Omega-3 Fatty Acids

Introduction

Omega-3 fatty acids (also referred to as n-3 polyunsaturated fatty acids) in the diet come from two sources: marine (fish, krill and algae) and land plants. The marine omega-3 fatty acids, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and icosapent ethyl (an ethyl ester of EPA) are the forms of omega-3s with cardiovascular bioactivity. Alpha-linolenic acid from land plants has little apparent cardiovascular bioactivity and <5% is converted to EPA/DHA.

Animal, in vitro and human studies have described a wide range of anti-atherosclerotic and antithrombotic effects for EPA/DHA. Epidemiologic studies have found consistent relationships between high levels of fish intake and lower risk of coronary death. On the other hand, lowering high triglyceride levels with EPA/DHA supplements can increase low-density lipoprotein cholesterol (LDL-C) levels in some patients, the cardiovascular effects of which are unknown.

Early randomized trials of increased oily fish intake and EPA/DHA supplements found 20% to 30% reduction in fatal coronary artery disease (CAD) events in post-MI patients. Two trials performed in the statin era (JELIS and REDUCE-IT) have found omega-3 supplements to reduce cardiovascular events in statin-treated patients. JELIS was performed in Japanese patients with high dietary intake of omega-3 fatty acids. Thus, the generalizability of JELIS’ findings to Western populations with low dietary omega-3 intake is limited. REDUCE-IT was performed mainly in Western populations, in patients with elevated LDL-C and triglycerides and with established atherosclerotic cardiovascular disease (ASCVD), or with diabetes and other risk factors for ASCVD. Icosapent ethel, which was administered in 4 g doses daily, significantly reduced the risk of cardiovascular events. However, a biomarker analysis in REDUCE-IT participants revealed that the mineral oil used as a placebo may have increased the risk of ASCVD events, putting the results of REDUCE-IT into question. The 2018 multi-society cholesterol guideline did not recommend omega-3 supplements to prevent ASCVD events in the US population. Figure 28-1 shows the approximate triglyceride reduction per gram of EPA+DHA.

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Clinical Highlight I

• In high-risk patients with triglycerides ≥500 mg/dL who may potentially benefit from triglyceride-lowering to prevent pancreatitis, EPA/DHA formulations may be considered, especially for patients receiving high-intensity statin therapy or with other safety concerns.

Appropriate Use

The Food and Drug Administration (FDA) has approved proprietary formulations of EPA/DHA as an adjunct to diet and exercise for lowering triglycerides ≥500 mg/dL.

According to the package insert for the approved drugs, the effect of EPA/DHA on the risk of pancreatitis has not been determined. The 2018 multi-society guideline states that it is reasonable (COR IIa) to lower triglycerides whenever fasting triglycerides exceed 500 mg/dL to prevent acute pancreatitis. If triglycerides are constantly elevated or rising, to further reduce them, it is reasonable to implement a very low-fat diet and add omega-3 fatty acids.

The effect of EPA+DHA on cardiovascular morbidity and mortality has not been determined. Icosapent ethyl has been approved as an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization and unstable angina requiring hospitalization in adult patients with elevated triglyceride levels (≥ 150 mg/dL) and:

• Established cardiovascular disease or
• Diabetes mellitus and two or more additional risk factors for cardiovascular disease.

Mechanisms of Action and Metabolism

The mechanisms of EPA/DHA-related lipid changes are not well understood. Potential mechanisms of action include decreased synthesis of VLDL triglycerides in the liver, increased triglyceride clearance from circulating very low-density lipoprotein (VLDL) particles, clearance of plasma lipoprotein lipase activity, inhibition of acyl-CoA:1,2-diacylglycerol acyltransferase (DGAT) and increased mitochondrial and peroxisomal β-oxidation in the liver. EPA and DHA are poor substrates for the enzymes responsible for triglyceride synthesis and inhibit esterification of other fatty acids.

The mechanisms of action related to the reduction of cardiovascular events with icosapent ethyl are not completely understood, but are likely multi-factorial. EPA/DHA are mainly oxidized in the liver, similar to fats form dietary sources.

Dosing

The recommended dose to reduce cardiovascular events (icosapent ethyl) and/or lower triglycerides is 2 to 4 grams daily depending on the formulation and the patient’s response and tolerability. Algae and fish oil sources appear to be equivalent per mg EPA+DHA. Capsules should be swallowed whole, and not broken open, crushed, dissolved, or chewed.

Contraindication

Sensitivity (e.g., anaphylactic reaction) to fish, shellfish, omega-3 fatty acids, EPA, or DHA.

Safety

Pregnancy

There are no trial data available for pregnant or nursing mothers. Use during pregnancy only if the potential for benefit justifies the potential for harm to the fetus. Omega-3 ethyl esters are excreted in breast milk. If the decision is made to initiate omega-3 FA therapy, note that marine fish can be contaminated with mercury, so fish sources of omega-3 should be avoided by pregnant or nursing mothers.

Gastrointestinal

The predominant adverse effects of EPA/DHA are fishy eructation, altered taste, diarrhea, nausea, abdominal pain or discomfort and dyspepsia.

LDL-C

EPA/DHA may increase LDL-C levels in some patients. The icosapent ethyl formulation did not appear to have this effect in the trials reported to date.

Muscle

EPA/DHA have no apparent effects on muscle, making this therapy an option in patients who are unable to tolerate fibrate therapy and as an alternative to fibrates when using a high-intensity statin. Common side effects of icosapent ethyl include muscle and joint pain.

Liver

In patients with hepatic impairment, ALT and AST levels should be monitored periodically during therapy. Increases in ALT may occur without AST elevations in some patients.

Atrial Fibrillation

More frequent occurrences of symptomatic atrial fibrillation or flutter may occur in patients with paroxysmal atrial fibrillation, especially within the first 2 to 3 months of therapy.

Drug-Drug Interactions

Prolonged Bleeding Times

Prolongation of bleeding times within the normal limit has been observed in some EPA/DHA trials. No formal drug interaction studies have been performed, but patients receiving concomitant EPA/DHA and anticoagulant therapy and/or antiplatelet agents should be closely monitored.

Others

Omega-3 fatty acids are not metabolized by the cytochrome P-450 system and no interaction has been found with statin metabolism. In addition, the icosopent ethyl formulation does not interact with omeprazole, rosiglitazone, or warfarin.