Triglycerides, Remnant Cholesterol and Atherosclerotic Cardiovascular Disease

Introduction

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide.1 Elevated low-denisty lipoprotein-cholesterol (LDL-C) is an established risk factor for ASCVD and primary target of therapy for prevention of major adverse cardiovascular events.2,3 However, despite success in reducing LDL-C, significant residual cardiovascular risk remains.4 Emerging evidence suggests that triglycerides (TG) and /or the cholesterol content within triglyceride-rich lipoproteins (TGRL), (e.g., remnant cholesterol [RC]), may be important contributors to residual risk and should perhaps be targets of therapy.5

TGRLs are derived from the diet (chylomicrons and their remnants) and the liver (VLDL and their remnants) and circulate in the plasma. Lipoprotein lipase (LPL) lines the luminal surface of capillaries and hydrolyzes the TGs within the core of these TGRLs 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. Remnant particles peak early in the post-prandial state but are rapidly cleared from plasma when metabolism is intact. In the setting of altered metabolism, post-prandial remnant particles may accumulate and contribute to atherogenesis.8 Clinically, plasma TG concentrations serve as a surrogate measure of TGRL/remnants.9 An estimate of RC can be obtained by using the following equation: RC = total cholesterol minus LDL-C minus HDL-C.10 This method requires LDL-C to be directly measured or derived from Friedewald's equation, though with the caveat that this calculation underestimates LDL-C in moderate to severe hypertriglyceridemia. RC can also be measured directly using a variety of methods including ultracentrifugation, nuclear magnetic resonance (NMR), and a direct automated assay.11

Putative Mechanisms of TGRL-mediated Atherogenicity

There are several postulated mechanisms by which TGs, TGRLs and RC contribute to ASCVD. TGRLs and their remnants can readily penetrate the arterial wall and are are susceptible to retention within the connective tissue matrix, similar to LDL. However, once trapped in the subendothelial space, TGRLs 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).12

Additionally, elevated concentrations of TGRLs 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.13,14 The exact mechanism of TGRLs contribution 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)-α and interleukin (IL)-1β.15,16 This may lead to an impairment of endothelium-depndent vasodilation and increased oxiditave stress.17,18

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 induce production of cytokines (TNF-α), interleukins (IL-1, IL-6, IL-8) and proatherogenic adhesion molecules (intracellular adhesion molecule-1 and vascular cell adhesion molecule-1).19,20 These molecules facilitate migration of leukocytes to the site of inflammation. Additionally, TGRLs 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.21,22

Epidemiology

In an analysis from the Emerging Risk Factors Collaboration, including 302,430 individuals without known vascular disease from 68 long-term prospective studies and 2.79 million person-years of follow-up, fasting and nonfasting TG levels were associated with increased risk of coronary heart disease (CHD) (HR 1.37, 95% confidence interval, 1.31-1.42) after adjustment for nonlipid risk factors.23 However, the association was attenuated after adjustment for HDL-C and was found to be nonsignificant after adjustment for non-HDL-C. While debate continued as to the relative importance of the relationship between TG and ASCVD, the investigative agenda for the next decade largely transitioned from TG to HDL-C as a potential causal risk factor for ASCVD and a potential target of therapy. However, two large randomized controlled trials (RCTs) evaluating the efficacy of extended-release niacin to raise HDL-C versus placebo on background statin therapy in individuals with established ASCVD failed to demonstrate a reduction in vascular events.24,25 Thus, the pendulum has swung back to a focus on TG, TGRL and RC.

The evidence for the association of RC with ASCVD is more convincing. Varbo et al.26 demonstrated that each 1 mmol/L (39 mg/dL) increase in non-fasting RC (calculated as total cholesterol minus HDL-C minus LDL-C) associated with a 2.8-fold increase in risk of ischemic heart disease (IHD) independent of low HDL-C. In the Copenhagen City Heart Study and the Copenhagen General Population Study, non-fasting calculated RC was associated with a stepwise increase in risk of IHD, MI, and all-cause mortality.27 In a study by Jepsen et al.,28 both elevated levels of measured and calculated RC were associated with all-cause mortality in patients with IHD. More recently, a nested-case control study of 4,662 individuals from the China Kadoorie Biobank demonstrated that RC concentrations (measured by NMR spectroscopy) were associated with a 1.27-fold increased risk of MI and 1.20-fold increased risk of ischemic stroke.29

However, there have been several recent negative trials of RC. In the ARIC (Atherosclerotic Risk in Communities) cohort, RC was initially shown to correlate with CVD, though after adjustment for traditional risk factors, this association was no longer true.30 However, triglycerides in LDL (LDL-TG) were found to be associated with increased risk of CHD (HR 1.28; 95% CI 1.1-1.5) and ischemic stroke (HR 1.47; 95% CI 1.13-1.92) even after adjustment for traditional risk factors. Within the Jackson Heart and Framingham Offspring Cohort Studies, RC was initially found to be associated with CHD, though again this was attenuated by HDL-C and ultimately lost significant with inclusion of "real" LDL-C, which excludes intermediate density lipoprotein cholesterol and lipoprotein(a) cholesterol.31 These studies have shed light on the fact that further trials are needed regarding elucidating a causal role for these lipoproteins.

Genetic Studies

Genetic studies, particularly Mendelian randomization studies, suggest that TG are causal in the development of ASCVD. DNA variants can be used to assess if a biological marker that has an epidemiological association for risk of disease (i.e., ASCVD) is likely causal for the disease.32 Mendelian randomization studies of variants associated with TG are commonly affected by the pleiotropic effects of single nucleotide polymorphisms (SNPs) on multiple metabolic pathways affecting plasma lipids.33 To overcome the effects of pleiotropy, Do et al.34 used multivariable Mendelian randomization to separate the effects of TG from LDL-C and HDL-C on ASCVD using 185 SNPs associated with TG, LDL-C, and/or HDL-C. The strength of a SNP's effect on TG levels correlated strongly with the magnitude of the effect on ASCVD, after adjustment for the SNP's effects on LDL-C and HDL-C. This finding supported the notion that plasma TG levels are an independent causal risk factor for ASCVD. In another Mendelian randomization analysis from the Copenhagen City Heart Study, genetically lower concentrations of non-fasting plasma TGs were associated with reduced all-cause mortality.35 Holmes et al.36 also demonstrated an independent causal association between TG and ASCVD using a multiple SNP instrumental variable meta-analysis.

Furthermore, insights from variants in genes involved in plasma TGRL metabolism, namely LPL and those that modulate its function, including apolipoprotein A-V (APOA5), apolipoprotein CIII (APOC3), angiopoietin-like 3 (ANGPTL3), and ANGPTL4 are also associated with ASCVD.37,38 LOF mutations in APOA5 and LPL are associated with increased risk of events.39,40 Likewise, LOF mutations in APOC3, ANGPTL3, and ANGPTL4 are associated with a lower risk of ASCVD.41,42 APOE variants were found to be associated with ASCVD as well as RC and LDL-TG levels in the ARIC cohort.30

Pharmacology

Lifestyle modifications are the foundation for management of hypertriglyceridemia and can reduce plasma TG levels by up to 60%.43 With regards to pharmacological management, statins (though not primarily TG lowering drugs) reduce TG by 22-45%.44 Currently, three other classes of drugs are available for the management of hypertriglyceridemia: fibrates, niacin, and omega-3 fatty acids.

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.13,45 In the Helsinki Heart Study and VA-HIT (the Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial), gemfibrozil reduced the risk of ASCVD, without improvement in mortality.46,47 Similarly, the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study failed to demonstrate a reduction in mortality but was associated with a reduction in total CV events.48 The BIP (Bezafibrate Infarction Prevention) study failed to demonstate benefit with the use of bezafibrate versus placebo in reduction of events in patients with ASCVD.49 In the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study, addition of fenofibrate to statin simvastatin did not result in significant beneficial effects on CVD risk.50 However, in post-hoc analyses of subgroups with atherogenic dyslipidemia (low HDL-C and high TG) in each of these studies suggest benefit in those with overt hypertriglyceridemia (TG >200 mg/dL).51,52

Omega-3 Fatty Acids (OM3FA)

OM3FA play an essential role in cellular membrane formation and stability and serve as precursors for inflammatory mediators (eicosanoids, prostaglandins, protectins, resolvins, leukotrienes).53 JELIS (Japan EPA Lipid Intervention Study), an open-label blinded study of supplementation with 1.8g/day of eicosapentaenoic acid (EPA) and a statin (pravastatin 10 mg or simvastatin 5 mg) versus statin alone, demonstrated a statistically significant (p = 0.01) 19% reduction in major coronary events.54 In a subanalysis of JELIS evaluating individuals with TG >150 mg/dL and HDL-C <40 mg/dL, EPA treatment led to a 53% reduction in incident CAD (HR 0.47; 95% CI 0.23-0.98; p = 0.043).55

Several ongoing cardiovascular outcomes trials assessing different formulations and higher doses of OM3FA are currently underway. High-dose Icosapent ethyl (Vascepa; Amarin), a highly purified EPA only formulation, was evaluated in high risk patients in the REDUCE-IT [Reduction of Cardiovascular Events With EPA–Intervention] trial and demonstrated a 25% reduction in major adverse cardiovascular events according to topline results that are expected to be presented formally at the 2018 Scientific Sessions of the American Heart Association. The ongoing STRENGTH (Statin Residual Risk Reduction With Epanova in High CV Risk Patients With Hypertriglyceridemia) trial is evaluating the impact of Epanaova (omega-3-carboxylic acids; AstraZeneca), a combination of EPA+DHA, on ASCVD outcomes.

Niacin

Niacin, or nicotinic acid, inhibits adipose tissue lipolysis which reduces the flux of FFA to the liver and therefore leads to reduced hepatic VLDL synthesis. The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health) and HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) studies demonstrated that despite reduction in TG levels, no incremental benefit was observed from the addition of niacin to statin therapy. However, a subgroup analysis of patients with TG ≥200 mg/dL and HDL-C <32 mg/dL demonstrated a 37% reduction in cardiovascular events favoring the niacin group (HR = 0.64, p-0.032).56,38

Emerging TG Lowering Therapies

Insights from genetic studies have led to a new approach to therapeutic drug targeting. In particular, antisense oligonucleotide (ASO) and small interfering RNA (siRNA) technologies, which employ gene silencing strategies through specific mRNA degradation, are currently being pursued as therapeutic approaches to lower TG and RC levels.57 Volanesorsen (previously known as ISIS-APOCIIIRX) is a second generation ASO developed to inhibit apoCIII, binds to the APOC3 messenger RNA, and promotes its degradation.58 Volanesorsen reduced apoCIII levels by 80% with a concomitant reduction in TG level by up to 71% with an associated increase in HDL-C of 46% in early phase trials.59 The COMPASS and APPROACH studies are currently testing Volanesorsen in a phase III clinical trial program.

Evinacumab (REGN1500, Regeneron) is a human monoclonal antibody against ANGPTL3 that demonstrated the ability to reduce fasting TG levels by up to 70% and LDL-C levels by up to 23% in an early-phase trial.60 Similarly, a phase 1 randomized, double-blind, placebo-controlled trial of an ASO targeting hepatic ANGPTL3 (IONIS-ANGPTLRX, Ionis Pharmaceuticals) messenger RNA lowered TG levels by up to 63% and LDL-C by up to 33%.61 Pemafibrate, a selective PPAR-α modulator, is a novel compound currently under investigation for the treatment of hypertriglyceridemia in the PROMINENT (Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Diabetic Patients) trial.62

Conclusion

Findings from observational and genetic studies have determined a causal role of TGRL and/or RC as a risk factor for ASCVD. Additionally, critical genetic studies have identified precise targets for a new era of therapeutics. Ongoing randomized controlled trials testing these investigational agents on cardiovascular outcomes are eagerly awaited and will help answer the question of whether lowering of TGRL leads to clinically meaningful reduction in ASCVD events.

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Clinical Topics: Anticoagulation Management, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Heart Failure and Cardiac Biomarkers, Diet, Stress

Keywords: American Heart Association, Apolipoprotein C-III, Antibodies, Monoclonal, Angiopoietins, Atherosclerosis, Apolipoproteins E, Apoptosis, Brain Ischemia, Capillaries, Biomarkers, Pharmacological, Brachial Artery, Bezafibrate, Biological Specimen Banks, Adipose Tissue, Antigens, CD59, Cause of Death, Case-Control Studies, Cohort Studies, Cholesterol, HDL, Cholesterol, Cardiovascular Diseases, Cytokines, Dilatation, DNA, Double-Blind Method, Connective Tissue, Diabetes Mellitus, Coronary Disease, Confidence Intervals, Chylomicrons, Drug Delivery Systems, Endothelium, Factor V, Eicosapentaenoic Acid, Fasting, Fatty Acids, Omega-3, Fibric Acids, Follow-Up Studies, Fenofibrate, Gene Silencing, Fatty Acids, Nonesterified, Hydrolysis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertriglyceridemia, Infarction, Glycerol, Interleukin 1 Receptor Antagonist Protein, Inflammation, Gemfibrozil, Interleukin-6, Factor Xa, Interleukin-15, Interleukin-8, Leukotrienes, Life Style, Lipolysis, Macrophages, Magnetic Resonance Spectroscopy, Metabolic Networks and Pathways, Mendelian Randomization Analysis, Leukocytes, Metabolic Syndrome X, Liver, Mutation, Lipoprotein Lipase, Oxidative Stress, Oligonucleotides, Antisense, Peroxisome Proliferator-Activated Receptors, Niacin, Polymorphism, Single Nucleotide, Risk Factors, Pravastatin, Random Allocation, Risk Reduction Behavior, Phospholipids, Reactive Oxygen Species, RNA, Small Interfering, Simvastatin, RNA, Messenger, Triglycerides, RNA Stability, Prostaglandins, Tumor Necrosis Factors, Up-Regulation, Prospective Studies, Stroke, Plasminogen Activator Inhibitor 1, Myocardial Ischemia, Vascular Cell Adhesion Molecule-1, Vasodilation, Ultracentrifugation, Primary Prevention, Secondary Prevention


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