_______________________________________ Hyperlipidemias and Atherosclerotic Cardiovascular Disease
not be substituted for prescription products, as they may also contain unwanted cholesterol or fats or potentially harmful components, including toxins and oxidized fatty acids [192]. Omega-3 fatty acids also are readily available in the United States as prescription medications. One prescription medication is comprised of 900 mg of ethyl esters of omega-3 fatty acids, a combination of EPA (approximately 500 mg) and DHA (approximately 400 mg) [189]. A second available medication consists of 1,000 mg omega-3 in free fatty acid form, which is intended to improve the bioavailability [193]. This drug contains approximately 500–600 mg EPA, 150–250 mg DHA, and 150–350 mg other omega-3 fatty acids. Drug labeling dosage information indicates a dose of 4 g/day, taken as a single 4-g dose (four capsules) or as two 2-g doses (two capsules twice daily) [189]. In one study, a minimum dose of 500 mg per day of combined EPA/DHA was recommended for individuals without underlying overt ASCVD, and 800- 1,000 mg/day was recommended for individuals with CHD and heart failure [194]. A 2009 review validated the beneficial effects of EPA/DHA alone or in conjunction with fibrates in the reduction of triglycerides. It also further corroborated the safety profile of omega-3 polyunsaturated fatty acids [195]. In 2019, the FDA approved icosapent ethyl, a prescription omega-3 fatty acid, as an adjunctive therapy (to maximally tolerated statin therapy) to reduce the risk of cardiovascular events in adults with elevated triglyceride levels (≥150 mg/ dL), cardiovascular disease and/or diabetes, and at least two additional risk factors [232]. The omega-3 fatty acids EPA and DHA are safe and cost effective and are indicated as an adjunct to diet in patients with hypertriglyceridemias [109; 189]. They may be considered for triglyceride levels >1,000 mg/dL and may be used alone or in conjunction with HMG-CoA reductase inhibitors [109]. Omega-3 fatty acids are effective in the prevention of ASCVD. Their effect on cardiovascular morbidity and mortality has not been determined [189]. Adverse Effects Omega-3 fatty acids are remarkably well tolerated. Minor gastrointestinal symptoms (e.g., fishy aftertaste, eructation, diarrhea) may be observed in a dose-related manner [189]. Clinical trials have concluded that omega-3 fatty acids do not have adverse effects on plasma glucose levels, bleeding, levels of muscle or liver enzymes, or kidney or nerve function. Contaminants such as methylmercury, polychlorinated biphenyls, and dioxins may be concentrated in certain species of fish, such as shark, swordfish, king mackerel, and golden snapper. The FDA and the Environmental Protection Agency have issued a statement advising women who are or may become pregnant, breastfeeding mothers, and young children to avoid eating some types of fish and to eat fish and shellfish that are lower in mercury [196]. However, the levels of contaminants in omega-3 fatty acids, either as generic supplements or in the ethyl ester formulation, are well below acceptable levels
of toxicity due to extensive purification processes. In April 2009, the FDA posted a warning regarding the ethyl ester formulations of omega-3 fatty acids reporting anaphylactic or severe allergic reactions (i.e., rash, hives, itching, difficulty breathing, tightness in the chest, swelling of the mouth, face, lips, or tongue) and hemorrhagic diathesis [197]. Drug Interactions Due to their antiplatelet effect, omega-3 fatty acids may increase bleeding time in a dose-dependent manner [109; 189]. However, no cases have been reported, even when administered at high doses alone or in combination with anticoagulant medications. In patients receiving anticoagulant medication, it has been recommended that bleeding times be monitored during the first three to six months, the time normally required for omega-3 fatty acids to reach their maximum clinical effect. STEROLS AND STANOLS Mechanism of Action and Clinical Pharmacology Plant sterols and stanols, also known as phytosterols, are bioactive compounds structurally and physiologically similar to cholesterol. Sterols are present naturally in small quantities in many fruits, vegetables, nuts, seeds, cereals, legumes, vegetable oils, and other plant sources, and stanols occur in even smaller quantities in many of the same sources [57; 173; 174; 175; 176; 198; 199]. Omega-6 polyunsaturated fatty acids such as gamma- linoleic acid (GLA) are derived from linoleic acid. Omega-9 polyunsaturated fatty acids, unlike omega-3 and omega-6, are non-essential because they can be synthesized in humans. The most relevant omega-9 fatty acid is oleic acid, which is present in olive oil, and supplementation is not required. The lipid-lowering properties of omega-6 polyunsaturated fatty acids, and linoleic acid in particular, are related to their ability to alter various steps of the intestinal absorption of cholesterol. Specifically, they downregulate the intestinal expression of the cholesterol transporter NPC1L1, compete with cholesterol for binding to NPC1L1, lower the cholesterol esterification rate by ACAT2, decrease the amount of cholesterol secreted via the chylomicrons, and upregulate the expression of ATP-binding cassette-transporters ABCG5 and ABCG8 in intestinal cells, which may result in an increased excretion of cholesterol by the enterocyte back into the lumen [199]. The beneficial role played by omega-6 polyunsaturated fatty acids in the prevention of CHD results from their transformation into anti-inflammatory and vasodilatory eicosanoids, such as prostacyclin and lipoxin A4. Some studies, however, have recommended dietary reductions in omega-6 intake, based on the potential risk of increased transformation of omega-6 into pro-inflammatory, vasoconstrictive, pro- platelet aggregation eicosanoids, such as prostaglandin E2, thromboxane A2, and leukotriene B4. An advisory of the AHA has concluded that [200]:
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