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Omega-3 fatty acids

Long chain n-3 polyunsaturated fatty acids.

The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), i.e., the ester part, attached at one end to an ethanol molecule – the ethyl part.

Three types: alpha linolenic acid (ALA), eicopentaenoic acid (EPA) and docosahexaenoic acid (DHA).

Alpha-linolenic acid is an essential fatty acid derived from plant sources such as flaxseed, walnuts, soybean, and canola oils.

Fatty fish, such as salmon and hearing, and fish oils are high in EPA and DHA.

Humans have a low capacity to convert alpha – linolenic acid to EPA and DHA..

Used in combination with changes in diet to lower blood triglyceride levels in adults with severe (≥ 500 mg/dL) hypertriglyceridemia.

At high doses the effects can be significant (from 20% to 35% and even up to 45% in individuals with levels greater that 500 mg/dL.

Intake of large doses-2.0 to 4.0 g/day, of long-chain omega-3 fatty acids as prescription drugs or dietary supplements are generally required to achieve significant (> 15%) lowering of triglycerides.

Both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) lower triglycerides: higher levels of EPANDHAR associated with low risk of cardiovascular disease.

EPA and DHA play important roles in the synthesis of inflammatory mediators, intracellular, signaling, and gene expression, and the structure of cell membranes.

DHA appears to raise LDL-C more than EPA.

DHA raises HDL-C while EPA does not.

Long chain omega-3 fatty acids, eicopentaenoic acid and docosahexaenoic acid are derived primarily from fatty fish.

Omega-3 fatty acids are a family of polyunsaturated fatty acids. 

Omega-3 fatty acids are two essential fatty acids, so called because humans cannot manufacture it and must get it from food.

deficiencies of one or both essential fatty acids are rare, as their downstream products are present in ample amounts in the diet, and are stored in body fat to be released during lipolysis.

 Omega-3 fatty acids are mostly obtained from oily fish caught in northern waters. 

The fatty acid molecule is made up of 18 to 22 carbon atoms.

Greenland in Iniuit populations sustain themselves on a marine based diet have demonstrated substantially lower incidence of cardiovascular disease compared with the western counterparts.

Alpha-linolenic acid can be converted to EPA and DHA after ingestion, although the efficiency of conversion is low.

Folllowing ingestion ALA is converted into EPA and DHA, forms that are readily used in the body.

Supplementation with marine n-3 fatty acids eicopentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce the rate of death from coronary heart disease by 20% (Leon H et al).

High doses of EPA and DHA have been shown to reduce triglyceride levels by 30% or greater.

Both EPA and DHA reduce triglyceride rich lipoproteins by reduction in triglyceride synthesis or secretion, as well as by increased clearance the triglycerides from circulating  very low density lipoprotein particles.

Rated pregnancy category C.

It is excreted in breast milk and the effects on infants are not known.

Omega-3 acid ethyl esters are metabolized mostly in the liver.

Omega-3 acid ethyl esters reduce production of triglycerides in the liver, and enhance clearance of triglycerides from circulating very low-density lipoprotein (VLDL) particles.

EPA and DHA are available as over-the-counter dietary fish oil supplements but provide only small amounts of EPA and DHA about 300 mg per capsule.

Associated with fish and shellfish allergies.

Omega-3 fatty acids puts patients who are on anticoagulants at risk for prolonged bleeding.

Side effects include stomach ache, burping, and a bad taste.

Some on very high doses (8g/day) in clinical trials had atrial fibrillation.

 

Fish do not synthesize omega-3 fatty acids: they obtain them from the algae or plankton in their diets.

 

Grams of omega−3 per 3oz (85g) serving[
Common name grams omega−3
Herring, sardines 1.3–2
Mackerel: Spanish/Atlantic/Pacific 1.1–1.7
Salmon 1.1–1.9
Halibut 0.60–1.12
Tuna 0.21–1.1
Swordfish 0.97
Greenshell/lipped mussels 0.95[
Tilefish 0.9
Tuna (canned, light) 0.17–0.24
Pollock 0.45
Cod 0.15–0.24
Catfish 0.22–0.3
Flounder 0.48
Grouper 0.23
Mahi mahi 0.13
Red snapper 0.29
Shark 0.83
King mackerel 0.36
Hoki (blue grenadier) 0.41
Gemfish 0.40[
Blue eye cod 0.31
Sydney rock oysters 0.30
Tuna, canned 0.23
Snapper 0.22
Eggs, large regular 0.109
Strawberry or Kiwifruit 0.10–0.20
Broccoli 0.10–0.20
Barramundi, saltwater 0.100
Giant tiger prawn 0.100
Lean red meat 0.031
Turkey 0.030
Milk, regular 0.00

Prescription products of mega-3 fatty acids have significantly more potent dosage of about 1 g per capsule to reduce triglyceride levels, and are regulated by the FDA, unlike dietary supplements.

Peroxisome proliferator-activated receptor (PPAR) is a transcription factor that regulates gene expression in the liver, adipose tissue, and inflammatory cells.

Polyunsaturated fatty acids are ligands for PPAR effects adipose tissue metabolism and inflammatory cytokines production.

Polyunsaturated fatty acids inhibit the activation of nuclear factor kappa light chain enhancer for activated B cells during various inflammatory stimuli, and further down regulate signaling molecules including mitogen activated protein kinases that halt disease pathogenesis.

Long chain polyunsaturated fatty acids change the biologic pool of fatty acid substrate, altering the structure of biological membranes and membrane derived intracellular signaling molecules.

They can reduce the availability of arachidonic acid for eicosanoid production and have a dose depending decrease in  prostaglandin production.

This explains the action of lowering fasting triglycerides and increasing insulin sensitivity.

Nuclear factor kappa-light-chain enhancer of activated B cells or NFKB is a transcription factor  responsible for expression of genes including cyclooxygenase-2,  inducible nitric oxide, tumor necrosis  factor alpha involving inflammatory response.

Meta-analysis indicate that a daily intake of 250 mg of EPA and DHA reduce the risk of fatal coronary heart disease by 36%, and no additional benefit is noted from higher intakes. (Mozaffarian D Rimm EB).

Plant-derived omega-3 precursor alpha linolenic acid is very poorly converted to EPA and DHA consumption of the latter fatty acids from diet or supplementation is preferred.

A benefit from n-3 fatty acids has been demonstrated in reducing cardiovascular mortality and morbidity in patients surviving myocardial infarction and in patients with heart failure.

Omega-3 fatty acid supplements are not effective in primary prevention of coronary artery disease and cancer in healthy in individuals.

Omega-3 fatty acid supplementation is not effective in patients with diabetes without cardiovascular risk to prevent adverse vascular events.

Typically the Western diet lacks meaningful amount of marine-based foods and accordingly, omega 3 fatty acid levels are low.

In a double-blind study assigned 12,536 patients at high risk for cardiovascular events and impaired fasting glucose, and impaired glucose tolerance, or diabetes to receive 1 g capsules of at least 900 mg of ethyl esters of n-3 fatty acids or placebo daily and to receive either insulin or standard care, the primary outcome was death from cardiovascular causes: daily supplementation with fatty acids did not reduce the rate of cardiovascular events in these patients (The ORIGIN Trial Investigators).

In a meta-analysis of 14 randomizes, double blind placebo controlled studies involving 20,485 patients with existing CV disease supplementation with O-3 fatty acids did not reduce overall CV deaths sudden cardiac death, myocardial infarction, CHF, TIA’s and stroke (Kwak SM et al).

In a double-blind, placebo controlled trial patients with multiple cardiovascular risk factors for atherosclerotic vascular disease but not myocardial infarction were randomly assigned to n-3 fatty acids 1 g daily or placebo in the form of olive oil: The primary endpoint was cumulative rate of death, nonfatal MI and nonfatal stroke-there was no reduction in cardiovascular mortality and morbidity with the use of n-3 fatty acids (The Risk and Prevention Study Collaborative Group).

There are other omega-3 fish oil based prescription drugs on the market that have similar uses and mechanisms of action.

There is little difference in effect between dietary supplement and prescription forms of omega-3 fatty acids as to ability to lower triglycerides.

Ethyl ester products work less well when taken on an empty stomach or with a low-fat meal.

Prescription omega-3 products are more concentrated, requiring fewer softgels for the same daily dose.

Results of many previous trials of n-fatty acids with a meta-analysis involving 78,000 patients did not show that groups received n-3 fatty acids had a lower risk of major adverse cardiac of cardiovascular events than those receiving placebo.

Omega 3 fatty acids-per capita intake 0.1 to 0.2 g/d.

Omega 3 fatty acids-consumption associated with a reduced risk of total stroke and thrombotic infarction primarily among women who do not take aspirin.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intake inversely related to coronary artery disease mortality.

EPA reduces platelet aggregation, vasodilation, antiproliferation, plaque stabilization and reduction in lipid activities.

Omega 3 fatty acids-consumption inversely related to a reduced risk of fatal coronary heart disease and to a lesser extent non-fatal myocardial infarction.

Omega 3 fatty acids-grams of fatty acid per serving of fish 1.5 gm for dark meat fish, 0.4 gm for tuna fish, 0.5 gm for other fish, 0.3 gm for lobster, shrimp, and scallops.

Supplements in myocardial infarction survivors reduced sudden cardiac deaths by 45% and a 20% in all-cause mortality during a 3′ year follow-up.

Prospective studies indicate a reduced cardiovascular risk from 32-50% when an increased intake of omega-3 occurs.

Supplements omega-3 fatty acids should be added to those whose diet is insufficient in this type of fat.

Higher survival rates among individuals with high dietary intake of marine omega-3 fatty acids.

The AFFORD trial demonstrated that high-dose omega-3 fatty acids do not reduce AF recurrence or inflammation or oxidative stress markers.

n-fatty acid alpha-linolenic acid (ALA) is less effective, with meta-analyses showing that the risk of fatal coronary heart disease was 21% lower among subjects with a high intake of ALA than among subjects with a low intake, the difference was of borderline significance (Brouwer IA et al).

The addition of supplements among individuals with history of recent ventricular arrhythmias and an implantable cardioverter defibrillator the risk of sustained ventricular tachycardia or ventricular fibrillation was not reduced and in some patients seem to be proarrhythmic.

The active ingredient is concentrated omega-3-acid ethyl esters that are made from fish body oils that are purified and esterified

Benefits in preventing cardiovascular disease, depression, rheumatoid arthritis, cystic fibrosis, systemic lupus erythematosus and cognitive decline have been seen (Fetterman JW).

Epidemiology studies suggest diets high in omega-3 long chain polyunsaturated fatty acids have a protective role in maintaining cognitive function.

A higher omega-3 index was linked to a larger hippocampus, the brain structure that plays a significant part in memory and learning.

Higher consumption of omega-3s was linked to improved abstract reasoning or the capability of understanding complex concepts making use of logical thinking.

Individuals who had the APOE4 genetic variation with higher consumption of omega-3s had a reduced risk of small-vessel disease. This genetic variation is linked to vascular dementia and cardiovascular disease.

High intake alpha-linolenic acid is associated with an increased risk of prostate cancer in patient’s with low-grade disease (Giovannucci E).

The risk for developing aggressive, high-grade prostate cancer is 2.5 times greater in men with the highest percentages of docosahexaenoic (DHA)omega -3 fatty acid compared with those with the lowest levels of DHA (Fred Hurchison Cancer Research Center).

Intake of large doses may result in a fishy aftertaste, diarrhea and nausea.

In the laboratory tests such agents may reduce levels of alpha-tocopherol and beta-carotene levels.

May have anticoagulant and antiplatelet effects (Haller C).

High levels of intake may decrease triglyceride and increase LDL cholesterol levels (Farmer A).

Doses higher than 3 g per day may increase bleeding time (Lewis CJ).

Among patients with paroxysmal AF 24 weeks of Omega-3 fatty acids compared with placebo did not reduce recurrent episodes of atrial fibrillation over six months (Kowey PR et al).

n-fatty acids may prevent ventricular arrhythmias in patients following a myocardial infarction (Smith PT et al).

In a meta-analysis is about 1007 articles 14 randomized, placebo-controlled trials and involving 20,483 patients with a history of cardiovascular disease, supplementation with Omega 3 fatty acid did not reduce the risk of overall cardiovascular events, all-cause mortality, sudden cardiac death, myocardial infarction, congestive heart failure, or TIA and stroke. (Kwak SM et al).

In the above study the country a location, geographic area, duration of treatment, dosage of EPA or DHA, concomitant medication use sub analysis showed no significant preventive effect of cardiovascular events.

In a meta-analysis of 732,000 patients on EPA plus DHA (eicosapentaenoic and docosahexaenoic) produces a non-statistically significant 6% reduction in coronary heart disease (Alexander D).

In the above study EPA plus DHA significantly reduced coronary heart risk by 16% among patients with elevated serum triglyceride levels and 14% with elevated low density lipoprotein cholesterol.

 

Combinations of EPA and DHA produce a graded reduction in triglyceride levels then when either is used alone.

Icosapent reduces triglyceride levels by 20-30%, while a combination of EPA/DHA products reduce triglyceride levels by up to 40%.

Icosapent shows a significant reduction in cardiovascular mortality and ischemic events in patients with elevated triglyceride and establishedcardiovascular disease or diabetes.

 

Icosapent ethyl has literally no effect on low density lipoprotein cholesterol or high density lipoprotein cholesterol, because it does not contain DHA, which can raise LDL-C and HDL-C.

In a randomized placebo controlled trial of 25,871 patients vitamin D3 at 2000 international units per day and marine n-3 fatty acids of 1 g per day in the primary prevention of cardiovascular disease and cancer among men 50 years of age or older and women 55 years of age or older in the US: supplementation with n-3 fatty acids did not result in lower incidence of major cardiovascular events or cancer than placebo (Manson JE).

ASCEND trial show the use of omega-3 fatty acids had no effect on the primary prevention of call vascular disease in patients with diabetes.

 

In statin-treated patients at high cardiovascular risk with elevated triglyceride levels and low levels of high-density lipoprotein cholesterol treated with omega 3 fatty acids, achieved levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that we’re not associated with major adverse cardiovascular outcomes.

 

A large number of observational studies, randomized controlled trials (RCTs), and multiple trial meta-analyses, the research has generated inconsistent signals for n-3 fatty acids role in CVD prevention.

 

Recent RCTs continue to provide mixed and discordant results.

 

Reduction of Cardiovascular Events with Icosapent Ethyl – Intervention Trial (REDUCE-IT), which tested 4 g/d of icosapent ethyl (a purified eicosapentaenoic acid (EPA)-only formulation) vs mineral oil placebo, found 25% relative risk reduction in CVD events.

 

A Study of Cardiovascular Events In Diabetes (ASCEND), which tested 1 g/d of EPA+DHA (1.2:1 ratio) in patients with diabetes, had overall null results.

 

Vitamin D and Omega-3 Trial (VITAL), which tested 1 g/d of EPA+DHA (1.2:1 ratio) vs olive oil placebo in the primary prevention of CVD found 28% risk reduction in myocardial infarction (MI) but no statistically significant reduction in stroke or major CVD events.

 

STRENGTH trial which tested 4 g/d formulation of EPA+DHA vs corn oil placebo in high-risk patients, did not reduce CVD events, albeit there was a 9% relative risk reduction in coronary heart disease (CHD) events.

 

Omega-3 Fatty Acids in Elderly with Myocardial Infarction (OMEMI) trial, which tested 1.9 g/d of EPA+DHA in post-MI patients, was underpowered and had null results.

 

If n-3 FA supplementation is beneficial may depend on: the population being treated (primary vs secondary prevention and background statin use), the formulation being used (EPA+DHA or EPA alone), the dose or duration of treatment, or the type of end point (CHD vs CVD). 

 

Discordant results of the 2 trials: strong CVD risk reduction in REDUCE-IT and null results in STRENGTH.

 

Thirteen randomized trials, using a relatively higher dose of n-3 FAs (total of at least 840 mg/d) with at least 1000 participants and lasting at least 2 years, significantly lowered the risk of MI but had no significant association with the risk of stroke.

 

VITAL trial had a lower incidence of MI and composite CHD (MI, coronary revascularization, and CHD death) in the treatment group despite the lack of benefit for the composite primary CVD end point.

STRENGTH trial results, suggested reduction in CHD events. 

 

A Cochrane review assessing both marine and plant n-3 FAs (EPA, DHA, and linolenic acid) for primary and secondary prevention of CVD10 concluded that there was moderate-to-low certainty evidence that n-3 FA supplementation would slightly decrease CHD events and mortality.

 

Randomized control trials with EPA/DHA treatment in  a total of 40 studies with a combined 135,267 participants:  Overall, there was no association of n-3 FAs with CVD event risk reduction.

 

A significant reduction in the risk of MI as well as CHD events was found with high certainty. 

 

Moderate certainty was reported for fatal MI and low certainty for CHD mortality.

 

Dose-response relationships for MI: with higher doses associated with greater risk reduction

Rated pregnancy category C.

It is excreted in breast milk and the effects on infants are not known.

Omega-3 acid ethyl esters are metabolized mostly in the liver.

Omega-3 acid ethyl esters reduce production of triglycerides in the liver, and enhance clearance of triglycerides from circulating very low-density lipoprotein (VLDL) particles.

However, the response for MI, fatal MI, and CHD was not found to be linear.

 

Findings do not support the concept that achieving higher EPA plasma levels through pharmacological means reduces adverse cardiovascular outcomes, nor were higher DHA levels associated with harm.

 

Participants were randomized to receive 4 g daily of 3 carboxylic acid (CA) or an inert comparator, corn oil.

 

Among patients treated with -3CA, the highest achieved tertiles of EPA and DHA were associated with neither benefit nor harm in patients at high cardiovascular risk.

Large scale randomized trials have both supported and denied the beneficial effects of omega-3 fatty acids in coronary heart disease.

Icosapent ethyl (Vascepa)  is the lone available EPA-only prescription product.

Omega-3-acid ethyl esters (Lovaza) and omega-3 carboxylic acids (Epanova) contain both EPA and DHA.

For Lovaza, each 1000 mg softgel capsule contains 840 mg omega-3 fatty acids: eicosapentaenoic acid ethyl ester (460 mg) and docosahexaenoic acid ethyl ester (380 mg).

 

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