dysfunction is unclear, but these particles likely lead to increased production of reactive oxygen species and induce endothelial apoptosis by increased secretion of tumor necrosis factor (TNF)- and interleukin (IL)-1.^13,14 This may lead to an impairment of endothelium-dependent vasodilation and increased oxidative stress.^{12, 15}

Activation of inflammation is another proposed mechanism by which TGRL promote atherogenesis. LPL-mediated hydrolysis of TGRL leads to the production of oxidized FFA and TGRL remnants, which induces the production of several cytokines (TNF-α), interleukins (IL-1, IL-6, IL-8) and proatherogenic adhesion molecules (intracellular adhesion molecule-1 and vascular cell adhesion molecule-1).¹⁶ These molecules facilitate migration of leukocytes to the site of inflammation. Additionally, TGRL lead to activation of the coagulation cascade through assembly of the prothrombinase complex and upregulation of the expression of the plasminogen activator inhibitor-1 gene and the plasminogen activator inhibitor-1 antigen.^{16, 17}

Pharmacology

The 2018 ACC/AHA Cholesterol Guideline provides a class I recommendation for identification and treatment of secondary factors in adults 20 years of age or older with moderate hypertriglyceridemia (fasting or nonfasting TG 175-499 mg/dL). This recommendation includes the treatment of lifestyle factors (obesity and metabolic syndrome) and secondary factors (diabetes, chronic liver or kidney disease, nephrotic syndrome, hypothyroidism), including medications that may contribute to hypertriglyceridemia (Class of Recommendation [COR] I, Level of Evidence B-NR). Lifestyle modification is the foundation for management of hypertriglyceridemia and can reduce plasma TG levels by up to 60 percent.¹⁸

Regarding pharmacological management, statins (though not primarily TG-lowering drugs) reduce TG by 22-45 percent.¹⁹ In adults aged 40-75 years with moderate or severe hypertriglyceridemia (>500 mg/dL) and an estimated ASCVD risk ≥7.5 percent over the ensuing 10 years, initiation of statin therapy is recommended (COR IIa). Table 1 summarizes the 2018 ACC/AHA Cholesterol Guideline recommendations for the management of hypertriglyceridemia. Currently, three classes of drugs other than statins are available for the management of hypertriglyceridemia: fibrates, niacin and omega-3 polyunsaturated fatty acids.

Omega-3 Fatty Acids (OM3FA)

OM3FA play an essential role in cell membrane function and stability and serve as precursors for inflammatory mediators (eicosanoids, prostaglandins, protectins, resolvins, leukotrienes).²⁰ In JELIS, an open-label blinded study in Japan that investigated the addition of 1.8 g/day of eicosapentaenoic acid (EPA) to statin therapy (pravastatin 10 mg or simvastatin 5 mg) vs. statin alone, a statistically significant (p=0.01) 19 percent reduction in major coronary events was observed.²¹ In a subanalysis of JELIS, evaluating individuals with TG >150 mg/dL and HDL-C <40 mg/dL, EPA treatment led to a 53 percent reduction in incident coronary artery disease (hazard ratio [HR], 0.47; p=0.043).²²

The landmark REDUCE-IT trial, a randomized, double-blind, placebo-controlled trial, examined the effect of high-dose EPA in addition to statin treatment in 8,179 patients with high cardiovascular risk and elevated TG.4 Eligible patients were required to have baseline fasting TG levels between 135-500 mg/dL despite appropriate statin treatment (median LDL-C was 75 mg/dL). This requirement was to address the issue that previous trials testing OM3FA did not specifically enroll patients with elevated TG. Importantly, REDUCE-IT assessed a significantly higher dose of EPA (4 grams/day) than prior OM3FA studies – and pure EPA rather than combination EPA/DHA.

REDUCE-IT demonstrated a 25 percent reduction in the composite primary endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization or unstable angina (HR, 0.75; p<0.001). Important secondary endpoints were similarly reduced, including the hard endpoint of cardiovascular death (HR, 0.80; p=0.03).

The EPA arm in REDUCE-IT demonstrated a significant decrease in TG levels at one year (by 18.3 percent), while the placebo arm had a small rise in TG levels (by 2.2 percent). LDL-C levels also were increased in the EPA and placebo groups: 3.1 percent vs. 10.2 percent, respectively. The mineral oil placebo pills (used to maintain blinding) may have contributed to raising LDL-C levels in the placebo group, though the magnitude of the increase in LDL-C observed cannot entirely explain the difference in outcomes between the two groups.

Overall, REDUCE-IT demonstrated a significant cardiovascular benefit from adding EPA to statin treatment for high-risk patients with elevated TG levels.

The ongoing STRENGTH trial (NCT02104817) is evaluating the impact of a high-dose omega-3-carboxylic acids formulation, a combination of EPA+DHA, on ASCVD outcomes.

Fibrates

Fibrates or fibric acid derivatives exert their lipid-modifying effects by activating the peroxisome proliferator-activated receptor, a nuclear receptor that increases expression of LPL, APOA1 and other lipid-related genes.²³ In the Helsinki Heart Study and VA-HIT, gemfibrozil reduced the risk of ASCVD, without improvement in mortality.^24,25 Similarly, the FIELD study failed to demonstrate a reduction in mortality but was associated with a reduction in total cardiovascular events.²⁶

The BIP study did not demonstrate a benefit with the use of bezafibrate vs. placebo in reduction of cardiovascular events in patients with ASCVD.²⁷ In the ACCORD study of patients with diabetes, addition of fenofibrate to simvastatin did not result in significant beneficial effects on CVD risk.²⁸ However, the post-hoc analyses in each of these studies suggested benefit with the use of a fibrate in the subgroups with overt atherogenic dyslipidemia (TG >200 mg/dL).^29,30

Niacin

Niacin, or nicotinic acid, inhibits adipose tissue lipolysis and thus reduces the flux of FFA and hepatic VLDL synthesis. The AIM-HIGH and HPS2-THRIVE studies demonstrated that despite reduction in TG levels, no incremental benefit was observed from the addition of niacin to statin therapy.^31,32 However, a subgroup analysis of patients with TG ≥200 mg/dL and HDL-C <32 mg/dL demonstrated a 37 percent reduction in cardiovascular events favoring the niacin group (HR, 0.64; p=0.032), similar with observations in the fibrate trials.^33,34

Conclusion

Observational epidemiology and genetic analyses consistently demonstrate an association between TGRL/RC and ASCVD. The results of the landmark REDUCE-IT trial come on the heels of several failed OM3FA trials and demonstrate improved cardiovascular outcomes with high-dose EPA in high-risk patients with hypertriglyceridemia. These results also suggest that the relationship between TGRL/RC and ASCVD may be causal rather than just mere association. Fortunately, additional trials testing OM3FA and other TG-lowering agents will be reporting in the near future and will help to clarify the role of TG-lowering therapies in mitigating cardiovascular risk.

---

This article was authored by Pratik Sandesara, MD, and Devinder Singh Dhindsa, MD, cardiovascular medicine fellows at Emory Clinical Cardiovascular Research Institute, Emory University School of Medicine; and Michael Shapiro, DO, FACC, associate professor of medicine and radiology at Oregon Health & Science University and a member of ACC's Prevention of Cardiovascular Disease Section.

References

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;63:2889-2934.
2. Jacobson TA, Ito MK, Maki KC, et al. National lipid association recommendations for patient-centered management of dyslipidemia: part 1--full report. J Clin Lipidol 2015;9:129-169.
3. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-563.
4. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Eng J Med 2019;380:11-22.
5. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. J Am Coll Cardiol 2018;Nov 8:[Epub ahead of print].
6. Toth PP. Triglyceride-rich lipoproteins as a causal factor for cardiovascular disease. Vasc Health Risk Manag 2016;12:171-83.
7. Rosenson RS, Davidson MH, Hirsh BJ, et al. Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease. J Am Coll Cardiol 2014;64:2525-40.
8. Maggi FM, Raselli S, Grigore L, et al. Lipoprotein remnants and endothelial dysfunction in the postprandial phase. J Clin Endocrinol Metab 2004;89:2946-50.
9. Varbo A, Nordestgaard BG. Remnant lipoproteins. Curr Opin Lipidol 2017;28:300-7.
10. Miller YI, Choi SH, Fang L, Tsimikas S. Lipoprotein modification and macrophage uptake: role of pathologic cholesterol transport in atherogenesis. Subcell Biochem 2010;51:229-25.
11. Vogel RA, Corretti MC, Plotnick GD. Effect of a single high-fat meal on endothelial function in healthy subjects. Am J Cardiol 1997;79:350-4.
12. Anderson RA, Evans ML, Ellis GR, et al. The relationships between post-prandial lipaemia, endothelial function and oxidative stress in healthy individuals and patients with type 2 diabetes. Atherosclerosis 2001;154:475-83.
13. Toth PP. Triglyceride-rich lipoproteins as a causal factor for cardiovascular disease. Vasc Health Risk Manag 2016;12:171-83.
14. Shin HK, Kim YK, Kim KY, et al. Remnant lipoprotein particles induce apoptosis in endothelial cells by NAD(P)H oxidase-mediated production of superoxide and cytokines via lectin-like oxidized low-density lipoprotein receptor-1 activation: prevention by cilostazol. Circulation 2004;109:1022-8.
15. Steinberg HO, Tarshoby M, Monestel R, et al. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest 1997;100:1230-9.
16. Olufadi R, Byrne CD. Effects of VLDL and remnant particles on platelets. Pathophysiol Haemost Thromb 2006;35:281-91.
17. Reiner Z. Hypertriglyceridaemia and risk of coronary artery disease. Nat Rev Cardiol 2017; 14:401-11.
18. Watts GF, Ooi EM, Chan DC. Demystifying the management of hypertriglyceridaemia. Nat Rev Cardiol 2013;10:648-61.
19. Stein EA, Lane M, Laskarzewski P. Comparison of statins in hypertriglyceridemia. Am J Cardiol 1998;81:66B-69B.
20. Ganda OP, Bhatt DL, Mason RP, et al. Unmet need for adjunctive dyslipidemia therapy in hypertriglyceridemia management. J Am Coll Cardiol 2018;72:33-43.
21. 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;369:1090-8.
22. Saito Y, Yokoyama M, Origasa H, et al. Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS). Atherosclerosis 2008;200:135-40.
23. Rosenson RS, Davidson MH, Hirsh BJ, et al. Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease. J Am Coll Cardiol 2014;64:2525-40.
24. 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. N Engl J Med 1987;317:1237-45.
25. Rubins 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. N Engl J Med 1999;341:410-8.
26. Keech A, Simes RJ, Barter P, et al. 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.
27. Bezafibrate Infarction Prevention (BIP) Study. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation 2000;102:21-7.
28. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.
29. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 2010;375:1875-84.
30. Wang D, Liu B, Tao W, et al. Fibrates for secondary prevention of cardiovascular disease and stroke. Cochrane Database Syst Rev 2015 Oct 25;CD009580.
31. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67.
32. HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203-12.
33. Guyton JR, Slee AE, Anderson T, et al. Relationship of lipoproteins to cardiovascular events: the AIM-HIGH Trial (atherothrombosis intervention in metabolic syndrome with low hdl/high triglycerides and impact on global health outcomes). J Am Coll Cardiol 2013;62:1580-4.
34. TG and HDL Working Group of the Exome Sequencing Projec, Crosby J, Peloso GM, Auer PL, et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014;371:22-31.

Keywords: ACC Publications, Cardiology Magazine, Adipose Tissue, American Heart Association, Angina, Unstable, Apolipoprotein A-I, Atherosclerosis, Apoptosis, Bezafibrate, Brachial Artery, Cardiovascular Diseases, Capillaries, CD59 Antigens, Cell Membrane, Cholesterol, VLDL, Chylomicrons, Coronary Artery Disease, Connective Tissue, Cytokines, Diabetes Mellitus, Dilatation, Double-Blind Method, Eicosapentaenoic Acid, Factor V, Factor Xa, Fasting, Endothelium, Fatty Acids, Nonesterified, Fatty Acids, Omega-3, Fatty Acids, Unsaturated, Fenofibrate, Fibric Acids, Glycerol, Gemfibrozil, Hydrolysis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertriglyceridemia, Hypothyroidism, Inflammation, Interleukin 1 Receptor Antagonist Protein, Interleukin-13, Interleukin-6, Interleukin-8, Leukocytes, Life Style, Leukotrienes, Lipolysis, Lipoprotein Lipase, Lipoproteins, Liver, Macrophages, Macrophages, Metabolic Syndrome, Myocardial Infarction, Nephrotic Syndrome, Niacin, Mineral Oil, Oxidative Stress, Obesity, Peroxisome Proliferator-Activated Receptors, Phospholipids, Plasminogen Activator Inhibitor 1, Pravastatin, Prostaglandins, Reactive Oxygen Species, Risk Factors, Stroke, Simvastatin, Tumor Necrosis Factors, Triglycerides, Up-Regulation, Vasodilation, Vascular Cell Adhesion Molecule-1

< Back to Listings