Omega 3 studies Report

[Guest guest]

Dr Lee Hooper's meta-analysis of omega-3 studies published in the

British Medical Journal in late March caused headlines around the

world that have frightened many people away from these critically

important essential fatty acids. ANH now provides its rebuttal. We

provide, for your information, our full press release issued today.

We encourage you to disseminate this information to all of your

contacts who may be concerned about this issue.

You can link to the full article at the following URL:

http://www.alliance-natural-health.org/_docs/ANHwebsiteDoc_231.pdf

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ANH Press Release

19 April 2006

META-ANALYSIS: a new tool to discredit natural health supplements?

By Dr Verkerk, Executive & Scientific Director, Alliance for

Natural Health

On 24 March 2006, The British Medical Journal' published a meta-

analysis (a study of other studies) on omega-3 fatty acids [1] that

prompted headlines around the world to the effect that " fish oils

don't work " . This is not the first time a meta-analysis has

triggered headlines that discredit natural health supplements.

The vitamin E meta-analysis of 2004

In November 2004, Dr Edgar and colleagues published

electronically in the ls of Internal Medicine a meta-analysis

[2] that provided headlines as bizarre as " High dose vitamin E death

warning " (this headline was run by none other than the BBC on 11

November 2004). The meta-analysis appeared to be pitched to tarnish

the reputation of vitamin E, a nutrient in which many are known to

be deficient. Among many of its problems, the study failed to show

how healthy people would respond to supplemental intakes of vitamin

E and it only included studies on synthetic vitamin E (dl-alpha-

tocopherol). It therefore omitted any consideration of the effects

of the seven other related compounds that make-up full spectrum,

natural vitamin E, as found in vegetable oils. Interestingly, the

body's absorption of the most important dietary form (gamma-

tocopherol) is hindered by high doses of synthetic vitamin E, and

this could have explained the negative results found by et

al.

The overall conclusion that high-dose vitamin E causes increased

mortality could also have been a statistical artefact, with no

biological relevance. Since the study assessed all-cause mortality,

and not just cardiovascular mortality, other factors could easily

have contributed to the greater death rate in the higher dose

vitamin E group found when trials were pooled. It should be noted

that the increased death rate was marginal; just 63 additional

deaths per 10,000 persons, compared with the control group. Given

that the confidence interval ranged from 6 to 119, this increased

death rate cannot be said to be statistically significant.

Prior to this meta-analysis on vitamin E, market research data from

Frost & Sullivan showed that vitamin E was the second most consumed

single vitamin supplement, after vitamin C, in Europe. High-dose

Vitamin E could have easily been perceived by Big Pharma as a threat

to its huge cardiovascular drug market, comprised of statins, beta-

blockers and ACE-inhibitors. In fact, Big Pharma had demonstrated

such a strong interest in vitamins that it established an illegal

cartel to control the markets and prices of a range of key vitamins,

including vitamin E. Fortunately for the consumer, the conspiracy

was eventually exposed and pharma companies like BASF and Hoffman-La

Roche, as well as some of their top executives, got busted. Fines

imposed by the US Justice Department in the US (May 1999) and,

separately, by the European Commission (November 2001), which

amounted to hundreds of millions of dollars in the US and similar

amounts in Europe, are still among the largest ever imposed

following an anti-trust investigation. Undeterred by this

prosecution, Big Pharma continued its campaign against supplements,

with the meta-analysis on vitamin E appearing in the peer-reviewed

journal ls of Internal Medicine just three years later.

The antioxidant vitamin meta-analysis of 2003

A year earlier, in June 2003, another meta-analysis appeared. This

one was published in the prestigious medical journal, the Lancet, by

Dr Marc Penn and colleagues from the Cleveland Clinic [3]. These

authors asserted that beta-carotene, vitamin A and other antioxidant

vitamins such as vitamin E, were harmful. These authors re-iterated

yet again negative results from a very small clutch of studies on

synthetic vitamins like synthetic beta-carotene and vitamin E, which

were once more administered to diseased or high risk subjects, and

often for inadequate periods of time.

Following the publication of the meta-analysis, the lead author was

quoted in the media saying that people should stop taking

supplements containing vitamins A, beta-carotene and E. These

conclusions, some of which were carried over into the vitamin E meta-

analysis the following year, are profound misinterpretations of the

existing evidence base, and most certainly cannot be applied to the

role of these vitamins in reducing risks of chronic diseases such as

cancer and cardiovascular disease in healthy people. Nor can these

conclusions be applied to supplements containing natural forms of

these vitamins.

Back to the omega-3 meta-analysis of 2006

Last month's attack on fish oils prompted by the meta-analysis by Dr

Lee Hooper and his colleagues, as published in the BMJ, must surely

be seen in the same light as the two meta-analyses discussed above.

Put bluntly, the meta-analysis appears to be, once more, a vehicle

to generate negative headlines. In fairness, even the authors have

now conceded that they were " misquoted in much of the press. " [4]

The scientific evidence for long chain omega-3 benefits on lowering

triglycerides and other risk factors in heart disease, as well as

clear, beneficial immune system modulation and behavioural effects,

have been regarded by scientists, doctors and health authorities

around the world as conclusive. This evidence has formed the basis

of recommendations to consume oily fish or fish oil supplements by

many governments. Where governments have stipulated a limit on the

maximum amount to be consumed, such as no more than three portions

of oily fish weekly, this has served mainly as a means to limit

intake of heavy metals like mercury, or other contaminants such as

dioxins or PCBs common in most wild fish [5]. Peculiarly,

governments have appeared shy of recommending high-quality fish oil

supplements which are often guaranteed as being free of any

significant levels of these contaminants. This is particularly

relevant given that specific batches of several low cost, mass

market fish oil product lines have recently had to be withdrawn from

the UK market owing to dioxin contamination (e.g. several Seven Seas

[owned by pharma giant Merck] fish oil product batches were

withdrawn on 14th March 2006, and on 11th March 2006 high street

pharmacy chain Boots withdrew two batches of its own brand fish oil

product).

In closely scrutinising Hooper et al''s paper, one thing becomes

apparent: the findings are not nearly as damning as those suggested

by the negative headlines on omega-3 fats that rebounded around the

world for over a week. In fact, to the contrary; when it comes to

the studies with fish oils only, the news appears just as rosy as we

had all thought.

Ten out of 12 randomised control trials considered in the meta-

analysis that assessed these oils in relation to total mortality

point to positive findings. The same can be said for all three

cohort studies considered by the meta-analysis authors. That's

thirteen out of fifteen studies showing favourable results for

higher intakes of omega-3 fats. The remaining two studies have been

presented as showing very slightly negative findings, but in both

cases the studies deal with existing disease states, either angina

or coronary artery bypass grafts. The negative effects, in both

cases, are so small that they could be regarded as having little or

no biological relevance (in one study there was half a percent

greater mortality in the treatment compared with control, while in

the other there was a little over a 2% difference). The meta-

analysis authors themselves considered both studies as being of

medium to high risk of bias, which might in itself explain or at

least contribute to such variations.

So, while the world was assaulted with headlines such as " The

benefits of fish and linseed oils as elixir of life are another

health myth " (this example being courtesy of The Times newspaper),

we could have just as easily, and much more correctly, read

headlines along the lines of: " New meta-analysis reinforces the

health benefits of fish oils. " But perhaps fewer newspapers would

have sold on 24 and 25 March 2006.

Smearing the data with margarine

Even when Hooper and co-workers included studies with plant-derived,

short chain omega-3 fats, such as those found in certain vegetable

oils (e.g. flax) including margarines, the overall trend still

pointed to reduced mortality for those consuming higher intake

levels of all forms of omega-3.

The study that was presented as having the most pronounced apparent

negative effect was one published in 2002 by Groningen University's

Dr Wanda Bemelmans and colleagues [6]. The study, known as the

MARGARIN trial, investigated the effect on heart disease risk of a

Unilever margarine enriched with alpha-linolenic acid (ALA), an

important short-chain omega-3 found to be rich in Mediterranean

diets, well known for their health promoting properties. The study

also aimed to assess the effect of group education on the benefits

associated with consuming a typical Mediterranean diet. Importantly,

the subjects in the study all had multiple cardiovascular risk

factors; nearly half were smokers and took anti-hypertensive drugs,

while over 40% had family histories of cardiovascular risk.

Bemelmans and colleagues' own findings, in contrast to their

interpretation of these findings in the Hooper et al meta-analysis,

are overwhelmingly positive. They demonstrate clearly the beneficial

effects of ALA-enriched margarine on reducing heart disease risk.

The study also shows that group education led to healthier diets,

with increased consumption of fish, and consequently lower heart

disease risk factors. These findings are actually fully in line with

another major study, the Lyons Diet Heart Study, published in 1994

in the Lancet, which actually provided the inspiration for Bemelmans

and colleagues' MARGARIN trial.

So, how was this study distorted to give the impression that omega-3

fats might be bad for you? This is down to the very small number of

deaths recorded, which could just as easily be a function of chance

rather than any treatment effect. The study included only four

deaths out of 266 subjects in total. The omega-3 meta-analysis

authors managed to blacken this study because 3 out of 4 of these

deaths (again from all-causes, not just cardiovascular disease)

occurred in the high ALA, treatment group, while only one was in the

low ALA, control group. This small number of deaths could easily

have been a function of random, `statistical clustering',

particularly given that risk factors appeared lower in the high ALA

treatment group.

Dr Bemelmans has actually gone on public record since the release of

Hooper et al''s meta-analysis questioning the way in which her study

has been used, and how her and her co-authors' positive findings

have been used to demonstrate negative findings in the meta-

analysis.

Just as importantly, since the omega-3 sources are vegetable oils in

margarine, it is not surprising that the benefits are perhaps less

pronounced given the inefficient and limited conversion by the human

body of plant-derived omega-3s to key long chain fatty acids like

eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that are

abundant in fish oils. Additionally, harmful trans fats in margarine

could have been an additional confounding factor.

Cutting to the chase

Looking at all of the data in the omega-3 meta-analysis, the only

area where it is possible to interpret a tendency towards very

slightly negative effects, is in the case of randomised control

trials (but not cohort studies) looking at the effects of omega-3

fats on cancer and stroke. However, these results could just as

easily be the result of bias or confounding factors, inadequate

periods of supplementation, or even the effects of contaminants in

fish or fish oil capsules.

For the BMJ''s own view on the subject, it is worth referring to the

Editorial published on 24 March which focuses on Hooper et al''s

meta-analysis. Contrary to the thrust of the meta-analysis itself,

and the related media, the Editorial takes a rather positive line on

omega-3s, and demonstrates concern over dwindling supplies of marine-

derived omega-3s. Citing directly from the Editorial:

" For the general public some omega 3 fat is good for health…..

Adequate intake of omega 3 fats is particularly important for women

of childbearing age…… We are faced with a paradox. Health

recommendations advise increased consumption of oily fish and fish

oils, within limits, on the grounds that intake is generally low.

However, industrial fishing has depleted the world's fish stocks by

some 90% since 1950, and rising fish prices reduce affordability

particularly for people with low incomes. Global production trends

suggest that, although fish farming is expanding rapidly, we

probably do not have a sustainable supply of long chain omega 3

fats. "

Additionally, there are now many Rapid Responses published in the

BMJ which reinforce problems with the authors' conclusions. These

can be found at:

http://bmj.bmjjournals.com/cgi/eletters/332/7544/752.

Let you be the judge. I don't believe many people who read the full

Hooper et al meta-analysis, as well as the BMJ editorial and Rapid

Responses, would stop taking fish oil supplements. The problem is

that only a tiny proportion of the population will do this. Many

more will succumb to the negative headlines triggered by the meta-

analysis and, contrary to the vast weight of evidence, they now run

the risk of going against government advice to increase consumption

of oily fish or fish oil supplements at recommended doses.

Those very few who interrogate the evidence considered by Hooper and

colleagues might actually decide to alter their sources of omega-3

fats, shifting in the direction of high quality fish oil supplements

and away from vegetarian sources of omega-3 and even oily fish,

which runs the risk of contamination. This way, they can be

guaranteed specific amounts of long-chain EPA and DHA, as well as

being confident they are consuming products that are certified as

free from contaminants.

So, despite the headlines, there is no new evidence clouding the

efficacy of fish oils or long chain essential fatty acids. In fact,

if the meta-analysis had included other health benefits such as

immune system function, cognitive and behavioural function and joint

health, the case for marine-derived omega-3s would have looked even

stronger. So strong, in fact, one wonders if the media couldn't be

sued by fish oil supplement manufacturers for damages. But things

are rarely this simple.

We are left wondering about those negative headlines. Could there

have been a motive for the negative spin?

Pharma fish oils

Just as we've seen Big Pharma control vitamin and mineral markets

globally, both legally and illegally, is it not possible that this

most recent skewed meta-analysis is part of a plan to discredit fish

oils consumed increasingly by the masses?

When you peruse the competing interests declared in the BMJ paper,

the only possible link given is that speaker fees have been paid to

one of the authors by a company, Solvay, that markets a product

called Omacor. Solvay is not a small marketing outfit. It is part of

an international chemical and pharmaceutical group, headquartered in

Brussels, which employs some 33,000 people across 50 countries.

Omacor also happens to be the first prescription-only fish oil. As a

licensed medicine, unlike the much more common fish oil food or

dietary supplements, it can brandish extensive health and medicinal

claims. Omacor, manufactured by Pronova Biocare in Norway (a

private, limited company owned by Ferd Private Equity Fund), is

prescribed primarily for reducing triglycerides (a major heart

disease risk factor) and is positioned firmly as a stable mate with

cholesterol-reducing statin drugs. In other words, the evidence for

taking high quality fish oils is so convincing, drugs companies

perhaps now want a slice of the action.

And the timing for the release of the meta-analysis does appear most

fortuitous. In November 2004, Omacor was approved as a drug by the

US Food & Drug Administration. In September 2005, Solvay

Pharmaceuticals and Pronova Biocare signed a licensing agreement for

exclusive distribution rights for distribution into India, Pakistan,

Sri Lanka, Thailand, Vietnam, Singapore, Malaysia, China, Hong Kong

and New Zealand.

Furthermore, on 1 December 2005, EPAX Sales and Production de-merged

from Pronova Biocare to enable Pronova to focus exclusively on the

production of prescription-only Omacor. EPAX, also based in Norway,

will continue to produce concentrated omega-3 oils for the `poor-

cousin', dietary supplement industry.

Is the way actually being paved to encourage patients to elect for

the prescription-only fish oil version, resplendent with all the

health claims allowed under a drugs regime and banned in the food or

dietary supplement sector? Even if these processes are only

coincidental, and we currently have no direct evidence to suggest

otherwise, the effect is the same.

The crying shame from a public health and disease prevention

perspective, is that some of the most robust evidence for taking

fish oils relates to their early, protective effects against heart

disease. And that's why the free availability of high quality fish

oil supplements is so important; people only take drugs when they

become sick.

So now, those people – and there may be many – who have been

unfairly frightened away from fish oil supplements might believe

that they need to wait until they're sick in later life before their

trusted doctors can prescribe the fish oil supplements they should

have been consuming all along.

It is indeed a topsy-turvy world of lies, damn lies — and statistics.

REFERENCES

Hooper L, RL, on RA, Summerbell CD, Ness AR,

HJ, Worthington HV, Durrington PN, Higgins JP, Capps NE, Riemersma

RA, Ebrahim SB, Davey G. Risks and benefits of omega 3 fats

for mortality, cardiovascular disease, and cancer: systematic

review. British Medical Journal, 2006; 332 (7544): 752-60.

ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ,

Guallar E. Meta-analysis: high-dosage vitamin E supplementation may

increase all-cause mortality. ls of Internal Medicine, 2005; 142

(1): 37-46.

Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ. Use of

antioxidant vitamins for the prevention of cardiovascular disease:

meta-analysis of randomised trials. Lancet, 2003; 361(9374): 2017-23.

Hooper L, RL, on RA, Summerbell CD, Ness AR,

HJ, Worthington HV, Durrington PN, Higgins JP, Capps NE, Riemersma

RA, Ebrahim SB, Davey G. Rapid Response in British Medical

Journal: Authors reply - omega 3s and health.

http://bmj.bmjjournals.com/cgi/eletters/332/7544/752#131349 [last

accessed 19 April 2006].

Scientific Advisory Committee on Nutrition / Committee on Toxicity

(UK). Advice on fish consumption: benefits and risks. Food Standards

Agency / Department of Health. 2004. 204 pp.

Bemelmans WJ, Broer J, Feskens EJ, Smit AJ, Muskiet FA, Lefrandt JD,

Bom VJ, May JF, Meyboom-de Jong B. Effect of an increased intake of

alpha-linolenic acid and group nutritional education on

cardiovascular risk factors: the Mediterranean Alpha-linolenic

Enriched Groningen Dietary Intervention (MARGARIN) study. American

Journal of Clinical Nutrition, 2002; 75(2): 221-7.

For further information, please contact:

Alliance for Natural Health

The Atrium, Dorking,

Surrey RH4 1XA, United Kingdom

Tel: +44 (0)1252 371 275

Email: info@...

This article may be copied, downloaded, printed and distributed

freely as long as it is not modified in any way.

Web: www.anhcampaign.org

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For the British Medical Journal Rapid Response to the Hooper et al

meta-analysis, published by ANH Medical Director, Dr Damien Downing,

see:

http://bmj.bmjjournals.com/cgi/eletters/332/7544/752#131920