Prescription Omega-3 Fatty Acids and Their Lipid Effects: Physiologic Mechanisms of Action and Clinical Implications

Harold E Bays; Ann P Tighe; Richard Sadovsky; Michael H Davidson


Expert Rev Cardiovasc Ther. 2008;6(3):391-409. 

In This Article

Biochemistry & Nutritional Aspects of Omega-3 Fatty Acids

Omega-3 fatty acids are polyunsaturated fats in which the first double bond counting from the terminal (omega) methyl group is at carbon 3.[74] Major omega-3 fatty acids include a-linolenic acid (ALA [18:3N-3]), EPA (20:5N-3) and DHA (22:6N-3).[75,76] In general, fatty acids are of varying sizes, which affects function. Short chain fatty acids usually have less than six carbons. An example would be butyric acid, which is a four-carbon fatty acid found in butterfat. Medium chain fatty acids usually have six to 12 carbons. An example would be lauric acid, a 12-carbon fatty acid that is the main component of coconut oil. ALA, EPA and DHA are all considered long-chain fatty acids because each have 12 carbons or more.

ALA is an 'essential' fatty acid, because it cannot be synthesized in humans and, thus, must be consumed in the diet. ALA is a plant-derived omega-3 fatty acid that can be converted to EPA and DHA in mammals.[76] However, the conversion of ALA to EPA is modest (<1%) and the subsequent conversion of EPA to DHA is also very low.[76] Thus, while not necessarily essential fatty acids, preformed EPA and DHA are best obtained through dietary sources.

The best dietary sources of EPA and DHA include fatty or oily marine seafood, such as salmon, herring, mackerel, halibut and tuna.[77] Some fresh-water fish may contain significant amounts of omega-3 fatty acids, and include lake herring, lake trout, freshwater salmon and whitefish.[196] The omega-3 fatty acid content of these fish may be increased with farming.[77] Some concerns have been raised about the environmental impact and residual pesticide and antibiotic content of selected types of fish.[197] However, the risks from contaminants potentially contained in oily fish consumption may be outweighed by the potential benefits.[78] The American Heart Association (AHA) has acknowledged that EPA and DHA 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.[77] While reducing TG levels may have cardiovascular benefits, it is unclear as to how much (if any) of these before-mentioned benefits are related to omega-3 fatty acid's TG-lowering effects and how much is due to TG-independent effects.

Omega-3 fatty acids reduce TG levels in humans.[79,80,81] The amount of EPA and DHA typically administered for the treatment of hypertriglyceridemia is 2-4 g/day.[77] EPA and DHA have similar TG-lowering effects,[82] and lower both fasting[83,84] and postprandial[82,83] TG levels. P-OM3 (4 g/day for ≥6 weeks) significantly reduces TG levels in subjects with severe hypertriglyceridemia ( Table 3 ).[85] While ALA is an omega-3 fatty acid, it does not significantly reduce TG levels at typically administered doses.[86,87]

P-OM3 may reduce TG levels more effectively than fish oil formulations containing less omega-3 fatty acids, and may have greater bioavailability.[88] Owing to the requirements in achieving a prescription status, P-OM3 has undergone more rigorous safety and efficacy evaluation and verification than dietary supplement omega-3 fatty acids.[89,90,91] Selected dietary supplement omega-3 fatty acids do not appear to contain contaminants in sufficient concentrations to pose a potential health risk.[89] However, individual supplements vary considerably in the amount of their omega-3 fatty acid content. P-OM3 has undergone the processes necessary to achieve FDA approval, verifying its consistent omega-3 fatty acid content.[90]

The most common drug-related adverse experiences attributable to P-OM3 include a mild, numerical increase in eructations (belching) and dyspepsia,[92] which are substantially mitigated by the purification process used for P-OM3.[89] P-OM3 does not have any known, clinically significant drug interactions. Some reports have suggested that omega-3 fatty acids may impair platelet aggregation and increase bleeding times.[93,94] Clinical trial data suggest that P-OM3 does not increase clinical bleeding, even in patients receiving warfarin anticoagulants, aspirin and other older antiplatelet agents.[89,95,96] P-OM3 has also been described to sometimes increase levels of liver transaminases, such as alanine aminotransferase. Thus, alanine aminotransferase levels should be monitored periodically during P-OM3 therapy.[92] Finally, studies of omega-3 fatty acids, including P-OM3, have often reported a transient increase in glucose levels, but not increases in measures of long-term glucose control, such as fructosamine or hemoglobin A1C.[27]


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