Long Chain Omega-3 Dietary Supplements: A Review of the National Library of Medicine Herbal Supplement Database

Abstract

Background:

Dietary fish oil supplements are increasingly used as an alternative to prescription-grade omega-3 fatty acids (P-OM3) for the treatment of hypertriglyceridemia. The content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in these supplement products varies widely and may result in a suboptimal response. The aim of this study was to review marketed fish oil supplements and to develop a reference for clinicians to compare products.

Methods:

The National Library of Medicine Herbal Supplement Database was systematically searched using fish oil, EPA, DHA, and omega-3 fatty acid as search terms. Daily doses needed to achieve the Food and Drug Administration (FDA)-approved dose (RxDose) (3,360 mg of combined EPA and DHA) were calculated from the milligrams of EPA and DHA per serving, and suggested retail prices were used to calculate monthly cost of each product. A “usage criteria” was set to highlight products at the RxDose with a monthly cost of <$50, daily servings <8, daily amount of vitamins A and D less than or equal to the U.S. Dietary Reference Intake upper limit defined as 10,000 and 4,000 IU, respectively, and if the product was U.S. Pharmacopeia verified.

Results:

A total of 163 products were identified, and 102 nonliquid and liquid products met our entry criteria. The median amount of EPA and DHA per serving in the nonliquid products was 216 mg and 200 mg, respectively, and the median number of servings at the RxDose was 11.2 at a median monthly cost of $63.49. The median amount of EPA (460 mg) and DHA (400 mg) per serving in the liquid products was higher than the nonliquid products. Thus, the median number of servings at the RxDose was only 3.6 teaspoons and the median monthly cost of $13.60. Only 22% of products met our “usage criteria.”

Conclusions:

The amount of EPA and DHA per recommended serving in these products was highly variable. Clinicians should heighten their scrutiny in terms of selection of the appropriate product.

Introduction

U se of dietary supplements has become very common, with the existence of over 30,000 supplements and addition of more than 1,000 new products annually. The use of dietary supplements by adults (20 years and older) is estimated to range from 20% to 70%, with higher usage among women and whites of all ages within United States. Thus, consumer expenditure for dietary supplements is in excess of $23 billion annually.^1
–3

According to a recent report of a survey of 6,012 responders that was gathered by consumerlab.com, fish oil or omega-3 fatty acid (omega-3 FA) is now the top dietary supplement among those people who use multiple dietary supplements. Seventy four percent of responders to this survey indicated that they use fish oil supplements.⁴ Consumers are spending more than $13 billion worldwide on omega-3 FA dietary supplements,⁵ likely due to the substantial benefits reported in both the medical and lay literature, particularly related to diseases of the cardiovascular system^{6

–15} and reduction in serum triglycerides levels,^16

–19 as well as their recommended use in published guidelines.^20,21 A 30-year follow-up analysis of the Chicago Western Electric Study reported favorable effects of fish oil consumption for subjects who consumed 35 grams of fatty fish compared to those who consumed none. Patients who consumed fish had a 0.62 and 0.56 relative risk estimate of death from coronary heart disease (CHD) and nonsudden death from myocardial infarction, respectively.⁶ Other epidemiologic studies have shown a 50% lower mortality rate among those who consume at least 30 g of fish per day.⁷

The effect of omega-3 FA in relation to reduction of CHD was investigated in four large randomized trials. The first controlled trial of dietary fish consumption, the Diet and Reinfarction Trial (DART), randomized men who had a myocardial infarction to receive or not to receive dietary advice, including an increase consumption of fatty fish. A 29% decrease in all-cause mortality was reported in patients who consumed fatty fish twice per week (corresponding to about 300 grams of fatty fish every week).⁸ The GISSI Prevenzione study, a large randomized secondary prevention interventions trial, randomized 11,324 patients following a recent myocardial infarction to 1 gram daily of n-3-polyunsaturated fatty acid, 300 mg daily of vitamin E, both, or none for 3.5 years. Treatment with n-3-polyunsaturated fatty acid, but not vitamin E, significantly lowered the risk of sudden death.⁹ Moreover, the GISSI-HF trial¹⁰ demonstrated beneficial effects of 1,000 mg of n-3-polyunsaturated fatty acid compared to placebo on mortality and hospital admissions for cardiovascular reasons in chronic heart failure patients (New York Heart Association class II–IV). In the Japan Eicosapentaenoic Acid Lipid Intervention Study (JELIS), 18,645 patients with previous history of hypercholesterolemia were randomly assigned to receive either 1,800 mg of eicosapentaenoic acid (EPA) daily with a statin or statin only for a median follow-up of 4.6 years. Patients randomized to EPA plus a statin had a 19% relative risk reduction in major coronary events compared to the statin-only group. ¹¹ In contrast, the Alpha Omega Trial showed no difference in major cardiovascular events between patients with a previous myocardial infarction randomized to four trial margarines supplemented with low doses of either EPA and docosahexanoic acid (DHA) (approximately 400 mg combined); α-linolenic acid (ALA) alone (2 grams); EPA, DHA, and ALA combined; or placebo that were also receiving state-of-the-art antihypertensive, antithrombotic, and lipid-lowering therapy.¹² The authors conjecture that the lack of benefit seen in these patients with omega-3 FA supplementation might have been obscured by the high prevalence (>85%) of concomitant “life-saving” cardiovascular pharmacotherapy and or that the doses of omega-3 FA were too low. However, this speculation that the dose of omega-3 FA was too low was expunged by the finding from the OMEGA study, which showed no benefit of 1,000 mg of omega-3 FA esters compared to placebo in postmyocardial infarction patients treated for 1 year.¹³

The American Heart Association (AHA) recommends that patients without any documented history of CHD consume at least two servings of fatty fish per week, and patients with a history of or documented CHD to consume at least 1 gram daily of EPA and DHA, preferably from a fatty fish source, and if necessary to consider EPA plus DHA supplementation with a physician's supervision. There are numerous clinical trials that demonstrate that large doses (>2 grams/day) of combined EPA and DHA significantly lower serum triglycerides. The percent reduction is chiefly dependent on the baseline triglyceride level, with larger reductions seen with higher baseline levels. Thus, the AHA advocates that patients who have high triglycerides consume 2–4 grams daily of EPA and DHA supplementation with physician supervision.²⁰ The United Kingdom National Institute for Health and Clinical Excellence (NICE) secondary prevention guidelines also recommend the consumption of at least 7 grams of omega-3 FA from fatty fish or 1 gram of per week of omega-3 FA ethyl ester treatment if within 3 months of a myocardial infarction.²¹

ALA, an omega-3 FA, cannot be synthesized by humans and therefore is considered an essential fatty acid and must be obtained from dietary sources. ALA is found mainly in plant-based foods such as walnuts, flaxseed, and olive oils. However, in humans, the conversion of ALA to EPA and EPA to DHA is minimal and estimated to range from 5–10% and 2–5%, respectively.¹⁴ Moreover, the beneficial effects of ALA on cardiovascular diseases is yet to be defined. Thus, ALA should not be used as a substitute for EPA and DHA when treating hypertriglyceridemia.¹⁵

Lovaza^®, prescription omega-3 FA (P-OM3) is a combination of highly concentrated purified ethyl esters of omega-3 FA, principally EPA and DHA, that is Food and Drug Administration (FDA) approved for treatment of hypertriglyceridemia (>500 mg/dL) as an adjunct to diet.²² The daily dose is 4 grams/day taken as a single 4-gram dose or as two 2-gram doses. Each 1-gram capsule provides 465 mg of EPA and 375 mg of DHA. Randomized clinical trials of P-OM3 have demonstrated reductions in serum triglycerides up to 45% at the FDA-approved dose.

As mentioned above, fish oil or omega-3 FA is now the top dietary supplement among those people who use multiple dietary supplements. There are also many different herbal supplements that are labeled to contain omega-3 FA, EPA and DHA, or fish oil, but there is a controversy regarding the validity of the claimed label in terms of the amount of EPA and DHA because these products are not regulated by the FDA with the same standards as prescription drug products. The amount of EPA and DHA in a 1-gram capsule of fish oil supplements can vary widely¹⁵ from product to product. This variation ultimately impacts the total number of capsules that must be taken daily to obtain sufficient amounts of EPA and DHA for the treatment of hypertriglyceridemia as well as the total daily cost to the consumer. Lower-potency products necessitate higher capsule burden, which could affect adherence²³ as well as the incidence of side effects. In addition, higher capsule burden results in enhanced calories and fat intake, and some products also contain fat-soluble vitamins, which raises another concern. If the consumer is not educated about the amount of EPA and DHA in each gram of fish oil, this might result in suboptimal triglyceride lowering. Also, the existence of environmental contaminants such as dioxins, polychlorinated biphenyls, and methyl mercury in the fish oil supplements can offset the benefits from taking fish oil supplements.

Currently, many health-care organizations and third-party payers have limited Lovaza^® to their nonformulary list of medications, and the rationale that they use for prescribers is that many herbal supplement fish oil products exist at a lower costs. Unfortunately, the information that is offered to prescribers and patients is often incomplete as to which product(s) the Formulary Committee are recommending and the number of capsules that should be taken based on the labeled content of EPA and DHA.²⁴

The purpose of this review was to conduct a search of dietary fish oil supplements and develop a reference for clinicians to compare different products in terms of EPA- and DHA-labeled content, to determine the daily doses of each product needed to achieve the FDA-approved dose (3,360 mg) of combined EPA and DHA in P-OM3, and to calculate the consequential monthly cost, saturated fat, cholesterol, and vitamin intake at this daily dose.

Methodology

Identification of products

The United States National Library of Medicine Dietary Supplements Labels Database (USNLADSLD)²⁵ was used to search for information about labeled ingredients of fish oil and or omega-3 FA dietary supplements. This database contains information on the ingredients of over 4,000 dietary supplement products sold in the United States. The database can be searched by brand name, uses noted on product label, specific active ingredients, and the manufacturer. Data were extracted between October 18, 2009, and January 15, 2010, using the following search terms: Fish oil, omega-3 FA, omega, EPA, DHA, eicosapentaenoic acid, and docosahexaenoic acid. The data that were collected and summarized include: Manufacturer/distributer, product name, dosage form, serving size, calories, saturated fat, cholesterol, EPA, DHA, and vitamins A, C, D, and E per serving. Only products containing both EPA and DHA were evaluated. To reduce the potential for bias, we excluded products likely not intended for the treatment of hypertriglyceridemia by limiting products to those with EPA, DHA, fish oil, omega-3 FA, omega, cardio, or krill oil as part of the product name on the label.

Data extraction and analysis

Products were stratified and evaluated on the basis of the dosage formulation (liquid vs. nonliquid). The amount in milligrams of EPA and DHA in each product was used to calculate the serving size per day that would be needed to achieve approximately 3,360 mg of omega-3 FA, which is the FDA-approved dose (RxDose) of prescription grade omega-3 FA ester for the treatment of high serum triglyceride levels. The suggested retail price per day for each product was obtained from websites of the individual manufacture or the supplier website and was used to calculate the monthly cost for each product at the RxDose. Calories, saturated fat, cholesterol, and vitamins D, E, C, and A were evaluated on the basis of the daily dosage of each product to achieve the RxDose of combined EPA and DHA. The ratio of DHA/EPA was also summarized for each product. The products that were United States Pharmacopeia (USP) verified were identified using the USP website.²⁶ Any USP-verified products can claim that what is on the label is in fact in the bottle with all the listed ingredients in the declared amount, the supplement does not contain harmful levels of contaminants, the supplement will break down and release ingredients in the body, and the supplement has been made under good manufacturing practices.

A predefined “usage criteria” was set to highlight products at the RxDose with a monthly cost of <$50, number of daily servings <8 (twice the capsule burden of P-OM3), and daily amount of vitamin A and D less than or equal to the United States Dietary Reference Intake upper limit (USDRIUL) defined as 10,000 and 4,000 IU, respectively.²⁷ We assumed the product did not contain vitamin A or D if it was not indicated on the product label. The monthly cost of $50 was selected because it appears to be within the middle of the range for third-tier co-payments for cardiovascular medication by several major Pharmacy Benefit Manager^28,29 and Preferred Provider Organizations.³⁰ The number of daily servings was <8 because studies have documented a reduction in medication adherence with an increase in pill burden.³¹ Vitamins A and D were included in the usage criteria because these two vitamins are the vitamins for which there is the greatest likelihood of exceeding the USDRIUL. Finally, we defined a second tier “usage criteria” for products that were USP verified.

Statistical analysis

Descriptive statistics were performed using SigmaPlot (Systat Software, Inc, San Jose, CA) for Windows version 11.2. Medians [25%–75% percentile] were reported for values not considered normally distributed. All other values are reported as mean±standard deviation (SD).

Results

A total of 163 products were identified using the predefined search terms. Of these, 124 products contained both DHA and EPA that were than stratified to liquid (n=14) and nonliquid (n=110) products (consisting of softgels, powder packets, and gummy bears dosage forms). Three nonliquid products were earlier versions of an existing product and were excluded from analysis, thus leaving 107 products. Finally, one liquid product and 19 nonliquid products were excluded from analysis because the product label did not include EPA, DHA, fish oil, omega-3 FA, omega, cardio, or krill oil, leaving a final sample size of 13 liquid and 88 nonliquid products.

Each product, manufacturer, bottle size (milliliters or number of doses), suggested retail price, recommended serving size, amount of EPA and DHA in milligram per serving size, the calculated number of teaspoons or doses needed to equal the RxDose, the calculated monthly cost, calories per day, saturated fats per day, cholesterol per day, vitamins D and A per day at the RxDose, and USP verification are listed in Table 1 (nonliquid) and Table 2 (liquid). The products that met the predefined “usage criteria” are shaded. Only 16% (14 of 88) of the nonliquid products met our “usage criteria,” and none of the products was USP verified. Sixty three percent (5 of 8) of the nonliquid products with reported amounts of vitamins contained greater than or equal to the USDRIUL of vitamin A or D at the RxDose. Sixty nine percent (9 of 13) of the liquid products met our “usage criteria,” and none of these products was USP verified. Thirty three percent (2 of 6) of the liquid products with reported amount of vitamins contained greater than or equal to the USDRIUL of vitamin A or D at the RxDose. Only one of 101 products included in this review was USP verified.

Table 1.

Content and Cost of Nonliquid Formulations of Omega-3 Fatty Acid Dietary Supplements

Manufacturer and product ^a	Bottle size (#)	SRP ($)	Serving size (#)	EPA (mg)	DHA (mg)	Number of servings needed to equal 3,360 mg EPA and DHA (#)	Monthly costs at a serving needed to equal 3,360 mg EPA and DHA ($)	Calories per day at a serving needed to equal 3,360 mg EPA and DHA (C)	Saturated fats per day at a serving needed to equal 3,360 mg EPA and DHA (g)	Cholesterol per day at a serving needed to equal 3,360 mg EPA and DHA (mg)	Vitamin D at a serving needed to equal 3,360 mg EPA and DHA (IU)	Vitamin A at a serving needed to equal 3,360 mg EPA and DHA (IU)	USP-verified dietary supplements
Schiff Products, Inc. Schiff Omega 3 Fish Oil	100	16.69	1 soft gel	18	12	112	561	1,120					No
Cromega Corp.Coromega Child Brain and Body High Omega and DHA Lemon Lime squeezers	60	39.99	1 packet	36	200	14	285	285	0	142			No
Nordic Naturals, Inc.Nordic Naturals Omega Woman, Lemon, 500 mg	120	24.99	2 soft gels	36	24	112	700	1,008					No
Inverness Medical Innovations, Inc.Inverness Protegra Cardio Formula			1 soft gel	45	30	45						224,000	No
Schiff Products, Inc.Schiff MegaRed Omega 3 Krill Oil, 300 mg	60	29.99	1 soft gel	45	27	47	700						No
Nature SunshineNatures Sunshine DHA Softgel Capsules	60	26.95	1 capsule	50	250	11	151						No
New ChapterNew Chapter Supercritical DHA 100	60	31.95	1 soft gel	50	150	17	268						No
Neutraceutical CorporationsKal Ultra Omega 3 6 9	100	12.65	1 soft gel	72	48	28	106	420					No
TwinLab CorporationsTwinlab Krill Essentials Cardio Krill Oil	60	39.99	1 soft gel	75	45	28	560	140				1,400	No
Naturals Factors Nutritional Products Inc.Natural Factors Wild Alaskan Salmon Oil 1000 mg	180	19.95	1 capsule	80	70	22	75	224		224			No
Puritans PridePuritans Pride Salmon Oil	200	5.99	2 soft gels	80	120	34	30	336		336			No
Puritans PridePuritans Pride Cholest Wise	120	39.49	2 soft gels	90	60	45	442	448					No
Vitamin World, Inc.Vitamin World Cholest Solutions, Softgels	120	39.99	2 soft gels	90	60	45	448	448					No
Pharmavite,LLCOlay Essential Balanced Omega 3/6			1 soft gel	93.6	187.2	12		60					No
GNC, Inc.GNC DHA 250 mg	60	10.99	1 soft gel	100	250	10	53						No
Natural Organics, Inc.Natures Plus Animal Parade Omega 3 6 9 Junior Softgels	90	17.12	2 soft gels	100	200	22	128	224	0				No
Nature Bounty, Inc.Nature Bounty Cod Liver Oil	100		1 soft gel	110	100	16		160		80	3,200	42,624	No
Nature Bounty, Inc.Nature's Bounty Fish Flax & Borage Oil 1200 mg			1 soft gel	120	80	17		168					No
Radiance VitaminsRadiance Flax, Fish & Borage Oils			1 soft gel	120	80	17		168					No
Natrol, Inc.Natrol Omega 3-6-9 Lemon Flavor	60	8.59	1 soft gel	135	85	15	66	229	0	153			No
Pure Prescriptions Inc.Pure Prescriptions Pure NKO	60	50.00	2 soft gels	150	90	28	700					2,800	No
American Health Inc.American Health Salmon Oil-1000 MG	120	10.49	2 soft gels	160	240	17	44	336	8.4				No
Nature Bounty, Inc.Nature's Bounty Salmon Oil 1000 mg Softgels			2 soft gels	160	240	17		336	8.4				No
Radiance VitaminsRadiance Salmon Oil 1000 mg			2 soft gels	160	240	17		336	8.4	168			No
GNC, Inc.GNC Cod Liver Oil-01/28/2008			1 soft gel	173	120	12		115			1,548	14,335	No
GNC, Inc.GNC Triple Cod Liver Oil	90	9.25	1 soft gel	173	120	12	36	115			1,548	14,335	No
21st Century Health Care, Inc.21st Century fish oil 1000 mg Omega 3	300	16.49	1 soft gel	180	120	11	19	112	0				No
American Health Inc.American Health Cardio Smart	60	26.29	2 soft gels	180	120	22	294	224					No
American NutritionAN MaxEPA Omega 3- 1000 mg	200	24.95	1 soft gel	180	120	11	42	112	5.6	112			No
GNC, Inc.GNC Salmon Oil 1000	180	13.39	1 soft gel	180	120	11	25	112			1,512	14,000	No
Life Enhancements Products, Inc.Life Enhancements Omega-3 HeartFelt	180	17.85	1 capsule	180	120	11	33	101					No
Natrol, Inc.Natrol Omega 3 Fish Oil 1200 mg	60	8.49	1 soft gel	180	120	11	48	168	0	112			No
Nature Bounty, Inc.Nature's Bounty Fish Oil 1000 mg	110	8.00	1 soft gel	180	120	11	24	112		0			No
Nordic Naturals, Inc.Nordic Naturals Cod Liver Oil Softgels, Lemon, 1000 mg	90	21.95	2 softgels	180	280	15	107	263	5.8	73	29	5,113	No
NutraSanusNutraSanus Omega 3 1000 mg	60	9.95	1 capsule	180	120	11	56	112	11.2				No
Physicians FormulasPhysician Formulas Wild Fish Oil, 1000 mg	120	26.95	1 capsule	180	120	11	76						No
Puritans PridePuritans Pride Fish Oil 1000 mg	200	21.95	1 soft gel	180	120	11	37	112		0			No
Puritans PridePuritans Pride Heart Assure			2 soft gels	180	120	22		224					No
Puritans PridePuritans Pride Heart Essentials			2 soft gels	180	120	22		224					No
Radiance VitaminsRadiance Distilled EPA, Natural Fish Oil			1 soft gel	180	120	11		112		0			No
Rexall Sundown, Inc.Sundown Fish Oil 1000 MG			1 soft gel	180	120	11		112		0			No
Enzymatic Therapy, Inc.Enzymatic Therapy Eskimo-3 Fish Oil	105	21.50	3 soft gels	210	130	30	182	445	14.8	148			No
Nature Bounty, Inc.Nature's Bounty Cholesterol-free Fish Oil 1200 mg Softgels			1 soft gel	216	144	9		93	0				No
Radiance VitaminsRadiance Cholesterol Free Fish Oil 1200 mg			1 soft gel	216	144	9		93		0			No
Radiance VitaminsRadiance Fish Oil 1200 mg			1 soft gel	216	144	9		93		0			No
TwinLab CorporationsTwinLab Omega-3 Fish Oil	100	19.95	1 soft gel	234	156	9	52	129	4.3	43			No
Design for HealthDesign For Health Omega Synergy			2 soft gels	240	160	17		420	16.8				No
Costco Wholesale Corporations (CWC), Inc.Kirkland Fish Oil Concentrate Extra Strength	180	17.95	1 soft gel	240	200	8	23	76	3.8	0			No
Costco Wholesale Corporations (CWC), Inc.Kirkland Signature Enteric Coated Fish Oil Concentrate	200	21.95	1 soft gel	240	200	8	25	76	3.8	0			No
Nordic Naturals, Inc.Nordic Naturals Complete Omega	180	47.95	2 soft gels	270	180	15	119						No
TwinLab CorporationsTwinLab Dr. Greene Omega-3 Fish Oil	100	19.95	1 soft gel	270	180	8	45	75	0				No
Natrol, Inc.Natrol Cardio Omega Solutions	60	12.78	2 soft gels	290	210	13	86						No
Bronson LaboratoriesBronson Laboratories Super EPA 500	100	15.98	1 soft gel	300	200	7	32	67	0				No
J.R. Carlson LaboratoriesCarlson Super Omega 3 Fish Oil 1000 MG	250	57.90	1 soft gel	300	200	7	47	60					No
Natrol, Inc.Natrol Omega-3 Glucosamine	90	26.99	3 soft gels	300	200	20	181	302					No
PharmanexPharmanex Optimum Omega	60	12.50	2 soft gels	300	200	13	84						No
Puritans PridePuritans Pride Super Omega-3 1000 mg	250	18.99	1 soft gel	300	200	7	15	67		0			No
Vitamin ShoppeVitamin Shoppe EPA DHA Omega 3 Fish Oil-01/25/2008	300	40.99	1 soft gel	300	200	7	28	67					No
Vitamin World, Inc.Vitamin World Super EPA Fish Oil, Softgels			1 soft gel	300	200	7		67	0	0			No
Natrol, Inc.Natrol Extreme Omega Lemon Flavor	60	16.49	1 soft gel	323	215	6	52	94	0	31			No
Nordic Naturals, Inc.Nordic Naturals Omega 3, 1000 mg	60	15.26	2 soft gels	330	220	12	93	220	7.3				No
Weil Nutritional SupplementWeil Cardio Support Formula	30	18.19	1 soft gel	333	167	7	122						No
Weil Nutritional SupplementWeil Omega 3 Complex	90	17.50	1 soft gel	333	167	7	39						No
Cromega Corp.Cromega Omega 3 Dietary Supplement, Orange Flavor packet	30	21.99	1 packet	350	230	6	127	116	2.9	46			No
Cromega Corp.Cromega Omega 3 Dietary Supplement, Orange Flavor with a hint of chocolate	90	44.99	1 packet	350	250	6	84	112	2.8	45			No
Natrol, Inc.Natrol Omega-3	60	4.78	2 soft gels	360	240	11	27	224					No
Nature Made Nutritional ProductsNature Made Omega 3 Fish Oil 1200 MG	100	10.49	2 soft gels	360	288	10	33	259	10.4	259			Yes
Puritans PridePuritans Pride Triple Omega 3-6-9	60	13.39	3 soft gels	360	240	17	113	504					No
Rexall Sundown, Inc.Sundown Cholesterol Free Fish Oil 1000 mg			2 soft gels	360	240	11		224	5.6	0			No
TwinLab CorporationsTwinLab Complete EFA Omega	90	21.99	3 soft gels	360	240	17	123	672	0				No
Vitamin World, Inc.Vitamin World Triple Omega 3-6-9	240	41.99	3 soft gels	360	240	17	88	588					No
Barlean's Organic OilBarlean's Total Omega 3-6-9 Softgels	180	29.71	3 soft gels	390	200	17	85	513	4.4	85			No
Naturals Factors Nutritional Products Inc.Natural Factors Rx Omega-3 Factors	120	16.70	1 soft gel	400	200	6	23	56	0				No
Naturals Factors Nutritional Products Inc.Natural Factors RxOmega-3 Factors Fish & Flax Oil	120	19.95	2 soft gels	400	200	11	56	224					No
Nature Made Nutritional ProductsNature Made Fish Oil	180	14.99	2 soft gels	432	280	9	24	236					No
Nature Bounty, Inc.Nature's Bounty Odorless Fish Oil 1200 mg	60	7.98	2 soft gels	432	288	9	37	233		140			No
American NutritionSource Naturals ArcticPure Ultra Potency Omega 3 Fish Oil	60	19.50	1 soft gel	450	340	4	42	43	0	64			No
Nordic Naturals, Inc.Nordic Naturals Omega Blood Sugar	60	21.21	2 soft gels	455	315	9	93						No
Now FoodsNow Foods Ultra Omega 3	180	39.99	1 soft gel	500	250	5	30	45	2.2	0			No
Shaklee CorporationShaklee Omega Guard	90	30.55	3 soft gels	545	360	11	113	223	0	0			No
TwinLab CorporationsTwinLab Mega Twin EPA Fish Oil	60	27.95	1 soft gel	550	215	4	61	44		53			No
GNC, Inc.GNC Triple Strength Fish Oil	120	38.99	1 soft gel	647	253	4	36	56					No
Nordic Naturals, Inc.Nordic Naturals Ultimate Omega, Lemon Taste	120	49.95	2 soft gels	650	450	6	76						No
Nature Made Nutritional Products, Nature Made Double Strength Fish Oil 1200 mg, premium softgels	100	11.99	2 soft gels	672	552	6	20	137		28			No
AmeriSciences, LP.AmeriSciences Omega Max	60	32.97	2 soft gels	720	480	6	92	112					No
Clinician's Choice, Inc.Clinicians Choice Premium Omega 3	60	28.00	1 soft gel	800	400	3	39	56					No
Neutraceutical Science Institute (NSI)NSI 42 Mega EFA Omega 3 EPA and DHA	240	79.99	2 soft gels	800	400	6	56	140	0				No
Nordic Naturals, Inc.Nordic Naturals EPA Lemon, 1000 mg	120	49.95	2 soft gels	900	200	6	76	110	1.2				No

Products are sorted from low to high EPA content. Shading indicates product meets predefined “usage criteria.”

SRP, suggested retail price; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; USP, United States Pharmacopeia.

Table 2.

Content and Cost of Liquid Formulations of Omega-3 Fatty Acid Dietary Supplements

Manufacturer and product	Bottle size (mL)	SRP ($)	Serving size (teaspoon)	EPA ^a (mg)	DHA (mg)	Number of teaspoons needed to equal 3,360 mg EPA and DHA (#)	Monthly costs at a serving needed to equal 3,360 mg EPA and DHA ($)	Calories per day to equal 3,360 mg EPA and DHA (C)	Saturated fats per day at a serving needed to equal 3,360 mg EPA and DHA (g)	Cholesterol per day at a serving needed to equal 3,360 mg EPA and DHA (mg)	Vitamin D at a serving needed to equal 3,360 mg EPA and DHA (IU)	Vitamin A at a serving needed to equal 3,360 mg EPA and DHA (IU)	USP-verified dietary supplements
Nordic Naturals, Inc.Nordic Naturals Children's DHA Liquid	120	15.95	½	205	313	3.24	25.86	149	3				No
American NutritionSource Naturals Arctic Pure Attentive Child DHA	200	23.98	½	212	370	2.89	20.77	115	3	58			No
Design for HealthDesigns For Health Genuine Norwegian Cod Liver Oil (7 oz)	210	20.00	1	330	460	4.25	12.15					2127	No
J.R. Carlson LaboratoriesCarlson Kids Very FinestFish Oil-Lemon (6 oz)	180	24.90	½	400	250	2.58	21.45	103	3	39			No
Nordic Naturals, Inc.Nordic Naturals Arctic Cod Liver Oil, Orange Liquid	240	42.95	1	450	700	2.92	15.69	131	3	41	15	2557	No
Nordic Naturals, Inc.Nordic Naturals Arctic Cod Liver Oil, Peach Liquid	240	42.95	1	450	700	2.92	15.69	131	3	41	15	2557	No
GNC, Inc.GNC Liquid Norwegian Cod Liver Oil-01/28/2008 (473 ml)	473	14.99	1	460	377	4.01	3.82	161	4	120	1847	18466	No
TwinLab CorporationsTwinLab Emulsified Norweigian Cod Liver Oil Mint Flavor 12 Fl oz.	360	14.58	3	516	344	35.16	14.24	703	12	234	15120	151305	No
TwinLab CorporationsTwinLab Cod Liver Oil, Cherry	390	10.99	1	554	369	3.64	3.08	146	4	91	1682	16800	No
Enzymatic Therapy, Inc.Enzymatic Therapy liquid Eskimo-3 Fish Oil (3.5 oz)	105	21.50	1	645	400	3.22	19.75	129	5	64			No
Now FoodsNow Foods Omega-3 Fish Oil, Lemon	200	16.99	1	740	475	2.77	7.05	111	3	41			No
Natures AnswerNature Answer Liquid Omega 3	480		1	800	500	2.58		116	4	52			No
TwinLab CorporationsTwinLab Emulsified Super Max EPA 12 FL OZ.	360	22.49	6	2028	1352	5.96	3.73	298	6				No

Products are sorted from low to high EPA content. Shading indicates product meets predefined “usage criteria.”

SRP, suggested retail price. EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; USP, United States Pharmacopeia.

The mean±SD or medians [25%–75% percentile] for the serving size of the products, amount of EPA and DHA per serving, ratio of DHA to EPA, the RxDose, suggested retail price, monthly costs at the RxDose, and calories, saturated fats, cholesterol, and vitamin content per RxDose are listed in Tables 3 and 4 for liquid and nonliquid formulations, respectively. The median amount of EPA and DHA per serving in the nonliquid products was 216 mg and 200 mg, respectively. Thus, the median number of servings needed to achieve the RxDose was 11.2, and the corresponding median monthly cost at this dose was $63.49. At the RxDose, the median additional cholesterol and calories that would be consumed per day was 45 mg and 140, respectively. A limited number of product labels listed the vitamin content, and these amounts were highly variable between products. The mean±SD amount of vitamin D was 1,568±1,122 IU and the median (25%–75% percentile) amount of vitamin A was 14,167 IU (3,957–28,479) at the RxDose, respectively. The median amounts of EPA (460 mg) and DHA (400 mg) per serving in the liquid products were numerically higher than the nonliquid products. Thus, the median number of servings needed of the nonliquid products to obtain the RxDose was only 3.6 teaspoons, and the corresponding median monthly cost at this dose was only $13.60. At the RxDose, the median additional cholesterol (55 mg) and calories (132) that would be consumed per day were numerically similar to the nonliquid formulations. The median vitamins A and D content at the RxDose was below the USDRIUL. The median ratio of DHA/EPA for liquid and nonliquid formulations was 0.67 (0.81 for P-OM3).

Table 3.

Summary of Nonliquid Dosage Forms of Omega-3 Fatty Acid Dietary Supplements

Variable	N^a	Mean±SD or median (25%–75% percentile)
Serving size of products	88	1.0 (1.0–2.0)
Number of serving needed to equal 3,360 mg EPA and DHA	88	11.2 (7.6–16.8)
Suggested retail price ($)	70	20.58 (14.99–30.55)
Monthly costs at a serving needed to equal 3,360 mg EPA and DHA ($)	70	63.49 (36.39–119.43)
Calories per serving	74	10.0 (10.0–20.0)
Calories per day at a serving needed to equal 3,360 mg EPA and DHA	74	140.0 (93.7–264.0)
Saturated fats per serving size (g)	34	0.3 (0–0.5)
Saturated fats at a serving needed to equal 3,360 mg EPA and DHA (g)	34	2.5 (0–5.8)
Cholesterol per serving size (mg)	33	5.0 (0–10.0)
Cholesterol at a serving needed to equal 3,360 mg EPA and DHA (mg)	33	44.8 (0–119.0)
Vitamin D per serving size (IU)	5	121.4±72.4
Vitamin D at a serving needed to equal 3,360 mg EPA and DHA (IU)	5	1,567.5±1,122.0
Vitamin E per serving size (IU)	40	7.5 (1.6–26.0)
Vitamin E at a serving needed to equal 3,360 mg EPA and DHA (IU)	40	83.7 (15.4–257.0)
Vitamin C per serving size (mg)	4	12.0 (11.8–131.0)
Vitamin C at a serving needed to equal 3,360 mg EPA and DHA (mg)	4	117.3 (68.4–5,682.6)
Vitamin A per serving size (IU)	8	1,250.0 (225.0–1,957.0)
Vitamin A at a serving needed to equal 3,360 mg EPA and DHA (IU)	8	14,167.2 (3,956.5–28,479.2)
EPA content per serving size (mg)	88	216.0 (160.0–360.0)
DHA content per serving size (mg)	88	200.0 (120.0–240.0)
DHA/EPA	88	0.67 (0.67–0.69)

Combined milligrams of EPA and DHA per dosage unit ranged from 30 mg to 1,200 mg.

Sample size varies due to differences in product content or the suggested retail price was not available.

SD, standard deviation; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid.

Table 4.

Summary of Liquid Dosage Forms of Omega-3 Fatty Acid Dietary Supplements

Variable	N^a	Mean±SD or median (25%–75% percentile)
Serving size of products (teaspoon)	13	1.0 (1–1)
Number of serving (teaspoons) needed to equal 3,360 mg EPA and DHA	13	3.6 (2.9–5.3)
Suggested retail price ($)	12	20.75 (15.47–24.44)
Monthly costs at a serving needed to equal 3,360 mg EPA and DHA ($)	12	13.60±7.74
Calories per Serving	12	40.0 (31.5–45.0)
Calories per day at a serving needed to equal 3,360 mg EPA and DHA	12	131.5 (115.9–154.9)
Saturated fats per serving size (g)	12	1.0 (0.8–1.3)
Saturated fats at a serving needed to equal 3,360 mg EPA and DHA (g)	12	3.4 (2.9–4.4)
Cholesterol per serving size (mg)	10	17.55±6.82
Cholesterol at a serving needed to equal 3,360 mg EPA and DHA (mg)	10	54.7 (40.9–91.0)
Vitamin D per serving size (IU)	5	430.0 (5.0–460.5)
Vitamin D at a serving needed to equal 3,360 mg EPA and DHA (IU)	5	1,681.8 (14.6–5,164.9)
Vitamin E per serving size (IU)	2	8.0 (8.0–8.0)
Vitamin E at a serving needed to equal 3,360 mg EPA and DHA (IU)	2	23.4 (23.4–23.4)
Vitamin C per serving size (mg)	1	100 (100–100)
Vitamin C at a serving needed to equal 3,360 mg EPA and DHA (mg)	1	425.3 (425.3–425.3)
Vitamin A per serving size (IU)	6	2,589.0 (875.0–4,600.0)
Vitamin A at a serving needed to equal 3,360 mg EPA and DHA (IU)	6	9,678.3 (2,556.5–18,466.0)
EPA content per serving size (mg)	13	460.0 (382.5–668.8)
DHA content per serving size (mg)	13	400.0 (362.8–550.0)
DHA/EPA	13	0.67 (0.63–1.54)

Sample size varies due to differences in product content or the suggested retail price was not available.

SD, standard deviation; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid.

Discussion

On June 25, 2007, the FDA published dietary supplement Current Good Manufacturing Practices (cGMP), which require that proper controls be in place by dietary supplement companies to ensure products are manufactured and processed in a consistent manner and produce high-quality products that are not adulterated with impurities or contaminants (such as natural toxins, heavy metals, glass, microbes, and pesticides) and that they are accurately labeled. Other major requirements are that these companies provide a phone number on the product label for consumers to call to report adverse events and complaints and that each company maintain records of these reports for 6 years and contact the FDA through MedWatch within 15 days of any serious adverse effects that are reported. In an effort to limit any disruption for dietary supplements produced by small companies, the FDA staggered these rules with a 3-year phase-in for small companies. The final cGMP was effective in June, 2008, for large companies; the cGMP for companies with less than 500 employees was effective in June, 2009, and these regulation became effective June, 2010, for companies with fewer than 20 employees.³² These updated FDA regulations should add an additional level of confidence for the consumer and practitioners. However, the assumption is that the FDA has the appropriate resources to enforce these regulations. In addition, dietary supplement products are not reviewed by the FDA before they are marketed, unlike prescription medications. The FDA is responsible to take action against any unsafe dietary supplement product that is marketed or product claims are false and misleading.³³

The benefit of omega-3-FA in regard to treatment of high triglycerides is well documented.³⁴ On the basis of the AHA, the recommended dose of combined EPA and DHA for hypertriglyceridemia is 2–4 grams and should be used under a physician's care to monitor for safety and efficacy. Currently, Lovaza^® is the only FDA-approved P-OM3 product for treating hypertriglyceridemia. Although we do not routinely advocate this, dietary fish oil supplements are commonly recommended as an alternative to P-OM3 for treatment of hypertriglyceridemia.¹⁵ In situations where P-OM3 is not an option for patients with hypertriglyceridemia, products such as those meeting our “usage criteria” could be recommended.

This is the first review of omega-3-FA dietary supplements that includes a breakdown of the product content on the basis of the product label, calculations of the daily dose of each product needed to achieve the RxDose of P-OM3 FA, the consequential monthly cost, and saturated fat, cholesterol, and vitamin intake at this daily dose. This review was conducted to provide a resource for clinicians when selecting dietary supplements of omega-3 FA as a substitute for P-OM3. The data in this review will help the patient select the most appropriate product and dose. Our review assumes that the manufacturers are in compliance with FDA cGMP regulations and that the labeled contents are accurate.

We found that there is a wide variation of EPA and DHA content, cost, type of dosage formulations, vitamin content, cholesterol, and other fats in these herbal supplement products. The EPA and DHA per serving size ranged from 18 mg and 12 mg, respectively, up to 900 mg of EPA and 552 mg of DHA per serving size for the nonliquid supplements. Thus, the number of servings needed per day to achieve the RxDose would range from as little as three and up to 112 and the consequential monthly cost ranged from $15 to $700. This provides a challenge for the untrained consumer and potential barriers to adequate lipid reductions and adherence to therapy. Adherence to treatment is the most important key of success of any drug therapy. The number of tablets and the cost of medication may be the top two concerns of patients. Increase in number of pills is highly associated with low adherence, and low adherence is associated with a broad range of adverse outcomes.^35,36 Because the median amounts of EPA and DHA per recommended serving of the liquid formulations were higher than the nonliquid formulation, the median number of servings to reach the RxDose was only 3.6 teaspoons. Therefore, the median cost per month at the RxDose was less that the nonliquid formulations. However, oxidation of the fatty acids (reduce shelf-life) could be more of an issue with the liquid formulations, unless the manufacturer has taken appropriate measures to reduce this. Also dysgeusia (distortion of the sense of taste) and “fish burp” are more common with liquid products.

This review provides practitioners with a reference for various products that have met our predefined “usage criteria” with a monthly cost of <$50, number of daily servings <8, and daily amount of vitamins A and D greater than or equal to the USDRIUL defined as 10,000 and 4,000 IU, respectively. Fourteen of the nonliquid products and nine of the liquid products met these criteria. However, none of these products was verified by the USP.

Several of the products included in this review indicated their vitamin content. The median (14,167 IU) amount of vitamin A that would be consumed per day at the RxDose of the nonliquid formulations exceeded the USDRIUL. Five of the eight nonliquid products and two of the six liquid products that listed their vitamin A content would exceed 10,000 IU daily if consumed at the RxDose for the treatment of hypertriglyceridemia. This should be an important factor when selecting one of these products.

Our review has several limitations. Only omega-3 FA or fish oil supplements within the USNLADSLD were included. This potentially would exclude other available products, but using a single database does allow our findings to be reproduced. Also more products may have been registered or updated since January 15^th, 2010, the last day at which these data were uploaded. We used the manufacturer's suggested retail price when calculating the consequential monthly cost of each product. The actual cost consumers pay for these products could be considerably lower. Also, the suggested retail price was not available for some products, which excluded them from evaluation based on our “usage criteria.” Finally, the accuracy of the label content within each product is solely dependent on the manufacturer.

Conclusion

The amount of EPA and DHA per recommended serving in the products reviewed in this study was highly variable. Thus, products with lower content require larger daily doses, which may impact monthly cost, fat-soluble vitamin intake, calories, fat, and cholesterol intake, and possibly an increase intake of environmental contaminants. Only one of 101 of evaluated products in this review was USP verified. These considerations should compel both clinicians and patients to heighten their scrutiny in terms of selection of the appropriate product.

Author Disclosure Statement

No competing financial interests exist.

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