Prescription Omega-3 Fatty Acids and Their Lipid Effects
Prescription Omega-3 Fatty Acids and Their Lipid Effects
Hypertriglyceridemia is a risk factor for atherosclerotic coronary heart disease. Very high triglyceride (TG) levels (≥500 mg/dl [5.65 mmol/l]) increase the risk of pancreatitis. One therapeutic option to lower TG levels is omega-3 fatty acids, which are derived from the oil of fish and other seafood. The American Heart Association has acknowledged that fish oils may decrease dysrhythmias, decrease sudden death, decrease the rate of atherosclerosis and slightly lower blood pressure, and has recommended fish consumption or fish oil supplementation as a therapeutic strategy to reduce cardiovascular disease. A prescription omega-3-acid ethyl esters (P-OM3) preparation has been available in many European nations for at least a decade, and was approved by the US FDA in 2004 to reduce very high TG levels (≥500 mg/dl [5.65 mmol/l]). Mechanistically, most evidence suggests that omega-3 fatty acids reduce the synthesis and secretion of very-low-density lipoprotein (VLDL) particles, and increase TG removal from VLDL and chylomicron particles through the upregulation of enzymes, such as lipoprotein lipase. Omega-3 fatty acids differ mechanistically from other lipid-altering drugs, which helps to explain why therapies such as P-OM3 have complementary mechanisms of action and, thus, complementary lipid benefits when administered with statins. Additional human studies are needed to define more clearly the cellular and molecular basis for the TG-lowering effects of omega-3 fatty acids and their favorable cardiovascular effects, particularly in patients with hypertriglyceridemia.
Hypertriglyceridemia, which is defined as a triglyceride (TG) blood concentration of 150 mg/dl or higher, is a common dyslipidemia encountered in clinical practice and occurs with or without elevated cholesterol levels. In the Framingham Offspring Study, 11.7% of women and 22.3% of men had TG levels that were higher than 200 mg/dl (2.26 mmol/l). The Third National Health and Nutrition Examination Survey (NHANES III) of 8814 adult Americans found that 25% of women and 35% of men had a TG level of 150 mg/dl or higher (≥1.69 mmol/l). The obesity epidemic, along with its metabolic con-sequences, is an important contributor to the rising prevalence of hypertriglyceridemia.
For patients with very high TG levels (≥500 mg/dl [5.65 mmol/l]), the initial therapeutic goal is to lower TG levels to prevent pancreatitis, which is a potentially life-threatening complication of severe hyper-tri-glyceri-demia. The risk of pancreatitis is especially increased when TG levels are found to be above 1000 mg/dl (11.3 mmol/l). When TG levels are above 1000 mg/dl (11.3 mmol/l), this is usually the result of a secondary cause of hypertriglyceridemia occurring in individuals with one of the more common genetic hyper-tri-glycerid-emic disorders (see "Examples of Factors Contributing to Hypertriglyceridemia") such as familial hypertriglyceridemia and familial combined hyperlipidemia (FCH), both of which occur in 3% or fewer of the population. Familial hyper-tri-glycerid-emia (hyper-pre-beta-lipo-protein-emia) may possibly be due to the presence of a lipoprotein lipase (LPL) inhibitor that results in increased chylomicron and VLDL levels, and is clinically manifested by pancreatitis and eruptive xanthomas, especially when accompanied by secondary causes that exacerbate hypertriglyceridemia, such as hypothyroidism, uncontrolled diabetes mellitus or excessive alcohol intake with fatty liver. FCH is probably due to a variety of apolipoprotein defects, which results in elevations in TG (with the same potential symptoms, as mentioned previously), but also with elevated cholesterol and apo-lipo-protein B-100 (apoB-100) levels. HDL cholesterol (HDL-C) levels may be decreased, and LDL particles may be small and dense and, thus, potentially more atherogenic. FCH is the most common form of nonpolygenic, heritable dys-lipid-emia, and is found in 10-20% of survivors of myo-cardial infarction and approximately 20% of patients with coronary heart disease (CHD) under the age of 60 years. Both familial hypertriglyceridemia and FCH may increase CHD risk.
Severe hypertriglyceridemia may also represent more rare, under-lying genetic dyslipidemias, such as LPL deficiency or homozygous apolipoprotein C-II (apoC-II) deficiency, which occur in approximately 1:1,000,000 people (see "Examples of Factors Contributing to Hypertriglyceridemia"). In both cases, diagnosis usually occurs during childhood or young adulthood, with the presentation of recurrent pancreatitis, eruptive cutaneous xanthomata, hepatosplenomegaly and lipemia retinalis. Untreated TG levels are usually found to be greater than 2000 mg/dl. Both also result in a 'chylo-micron-emia syndrome', defined as elevated chylo-microns, marked increase in TG levels, and the clinical signs and symptoms described above.
While VLDL particles normally constitute approximately 90% of the TG-containing lipoproteins, and while levels of both VLDL and chylomicron-associated TG increase after meals, it is the profound increase in TG levels associated with chylomicrons (most often in patients with an under-lying, inherent, genetic defect) that is most described to contribute to pancreatitis. Chylomicrons are TG-rich lipo-protein particles that predominantly carry post-prandial/post-absorptive TG. Marked increases in chylo-microns are hypo-thesized to impair circulatory flow in pancreatic capillary beds, leading to ischemia-induced disruption in acinar structure and exposing the TG-rich particles to pancreatic lipase, leading to necrosis, edema and inflammation.
Therapeutic interventions to treat hypertriglyceridemia include increased physical exercise and a low-calorie diet with reduced consumption of high-glycemic index carbohydrates and alcohol. Other interventions, depending on the patient population, may include lipopheresis, heparin-ization and insulin. Statins and ezetimibe are approved lipid-altering drugs that may modestly reduce TG levels. However, they are mainly used to lower LDL cholesterol (LDL-C) levels. Other lipid-altering agents that are used more specifically to reduce TG levels include niacin, fibrates and omega-3 fatty acids.
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are long-chain, polyunsaturated, omega-3 fatty acids that effectively lower TG levels ( Table 1 ). EPA and DHA may be used as monotherapy, or as adjunctive therapy to fibrates and/or nicotinic acid to lower TGs to prevent pancreat-itis in patients with very high TG levels. Fish consumption and supplements are dietary sources of omega-3 fatty acids. A prescription combination of omega-3-acid ethyl esters (P-OM3; Lovaza™ Capsules, Reliant Pharmaceuticals, Inc.) is available that contains concentrated forms of EPA (~465 mg), DHA (~375 mg) and other omega-3 fatty acids (~60 mg), for a total of at least 900 mg of omega-3 fatty acids per each 1-g gel capsule. P-OM3 is approved by the US FDA for the treatment of very high TGs (≥500 mg/dl [5.65 mmol/l]) in adult patients. This review examines the pathophysiology of hyper-tri-glycerid-emia and possible mechanisms for the TG-lowering effect of omega-3 fatty acids.
Hypertriglyceridemia is a risk factor for atherosclerotic coronary heart disease. Very high triglyceride (TG) levels (≥500 mg/dl [5.65 mmol/l]) increase the risk of pancreatitis. One therapeutic option to lower TG levels is omega-3 fatty acids, which are derived from the oil of fish and other seafood. The American Heart Association has acknowledged that fish oils may decrease dysrhythmias, decrease sudden death, decrease the rate of atherosclerosis and slightly lower blood pressure, and has recommended fish consumption or fish oil supplementation as a therapeutic strategy to reduce cardiovascular disease. A prescription omega-3-acid ethyl esters (P-OM3) preparation has been available in many European nations for at least a decade, and was approved by the US FDA in 2004 to reduce very high TG levels (≥500 mg/dl [5.65 mmol/l]). Mechanistically, most evidence suggests that omega-3 fatty acids reduce the synthesis and secretion of very-low-density lipoprotein (VLDL) particles, and increase TG removal from VLDL and chylomicron particles through the upregulation of enzymes, such as lipoprotein lipase. Omega-3 fatty acids differ mechanistically from other lipid-altering drugs, which helps to explain why therapies such as P-OM3 have complementary mechanisms of action and, thus, complementary lipid benefits when administered with statins. Additional human studies are needed to define more clearly the cellular and molecular basis for the TG-lowering effects of omega-3 fatty acids and their favorable cardiovascular effects, particularly in patients with hypertriglyceridemia.
Hypertriglyceridemia, which is defined as a triglyceride (TG) blood concentration of 150 mg/dl or higher, is a common dyslipidemia encountered in clinical practice and occurs with or without elevated cholesterol levels. In the Framingham Offspring Study, 11.7% of women and 22.3% of men had TG levels that were higher than 200 mg/dl (2.26 mmol/l). The Third National Health and Nutrition Examination Survey (NHANES III) of 8814 adult Americans found that 25% of women and 35% of men had a TG level of 150 mg/dl or higher (≥1.69 mmol/l). The obesity epidemic, along with its metabolic con-sequences, is an important contributor to the rising prevalence of hypertriglyceridemia.
For patients with very high TG levels (≥500 mg/dl [5.65 mmol/l]), the initial therapeutic goal is to lower TG levels to prevent pancreatitis, which is a potentially life-threatening complication of severe hyper-tri-glyceri-demia. The risk of pancreatitis is especially increased when TG levels are found to be above 1000 mg/dl (11.3 mmol/l). When TG levels are above 1000 mg/dl (11.3 mmol/l), this is usually the result of a secondary cause of hypertriglyceridemia occurring in individuals with one of the more common genetic hyper-tri-glycerid-emic disorders (see "Examples of Factors Contributing to Hypertriglyceridemia") such as familial hypertriglyceridemia and familial combined hyperlipidemia (FCH), both of which occur in 3% or fewer of the population. Familial hyper-tri-glycerid-emia (hyper-pre-beta-lipo-protein-emia) may possibly be due to the presence of a lipoprotein lipase (LPL) inhibitor that results in increased chylomicron and VLDL levels, and is clinically manifested by pancreatitis and eruptive xanthomas, especially when accompanied by secondary causes that exacerbate hypertriglyceridemia, such as hypothyroidism, uncontrolled diabetes mellitus or excessive alcohol intake with fatty liver. FCH is probably due to a variety of apolipoprotein defects, which results in elevations in TG (with the same potential symptoms, as mentioned previously), but also with elevated cholesterol and apo-lipo-protein B-100 (apoB-100) levels. HDL cholesterol (HDL-C) levels may be decreased, and LDL particles may be small and dense and, thus, potentially more atherogenic. FCH is the most common form of nonpolygenic, heritable dys-lipid-emia, and is found in 10-20% of survivors of myo-cardial infarction and approximately 20% of patients with coronary heart disease (CHD) under the age of 60 years. Both familial hypertriglyceridemia and FCH may increase CHD risk.
Severe hypertriglyceridemia may also represent more rare, under-lying genetic dyslipidemias, such as LPL deficiency or homozygous apolipoprotein C-II (apoC-II) deficiency, which occur in approximately 1:1,000,000 people (see "Examples of Factors Contributing to Hypertriglyceridemia"). In both cases, diagnosis usually occurs during childhood or young adulthood, with the presentation of recurrent pancreatitis, eruptive cutaneous xanthomata, hepatosplenomegaly and lipemia retinalis. Untreated TG levels are usually found to be greater than 2000 mg/dl. Both also result in a 'chylo-micron-emia syndrome', defined as elevated chylo-microns, marked increase in TG levels, and the clinical signs and symptoms described above.
While VLDL particles normally constitute approximately 90% of the TG-containing lipoproteins, and while levels of both VLDL and chylomicron-associated TG increase after meals, it is the profound increase in TG levels associated with chylomicrons (most often in patients with an under-lying, inherent, genetic defect) that is most described to contribute to pancreatitis. Chylomicrons are TG-rich lipo-protein particles that predominantly carry post-prandial/post-absorptive TG. Marked increases in chylo-microns are hypo-thesized to impair circulatory flow in pancreatic capillary beds, leading to ischemia-induced disruption in acinar structure and exposing the TG-rich particles to pancreatic lipase, leading to necrosis, edema and inflammation.
Therapeutic interventions to treat hypertriglyceridemia include increased physical exercise and a low-calorie diet with reduced consumption of high-glycemic index carbohydrates and alcohol. Other interventions, depending on the patient population, may include lipopheresis, heparin-ization and insulin. Statins and ezetimibe are approved lipid-altering drugs that may modestly reduce TG levels. However, they are mainly used to lower LDL cholesterol (LDL-C) levels. Other lipid-altering agents that are used more specifically to reduce TG levels include niacin, fibrates and omega-3 fatty acids.
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are long-chain, polyunsaturated, omega-3 fatty acids that effectively lower TG levels ( Table 1 ). EPA and DHA may be used as monotherapy, or as adjunctive therapy to fibrates and/or nicotinic acid to lower TGs to prevent pancreat-itis in patients with very high TG levels. Fish consumption and supplements are dietary sources of omega-3 fatty acids. A prescription combination of omega-3-acid ethyl esters (P-OM3; Lovaza™ Capsules, Reliant Pharmaceuticals, Inc.) is available that contains concentrated forms of EPA (~465 mg), DHA (~375 mg) and other omega-3 fatty acids (~60 mg), for a total of at least 900 mg of omega-3 fatty acids per each 1-g gel capsule. P-OM3 is approved by the US FDA for the treatment of very high TGs (≥500 mg/dl [5.65 mmol/l]) in adult patients. This review examines the pathophysiology of hyper-tri-glycerid-emia and possible mechanisms for the TG-lowering effect of omega-3 fatty acids.