4186 Current Pharmaceutical Design, 2009, 15, 4186-4190

1381-6128/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

PUFA for Human Health: Diet or Supplementation?

P. Abete1,*, G. Testa

1, G. Galizia

1, D. Della-Morte

1, F. Cacciatore

1,2 and F. Rengo

1,2

1Dipartimento di Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, Cattedra di Geriatria, Università degli

Studi di Napoli “Federico II”, Naples, 2Istituto Scientifico di Campoli/Telese, Fondazione Salvatore Maugeri, IRCCS,

Benevento, Italy

Abstract: Large doses of omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are used to

treat several diseases including hypertriglyceridemia in humans. Modest levels of EPA and DHA may be obtained from

food, particularly from fatty fish. This review presents the literature examining the differences between omega-3 fatty acid

dietary supplementation and prescribed omega-3-acid ethyl esters (P-OM3). Reports published between 1995 and 2007

containing sources, recommended intake, and differences in the various formulations of omega-3 fatty acids were sought

in PubMed and the Food and Drug Administration (FDA) Websites. However, lack of head-to-head clinical trials using

both P-OM3 and dietary-supplement omega-3 fatty acids is the greatest limitation of this review. Although many kinds of

omega-3 fatty acid dietary supplements are available, the efficacy, quality, and safety of these products are questionable

because they are beyond any pharmaceutical control. Thus, P-OM3 is the only FDA approved omega-3 fatty acid product

which is available in the United States as an adjunct to diet to improve human health.

Keywords: Omega-3 fatty acids, diet, supplementation, triglycerides.

INTRODUCTION

Polyunsaturated fatty acids consist of two classes of essential fatty acids, omega-6 and omega-3 [1-3]. Eicosa-pentaenoic acid (C20: 5n-3, EPA) and docosahexaenoic acid (C22: 6n-3, DHA) represent the class of omega-3 fatty acids, commonly known as fish oil because of their marine derivation [4]. In the last three decades experi-mental, clinical and epidemiological evidence showed that this class of nutrients provided protective effects against coronary heart disease probably through a reduction in triglyceride circulating levels [5,6]. However, the DART study [7] and the GISSI Prevention trial [8] strongly supported the antiarrhythmic effects of polyunsaturated fatty acids. Both studies were conducted on patients who, after myocardial infarction (post-MI), received a diet rich in fish (200-400 g/ week), or fish oil capsule (500-850 mg/day of EPA/DHA). Cardiac death and total mortality were significantly reduced (30-45%) within 3-4 months of treatment. Despite diffe-rences in the two studies, the absence of a significant reduction in the incidence of recurrent non-fatal MI, compared with significant reductions in sudden death and recurrent fatal MI, indicated a protective mechanism that prevented fatal arrhythmias rather than anti-thrombotic or anti-atherosclerotic effects [9,10]. There was also evidence of benefits to other cardiovascular risk factors including a decrease in platelet aggregation [11], a fall in heart rate [12], and a small drop in blood pressure [13]. Moreover, omega-3 fatty acids were also demonstrated to be helpful in several disease such as inflammatory bowel disease, asthma, cystic fibrosis, rheumatoid arthritis, depression disorders, and cognitive impairment [14]. The regulation of gene expres-

*Address correspondence to this author at the Dipartimento di Medicina Clinica e Scienze Cardiovascolari ed Immunologiche, University of Naples

Federico II, 80131 Napoli, Italy; Tel: +39-081-7462270; Fax: +39-081-7462339; E-mail: p.abete@unina.it

sion seems to be among the omega-3 fatty acid mechanisms of action [15]. This article examines the efficacy of diet or supplementation with polyunsaturated fatty acids on human health.

EFFECTS OF OMEGA-3 FATTY ACIDS ON TRIGLYCERIDE REDUCTION

Some reports indicated that, in addition to established cardiovascular risk factors, hypertriglyceridemia may be an independent coronary heart disease risk factor [16]. Cholesterol-enriched remnant lipoproteins, which are rich in triglycerides, are known to promote atherosclerosis and consequently, development of coronary heart disease [17]. In fact, as blood triglycerides rise to 200 mg/dl there are strong correlations with increases in very-low-density lipoprotein (VLDL) -cholesterol and atherogenic remnant lipoproteins [17].

Triglyceride levels were indicated as a therapeutic target in the National Cholesterol Education Program (NCEP) guidelines [16]. In this program, the last Adult Treatment Panel (ATP III) lowered the threshold for normal triglyceride levels from <200 mg/dL to <150 mg/ dL. Accordingly, the American Heart Association recom-mends use of omega-3 fatty acids to reduce the risk of coronary heart disease and to lower triglyceride blood levels [17]. In subjects with triglyceride levels >200 mg/dL, when low-density lipo-protein (LDL) -cholesterol levels are lowered, the level of non-high-density lipo-protein (non-HDL) -cholesterol, (calculated by subtracting high-density lipoprotein (HDL) -cholesterol from total cholesterol), is a secondary therapeutic target. Non-HDL-cholesterol is the sum of very low-density lipoprotein (VLDL) -cholesterol and LDL-cholesterol i.e. “bad choles-terol”. Since non-HDL-cholesterol also encom-passes VLDL-cholesterol, it represents the concentrations of

PUFA for Human Health Current Pharmaceutical Design, 2009, Vol. 15, No. 36 4187

all atherogenic lipoproteins better than LDL-cholesterol alone in individuals with high triglyceride levels [17].

The ability of omega-3 fatty acids to lower serum triglyceride levels was observed in several studies on normal volunteers and patients with hypertriglyceridemia. A recent review analyzing crossover and parallel studies showed 25% and 34% reductions in serum triglyceride levels in patients with low or high baseline levels (<177 mg/dL or 177 mg/dL) respectively, with a dosage of 4 g/day of omega-3 fatty acids [6]. Interestingly, in subjects with triglyceride levels >150 mg/dL clinical trials showed supplementation with omega-3 fatty acids EPA and/or DHA at dosages of 3.4-4 g/day decreased circulating triglycerides by an average of 29% [18]. The efficacy of omega-3 fatty acids in lowering triglycerides was studied in several clinical trials [19-25] (Fig. 1) which clearly indicated that the ability of omega-3 fatty acids to reduce triglyceride levels was dose-dependent and was more significant as baseline levels were higher [26].

Despite this evidence, the mechanisms underlying the effects of omega-3 fatty acids on circulating lipid profiles still remain to be elucidated. There are several hypotheses: inhibition of the triglyceride-synthetic enzyme acylCoA: 1,2-diacylglycerol acyltransferase, decreased lipogenesis, or increased peroxisomal or mitochondrial -oxidation in the liver [27].

OMEGA-3 FATTY ACIDS AND FOOD

Omega-3 fatty acids are essential fatty acids and, since the enzymes involved in their synthesis are not present in mammalian cells, they must come from the diet [1,4]. The short-chain omega-3 fatty acid i.e. -linolenic acid is derived from plants and, in mammalian cells, undergoes conversion into EPA and subsequently DHA but reaction rates are very

low [28]. For this reason seed oils, like canola, soybean, flaxseed, and walnut, are a valid source of omega-3 fatty acids. Nevertheless, as omega-3 and omega-6 fatty acid are elongated by the same enzyme (a desaturase), high intake of omega-6 fatty acids might lead to competitive inhibition of the -linolenic acid conversion to the long-chain EPA and DHA [29-31].

In the United States, the average intake of long-chain omega-3 fatty acids is about 100-200 mg/day [32], with fatty fish being the most concentrated food source of EPA and DHA [5]. In general, the more ‘oily’ (i.e., fatty) fish species, like albacore tuna, sardines, salmon, mackerel and herring contain the highest concentrations of omega-3 fatty acids [33].

However, to manage hypertriglyceridemia effectively, increased intake of fatty fish is not advised because con-sumption of four 120 gr servings of canned albacore tuna, is needed to achieve a reasonable daily amount (approximately 4 g) of EPA and DHA [34]. Moreover, some species of fish (shark, king mackerel, swordfish, and tilefish) often contain high levels of methyl mercury, dioxins, polychlorinated-biphenyls (PCBs), and other environmental contaminants [5,35]. At present, pregnant woman or nursing mothers should limit fish intake to 180 gr/week, according to Environmental Protection Agency and FDA recom-mendations [36].

OMEGA-3 FATTY ACID INTAKE RECOMMEN-DATIONS

Several studies demonstrated the beneficial role of omega-3, EPA and DHA, in reducing risk of CHD [5,37,38]. The American Heart Association recommends consumption of fatty acids at least twice a week including foods rich in -

Fig. (1). Triglycerides levels reduction by omega-3-acid ethyl esters (P-OM3, 4 g/day) in patients with hypertriglyceridemia. The reduction

of triglycerides ranges from -27 to -45 % from baseline.

4188 Current Pharmaceutical Design, 2009, Vol. 15, No. 36 Abete et al.

linolenic acid (e.g., flaxseed oil, walnuts), in patients without documented CHD, and 1 g/day of EPA and DHA in patients with documented CHD [5]. In hypertriglyceridemic patients, the effects of EPA and DHA remain to be determined. In patients with triglyceride levels ranging from 200 to 499 mg/dL, the NCEP ATP III still consider diet and lifestyle modifications as the core therapeutic strategy while the pharmacological therapy with agents such as fibrates and nicotinic acid is considered additional. The highly concentrated omega-3-acid ethyl ester preparations (i.e. Omacor® ), are approved for hypertriglyceridemic patients as an addition to treatment with fibrates, nicotinic acid and diet. According to the AHA, high doses (2-4 g/day) of omega-3 fatty acids should be used only under the physician’s care [5]. In fact, as the FDA also advised, unsu-pervised intake of omega-3 fatty acids (EPA and DHA) should not exceed 3 g/day and only 2g/day should be supplied by dietary supplements. Underlying these limi-tations are, in fact, concerns about longer bleeding time, LDL cholesterol levels, and glycemic control in non-insulin dependent diabetic patients [36]. Even when treating very high triglyceride levels to prevent pancreatitis, adminis-tration of EPA and DHA should be approached in a clinical setting. Since patients do not consider omega-3 fatty acid supple-ments as medication, the physician should pay particular attention to appropriate use of these products, especially in patients taking other drugs.

OMEGA-3 FATTY ACID ETHYL ESTERS AS DRUG FORMULATION

A prescription formulation of omega-3-acid ethyl esters (P-OM3) to be used as a lipid-lowering agent was first approved by the FDA in November 2004. This class of medications was approved for use in combination with diet in patients with triglyceride levels 500 mg/dL. To achieve a high concentration when provided as trigly-cerides, omega-3 fatty acids are prepared as ethyl esters or free fatty acids. In fact, the ethyl ester content of the omega-3 fatty acids in each capsule is at least 900 mg and is provided as a combination of EPA (approximately 465 mg), DHA (approximately 375 mg), and other omega-3 fatty acid esters (approximately 60 mg). To reach the recommended intake doses can be four capsules once or two capsules twice daily [39]. To meet FDA requirements for prescription products, Current Good Manufacturing Practice standards of consistency and purity have to be ensured [39]. Thus P-OM3 preparations have to comply with established upper limits of acceptability for heavy metals, PCBs, dioxins, and other contaminants [39]. Moreover, one of the major problem with omega-3 fatty acid therapy is the number of pills to take. However, there are many highly concentrated over-the-counter pills/ liquids that offer patients similar efficacy with fewer pills to take. In the United States there are very reputable brands and some are backed by independent verifiers of content.

ANTI-THROMBOTIC AND SIDE EFFECT OF OMEGA-3 FATTY ACIDS

It is well established that arachidonic acid (an omega-6 fatty acid) metabolites contribute to a pro-atherogenic state

that can be lowered by omega-3 fatty acids. Consumption of omega-3 fatty acid EPA and DHA can inhibit arachidonic acid synthesis, thus lowering tissue levels. The EPA-derived eicosanoids show an anti-thrombotic effect as they produce less platelet aggregation and are less vasoconstrictive than arachidonic acid-derived eicosanoids [40]. In addition to these direct effects, omega-3 fatty acids were recently demonstrated to lower thrombin levels in a vitamin K-dependent manner [40]. Nevertheless, no studies have reported any clinically relevant bleeding event when patients were treated with FDA-approved doses of P-OM3 (3.4 g EPA and DHA/day) [41]. In studies on re-stenosis and by-pass graft, administration of high-dose omega-3 fatty acids combined with aspirin was safe even though there was no evidence that omega-3 fatty acids prevented re-stenosis after coronary angioplasty [42,43]. It appears advisable to screen patients undertaking treatment with P-OM3 for signs and symptoms of bleeding before and during treatment, even though additional blood testing is not required when P-OM3 are used at approved doses. The most common adverse events in patients treated with P-OM3 are shown in Fig. 2 [29]. P-OM3 should be used with caution in persons with known sensitivity or allergy to fish [32].

OMEGA-3 FATTY ACID SUPPLEMENTATION

Omega-3 fatty acids are also available as dietary supplements in the form of triglycerides, ethyl esters, or free fatty acids. The most common omega-3 fatty acid dietary supplements are based on 180 mg of EPA and 120 mg of DHA per 1000 mg fish oil capsule in the trigly-ceride form [44]. In management of hypertriglyceridemia, dietary-supplement omega-3 fatty acids present some limitations compared with P-OM3. In fact, when dosing per capsule, omega-3 fatty acids contained in P-OM3 are more concentrated than dietary supplement formulations [6]. The high concentrations of omega-3-acid ethyl esters ( 80%) in P-OM3 appear to have greater bioavailability and to reduce triglyceride levels more effectively than less concentrated formulations [45]. In a clinical study investigating three different omega-3 concentrations, for 14 days 101 subjects received 5.1 g per day of EPA and DHA ethyl esters provided in three concentrations: 62.5%, 80% and 85% of total fatty acids. Although the same quantity of omega-3 fatty acids was administered, patients taking the more concentrated formulations showed higher EPA/DHA levels in serum phospholipids and greater reductions in serum triglyceride and VLDL-cholesterol levels. Total and non-HDL-cholesterol were significantly reduced from baseline with all three formulations. Thus, the highest concentration of omega-3 acid ethyl esters (80%) appeared to have greatest uptake and emerged as the most powerful agent for reducing triglycerides and VLDL-cholesterol [45]. This study demonstrated that uptake and the lipid-lowering properties of highly concentrated omega-3 fatty acid formulations are better than the same quantity of omega-3 fatty acids in less-concentrated formulations.

In a previous clinical trial 20 male patients with primary hypertriglyceridemia were treated for 4 weeks with daily supplements (15 g, 15-18 capsules) of oil, which provided approximately 6 g polyunsaturated fatty acid, of either fish or vegetable origin. Although this number of pills was

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needed to attain similar doses of EPA plus DHA as in P-OM3, the approach seemed to be really unreasonable [46].

Different manufacturers produce dietary supplements with different degrees of efficacy, purity, and safety. When the fatty acid, cholesterol, and vitamin A and E content was assessed in eight commercially available capsules along with cod liver oil, EPA content ranged from 8.7-26.4% with a mean of 17.3% (82.4% of labelled content), and DHA content from 8.9-17.4% with a mean of 11.5% (90.0% of labelled content) [47]. Similarly, 41 omega-3 fatty acid dietary supplements were analysed and only 53% of claimed EPA content was found [48]. Finally, dietary supplements did not undergo the same standards and supervision required for approval as a prescription drug from the FDA [49]. Even though the American Heart Association recommends 1 g/day of EPA and DHA for cardiovascular protection in patients with documented CHD, it is very difficult to make

1 g/day dose of EPA and DHA available with dietary-supplement omega-3 fatty acids. Although EPA and DHA are present in dietary supplements, practitioners can not guarantee their purity and batch-to-batch consistency. In fact, manufacturers of dietary supplements do not need FDA approval for their structure/function claims, and according to FDA regula-tions, dietary supplements should not be used to treat or prevent any disease [50]. At present, data from clinical trials using P-OM3 and dietary supplements of omega-3 fatty acids are not available, and therefore, P-OM3 is the only pharmaceutical omega-3 fatty acid product approved for treatment .

CONCLUSIONS

P-OM3 seems to be the most efficacious approach, in addition to diet, in the management of diseases in humans. P-OM3 manufacturing ensures a concentrated form of EPA and DHA that is effective and safe. Thus, P-OM3 should be safely used by practitioners at therapeutic doses for those diseases where omega-3 fatty acids have been shown to be

effective. Even though dietary-supplements with omega-3 fatty acids are frequently used by practi-tioners as an alternative to P-OM3, they are not approved by the FDA for the treatment of any diseases, including hypertrigly-ceridemia. In fact, the purity of dietary-supplement omega-3 fatty acids frequently does not meet FDA standards. Finally, the bioavailability of EPA and DHA ethyl esters in P-OM3 is greater than the EPA and DHA formulations in dietary supplements.

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Received: August 6, 2009 Accepted: August 19, 2009

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