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Omega-3 Fatty Acid Fish Oil Dietary Supplements for Disease Management: Are They Appropriate for Patients?

Perceptions of Fish Oil Dietary Supplements (FODS)
According to 2008 national health statistics, fish oil dietary supplements (FODS) are the most commonly used supplements among U.S. adults.1 There is a general public perception that consumption of fish is a healthy dietary habit.2 This perception may be responsible for a greater than threefold increase in the use of FODS among older adults in the U.S. over the past decade.3 Individual perceptions of the benefits of fish and FODS cover a wide spectrum. These perceptions include the idea that FODS may improve general health, reduce atherogenic lipids, and improve brain and heart function, and that fish serves as a good source of protein.2,4

Daniel E. Hilleman, PharmD, one of the authors of this article, conducted a survey of 496 patients with known cardiovascular disease who indicated that they were taking either a FODS or a prescription omega-3 fatty acid (OM3FA) product. Of these patients, 40 percent indicated that they were taking the product for general health, while 60 percent reported taking FODS for a specific health benefit.4 These specific health benefits typically corresponded to the medical conditions of the individual survey respondents. Myocardial infarction and coronary disease were most commonly mentioned.5 Only 10 percent of cardiology patients indicated they were using the product for lipid disorders.4

The same survey also showed that, among the patients known to be using either FODS or a prescription OM3FA product, only 9 percent (45 of 496 patients) indicated that their physician told them to use the product.4  About half (n = 22) of those patients said their physician wrote a prescription for omega-3-acid ethyl esters (an OM3FA drug product containing a mixture of eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]), yet only nine of those patients were actually filling the prescription.4 Fewer than one in four of the 496 patients could identify that OM3FAs were the active ingredients in their FODS or prescription OM3FA product, and less than 5 percent knew the actual amount of active ingredient in the product they were using.4 The number of pills (capsules or dosage units) taken each day ranged from 1 to 8.

The majority of patients (73 percent) in Hilleman’s survey said they bought the same FODS at each purchase.4 However, only 17 percent of patients indicated that they bought their FODS in a pharmacy.4 Given that the vast majority of patients are buying their FODS outside of pharmacies, pharmacists and other healthcare providers need to be proactive when taking patient histories and document the use of these products at times other than when they are purchased. A complete history of patient use of prescription and non-prescription products, including dietary supplements, should be taken each time a patient visits his or her pharmacy and/or treating provider. An additional concern is that research shows that some pharmacists have a knowledge gap about the safety and efficacy of common dietary supplements.6 Pharmacists need additional education and training about commonly used dietary supplements, including FODS, since they are not approved by the Food and Drug Administration (FDA) to treat disease.

Fish Oil Dietary Supplements (FODS) versus Prescription Omega-3 Fatty Acids (OM3FAs) for Patient Care
For patients with elevated triglyceride (TG) levels, the American Heart Association has recommended 2–4 g/day of EPA+DHA.7 To achieve this goal, patients may choose to take FODS on their own instead of taking prescription products indicated as an adjunct to diet to reduce TG levels in adults with severe (≥500 mg/dL) hypertriglyceridemia. Some managed-care plans require patients to fail on FODS before covering prescription products. Although FODS are widely available, dietary supplements are not subject to the strict regulations governing over- the-counter drug approval by the FDA, so their content and chemical integrity are not regulated in a rigorous manner.8

Additionally, their efficacy and safety are not regulated prior to marketing and are not well documented.8 Additionally, the low EPA and DHA content of FODS may require patients to take ≥10 capsules/day in an attempt to reach a therapeutic dose of EPA or EPA+DHA equivalent to prescription OM3FA 4 g/day,9 potentially negating any cost advantage.

Oil extracted from marine animals is a common source of FODS but it also is an extremely unstable product. Fish oil is obtained primarily from processing plants during the manufacturing of fishmeal from whole or filleted fish bodies.10,11 To aid in the coagulation of tissue protein and expression of the oils, the harvested fish are cooked at about 100°C.10 OM3FAs are susceptible to free radical damage during such manufacturing processes, and the damage is accelerated in the presence of light and contaminants.10 Free radicals contribute to oxidative modification of OM3FAs, which may interfere with the intended biological or potential clinical benefit of FODS.12,13

Independent studies from various laboratories have verified concerns about the OM3FA content and integrity of FODS. A study funded by the U.S. Department of Agriculture found that 74 percent of 47 FODS tested contained less than the amounts of EPA and/or DHA indicated on their labels.14 A scientific study in New Zealand of 36 FODS demonstrated that more than 80 percent had unacceptably high levels of lipid peroxides, an indication of lipid decomposition.15 Of those tested, only three (8 percent) met international standards for acceptable peroxide and total oxidation levels. Additionally, FODS sold in North America have been shown to have unacceptably high levels of lipid peroxides.16 An elevated peroxide value indicates high levels of primary oxidation and hydroperoxides, which can interfere with any intended biological antioxidant activity.

Recently presented data highlighted the fatty acid content issues of leading FODS (by sales) in the U.S. with respect to saturated fat, EPA, and DHA.17 Also measured were the extent of oxidative damage in the oil compared to a prescription form with respect to purity and the ability to prevent human low-density lipoprotein (LDL) oxidation in vitro.17 This research was presented by R. Preston Mason, PhD, co-author of this article, at the 2015 meeting of the Academy of Managed Care & Specialty Pharmacy (AMCP).17 The fatty acid content of six FODS was determined and more than 30 fatty acids were identified in the FODS samples, including 10 to 14 saturated fatty acids in each sample, comprising as much as 36 percent of total fatty acid content (Figure 1).17 Additionally, OM3FA levels varied widely among the FODS (33 to 79 percent), including levels of EPA (21 to 52 percent) and DHA (9 to 31 percent). This study also measured primary and secondary products of oxidation that are associated with fatty acids containing multiple double bonds, such as OM3FAs.18 All of the supplements exceeded recommended maxima for most of these oxidation products.18 By contrast, the prescription product did not produce significant levels of oxidation products under identical test conditions.18

Finally, the biological activity of the OM3FAs isolated from a leading FODS was compared to non-oxidized and oxidized preparations of EPA/DHA mixtures to determine their effects on small, dense LDL (sdLDL) oxidation.18 Oxidation of sdLDL was inhibited by >95 percent (P<0.001) with the non- oxidized OM3FAs but was not inhibited by the oxidized OM3FAs or the FODS isolate, which contained both oxidized and non-oxidized OM3FAs.17 The clinical translation of the lack of biological effect from oxidized FODS has been reported to include negative therapeutic effects on blood lipid levels12 and a lack of intended effectiveness on lipid or inflammatory parameter levels.19

Conclusion
Despite the widespread use of FODS in the U.S., there is substantial confusion about their benefits and appropriate use among both healthcare providers and patients. There is the perception that FODS produce various health benefits, including a reduction in atherogenic lipids and improvements in brain and heart function, but these have not been clinically proven. FODS are not approved by the FDA to treat or cure disease and are not categorized as over-the-counter drugs, but as dietary supplements, equating to less rigorous regulation regarding efficacy, safety, content, and chemical integrity. While containing varying amounts of desirable OM3FAs, leading FODS also contain more than 30 fatty acids, including significant levels of saturated fat. FODS also contain elevated levels of primary and secondary lipid oxidation products that interfere with their biological activity and may have adverse clinical implications. These data indicate that there is a need

for more education about the quality and appropriate use of FODS. As a product without rigorous FDA regulation and with varying levels of fatty acids and oxidation products, FODS are not an appropriate substitute for prescription products in patients diagnosed with certain medical conditions, such as very high TG levels.

Disclosure statement: Dr. Mason has no disclosures to report. Dr. Hilleman has no disclosures to report.

References are listed on page 47 of the PDF.

 

 

Article By:

R. PRESTON MASON, PhD
Department of Medicine, Cardiovascular Division
Brigham and Women’s Hospital
Harvard Medicine School
Boston, MA
Elucida Research LLC
Beverly, MA

DANIEL E. HILLEMAN, PharmD
Creighton University School of Pharmacy and Health Professions
Omaha, NE

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