Omega-3 Fatty Acids

Kristina Krupa; Kristina Fritz; Mayur Parmar

Omega-3 Fatty Acids

Author: Kristina N. Krupa Author: Kristina Fritz Editor: Mayur Parmar Updated: 2/28/2024 4:37:57 PM

Indications

Omega-3 fatty acids are polyunsaturated fatty acids (PUFAs) with at least one double bond between the third and fourth omega-end carbon. Currently, the 3 most clinically relevant omega-3 polyunsaturated fatty acids (PUFAs) are α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Oils containing these fatty acids originate in plant sources and can be found in fish, fish products, seeds, nuts, green leafy vegetables, and beans.[1][2]

The FDA has approved 2 prescription omega-3 fatty acids products: icosapent ethyl and omega-3-acid ethyl esters. Omega-3-carboxylic acids and omega-3-acid ethyl esters A are prescription omega-3 fatty acids formulations that have since been discontinued. Omega-3-acid ethyl esters, omega-3-carboxylic acids, and omega-3-acid ethyl esters A contain both EPA and DHA, whereas icosapent ethyl contains ethyl esters of EPA only.[3] Iosapent ethyl and omega-3-acid ethyl esters are approved for adults with very high triglycerides (≥500 mg/dL) as an adjunct to diet to decrease triglyceride levels and reduce cardiovascular events.[4][5][3][6]

These prescription omega-3 fatty acids products have also been recommended in adjunctive therapy in combination with statins to enhance the reduction of the total cholesterol/high-density lipoprotein cholesterol compared to statin alone.[7][8][9] However, some studies have urged physicians to proceed with caution when prescribing a statin/DHA omega-3 fatty acid combination due to the possibility of increased low-density lipoprotein (LDL) cholesterol.[7][10][11] DHA containing omega-3 fatty acids can be switched to EPA-only icosapent ethyl, which is not associated with increased LDL.[10][11]

FDA-Approved Indications

Severe hypertriglyceridemia in adults

Off-Label Uses

It is important to note that while these prescription omega-3 fatty acids products are the only FDA-approved products for the treatment of hypertriglyceridemia, ongoing research is currently investigating the significance of omega-3 fatty acids and their promising role in the treatment of conditions and ailments listed below:

Cardiovascular disease [1][12][13][14]
Hypertriglyceridemia (200 to 499 mg/dL) [4]
Type 2 diabetes [1]
Cancer [1][15][16][14]
Alzheimer disease and dementia [1]
Depression [1]
Visual and neurological/brain development [1]
Maternal health during pregnancy and child health [1]
Conditions benefiting from prebiotics [17]
Heart failure [18][13]
Intervertebral disc degeneration [19]
Attention deficit hyperactivity disorder [20][21]
Maternal depression [22]
Menopausal night sweats [23]
Rheumatoid arthritis [1][14]
Asthma [24][25][14]
Periodontal disease [1][26]
Epilepsy [27][28]
Diabetic retinopathy [2][29]
Chemotherapy adjunct [30][1][31]
Premenstrual syndrome [32]
Non-alcoholic fatty liver disease [33]

Omega-3 intake or supplementation has demonstrated benefits in treating the above conditions; controversy still exists for many of the above uses. More research with well-conducted clinical trials must be completed before definitive conclusions can be made.

Mechanism of Action

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Mechanism of Action

The mechanism of action of omega-3 fatty acids to lower triglycerides (FDA-approved use) is still not fully known. They are thought to lower triglycerides by suppressing lipogenic gene expression, increasing beta-oxidation of fatty acids, increasing the expression of lipoprotein-lipase (LPL), and influencing total body lipid accretion.[34][35][36]

Omega-3 fatty acids suppress lipogenic gene expression by decreasing the expression of sterol regulatory element-binding protein 1c, inhibiting phosphatidic acid phosphatase, and acyl-CoA:1,2-diacylglycerol acyltransferase (NGAT). Sterol regulatory element-binding proteins (SREBPs) are membrane-bound enzymes that, when cleaved, travel to the nucleus to transcribe enzymes involved in cholesterol, LDL, and fatty acid synthesis. When a diet is high in omega-3 fatty acids, the SREBPs (particularly 1c) are not activated because of negative feedback inhibition and lowers SREBP synthesis and the cholesterol synthesizing enzymes that it regulates, FPP synthase (farnesyl diphosphate synthase) and HMG-CoA reductase (3-hydroxy-3-methylglutaryl-CoA reductase).[37][38]

Beta-oxidation is the biological pathway used in the body to break down fat and convert it into energy.[35] Omega-3 fatty acids decrease the level of triacylglycerides in the body by increasing the rate of beta-oxidation by acting specifically on carnitine acetyltransferase 1 (CAT1) and acetyl-CoA carboxylase.[34][35] Carnitine acetyltransferase modifies fatty acid substrates to enter the inner mitochondrial membrane via carnitine-acylcarnitine translocation. Later, they are converted to acyl-CoA, a precursor substrate to acetyl-CoA used to create ATP in various metabolic pathways.[35] Additionally, EPA also indirectly increases beta-oxidation by slowing feedback inhibition.[35] EPA inhibits acetyl-CoA carboxylase, which is the enzyme that catalyzes the synthesis of malonyl-CoA, a strong inhibitor of CAT1.[35] By decreasing the amount of malonyl-CoA produced, CAT1 will have increased activity and use more triacylglycerides for beta-oxidation. Omega-3 fatty acids have also been shown to decrease the sensitivity of CAT1 to malonyl-CoA.[35]

Lipoprotein lipase (LPL) is an extracellular enzyme found on the endothelium of vascular tissue that functions to remove triacylglycerol components of chylomicrons, low-density lipoproteins (LDL), and very-low-density lipoproteins (VLDL) in the blood.[39][40][41] A diet high in omega-3 fatty acids has been shown to increase the expression of LPL and subsequent lipoprotein lipase protein on the endothelial lining and decrease the size of chylomicrons.[42] Increasing the amount of lipoprotein lipase and decreasing LDL, VLDL, and chylomicron size can lower triglycerides in patients with hypertriglyceridemia.

Omega-3 fatty acids are also believed to reduce high triglycerides by influencing total body lipid accretion. Several studies have found that prolonged use of omega-3 fatty acids for more than 6 weeks can increase the body's metabolic rate and decrease total body fat.[43][35][44] More specifically, study participants showed increased lean muscle mass, decreased fat mass, increased resting metabolic rate, increased energy expenditure during exercise, and increased fat oxidation during rest and exercise.[43][35][45][44] This occurs due to omega-3 fatty acids' ability to act as a ligand for peroxisome proliferator-activated receptors (PPARs), whose transcription factor activity can change gene expression in energy homeostasis.[43][46] PPARs regulate both fatty acid metabolism (beta-oxidation) and glucose metabolism and can change the basal metabolism of the cell.[47] The increase in fat oxidation and energy needs by changes in body composition is thought to be another mechanism by which omega-3 fatty acids help lower the triglyceride levels in the blood.

Additional mechanisms of action for omega-3 fatty acids explain the beneficial effects on the brain, brain development, cancer, diabetes, rheumatoid arthritis, irritable bowel disease, and the cardiovascular system outside triglyceride regulation. Most of these effects are attributed to omega-3 fatty acids' anti-inflammatory actions. Omega-3 fatty acids have been shown to modulate several inflammatory pathways.[18][48][15][49][50] These include the following:

Inhibition of leukocyte chemotaxis
Inhibitions of adhesion molecule expression (like leukocyte-endothelial adhesive interactions)
Inhibition of cyclooxygenase (COX) activity and its subsequent eicosanoid production (eg, leukotrienes and prostaglandins from arachidonic acid)
Inhibition of pro-inflammatory cytokines (eg, TNF-α, IL-1, IL-6)
Increase production of inflammation-resolving resolvins, maresins, lipoxins, and protectins
Inhibition of pro-inflammatory transcription nuclear factor kappa B (nuclear factor-kB) activation
Activation of anti-inflammatory transcription factor NR1C3
Activation of PPARs
Activation of G protein-coupled receptor GPR120
Altering phospholipid fatty acid composition
Disrupting lipid rafts

Although many cancers are aided by omega-3 fatty acids' anti-inflammatory effect and the tumor growth of non-small-cell lung cancer is reduced by inhibiting acetyl-CoA carboxylase (decreasing fatty acid production), other antineoplastic mechanisms of omega-3 fatty acids can be beneficial for other cancers, such as breast cancer, colorectal cancer, leukemia, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, head and neck cancer, as well as lung cancer.[51][15] Omega-3 fatty acids activate AMPK/SIRT, which is involved in cell maintenance and repair, producing an antineoplastic effect useful in cancer treatment.[50][15]

Omega-3 fatty acids can stabilize and protect certain tissues with high-fat content, like neural and retinal tissue. Alzheimer disease, dementia, and cognitive function are improved by omega-3 fatty acids' ability to maintain cell membranes of neural tissues because DHA is an essential component of the brain's phospholipid membranes.[52][53][54] Additionally, macular degeneration can be helped by supplementing DHA for structural support and EPA-based eicosanoids for neovascular and cell survival because DHA and EPA are also integral components of retinal cell membranes.[55]

Omega-3 fatty acids have some cardioprotective effects that help protect against heart failure in patients with congestive heart failure (CHF). Omega-3 fatty acids, specifically DHA, decrease mitochondrial oxygen consumption without reducing ventricle power generation by altering the mitochondrial membrane phospholipid composition, protecting the heart from tiring.[18] EPA inhibits the apoptotic activity stimulated by saturated fatty acid cardiac lipotoxicity, protecting the heart from injury.[18] Omega-3 fatty acids can protect from arrhythmia by inhibiting inward sodium current in a dose-dependent manner, suppressing intracellular calcium (Ca²⁺) waves, and helping strengthen autonomic tone.[56] Omega-3 fatty acids can also vasodilate and decrease blood pressure or afterload to help the heart pump more easily because they stimulate nitrous oxide (NO) release from vascular endothelial tissue.[18] Omega-3 fatty acids also protect the heart through their antithrombotic and antiatherosclerotic abilities. Omega-3 fatty acids have been shown to suppress platelet-derived thromboxane A2 (TxA2) synthesis, constrict blood vessels, aid in platelet aggregation, and reduce the production of matrix metalloproteinases released by macrophages when there is endothelial injury.[18][57]

It should be noted that numerous studies continue to determine the exact mechanisms by which omega-3 fatty acids have a pharmacological effect. Many studies with conflicting data challenge the current understanding of how omega-3 fatty acids can help other conditions beyond hypertriglyceridemia.

Pharmacokinetics

Absorption: Digestion of omega-3 fatty acids begins in the stomach with gastric lipases that break down triacylglycerols into diacylglycerol and fatty acids.[1] Once broken down, they form fat globules broken down by pancreatic lipases and bile salts in the small intestines. The ethyl esters (icosapent ethyl, omega-3-acid ethyl esters, and omega-3-acid ethyl esters A) are principally broken down by pancreatic carboxylic acid ester lipase in the small intestine to form FFA-EPA and FFA-DHA.[1] Monoacylglycerols and the free fatty acids then passively diffuse into enterocytes as micelles.[1] Various fatty acid transport proteins in the enterocyte membrane can also transport fatty acids into enterocytes.[58] Once within the enterocyte, the fatty acids are re-performed into triacylglycerols in the endoplasmic reticulum that bind to apolipoproteins to form chylomicrons.[1][58] Chylomicrons are exocytosed into the lymphatic system and ultimately enter circulation at the thoracic duct to reach target tissues.[1][58]

During digestion, the ethyl esters are principally broken down by pancreatic carboxylic acid ester lipase, an enzyme with activity enhanced by high-fat meals.[1] Moreover, the fat content of a meal can affect the absorption of ethyl esters.[1] Subsequently, absorption of the ethyl esters and icosapent ethyl (EPA formulation only) is decreased when fasting, so it is recommended they are consumed with food.[4] EPA is thought not to absorb as well as DHA and is metabolized faster; there is a higher ratio of DHA to EPA within the serum plasma.[58]

Distribution: EPA's volume of distribution is approximately 80L. The bioavailability of omega-3 fatty acids will be affected by the form they are found in, which can include triacylglycerols, free fatty acids, phospholipids, and ethyl esters.[1] The suggested bioavailability based on form (lipid structure) from highest to lowest is as follows: phospholipids, re-esterified triacylglycerols, triacylglycerols, free fatty acids, and ethyl esters.[59] However, the order is based on lipid structure only and does not reflect other factors that affect the bioavailability of omega-3 fatty acids, such as the fat content of a meal.[59]

In addition to the form of the omega-3 fatty acid, the chemical positioning may also affect bioavailability. Research suggests that omega-3 fatty acid content is greater in fish oil due to the acid typically being in the sn-2 position versus the sn-1 and sn-3 positions found in marine mammal oils.[59][1] Conversely, other sources state that omega-3 fatty acids bioavailability is increased in the sn-1 and sn-3 position due to increased accessibility for lipase hydrolysis, so controversy remains regarding how the position affects the bioavailability of the omega-3 fatty acids.[59][58] Bioavailability also varies depending on the dietary source. For example, krill oil is known to have high bioavailability compared to other marine sources.[59][58] Bioavailability of EPA only and both EPA/DHA formulations did not differ based on age or ethnicity; the combination formulation bioavailability differed based on gender. Women seem to have higher EPA serum levels than males in the mixed EPA/DHA formulations. However, research on the availability of EPA and DHA in over-the-counter supplements has indicated that age can play a factor in their levels within the plasma.[58] Research has also determined that serum EPA increases dose-dependent when administered with ethyl esters, but serum DHA does not.[6]

Metabolism: Omega-3 fatty acids undergo metabolism and oxidation in the liver, leading to the synthesis of VLDL to transport fatty acids in the plasma to various tissues. Omega-3 fatty acids-generated lipid signaling molecules are catalyzed by cyclooxygenase and lipooxygenase enzymes. While most DHA and EPA metabolism occurs via beta-oxidation in the liver (as discussed above), cytochrome P450 (CYP)-mediated metabolism is a minor pathway in the breakdown of DHA and EPA.[60]

Elimination: The route of elimination of omega-3 fatty acids is unknown. Compartmental studies have shown that approximate half-life values of ALA, DHA, and EPA are 1 hour, 20 hours, and 39 to 67 hours, respectively.[61][62] With repeated administration, the half-life of EPA is 37 hours, and DHA has a half-life of 48 hours.[59] Not all the prescription omega-3 fatty acid product half-lives have been established. The maximum plasma EPA and DHA levels can be determined within 5 to 9 hours post-administration.[59] However, persistent EPA and DHA serum levels will not be apparent until 2 weeks of daily supplementation.[59]

Administration

Humans do not possess the enzymes required to synthesize omega-3 fatty acids; therefore, they are considered essential fatty acids because they must be obtained from the diet. Omega-3 fatty acids are consumed in the human diet primarily as fish and plant sources but can also be consumed via prescription omega-3 fatty acid products.[59] Alpha-linoleic acid (ALA) is a common omega-3 fatty acid found in seeds and nuts and can be converted to DHA and EPA inside the body. However, research has found the conversion of DHA from ALA is particularly low, suggesting the importance of direct dietary intake of DHA.[1][63] Omega-3 fatty acids may be present in several forms, such as triacylglycerols, free fatty acids (FFA), phospholipids, and ethyl esters.[1] Icosapent ethyl, omega-3-acid ethyl esters, and omega-3-acid ethyl esters A are all in the ethyl ester form, whereas omega-3-carboxylic acids are in the free fatty acid form.[6]

Adult Dosage, Dosage Forms, and Strengths

The FDA-approved uses of omega-3 fatty acids for adults (older than 18) with hypertriglyceridemia (≥500 mg/dL) as an adjunct to diet and exercise.[3][4][6] Specific dosing is as follows:

Icosapent ethyl is administered as capsules with a daily dose of 4 g/d, as 2 2-gram capsules twice daily with meals.
Omega-3-acid ethyl esters are administered as capsules with a daily dose of 4 g/d taken as 4 capsules once daily with meals or 2 capsules twice daily with meals.
Omega-3-carboxylic acids are administered as capsules with a daily dose of 2 g/d taken as 2 capsules once daily or 4 g/d taken as 4 capsules once daily. Clinical trial administration was without regard to meals.
Omega-3-acid ethyl esters A are administered as capsules with a daily dose of 4 g/d taken as 4 capsules once daily with meals or 2 capsules twice daily with meals.

All omega-3 fatty acid supplements should be taken whole without being crushed, chewed, or dissolved in the mouth. If a dose is missed, the patient should take it as soon as they remember and not take a double dose if it is time for their next capsule. Various dietary supplements in different chemical forms are currently available over the counter but have not been FDA-approved; they are not required to show safety and efficacy before marketing the product.[3]

Special Patient Populations

Hepatic impairment: Dosing in patients with hepatic impairment is undefined.

Renal impairment: Dosing in patients with renal impairment is undefined.

Pregnant women: No human data exists for omega-3 fatty acid therapy dosing in patients who are pregnant; fetal harm is not expected based on data from fish oil.

Breastfeeding women: Recommendations during breastfeeding are for 1000 mg of DHA plus EPA.

Pediatric patients: The FDA does not approve omega-3 fatty acid therapy for patients younger than 18.

Older patients: No data indicates older patients will experience problems from using omega-3 fatty acids. Paradoxically, although many purported benefits of omega-3 fatty acids would help older adults, there is a lack of data focusing on this population of patients.[62]

Adverse Effects

The FDA-approved fatty acid prescriptions (icosapent ethyl, omega-3-acid ethyl esters, omega-3-carboxylic acids, and omega-3-acid ethyl esters A) are generally safe with benign effects such as fishy taste, eructation, dyspepsia, diarrhea, gas, nausea, and arthralgia.[4][64][65] Researchers noted adverse reactions in clinical trials for each FDA-approved omega-3 fatty acid product.[4][3][6]

Icosapent ethyl: arthralgia and oropharyngeal pain.
Omega-3-acid ethyl esters: eructation, dyspepsia, taste perversion, constipation, GI disorder, vomiting, increased ALT/AST, pruritus, rash.
Omega-3-carboxylic acids: Diarrhea, nausea, abdominal pain or discomfort, eructation, abdominal distension, constipation, vomiting, fatigue, nasopharyngitis, arthralgia, dysgeusia.
Omega-3-acid ethyl esters A: Eructation, dyspepsia, taste perversion, constipation, GI disorder, vomiting, increased ALT/AST, pruritus, rash.

Drug-Drug Interactions

Clinical trials with omega-3 fatty acids demonstrated prolongation of bleeding time. The prolonged bleeding time reported in these trials did not exceed normal limits or produce clinically significant bleeding episodes. No clinical trials have been conducted to thoroughly examine the effect of omega-3 fatty acids and concurrent anticoagulant therapy. Patients taking omega-3 fatty acids concurrently with anticoagulant medications or other drugs affecting coagulation (eg, anti-platelet agents) require periodic monitoring.

Contraindications

Caution and periodic monitoring are recommended in patients taking antiplatelet and anticoagulant medication due to the ability of omega-3 fatty acids to reduce platelet activity.[4][15] Additionally, omega-3 fatty acids are not considered allergenic, but the FDA labels state to use with caution in patients allergic to seafood. Omega-3 fatty acid products are contraindicated for those with hypersensitivity to the individual formulation.[4]

EPA and DHA can act as alternative substrates for CYP450 metabolism and are partially metabolized by the CYP450 metabolic pathway. However, significant inhibition of CYP450 enzymes by DHA or EPA has not been observed, and no drug-drug interactions have been established with medications that use the CYP450 metabolic pathway. EPA-exclusive supplements have shown to have no drug-drug interactions with other medications that may use the P450 metabolic pathway, such as omeprazole, warfarin, atorvastatin, and rosiglitazone. DHA has been shown to have no interactions with other statin drugs.

Monitoring

It is recommended that the healthcare provider monitor the direct low-density lipoprotein (LDL) cholesterol for patients taking the DHA-containing products omega-3-acid ethyl esters, omega-3-acid ethyl esters A, and omega-3-carboxylic acids due to DHA’s association with an increase in LDL cholesterol.[6]

In patients with dyslipidemia, icosapent ethyl is an option since it has no association with increased LDL cholesterol.[3][4][6] For patients with hepatic impairment, monitoring of the AST and ALT should also be done.[6] In patients with paroxysmal or persistent atrial fibrillation, the prescription products containing omega-3-acid ethyl esters and omega-3-acid ethyl esters A are possibly associated with increased recurrences of symptomatic atrial fibrillation or flutter.[6]

Toxicity

EPA and DHA are considered generally safe. The FDA recommends that daily intake not exceed 3 g/d of EPA and DHA combined, with no more than 2 g/d deriving from supplements.

Caution is necessary when taking high doses as it may reduce immune function because of inflammatory response changes and cause bleeding problems. EPA and DHA are not carcinogenic or mutagenic in human models, but icosapent ethyl (EPA-only formulation) has shown benign neoplasm growth in murine models.

The FDA-approved fatty acid prescriptions (icosapent ethyl, omega-3-acid ethyl esters, omega-3-carboxylic acids, and omega-3-acid ethyl esters A) are all pregnancy category C drugs, and it is unknown if the drug can cause fetal harm or can affect reproductive capacity. Conversely, some studies concluded that pregnant mothers should incorporate DHA into their diet via high-DHA-content food or supplements to increase latency and birth weight.[66]

Additionally, it is not recommended that nursing mothers take DHA or EPA supplements because they can be highly concentrated (possibly 6 to 14 times serum levels), requiring only 200 to 300 mg DHA intake per day in a nursing mother.[67]

Methyl mercury, a toxic organometallic cation, is found in fish. Individuals who use fish as their primary source of omega-3 fatty acids or pregnant and nursing women should limit their intake to 2 to 4 servings of fish a week or replace fish that are high in methyl mercury, such as swordfish, albacore tuna, dolphinfish, kingfish, and shark and replace with fish that have a lower amount of methyl mercury, such as salmon, herring, sardines, and trout.[68][69][70] Fortunately, DHA and EPA supplements do not contain methyl mercury.

Enhancing Healthcare Team Outcomes

Proper patient education on dosage and use of the prescription EPA-only icosapent ethyl and DHA/EPA formulations is necessary to ensure that the patient achieves the therapeutic benefits. The responsibility of the interprofessional healthcare team, which includes physicians, nurse practitioners, physician assistants, nursing staff, and pharmacists, is to ensure the patient is aware of the possible adverse effects. This is especially important true for individuals on polypharmacy with multiple comorbidities, like those with hepatic and pancreatic impairment, those taking anticoagulants, and individuals with a possible fish sensitivity. Proper physician education on considerations when prescribing, monitoring, and stopping treatment is also necessary.

Current FDA guidelines approve DHA and EPA for use in patients with very high triglycerides in conjunction with proper diet and exercise. The patient should be encouraged to eat a balanced diet (low in cholesterol) and regular exercise. Routine monitoring should occur when prescribing icosapent ethyl (EPA only) and DHA/EPA formulation to patients with hypertriglyceridemia to check the level of triglycerides and AST and ALT for hepatic function. Care is also necessary when prescribing EPA and DHA to pregnant and nursing patients because of unknown toxicity to the fetus and infant. Pharmacists and clinicians should also inform the patient that better absorption of EPA and DHA occurs when co-administered with food.

The healthcare team should remain knowledgeable of other potential DHA and EPA indications. Fish oil is also available over the counter; patients may take supplements even when not recommended. The clinical team can help patients taking over-the-counter EPA and DHA supplements by informing them of foods they could incorporate into their diet if they want to stop them. Furthermore, physicians should inquire about patients' diets to ensure proper DHA and EPA levels and fish high in methyl mercury are avoided.

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