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Triglyceride-rich Lipoproteins and Cardiovascular Disease: Importance and Management Update for Pharmacists

Introduction

Cardiovascular disease is the leading cause of death among adults in the United States, accounting for 1 in every 3 deaths.1 Dyslipidemia, primarily an increase in low-density lipoprotein cholesterol (LDL-C), is a major risk factor for the development of atherosclerosis.2 Statins have become the most important therapeutic agents for reducing cardiovascular events primarily because of their LDL-C lowering effects.3 In the Cholesterol Treatment Trialists’ Collaboration meta-analysis, which included 21 trials comparing statins with a control group, the annualized event rate for a major vascular event was 2.8% for patients treated with a statin as compared with 3.6% for patients in the control group.4 Although the benefit of statin therapy observed in this meta-analysis was highly statistically meaningful, the absolute annual risk reduction with statin therapy was less than 1%.4 These data demonstrate that a substantial number of patients will experience a major vascular event despite statin treatment. This residual risk of adverse vascular events emphasizes the need to evaluate the potential role of other lipid components in the development of atherosclerosis. Recent data now strongly suggest that triglycerides and remnant lipoproteins are also a major causal risk factor for CVD. It also raises an important question about the role of drugs that are not statins and their impact on residual vascular risk.

The Role of Lipoproteins in Atherosclerosis

Cholesterol and triglycerides are relatively insoluble in water. To be transported through circulation and into tissues, they must be incorporated into macromolecular complexes referred to as lipoproteins.5,6 Lipoproteins are comprised of a central core of cholesterol and triglycerides covered by a unilamellar membrane, consisting primarily of amphipathic phospholipids and smaller quantities of proteins (apolipoproteins) and free cholesterol.5,6 The lipoproteins are classified according to their physical and chemical properties and vary in size, density, and function (Table 1).5,6

Table 1. Characterization of Lipoproteins by Size, Density, and Composition5,6
Lipoprotein Density Range (g/mL) Size (mm) Composition (%)
  Cholesterol Triglycerides
Chylomicrons < 0.95 100 – 1000 3 – 7 85 – 95
VLDL < 1.006 40 – 50 20 – 30 50 – 65
IDL 1.006 – 1.019 25 – 30 40 20
LDL 1.019 – 1.063 20 – 25 51 – 58 4 – 8
HDL 1.063 – 1.21 6 – 10 18 – 25 2 – 7
VLDL = very low-density lipoproteins; IDL = intermediate-density lipoproteins; LDL = low-density lipoproteins; HDL = high-density lipoproteins

Apolipoproteins, which reside on the surface of lipoproteins, serve as enzyme cofactors, cell membrane receptor ligands, and lipid transfer carriers that regulate the metabolism of lipoproteins and lipid uptake in tissue.5,6 Apolipoprotein B (APO-B) is the primary protein found in chylomicrons, very low-density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and LDL. The APO-B48 isoform synthesized in the intestine is unique to chylomicrons. The APO-B100 isoform synthesized in the liver is associated with VLDL, IDL, and LDL.5,6 Apolipoprotein A-I and A-II are the proteins predominantly associated with high-density lipoproteins (HDL).5 APO-C has 4 known isoforms and is associated with chylomicrons, VLDL, and HDL, while APO-E is associated with chylomicrons and IDL.

The role of lipids in the pathogenesis of atherosclerosis and its clinical manifestations has evolved over time based on the results of experimental investigations, epidemiologic studies, and clinical trials. APO-B related lipoproteins are known to be responsible for the development of atherosclerosis, intra-arterial plaque formation, and adverse vascular events.7 LDL has been considered the primary atherogenic APO-B lipoprotein.8 The penetration of LDL and remnant lipoproteins, primarily IDL, into the subendothelial space of the artery wall is thought to occur at areas of endothelial dysfunction.9 Other APO-B related lipoproteins, such as chylomicrons and VLDL are too large to infiltrate the arterial wall and have generally not been associated with an increased risk of atherosclerosis.7 An independent association of plasma triglycerides, which are the chief component of chylomicrons and VLDL with increased atherosclerotic events, remains controversial,10 though recently a spate of data from genetics and large-scale observations have shed important findings in support of their direct role in atherosclerosis. Alterations in the metabolism of triglyceride-rich lipoproteins by APO-C3 may have direct pro-inflammatory effects. These effects may include the induction of vascular cell adhesion molecule-1, an endothelial-leukocyte adhesion molecule implicated in the recruitment of monocytes, the precursor of foam cells in the atherosclerotic plaque, and contributors to ongoing inflammation implicated in plaque evolution and complication.11 Observational and genetic studies of variants associated with elevated remnant cholesterol levels has been shown to cause both low-grade inflammation as measured by c-reactive protein (CRP) levels and ischemic heart disease.12 Conversely HDL has traditionally been associated with protection against atherosclerosis, primarily because of its ability to facilitate the reverse transport of cholesterol from tissues back to the liver for disposal.13

The concept that LDL is bad cholesterol and HDL is good cholesterol does not adequately encompass the complexity of the pathogenic interplay between lipids and atherosclerosis. Chylomicrons and VLDL particles undergo remodeling once they reach the plasma after absorption from the intestine (i.e., chylomicrons) or after secretion from the liver (i.e.,VLDL). This remodeling produces remnant particles that are small enough to enter the vessel wall and accumulate in atherosclerotic plaque in both animals and humans.14,15 The remodeled chylomicrons and VLDL particles, referred to as remnants, have also been linked to the progression of coronary artery disease.16 Chylomicron and VLDL remnants are generated during the normal process of triglyceride metabolism.17 Chylomicrons and VLDL particles acquire various apolipoproteins upon entering the plasma, which stimulates lipoprotein lipase to hydrolyze triglycerides from these particles and, subsequently, creates smaller, denser remnants. Currently, there is no way to differentiate newly secreted chylomicrons, VLDL, and IDL from their respective remnants in plasma.7 As a result, triglyceride-rich lipoproteins (TRLs) measured in the blood represent the sum of newly secreted and remnant chylomicrons, VLDL, and IDL however, it is believed that only the remnant TRLs are associated with an increased risk of atherosclerosis.7

One way in which high triglycerides may lead to an increased risk of atherosclerosis is through the production of small, dense LDL particles. When VLDL particles interact with lipoprotein lipase or hepatic lipase, then triglycerides are removed, resulting in IDL and then LDL. Each time triglycerides are removed, the resulting particle becomes smaller. In the setting of hypertriglyceridemia, there is a proportionally larger volume of the VLDL particles comprised of triglycerides; so, when triglycerides are removed, it results in a smaller, denser LDL particle. These smaller, denser particles more easily migrate into the subendothelial space and are more easily taken up by macrophages to produce foam cells, which are associated with an increased risk of atherosclerosis. Thus, the higher the triglycerides, the more small, dense LDL particles are produced, leading to the increased risk of atherosclerosis.
LDL = low-density lipoprotein; VLDL = very low-density lipoprotein; IDL = intermediate-density lipoprotein

Genetics, Lipoproteins, and Atherosclerosis

Familial lipid disorders were originally defined by phenotype (i.e., changes in lipids and lipoproteins) as described in the Fredrickson Classification (Table 2).18 Several of these familial disorders are associated with very high triglyceride levels and an increase in TRLs.17 Lipoprotein lipase deficiency (Fredrickson Class I) is associated with genetic defects in APO-CII and APO-A5. This results in very severe triglyceride elevations (i.e., higher than 1000 mg/dL) and persistent fasting chylomicronemia. Patients with this disorder are more likely to develop pancreatitis before atherosclerotic vascular disease manifests.17 Dysbetalipoproteinemia (Fredrickson Class III) occurs secondary to a homozygous defect in APO-E2, which results in an increase in chylomicron and VLDL remnants.17 In this disorder, triglycerides and total cholesterol levels are increased, HDL levels are typically normal, and LDL is low. It may be associated with an increased risk of atherosclerosis (especially peripheral vascular disease), which often manifests in adulthood with the emergence of other risk factors, such as obesity, diabetes mellitus, alcohol abuse, or hypothyroidism.17 In other disorders associated with high triglycerides (e.g., familial hypertriglyceridemia, familial combined hyperlipidemia, and remnant hyperlipidemia), LDL-C and HDL-C can be remodeled into smaller and denser particles. Smaller denser LDL particles are more atherogenic, while smaller denser HDL-C may be functionally impaired. These disorders are often caused by multiple lipoprotein abnormalities.17

Table 2. Fredrickson Classification of Dyslipidemias18
Phenotype Elevated Lipoproteins Plasma Total Cholesterol Plasma Triglycerides Estimated Prevalence (%)
I Chylomicrons Normal or ↑ ↑↑↑ < 1.0
IIa LDL ↑↑ Normal or ↑ 20 – 80
IIb LDL and VLDL ↑↑ ↑↑ 10
III IDL ↑↑ ↑ 0.02
IV VLDL ↑ ↑↑ 1
V VLDL and chylomicrons ↑ ↑↑ 0.1
VLDL = very low-density lipoproteins; IDL = intermediate-density lipoproteins; LDL = low-density lipoproteins; HDL = high-density lipoproteins; ↑ = increased

Genetic studies have been able to more accurately define an association between triglycerides and TRLs and cardiovascular disease.10 Genome-wide association studies and Mendelian randomization studies have found that polymorphisms in APO-A5 are strong determinants of triglyceride concentrations.7 APO-A5 is a gene responsible for the synthesis of a protein associated with the synthesis of VLDL-C. There are patients with genetic variations in the function of APO-A5 variants, which increase triglycerides and TRLs. These patients were found to have an increased risk of ischemic heart disease that was 1.4 to 1.7 times greater than that of patients without the genetic variant.10 In these studies, genetically low HDL-C levels were not related to cardiovascular disease risk. APO-C3 inhibits lipoprotein lipase activity and reduces the uptake of TRLs by the liver.10 Individuals with a genetic loss of function in APO-C3 have been shown to have a 35% to 40% reduction in plasma triglycerides and a 24% to 41% reduction in ischemic heart disease.19,20 These genetic studies suggest that high concentrations of triglycerides and TRLs are causal risk factors for cardiovascular disease. As a result, several new therapeutic targets, such as omega-3 fatty acids, APO-C3 inhibitors, and lipoprotein lipase gene replacement therapy, should be explored for their ability to reduce the residual risk associated with triglycerides and TRLs.

Triglyceride Lowering Therapy

The American Heart Association (AHA) and the National Lipid Association (NLA) provide identical biochemical definitions of normal and elevated plasma triglyceride levels (Table 3).17,21 The primary therapeutic objective for patients with very high triglyceride levels (i.e., levels 500 mg/dL or higher) is to reduce the risk of pancreatitis. This typically requires both therapeutic lifestyle changes and pharmacologic therapy. For patients with high triglycerides (i.e., 200 to 499 mg/dL), the primary treatment goal is to reduce levels of atherogenic lipoproteins (both non–HDL-C and LDL-C) to reduce cardiovascular risk. Non–HDL-C is the subtraction of HDL-C from all lipids containing APO-B and, therefore, is also a target treatment goal along with LDL-C, especially in the setting of elevated triglyceride levels.21 Because of the measurement-related issues resulting from lipoprotein heterogeneity, non–HDL-C, a close and clinically useful approximation of APO B-containing lipids, is a stronger predictor of cardiovascular disease and a better primary target for modification than the typical measurement of LDL-C.21

Table 3. Categories of Hypertriglyceridemia as Defined by the AHA and NLA17,21
Category Triglyceride Levels (mg/dL)
Normal < 150
Borderline High 150 – 199
High 200 – 499
Very High ≥ 500
AHA = American Heart Association; NLA = National Lipid Association

Therapeutic Lifestyle Changes: Diet and exercise, with or without weight loss, are the foundational strategies for reducing triglyceride levels and cardiovascular risk.17,21 Plasma triglycerides are impacted by body weight, fat distribution, weight loss, macronutrient composition of the diet, and alcohol consumption. Comprehensive changes in nutrition can produce sizable changes (20% to 50%) in plasma triglycerides. Recommendations from the AHA include a 5% to 10% reduction in body weight if overweight or obese, reducing refined sugar and simple carbohydrate intake while increasing dietary fiber, reducing fructose and saturated fatty acid consumption, following a Mediterranean-style diet, and consuming marine-derived omega-3 fatty acids.17 The consumption of non-marine polyunsaturated fats has not been shown to reduce plasma triglycerides.17 Alcohol restriction is recommended by the NLA as a routine strategy to reduce triglycerides, while the AHA recommends complete alcohol abstinence along with reduced saturated fat intake for patients with very high triglycerides.17,21 The NLA further recommends that, for patients with very high triglyceride levels (i.e., levels 500 mg/dL or higher), a low-fat diet may be helpful.19 For patients with triglyceride levels lower than 500 mg/dL, sugars and refined carbohydrates should be replaced with a combination of unsaturated fats and proteins, which may reduce triglyceride and non–HDL-C concentrations.21

The specific impact of aerobic exercise on triglyceride levels is complex. The best evidence demonstrating the effect of aerobic exercise on triglyceride levels was a reported reduction of more than 20% when implemented in conjunction with a reduction in calorie intake (i.e., approximately 300 kcal/day or more).17 A general trend between the duration and intensity of exercise and the magnitude of triglyceride reduction has been observed, but this relationship is not universal.17 Patients with higher baseline triglyceride levels also appear to have a greater magnitude of effect in response to exercise. It seems reasonable that patients with hypertriglyceridemia consider aerobic exercise in addition to changes in diet.

Pharmacologic Therapy: The triglyceride-lowering effects of lipid-lowering therapy are summarized in Table 4.17 Substantial variability exists regarding the magnitude of the effect of individual drugs on plasma triglycerides and their effectiveness in individual patients. None of the lipid lowering drugs impacts triglyceride levels in isolation. Drugs that lower triglycerides also impact the levels of other plasma lipids. The most recent AHA cholesterol guidelines3 refer to the AHA Scientific Statement on triglycerides published in 2011.17 The NLA recommends that for patients with very high triglyceride levels (i.e., levels 500 mg/dL or higher) therapy is generally initiated with a fibrate, niacin, or an omega-3 fatty acid because these have shown a greater triglyceride-lowering effect and allow for a potentially greater reduction in the risk of pancreatitis.21 In patients with triglyceride levels between 200 and 499 mg/dL, therapy is generally started with a statin to reduce the risk of adverse cardiovascular events. Addition of other therapies may be considered based on the lipid response to the initial therapy selection.21

Table 4. Effect of Treatment  by Drug Class on Triglyceride Levels17,21
Drug Class Change in Plasma Triglyceride Levels
Fibrates 20% to 50% ↓
Statins 7% to 30% ↓
Immediate-release niacin 20% to 50% ↓
Extended-release niacin 10% to 30% ↓
Ezetimibe 5% to 10% ↓
Bile acid sequestrants 0 to 10% ↑
Omega-3 Fatty Acids 20% to 50% ↓

Statins: Statins competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in the conversion of mevalonate, which is eventually converted to cholesterol.2 Reducing the synthesis of cholesterol results in a compensatory increase in the synthesis of hepatic LDL receptors. The increase in LDL receptors leads to increases in LDL-C and VLDL-C particle uptake and elimination. As a result, LDL-C, APO-B, triglyceride, and total cholesterol plasma concentrations are reduced. Small increases in HLD-C occur as well. The greatest magnitude of effect is to lower LDL-C concentrations. Reduction in triglycerides with statins range from 7% up to 30%.17 In patients with normal or borderline high triglyceride levels, the impact of statins on triglycerides is negligible. As baseline triglyceride levels are increased, the magnitude of the effect of statins on lowering triglyceride levels increases.

Changes in LDL Cholesterol (%) According to Manufacturer Prescribing Information
mg Rosuvastatin Atorvastatin Simvastatin Lovastatin Pravastatin Fluvastatin Pitavastatin
5 -45   -26        
10 -52 -39 -30 -21 -22   -31 (1 mg)
20 -55 -43 -38 -27 -32 -22 -39 (2 mg)
40 -63 -50 -41 -31 -34 -25 -44 (4 mg)
80   -60 -47   -37 -35  

Changes in Triglycerides (%) According to Manufacturer Prescribing Information
mg Rosuvastatin Atorvastatin Simvastatin Lovastatin Pravastatin Fluvastatin Pitavastatin
5 -35   -12        
10 -10 -19 -15 -10 -15   -13 (1 mg)
20 -23 -26 -19 -10 -11 -12 -15 (2 mg)
40 -28 -29 -18 -14 -24 -14 -22 (4 mg)
80   -37 -24   -19 -19  

Statins are generally well-tolerated during long-term therapy. The most common safety concerns include statin-associated muscle symptoms, liver function abnormalities, new onset diabetes, and adverse neurocognitive effects.3 The adverse effect most commonly associated with statin discontinuation is muscle toxicity. It is estimated that about 10% to 15% of patients develop statin-associated muscle symptoms, with a smaller percentage that cannot tolerate any dose of statin.22 The benefit of statins outweighs the risk of statin use in most settings where statin-related adverse effects are seen.

Cholesterol Absorption Inhibitors: Ezetimibe inhibits the absorption of cholesterol from the small intestine by blocking the Niemann-Pick C1-Like 1 receptor, which mediates cholesterol absorption.23 The reduction in hepatic cholesterol leads to an increase in the transport of cholesterol from the plasma into the liver for disposal. The average decrease in LDL-C is 18%, with a 7% decrease in triglycerides.23 The increase in HDL-C is minimal (approximately 1%). Ezetimibe is one of the only non-statins that, when used in combination with a statin, demonstrated a reduction in cardiovascular disease risk beyond statin monotherapy.24

Ezetimibe is not substantially absorbed, not absorbed systemically; therefore, it is well tolerated. Although subjective side effects, such as fatigue, abdominal pain, diarrhea, arthralgia, and back pain, have been reported with ezetimibe, a direct cause-and-effect relationship has not been established. Isolated incidences of increased hepatic aminotransferase levels have been reported.24

Bile Acid Sequestrants: Bile acid sequestrants are compounds that function as ion exchange resins exchanging anions, such as chloride, for bile acids.2 These resins sequester bile acids from the enterohepatic circulation. Since cholesterol is the sole precursor of bile acids, the liver removes cholesterol and LDL-C from the plasma to produce more bile acids. Bile acid sequestrants are large polymers, which are not absorbed systemically. The primary effect of bile acid sequestrants is to reduce LDL-C, which is reduced in a dose dependent manner by approximately 15% to 30%.25 Bile acid sequestrants typically have no effect or may increase triglyceride levels.25

The most common side effects of bile acid sequestrants are related to the gastrointestinal tract. The most common side effect is constipation.2 Administration of stool softeners when a bile acid sequestrant is started is typically recommended. The other major adverse effect of bile acid sequestrants lies in their ability to bind other drugs in the gastrointestinal tract, reducing their absorption. The most reasonable approach to avoiding this interaction is to administer concomitant drugs 2 hours prior to or 4 hours after administration of a bile acid sequestrant.2,25

Nicotinic acid: Nicotinic acid or niacin is vitamin B3, which is an essential nutrient known to prevent pellagra.2 At supraphysiologic doses, niacin has significant lipid modifying effects. The mechanism of action of niacin by which it affects lipids is not well established. Niacin binds to the G protein receptors specific to niacin.26 These receptors inhibit cyclic adenosine monophosphate (cAMP), which reduces fat breakdown in adipose tissue and the availability of fatty acids for the production of triglyceride, VLDL-C, and LDL-C in the liver. Niacin also inhibits diacylglycerol acyltransferase-2 (DGAT2), which is important in hepatic triglyceride synthesis.26 The decrease in fatty acids also decreases synthesis of APO-C3, increasing VLDL-C clearance. The effects of niacin on HDL-C is also not completely understood. Niacin increases APO-A1 and reduces HDL-C hepatic catabolism. Niacin decreases cholesteryl ester transfer protein activity and, with the decrease in triglyceride levels, can raise HDL-C levels.26

Niacin is available in 3 different formulations, including an immediate release formulation, a sustained-release formulation, and an extended-release preparation.27 The extended release preparation is available only by prescription, while the other products are available as dietary supplements. The primary difference among these formulations is the rate of absorption of niacin from the formulations. Niacin is absorbed at 500 mg/hour, 100 mg/ hour, and 50 mg/hour with the crystalline formulation, extended-release formulation, and the sustained-release formulation, respectively.27 The clinical relevance of these differences results in a higher prevalence of flushing and gastrointestinal side effects with the immediate-release, rapidly absorbed crystalline formulation. The prevalence of flushing and gastrointestinal symptoms is considerably less with the long-acting, sustained-release formulation; however, the risk of hepatotoxicity is potentially greater with the long-acting preparation than with the immediate-release formulation. The extended-release formulation, engineered to produce rate of absorption in-between the other 2 formulations, carries the risk of both flushing and hepatotoxicity, but at rates lower than with the other 2 drugs.

Niacin has a broad-spectrum effect on plasma lipids, producing reductions in LDL-C and triglycerides and an increase in HDL-C.27 The average changes in lipids with niacin include a 5% to 25% decrease in LDL-C, a 15% to 35% increase in HDL-C, and a 20% to 50% reduction in triglycerides. Extended- and sustained-release niacin have a lesser triglyceride-lowering effect (-10% to -30%) compared with immediate-release niacin (-20% to -50%).17,27

Niacin has a substantial variety of adverse reactions, which complicates adherence.28 Flushing, itching, gastrointestinal upset, hepatotoxicity, hyperglycemia, and hyperuricemia. Use of niacin requires patients to follow specific steps to minimize flushing, such as taking a nonsteroidal anti-inflammatory agent 30 minutes prior to each dose, avoiding hot or spicy foods prior to taking a dose, taking the drug with a snack, and avoidance of missing doses, which can increase the intensity of flushing upon reinitiation of therapy.28

It is normally recommended that patients take an aspirin 30 minutes before taking niacin, along with a light snack, to reduce niacin-related flushing. However, clinical experience indicates that patients have a widely varying concept of what constitutes a light snack. One patient took his niacin with a heaping bowl of ice cream. So, in light of this, another recommendation for patients who have to take niacin is that the prophylactic administration of aspirin be taken directly before dinner is eaten and then followed by the administration of niacin. Niacin produces a prostaglandin-mediated flushing effect, which is mitigated by the antiprostaglandin activity of aspirin. Of course, this same antiprostaglandin activity may lead to stomach ulcers with prolonged use, so taking aspirin with dinner minimizes that risk. Also, taking niacin after dinner slows niacin absorption, which reduces the risk of flushing, and eliminates the need for an extra snack before bedtime, reducing overall calorie intake and avoiding potential weight gain. It is normally advised to take niacin at bedtime, so, if the patient does experience flushing, they may sleep through this effect. Taking niacin after dinner does increase the risk of flushing during evening hours, which can be further exacerbated with the consumption of hot liquids, such as soup with dinner or a hot drink afterward.

Fibrates: Gemfibrozil and various forms of fenofibrate are currently the only fibrates available in the United States. Fibrates work by activating the peroxisome proliferator-activated receptor alpha (PPAR-α).2 This activation leads to an increase in the activity of lipoprotein lipase and the inhibition of APO-C3. This leads to a decrease in plasma triglyceride levels and TRLs. The fibrates reduce LDL-C by 5% to 20%, increase HDL-C by 10% to 35%, and reduce triglyceride levels by 20% to 50%.2 For patients with very high triglyceride levels, fibrates may be associated with a small increase in LDL-C.

The most common side effects of fibrates are related to gastrointestinal intolerance. Fibrates alone or in combination with statins may be associated with myalgia.2 The risk of serious myopathy is most common with the use of gemfibrozil taken in combination with a statin.29 Because of this interaction between gemfibrozil and statins, which leads to an increase in myopathy, fenofibrate is the preferred fibrate if a patient is receiving a statin. Fenofibrate requires dosage adjustment for patients with renal dysfunction (i.e., CrCl less than 50 mL/min).30 For patients with renal dysfunction, gemfibrozil is the preferred fibrate, unless the patient is taking a statin. For a patient with renal dysfunction and also taking a statin, appropriate dose adjustment of fenofibrate or the use of another class of drug would be recommended. Fibrates are also associated with a potential for increased hepatic transaminase levels. These drugs also increase the viscosity of bile with an increased risk of gallstones, cholelithiasis, and pancreatitis.30

Omega-3 Fatty Acids: The omega-3 fatty acids include alpha-linoleic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA).31 Omega-3 fatty acids account for a small portion of the daily dietary fat intake, which are derived from 2 primary dietary sources—plants and fish.32 Oils from walnuts, flaxseed, and canola primarily contain ALA, which is a metabolic precursor of EPA and DHA. However, the conversion of ALA to EPA and DHA in the body is inefficient. As a result, achieving an adequate intake of EPA and DHA must be obtained through the diet either as fatty fish or omega-3 fatty acid capsules. In healthy individuals, the AHA recommends consumption of fatty fish at least 2 times a week, along with plant-derived omega-3 fatty acids from soybean products, walnuts, flaxseed oil, and canola oil.31 In patients with coronary heart disease, a combined intake of at least 1000 mg/day of EPA and DHA is recommended.33 When used in the treatment of hypertriglyceridemia, a dose of 2 to 4 g/day of EPA and DHA is recommended.32 ALA does not lower triglyceride levels and is not included in prescription omega-3 fatty acid products.

The mechanisms by which omega-3 fatty acids reduce plasma triglycerides are not completely understood. Omega-3 fatty acids reduce plasma triglyceride concentrations by reducing their synthesis, reducing their incorporation into VLDL, and enhancing their clearance from VLDL.17,31 Omega-3 fatty acids decrease hepatic lipogenesis by reducing the expression of sterol regulatory element-binding protein-1c.17 This leads to a decrease in the synthesis of cholesterol, fatty acid, and triglyceride-synthesizing enzymes. Omega-3 fatty acids also increase the β-oxidation of fatty acids, resulting in a reduction in available substrate required for triglyceride and VLDL synthesis, and inhibit key enzymes involved in hepatic triglyceride synthesis, including phosphatidic acid phosphatase and diacylglycerol acyltransferase.17,31 Omega-3 fatty acids also increase lipoprotein lipase activity, leading to increased triglyceride removal from circulating chylomicrons and VLDL.

In addition to their effects on plasma lipids, the omega-3 fatty acids modulate membrane protein function, cellular signaling, and gene expression. Dietary omega-3 fatty acids compete with omega-6 fatty acids for incorporation into cell membranes.34 If omega-6 fatty acids predominate in cell membranes, pro-inflammatory mediators, such as thromboxanes, prostaglandins, and leukotrienes, are produced via the cyclooxygenase and 5-lipoxygenase pathways. Conversely, the presence of omega-3 fatty acids promotes secretion of anti-inflammatory prostaglandins and less potent leukotrienes, resulting in the production of fewer inflammatory mediators. These pro-inflammatory and anti-inflammatory effects represent the primary pharmacological difference between omega-3 and omega-6 fatty acids.34

The administration of omega-3 fatty acids have also been associated with a reduction in macrophages in atherosclerotic plaque.35 As a result, plaque is less vulnerable to rupture and associated thrombosis.36 A recent paper by Nishio et al, which showed that combination therapy with EPA and a statin stabilized vulnerable plaques compared with statin alone, as well as reducing inflammatory markers. Another recent finding showed that EPA 1.8 g/day added to statin therapy reduced lipid volume, increased fibrous volume in coronary plaque, and reduced inflammatory cytokines.37,38 The favorable role of omega-3 fatty acids in the development of atherosclerosis is thought to result from a variety of effects on lipids, the endothelium, and platelets.39 EPA was found to inhibit LDL oxidation in a dose-dependent manner, while other triglyceride-lowering agents had no substantial effect as compared with vehicle treatment alone.40 It was also shown to inhibit glucose-induced membrane cholesterol crystalline domain formation through a potent antioxidant mechanism. EPA treatment in the Efficacy and Safety of AMR101 (Ethyl Icosapentate) in Patients With Fasting Triglyceride (Tg) Levels ≥ 500 and ≤2000 mg/dL (MARINE) and Effect of AMR101 (Ethyl Icosapentate) in Patients on Statins With High Tg Levels (≥ 200 and < 500 mg/dL) (ANCHOR) trials also showed a substantial reduction in multiple inflammatory markers, including intercellular adhesion molecule (ICAM)-1, oxidized (Ox)-LDL, lipoprotein-associated phospholipase A2 (Lp-PLA2), interleukin (IL)-6, and high-sensitivity C-reactive protein (hsCRP).41

Omega-3 fatty acids are available as either dietary supplements or as prescription products.32 The prescription products have undergone clinical testing to demonstrate efficacy and safety. All prescription products are available as soft gelatin capsules containing pure EPA alone or in combination with DHA derived from fish. There are more than 100 different dietary supplements sold as fish oil in the United States.42 Dietary supplement formulations include soft gels, liquids, powders, and gummies. The source of fish oil in these products may be derived from fish, krill, algae, or plants.43 Dietary supplement omega-3 fatty acid supplements are not subject to the same manufacturing regulations required for prescription drugs. The EPA and DHA content of dietary supplements may be inconsistent. An analysis of dietary supplements found an average of 68% of the claimed content of EPA and DHA.44 Another review of dietary fish oil supplements, which were identified in the National Library of Medicine Herbal Supplement Database, found that the combined content of EPA and DHA in 102 of these products ranged from as little as 30 mg per dose up to a maximum of 1452 mg per dose.42 This review found that a median of 11 supplement servings per day would be required to achieve a dose of 3.4 g per day of omega-3 fatty acids. This survey also found that dietary supplements contain other fats and cholesterol. This raises the concern about the purity and stability of dietary supplements. As the EPA and DHA content of dietary supplements varies widely among products, this may cause confusion for patients and practitioners. The monthly cost of these dietary supplements ranges from $15 to $700.42

Another survey involving cardiac patients using fish oil products found that dietary supplements are the most commonly used omega-3 fatty acids products.45 As a result, the majority of individuals using fish oils do so without physician supervision. In addition, the survey found that the vast majority of patients who use fish oils were not using these products properly. The majority of users did not know the following about their supplement: name of the active ingredients; dose of the active ingredients; or the number of capsules or tablets needed to be taken to achieve the recommended intake of omega-3 fatty acids. Approximately 1 in 4 users indicated that they used different brands of omega-3 fatty acids products. Finally, only 1 in 4 purchased their supplement in a pharmacy. This suggests that pharmacists may not be able to impact the selection of an omega-3 fatty acids supplement at the point of purchase in a manner consistent with a prescription product.

There are 3 prescription omega-3 fatty acids that are U.S. Food and Drug Administration (FDA) approved in the United States.31 A generic form of the omega-3-acid ethyl ester product has also been FDA approved. Prescription omega-3 fatty acids products are indicated only for the management of very high triglyceride levels (i.e., levels 500 mg/dL or higher). Prescription omega-3 fatty acids are approved for 4 gm/day to treat patients with triglyceride levels 500 mg/dL or higher. There is no published head-to-head comparative trial of the prescription omega-3 fatty acids products. In addition, the prescription products have a different quantity of EPA and DHA in each capsule (Table 5).46-48 As a result, it is difficult to reach valid conclusions about the relative efficacy and safety of these products. Table 6 summarizes the results of the studies with prescription omega-3 fatty acids involving patients with very high triglyceride levels (i.e., levels between 500 mg/dL and 2000 mg/dL).46,49,50 These patients were allowed to continue a statin plus ezetimibe, as long as the baseline triglyceride levels were 500 mg/dL or higher. The greatest reduction in triglyceride levels and VLDL-C, relative to placebo, occurred with the omega-3 ethyl esters (-52%, -41%); while those reductions were more modest with icosapent ethyl (-33%, -29%) and the omega-3 carboxylic acids (-21%, -21%). This difference may be partially explained by differences in baseline triglyceride and VLDL-C concentrations. There are also some differences in the effects of these products on other lipid parameters, which appear to result from the inclusion of DHA. Icosapent ethyl produces a small decrease in HDL-C (-4%), while the combination EPA-DHA products produce small increases in HDL-C (+5% and +9%). The combination EPA-DHA products also increase LDL-C (+26% and +45%) compared with a small reduction of LDL-C with icosapent ethyl (-5%). The clinical impact of the differential effect of these products on HDL-C and LDL-C is not known.

Table 5. Overview of Omega-3 Fatty Acids Prescription Products46-48
  DHA and EPA Combination Prescription Products EPA-Only Prescription Product
Generic name
(Brand name)		 Omega-3-carboxylic acids
(Epanova*)		 Omega-3-acid ethyl esters
(Lovaza, Omtryg*, generic product)		 Icosapent ethyl
(Vascepa)
DHA content per capsule 0.2 g 0.375 g None
EPA content per capsule 0.55 g 0.465 g 1 g
Daily dosage of omega-3 fatty acids
(schedule)		 2 g or 4 g
(2 or 4 capsules QD)		 4 g
(4 capsules QD or 2 capsules BID)		 4 g
(2 capsules BID)
*Not yet commercially available; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; QD = four times a day; BID = twice a day

Table 6. Percent Change in Lipid Parameters With the Prescription Omega-3 Fatty Acid Products in Patients With Very High Triglyceride Levels (≥ 500 mg/dL, ≤ 2000 mg/dL)46,49,50
  Omega-3-carboxylic acids Omega-3-acid ethyl esters Icosapent ethyl
Parameter
(mg/dL)		 Placebo
(Olive Oil)
n = 100		 4 g/d
n = 99		 Placebo
(Corn Oil)
n = 42		 4 g/d
n = 42		 Placebo
(Mineral Oil)
n = 75		 4 g/d
n = 76
Triglycerides -10 -31 +6.7 -45 +10 -27
Non–HDL-C -1 -8 -4 -14 +8 -8
HDL-C +2 +5 0 +9 0 -4
TC 0 -6 -2 -10 +8 -7
VLDL-C -11 -35 -1 -42 +14 -20
LDL-C +10 +26 -5 +45 -3 -5
APO-B +2 +6 NR NR +4 -4
HDL-C = high-density lipoprotein cholesterol; TC = total cholesterol; VLDL-C = very low-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; APO-B = apolipoprotein B; NR = not reported

Table 7 summarizes the results of the studies with prescription omega-3 fatty acids for patients with high triglycerides (higher than 200 mg/dL and lower than 500 mg/dL) despite treatment with statins.51-53 Although not FDA approved for this patient population, the NLA recommends that lipid-modifying therapy be individualized according to risk, using non–HDL-C as the primary lipid endpoint.21 As a result, the effect of these agents on this population is an important consideration for many practitioners. The magnitude of the reduction in triglyceride levels is somewhat more consistent in this patient population, with a range from 17% to 28%. There also appears to be a smaller difference in the effect of these products on LDL-C and HDL-C. It is important to note that the placebo response in the icosapent ethyl (EPA only) studies showed increases in the APO-B related parameters, while the placebo response in the combination EPA-DHA product studies found neutral or small decreases in the APO-B parameters. As a result, any attempt to compare the magnitude of the effect of these products on specific lipid parameters cannot be made.

Table 7. Percent Change in Lipid Parameters With the Prescription Omega-3 Fatty Acids Products in Statin-Treated Patients With High Triglyceride Levels (≥ 200 mg/dL, < 500 mg/dL)51-53
  Omega-3-carboxylic acids Omega-3-acid ethyl esters Icosapent ethyl
Parameter
(mg/dL)		 Statin + Placebo
(Olive Oil)
n = 215		 Statin + 4 g/d
n = 215		 Statin + Placebo
(Vegetable Oil)
n = 132		 Statin + 4 g/d
n = 122		 Statin + Placebo
(Unspecified)
n = 277		 Statin +
4 g/d
n = 226
Triglycerides -5.9 -20.6 -3.5 -28.2 +5.9 -17.5
Non–HDL-C -0.9 -6.9 -1.5 -7.9 +9.8 -5.0
HDL-C +2.2 +3.3 -1.1 +4.1 +4.8 -1.0
TC +0.5 -3.8 -1.5 -4.7 +9.1 -3.2
VLDL-C -5.9 -21.5 -4.8 -23.8 +15.0 -12.1
LDL-C +1.1 +1.3 -1.9 +3.4 +8.8 +1.5
APO-B +0.3 -2.1 -1.2 -3.8 +7.1 -2.2
HDL-C = high-density lipoprotein cholesterol; TC = total cholesterol; VLDL-C = very low-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; APO-B = apolipoprotein B

Prescription omega-3 fatty acid products are well-tolerated, with rates of treatment discontinuation similar to those of placebo.46-53 The most common side effects with the use of combination omega-3 fatty acids include eructation, nausea, diarrhea, and other mild gastrointestinal disturbances while the most commonly reported side effect associated with the EPA only product is arthralgia. Studies with the prescription products have found no adverse effect on liver function.49-53 When combined with statins, these products do not increase the risk of muscle symptoms or toxicity. The prescription omega-3 fatty acids products have not been shown to increase bleeding when used in combination with warfarin or antiplatelet drugs. Patients with a known allergy to fish or shellfish should consider using these products with caution.

Counseling the Patient with Hypertriglyceridemia

Patients with hypertriglyceridemia should be educated about what triglycerides represent, the risks of hypertriglyceridemia, and about the most effective methods for reducing the risks associated with hypertriglyceridemia.17 Patients should recognize that, along with cholesterol, triglycerides are the other major fat in the body. Excessive plasma triglycerides may lead to an increased risk of heart attack, stroke, and pancreatitis.7 Patients should be advised of what normal levels of plasma triglycerides are and which levels are associated with increased risk (i.e., high 200 to 499 mg/dL and very high 500 mg/dL or higher).17,21 Patients should be aware that triglyceride levels are only a part of their overall risk of heart attack and stroke. They should be counselled about other lipid parameters, including LDL-C and HDL-C, smoking, high blood pressure, overweight or obesity, family history of premature vascular disease, and diabetes.17

Patients should also be counseled about therapeutic lifestyle modifications. Patients have to appreciate that lifestyle modifications may have the substantial ability to lower their plasma triglyceride levels.17 Those who are overweight or obese should receive counseling concerning weight loss, and success is best achieved through a consult with a dietician; but simple changes to the diet can be meaningful. It is important to follow a diet that has reduced fat content, especially saturated fats, substituting complex carbohydrates for refined or simple sugars, with an appropriate balance of calories derived from proteins, carbohydrates, and fat. For many patients, it is helpful to avoid or reduce the intake of foods and drinks that contain a lot of sugar and carbohydrates, such as the following: white bread, fruit juice, soda, and sweets. Avoidance or a reduction in the intake of red meat, butter, fried foods, cheese, oils, and nuts may also be helpful. Patients should be advised to limit alcohol intake. Two alcoholic drinks per day, or less, are recommended for men and one alcoholic drink per day is recommended for women.

If medications are prescribed for patients with hypertriglyceridemia, counseling specific to the prescribed medications is mandatory. The most commonly used medications for the treatment of high triglyceride levels include fibrates, niacin, and omega-3 fatty acids.21 However, statins are the most commonly prescribed lipid-modifying medications and are likely to be used in patients with increased cardiovascular risk and high triglyceride levels.2,3 Statins have only a modest ability to lower triglyceride levels.17 The most common side effects from the use of statins include muscle toxicity, which usually manifests as muscle weakness or aching or cramping muscles.22 If a patient develops unexplained, persistent muscle symptoms while using a statin, they should contact their prescriber or pharmacist. In addition, statins may interact with other medications, including fibrates and niacin. Patients should be advised to check with their prescriber or pharmacist before taking any new medication. Ezetimibe has little effect on triglycerides.23 Bile acid sequestrants may have an adverse effect on triglyceride levels and patients with high triglycerides must be warned about this effect.25

Fibrates are generally well-tolerated, with gastrointestinal side effects being the most common.2 Patients with a history of kidney disease may have to take a lower dose or avoid these drugs altogether.30 Fibrates may increase the risk of gallstones and pancreatitis. Patients with a history of gallstones or pancreatitis must use fibrates with caution. Fibrates may cause muscle toxicity when used alone, but this is rare. It is more likely that muscle toxicity would occur if fibrates, especially gemfibrozil, are used in combination with a statin.

Niacin is available in both a dietary supplement form and a prescription only formulation.27 Patients have to understand that only the prescription form of niacin is the extended-release product, which should be used under the supervision of a physician. Patients should be counselled regarding the side effects of niacin, which include facial flushing, pruritus, and gastrointestinal upset.28 These side effects tend to lessen with continued use of the drug; but, if patients miss doses, flushing may recur at a greater intensity. Patients should be advised that niacin may raise blood sugar (a caution for those with diabetes) and uric acid (a caution for those with gout). The sustained-release dietary supplement formulations of niacin may be associated with a greater risk of hepatotoxicity than other forms of the drug. Patients should be advised that the niacin dose is typically titrated slowly over several weeks. Niacin should be taken at bedtime, along with a nonsteroidal anti-inflammatory agent that is taken 30 minutes prior to the dose. Patients should avoid hot or spicy foods prior to taking niacin, but the dose should be taken with a low-fat snack.28

Omega-3 fatty acids are also available as dietary supplements and as prescription products. The dietary supplements should not be used to treat hypertriglyceridemia. Prescription omega-3 fatty acids should be used with physician supervision. Side effects from the prescription omega-3 fatty acids are minimal and usually include gastrointestinal disturbances.32 There is no specific drug interaction with omega-3 fatty acids and the risk of muscle toxicity is not increased when these drugs are taken with statins. The omega-3 carboxylic acids may be taken on an empty stomach.42 The other prescription omega-3 fatty acid products should be taken with food.46,47

SUMMARY

There is substantial evidence that high triglycerides and TRLs are associated with an increase in cardiovascular risk.6,7,10,15,16 Very high triglyceride levels are also associated with an increased risk of pancreatitis.15 Data demonstrating that drug therapy added to statins can reduce cardiovascular events greater than what is achieved with statin treatment alone are limited.24,54 Studies with fenofibrate alone or in combination with a statin have failed to demonstrate a reduction in adverse outcomes. Further, the addition of niacin to statin therapy has not resulted in a reduction in cardiovascular events. The use of the omega-3 fatty acids has been shown to reduce adverse cardiovascular events for patients taking statins for secondary prevention; but several recent trials using low-dose omega-3 fatty acids failed to show additional benefit on top of statin therapy.31

For patients with very high triglyceride levels, drugs that have the greatest ability to reduce plasma triglycerides would be recommended initially21; these agents include fibrates, niacin, and omega-3 fatty acids. The selection of one of these agents should be based on the assessment of a patient's access to therapy and the potential risk of adverse effects and drug interactions. Lifestyle modifications should be instituted, in addition to one or more of these agents, to reduce the risk of pancreatitis. The addition of an LDL-C lowering agent to this therapy would be based on an assessment of overall cardiovascular risk.3

For patients with high triglyceride levels, lifestyle modifications and the initiation of a statin are typically the initial therapies.21 This recommendation is based on the increased risk for adverse cardiovascular events as the result of elevated triglyceride levels and TRLs. The goal of therapy for these patients, based on recommendations from the NLA, is non–HDL-C. If a lifestyle modification and statin therapy fail to achieve the goal non–HDL-C target, addition of a non-statin therapy is recommended.21

Case Study
AA is a Caucasian man, aged 55 years, who is referred by his primary care physician to your lipid clinic for follow-up.

PMH:

  • HTN x 6 years
  • GERD x 2 years
  • HF (Class 3) x 2 years
  • T2DM x 12 years
  • Severe Gout x 5 years (2 gout attacks in the last month)
  • CKD x 2 years

FH:

  • Mother is alive with HTN and HLD
  • Father alive with HTN, HLD, and T2DM
  • No siblings

SH:

  • Tobacco: 1 PPD x 17 years
  • Alcohol: 2 12 oz servings of beer every night
  • Exercise: walking while shopping for groceries
  • Diet: consists of mainly fast food and snacks on chips every day between meals

ALLERGIES:

  • NKDA

CURRENT MEDICATIONS:

  • Benazepril 40 mg daily
  • Carvedilol 25 mg BID
  • Spironolactone 25 mg daily
  • Aspirin 81 mg daily
  • Pantoprazole 40 mg daily
  • Allopurinol 300 mg daily
  • Colchicine 0.6 mg UD for gout attack
  • Metformin 1000 mg 1 tablet BID

VITALS:
BP – 135/87;
PR – 65;
RR – 19;
Ht  – 5'7";
Wt  – 200 lbs;
Waist Circumference – 40"

LABORATORY TESTS

Na 146 Hgb 19 Chol 250 AST 11
K 5.1 Hct 40 TG 510 ALT 13
Cl 99 Plt 275 HDL 39 Alk phos 59
HCO3 26 WBC 8.7 LDL ---- CrCl 48.8
Mg 1.7 BUN 21 A1C 5.9%  
Ca 9.2 SCr 1.6 FPG 102    

PMH = past medical history; FH = family history; SH = social history; HTN = hypertension; GERD = gastroesophageal reflux disease; HF = heart failure; T2DM = type 2 diabetes mellitus; CKD = chronic kidney disease; HLD = hyperlipidemia; PPD = packs per day; NKDA = no known drug allergies; BID = twice a day; BP = blood pressure; PR = pulse rate; RR = respiration rate; Na = sodium; K = potassium; Cl = chloride; HCO3 = bicarbonate; Mg = magnesium; Ca = calcium; Hgb = hemoglobin; Hct = hematocrit; Plt = platelet; WBC = white blood cell; BUN = blood urea nitrogen; SCr = serum creatinine; Chol = cholesterol ; TG = triglycerides; HDL = high-density lipoprotein; LDL = low-density lipoprotein; A1C = glycated hemoglobin; FPG = fasting plasma glucose; AST = aspartate aminotransferase; ALT = alanine aminotransferase; Alk Phos = alkaline phosphatase; CrCl = creatinine clearance

  1. What is this patient's LDL and Non-HDL cholesterol levels?
    • Answer:
      • LDL – usually use Friedewald equation to determine LDL; however, because the patient's triglycerides are > 400, this equation is not valid. Must use direct LDL measurement to determine LDL
      • Non-HDL = TC - HDL
      • Non-HDL = 250 - 39 = 211
  2. Is this patient indicated for pharmacological treatment at this time?
    • His TG level is > 500; so, TG levels must be treated first, before initiating statin therapy to reach non-HDL goals

  3. What medication(s) would you recommend to address the patient's elevated TG levels?
    • Options include niacin, fibrates, or fish omega-3 fatty acids
    • Niacin would not be the best option for this patient because he has a history of severe gout and has had 2 attacks in the recent past. Niacin can increase uric acid, which may exacerbate more gouty attacks. Niacin can also have an adverse effect on glycemic control for this patient with T2DM
    • For fibrates, there are the following 2 options: gemfibrozil or fenofibrate
    • Gemfibrozil is a viable option for this patient to decrease TG levels; however, statin therapy may be appropriate for this patient in the future and gemfibrozil may not be the best option because its use is not recommended and should be avoided concomitant with most statin therapies
    • Fenofibrate to decrease the TG levels is an option for this patient; however, the lower dose should be used because renal function is compromised. Gemfibrozil is the preferred fibrate for patients with renal dysfunction
    • Fish oils are indicated for patients with TG levels > 500; so, fish oils are an option for this patient because there is no known contraindication to therapy
    • Can start fish oils or low-dose fibrate therapy to treat the TG levels. Recommend starting prescription fish oils

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