Report on the bioavailability of ethyl ester and triglyceride forms of omega-3 fatty acids, EPA and DHA

Executive Summary

• Both forms of omega-3 fatty acids (EE, TG) can be digested and absorbed by the body.
• The rapidity of absorption into the body under acute conditions is less clinically important than
• the absolute levels in the body obtained during chronic supplementation.
• Both EE and TG forms have been shown to lower serum triglyceride and LDL-cholesterol levels
• in hyperlipidemic individuals.
• The only FDA-approved omega-3 fish oil product for hypertriglyceridemia, Lovaza™, contains
• EPA/DHA ethyl ester.
• The largest clinical study with EPA/DHA used the ethyl ester form in one of the lowest doses
• tested, and results demonstrated significant cardiovascular risk reduction.

Report on the bioavailability of ethyl ester and triglyceride forms of omega-3 fatty acids, EPA and DHA Fish oil products. EPA/DHA-containing products are widely used in the US for reducing primary and secondary
cardiovascular event risk. 1 Derived from fish oil, these omega-3 fatty acids are available in three formulations. The ethyl ester (EE) form goes through several purification steps, removing contaminants and concentrating the fatty acids. The reesterified triglyceride (TG) form processes the EE form back to a triglyceride, which is similar in chemical structure to unprocessed fish oil, but is more concentrated and results in a more expensive product. Free fatty acids (FFA) are similar to TG but adverse effects related to gastrointestinal discomfort and esophageal irritation preclude the use of this form in
commercial products. All forms are digested by the body and incorporated into lipids the body can use. All forms have been used clinically to reduce serum triglyceride levels and LDL cholesterol. 2-4 However, the only pharmaceutical preparation of EPA/DHA approved by the FDA is in the EE form.5

Bioavailability studies. Discrepancies in the bioavailability of  EPA/DHA forms have been reported, with some researchers concluding that the TG form is most bioavailable, while others report equivalent bioavailability. Based on fatty acid recovery from rat lymphs, incorporation of fatty acids into cells was delayed with EE relative to TG over 8 h, although bioavailability appeared to be equivalent at 24 h and over 28 days. 6 Another
study examined bioavailability of all three forms in humans by measuring serum levels of fatty acids, and the researchers concluded that bioavailability of TG was greater than that of EE, although fatty acids partitioned to tissues were not compared. 7 All three forms of fatty acids are digested with equivalent efficiency, 8 and once absorbed, dietary source has  no effect on lipid metabolism. 3,9

Most bioavailability studies have been performed in animal models, 10 and human studies have not thoroughly examined all of the variables that potentially modify fatty acid pharmacokinetics. Nutritional cofactors and lipid intake from diet, for example, of omega-6 PUFA and vitamin E, influence absorption of fatty acids, and health status and age can alter metabolic efficiency as well. 11 Duration of administration or varying doses may produce results that are different from study conditions. Since omega-3 fatty acids in foods or supplements are well tolerated by humans, slight variation in their bioavailability as tested in laboratory conditions likely have little impact on the health benefit derived by consumers concerned about meeting the daily recommended omega-3 fatty acid intakes.

Differences among study results may also derive from varying stability of each form. Results from one study indicated that after 10 weeks in a dark room temperature environment, EE was more stable from oxidation than TG. 12 Many commercial preparations, including Metagenics products, add antioxidants to EPA/DHA products to prevent oxidative degradation.Clinical benefit. Omega-3 fatty acids from many sources have demonstrated clinical benefit for reducing risk factors associated with heart disease, although head-to-head trials comparing efficacy among different forms of EPA/DHA are not available. 13

Although animal studies indicate slightly lower acute absorption of EE compared with TG, clinical results revealed that high concentration doses of EPA/DHA EE resulted in higher levels of EPA/DHA in serum phospholipids  and greater reduction of serum triglyceride and VLDL cholesterol levels relative to low concentration equivalent doses. 2 The 11,000-plus patient GISSI-Prevenzione trial used one of the lowest tested doses of ethyl ester fish oil at 850 mg per day of EPA/DHA. This study followed patients for up to 5 years with consistent low dose intake and resulted in significant decreases in both cardiovascular morbidity and  mortality. GISSI study participants were already exposed to the beneficial effects of a Mediterranean diet and represented a population at low risk for cardiovascular disease. Use of lowdose ethyl ester EPA/DHA has been predicted to have greater impact in populations with less favorable dietary habits. 14

Studies assessing administration of EPA/DHA on cardiovascular endpoints consistently support potent effects of each EPA/DHA form, 4 indicating that EE and TG forms of EPA/DHA are both good sources of omega-3 fatty acids.