Postgraduate Medicine: Volume 121: No.4

Richard Sadovsky, MD and Penny Kris-Etherton, PhD, RD

Abstract: Triglyceride (TG) levels can increase for numerous reasons, including a sedentary lifestyle, an unhealthy diet, especially one rich in refined carbohydrates, and comorbidities. According to the National Cholesterol Education Program (NCEP), the normal TG level is < 150 mg/dL. Patients with very high TG (VHTG) levels (≥ 500 mg/dL) should be promptly managed and treated to reach lipid treatment goals, as determined by the NCEP. Lowering TG levels is the primary management goal in these patients, while lowering low-density lipoprotein cholesterol and non–high-density lipoprotein cholesterol levels are secondary goals. Therapeutic lifestyle changes are often recommended initially for patients with elevated TGs; however, concomitant drug therapy is often required. Data show that intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can significantly decrease serum TGs, along with plasma concentrations of certain lipoproteins. Omega-3-acid ethyl esters are available by prescription or as dietary supplements. Clinical trials in adult patients with VHTGs show that four 1 g capsules of prescription omega-3 fatty acids, which contain 465 mg of EPA and 375 mg of DHA per capsule, can effectively decrease TG levels by up to 45%, and is generally well tolerated.

Keywords: omega-3; prescription omega-3; Lovaza^⨀; triglyceride; lipid

In the United States, very high triglycerides (VHTGs; ≥ 500 mg/dL) occur in about 3.8 million patients.^1,2 Patients with VHTG levels should be promptly managed and treated to reach lipid treatment goals to decrease their risk for subsequent health problems and improve their overall health. Several pharmacologic options are available, although the focus in this article is omega-3-acid ethyl ester fatty acids. Omega-3-acid ethyl esters are available by prescription or as dietary supplements. This article provides a brief overview of triglyceride (TG) metabolism and management of elevated TGs to treatment goals, and highlights prescription omega-3-acid (P-OM3) ethyl ester fatty acids in patients with VHTGs.

Lipoproteins serve as a transport system for cholesterol, TGs, and fat-soluble vitamins to and from tissues within the body.³ Dietary consumption, intestinal secretion, and hepatic production yield TGs in lipoproteins.⁴ Triglycerides, fat comprising glycerol esterfied with 3 fatty acids, act as an energy source to muscles and other cells. After energy demands are filled, TGs are stored in the liver and adipose tissue, and remaining TGs circulate in the plasma.⁵ There are 2 pathways of lipid transport—exogenous and endogenous pathways.⁶ Dietary lipids are transported via the exogenous pathway.⁷ Lipases hydrolyze dietary TGs in the intestinal lumen. Most TGs in the blood are absorbed from the small intestine.⁷ The small intestine absorbs cholesterol, fatty acids, and fat-soluble vitamins. Lipoprotein lipase hydrolyzes the TGs of chylomicrons (large lipoproteins that transport dietary lipids) and very low-density lipoproteins (VLDLs), followed by the release of free fatty acids.⁴ Free fatty acids are either oxidized or re-esterfied, or may bind to albumin. Cholesterol and phospholipids, as well as apolipoproteins are transferred to high-density lipoproteins (HDLs). The liver actively removes the remaining chylomicron remnants from circulation.³ Very low-density lipoproteins and low-density lipoproteins (LDLs) aid in the transport of lipids from the liver to peripheral tissues via the endogenous pathway.⁶ Endogenous cholesterol is removed from the tissues and transported to the liver via HDLs.³ A detailed diagram of lipoprotein metabolism is presented in Figure 1.⁸

In patients without hypertriglyceridemia, VLDL particles are converted to intermediate density lipoprotein particles and finally to LDL particles.⁹ In patients with hypertriglyceridemia, the conversion of VLDL particles to LDL is inhibited and can result in a concomitant low level of LDL-cholesterol (LDL-C) and a high level of very low-density lipoprotein-cholesterol (VLDL-C). When TGs are normalized, VLDL particles decrease in size and number, which may increase LDL-C concentration, especially with very significant decreases in TGs.⁹

Genetics can play an uncontrollable role in raising TG levels. This is often the case in patients with familial combined hyperlipidemia, dysbetalipoproteinemia, and hypertriglyceridemia. However, it is not uncommon for patients who present with hypertriglyceridemia to be obese,¹⁰ insulin-resistant, hypertensive, or diabetic.¹¹ Certain comorbidities (ie, type 2 diabetes, which affects about 19 million people in the United States,¹² chronic renal failure, and nephrotic syndrome) can also influence TG levels. Additionally, pregnancy, nonalcoholic fatty liver disease, hypothyroidism, paraproteinemia (ie, hypergammaglobulinemia), and autoimmune disorders (ie, systemic lupus erythematosis) can cause an increase in TG levels.^11,13 Generally, obesity and type 2 diabetes are metabolic stressors commonly associated with hypertriglyceridemia.¹¹

Lifestyle choices and habits can also negatively impact TG levels. Increased TG levels can result from physical inactivity and high carbohydrate diets (> 60% of diet).¹⁴ In patients who consume excess alcohol, an increase in TG levels is often caused by increased VLDL, sometimes with chylomicronemia.¹¹ Additionally, certain medications, such as ß-blockers, antipsychotic medications, estrogen, protease inhibitors, corticosteroids, and retinoids, can influence TG levels.^13,15,16

Patients with an abnormal lipoprotein profile, including those with VHTGs, may be at risk for subsequent serious health problems.¹⁷ As noted, obesity is often associated with an abnormal lipoprotein profile. According to the US Department of Agriculture, the average American consumes about 2700 calories per day.¹⁸ From 1970 to 2000, the average American’s daily caloric intake increased by 530 calories (24.5%). Much of this increase was a result of excessive consumption of refined grain products, fats, oils, and sugars.¹⁸ The combination of decreased exercise and increased caloric intake has resulted in 145 million overweight or obese (body mass index ≥ 25 kg/m²) persons in the United States.^18,19 Excess fat is deposited in liver and muscle tissue, but the greatest amount of fat is stored in adipose tissue. In total, 90% of the lipids stored in adipose tissue are in the form of TGs.⁹

The National Cholesterol Education Program (NCEP) has issued guidelines for the management of patients with blood cholesterol abnormalities.¹³ Decreasing LDL-C levels remains the primary treatment target for lipid-lowering therapy. However, other targets should be considered, especially in patients with other comorbid conditions and/or in patients with VHTGs. For patients with VHTGs, lowering TG levels (normal concentration is < 150 mg/dL) is the primary management goal, while lowering LDL-C and non–HDL-C levels are secondary management goals (Figure 2). Most recent data point to non–HDL-C (total cholesterol minus HDL-C) as an important treatment target in patients who need to normalize their lipid profile. The NCEP recommends that when TG levels are elevated, the target non–HDL-C concentration should be 30 mg/dL higher than the LDL-C goal (LDL-C < 100 mg/dL is optimal).¹³ Non-HDL can act as a good measure of assessment for the treatment and management of lipid imbalance.²⁰

Patients should be examined for underlying causes of VHTGs, such as hypothyroidism or diabetes mellitus. Such conditions should be treated and monitored to control TG levels.²¹ Additionally, certain medications, eg, corticosteroids, protease inhibitors for human immunodeficiency virus, ß-adrenergic blocking agents, and estrogens, are known to cause a fluctuation and possible increase in TG levels.¹³ To decrease TG levels, these medications may need to be discontinued.⁷ The NCEP recommends that patients with VHTG levels (≥ 500 mg/dL) initiate multifaceted therapeutic lifestyle changes.^13,22 In obese patients with hypertriglyceridemia, weight reduction is considered a clinical mainstay.¹⁵ Reduction in alcohol consumption can benefit patients with VHTG levels.⁷ These patients should reduce their intake of saturated fats and cholesterol to < 7% of total calories and < 200 mg/dL, respectively. In patients with elevated LDL-C (≥ 160 mg/dL is high),¹³ intake of plant stanols/sterols (2 g/day) and increased intake of viscous fiber (10–25 g/day) may be beneficial.¹⁴ However, many patients (especially those with elevated LDL-C levels) need medical intervention in addition to therapeutic lifestyle and diet changes.¹³ In all cases, lipid profiles should be monitored after the initiation of therapeutic lifestyle and diet changes or pharmacologic therapy.

Patients’ overall health can be significantly influenced by the types of fat consumed. Heart-healthy diets low in saturated fat and trans fat and rich in unsaturated fats have been shown to decrease the risk of coronary heart disease. Fruits and vegetables generally contain no or negligible amounts of fat.⁹ The fat content for selected animal foods, fish, fruits, and vegetables is presented in Table 1.⁹ Some species of fish, such as salmon, herring, mackerel, and halibut, contain high concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Table 2).^9,22,23

Data show that intake of EPA and DHA can significantly decrease serum TGs, along with plasma concentrations of lipids and lipoproteins.^13,24,25 The American Heart Association (AHA) recommends regular intake of omega-3 fatty acids through fatty fish consumption twice weekly.¹⁰ However, the amount of EPA and DHA provided by the diet may not be enough to cause a significant decrease in TGs in certain patients.^10,26

Several mechanisms of action have been proposed to explain the effects of omega-3 fatty acids on serum TG levels. Eicosapentaenoic acid and DHA may reduce VLDL-TG synthesis as a result of modulation of transcription factors associated with hepatic fatty acid uptake, synthesis, and oxidation, and factors involved in the synthesis of TGs and assembly of VLDL.²⁷ Omega-3 fatty acids affect the 4 metabolic receptors that modulate TG levels. Reductions in TG levels are expected when omega-3 fatty acids stimulate all 4 receptors simulataneously.²⁸ In addition, omega-3 fatty acids may inhibit acyl coenzyme A (CoA):1,2-diacylglycerol acyltransferase, increase mitochondrial and peroxisomal β-oxidation in the liver, decrease lipogenesis in the liver, and increase plasma lipoprotein lipase activity.²¹ Increased lipoprotein lipase activity may increase conversion of VLDL particles to LDL particles, which can result in an elevation in LDL-C concentration.⁹ It has also been suggested that EPA and DHA inhibit the esterification of other fatty acids.²¹

Current pharmacologic treatment options to lower TGs include omega-3 fatty acids.²² Omega-3 fatty acids are available in capsule form as a prescription medication or as dietary supplements. Although readily available, dietary supplements are not approved by the US Food and Drug Administration (FDA) for the treatment of any specific disease or medical condition.²⁹ The FDA monitors the efficacy, safety, and development of prescription products; dietary supplements are not regulated as drugs.²⁹ Clinical trials show that P-OM3 at a dose of 4 g per day is effective and generally well tolerated in adult patients with VHTG levels.^21,30,31

Data indicate that daily consumption of 4 g of P-OM3 lowers TG levels significantly in patients with VHTG levels.^21,30,31 Only one P-OM3 has been approved by the FDA as a source of omega-3 fatty acids in the United States.³² Lovaza^® is indicated as an adjunct to diet to reduce TG levels in adult patients with VHTG levels (≥ 500 mg/dL).²¹ Prescription omega-3-acid is derived from natural sources (fish), not synthetically based. The EPA and DHA in P-OM3 primarily come from anchovy, jack mackerel, herring, sardine, menhaden, smelt, salmon, tuna, and marlin.^9,33 Each P-OM3 capsule undergoes a 5-step purification process to remove environmental toxins, short-chain fatty acids, oxidized fatty acids, cholesterol, proteins, and saturated fatty acids. Prescription omega-3-acid is composed of approximately 90% omega-3 fatty acids, and is available in 1 g capsules, which contain approximately 465 mg and 375 mg of EPA and DHA, respectively.^4,21

Prescription omega-3-acid was evaluated in a 16-week randomized, placebo-controlled, double-blind, parallel-group trial of patients with VHTGs.³⁰ After a dietary run-in of 4 weeks, patients were randomly assigned (1:1) to either P-OM3 (n = 22) or placebo (corn oil; n = 20). Patients were included based on age (18–75 years) and serum TG levels (between 500 and 2000 mg/dL). In patients receiving P-OM3, the mean TG, LDL-C, and HDL-C levels at baseline were 919 mg/dL, 79 mg/dL, and 30 mg/dL, respectively. Similarly, the mean TG, LDL-C, and HDL-C levels at baseline in the placebo group were 877 mg/dL, 96 mg/dL, and 28 mg/dL, respectively.³⁰ In the study population, mean percent changes in lipid concentrations from baseline showed that P-OM3 effectively decreased TG levels (−45%; P < 0.00001), VLDL-C levels (−32%; P < 0.001), and total cholesterol (−15%; P < 0.0001). Prescription omega-3-acid caused a 13% (P = 0.014) increase in HDL-C, and also a 31% (P = 0.0014) increase in LDL-C. Overall, 18 of 22 (82%) patients who received P-OM3 experienced at least a 35% reduction in TG levels (Figure 3). In contrast, patients receiving placebo had minor changes from baseline in their lipid profiles. With respect to TG levels, patients receiving placebo had a 15% increase. These patients had slight decreases in total cholesterol (−2%), VLDL-C (−1%), and LDL-C (−5%). The HDL-C level in the placebo group remained essentially unchanged (0%).³⁰

Another randomized, double-blind, parallel group study evaluated P-OM3 in patients with severe hypertriglyceridemia.³¹ Men and women aged 18 to 70 years with TG levels of at least 500 mg/dL but not greater than 2000 mg/dL were eligible for the study.³¹ After a 6-week dietary run-in, 20 patients were assigned to P-OM3, and 21 were assigned to placebo (corn oil). Median baseline TG, LDL-C, and HDL-C levels in the P-OM3 group were 801 mg/dL, 43 mg/dL, and 17 mg/dL, respectively. In patients receiving placebo, the median baseline values were 786 mg/dL, 60 mg/dL, and 18 mg/dL for TGs, LDL-C, and HDL-C, respectively. In patients receiving P-OM3, the median percent changes from baseline for TG and total cholesterol levels were −39% and −10%, respectively.³¹ After 2 weeks of treatment with P-OM3, there was a substantial reduction in TGs (Figure 4).³¹ Very low-density lipoprotein cholesterol decreased by 29%, and LDL-C increased by 17%. High-density lipoprotein cholesterol increased by 6% in the P-OM3 treatment group. In contrast, the percent changes in lipid concentrations from baseline in the placebo group were not statistically significant. In the placebo group, TGs, LDL-C, and HDL-C decreased by 8%, 4%, and 6%, respectively. Similarly, total cholesterol decreased by 6%, and VLDL-C decreased by 7%.³¹

Pooled analysis of both studies described previously (N = 84) showed that P-OM3 is effective in adult patients with VHTG levels (Table 3).^21,30,31 Median baseline levels in patients receiving P-OM3 were 816 mg/dL, 89 mg/dL, and 22 mg/dL for TGs, LDL-C, and HDL-C, respectively. Similarly, in the placebo group, median baseline TGs, LDL-C, and HDL-C levels were 788 mg/dL, 108 mg/dL, and 24 mg/dL, respectively. Percent changes from baseline in lipid parameters indicate that P-OM3 can decrease TG levels by up to 45%. Low-density lipoprotein cholesterol levels increased from a median baseline 89 mg/dL to 109 mg/dL (+45%). As stated previously, this increase may result from increased conversion of VLDL particles to LDL particles.⁹ High-density lipoprotein cholesterol increased by 9%, and non–HDL-C, VLDL-C, and total cholesterol decreased by 14%, 42%, and 10%, respectively.²¹

The dosing for P-OM3 is 4 g per day in total; however, the dosing schedule is flexible. Capsules may be taken as a single dose of 4 capsules (4 g) or two 2-g doses.²¹ The most common adverse events in patients receiving P-OM3 were eructation, infection, flu syndrome, and dyspepsia. Overall, 3.5% of patients treated with P-OM3 and 2.6% of patients treated with placebo discontinued treatment because of adverse events.²¹ Prescrption omega-3-acid is contraindicated in patients who exhibit hypersensitivity to any component of the medication. Prescrption omega-3-acid should be used with caution in patients with known sensitivity or allergy to fish. Trigylceride, LDL-C, and alanine aminotransferase levels should be monitored during therapy with P-OM3. Patients simultaneously receiving treatment with both P-OM3 and anticoagulants should be monitored periodically.²¹ Increases in LDL-C or alanine aminotransferase levels (without a concurrent increase in asparate aminotransferase) may occur in some patients after receiving P-OM3.²¹

Omega-3 fatty acid-containing products have been shown to increase hepatic concentrations of cytochrome P450 and activities of certain P450 enzymes in rats. In humans, a mixture of free fatty acids, EPA/DHA, and their free fatty acid-albumin conjugate was evaluated for the effect on cytochrome P450-dependent monooxygenase activities in liver microsomes. Free fatty acid, at the 23 μmol concentration, caused less than 32% inhibition of CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A. Free fatty acid-albumin conjugate, at the same concentration, resulted in < 20% inhibition of CYP2A6, 2C19, 2D6, and 3A. For CYP2E1, there was a 68% inhibition.²¹ In humans, drug–drug interactions due to inhibition of P450-mediated metabolism by EPA/DHA combinations are not expected to be clinically important.²¹ Prescription omega-3-acid is generally well tolerated in adult patients with VHTG levels.⁴ However, if TG levels do not adequately decrease after 2 months of therapy with P-OM3, therapy should be discontinued,²¹ and another therapy implemented.

In response to the increased prevalence of VHTG levels, government agencies and many health organizations have published recommendations for the treatment and management of patients. According to the NCEP, the first step is to initiate therapeutic lifestyle changes to decrease the intake of saturated fats, trans fats, and cholesterol. The NCEP also recommends plant stanols/sterols and viscous fiber for enhancing LDL-C lowering, as well as weight reduction, if indicated, and increased physical activity. After 12 weeks of therapeutic lifestyle changes, physicians should initiate pharmacologic therapy if initial goals have not been met. However, original therapeutic lifestyle and diet changes should continue even when lipid-lowering therapy is initiated.²¹ For patients who need to lower TG levels, the AHA recommends that patients take EPA and DHA daily (provided by a physician).¹⁰

As previously discussed in an earlier clinical trial that evaluated the efficacy of P-OM3 in the management of VHTGs, it may take up to 18 capsules per day of an omega-3 dietary supplement to approach the EPA and DHA content found in a 4 g dose of P-OM3.³⁰ Prescription omega-3-acid is clinically proven to significantly reduce TG levels (Table 3). Omega-3 dietary supplements are not approved by the FDA for the treatment of VHTG levels. Prescription omega-3-acid is well tolerated, and offers an effective treatment option in adult patients with VHTG levels (≥ 500 mg/dL).

Both authors were fully involved in the manuscript development and assume responsibility for the direction and content. The authors would like to thank Rose Snipes, MD, Rosemary Schroyer, MS, and, Amy Meadowcroft, PharmD, at GlaxoSmithKline for their critical review and assistance in the development of the manuscript. Editorial support was provided by Amanda McGeary, MS, at AlphaBioCom, LLC, with funding from GlaxoSmithKline.

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