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

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 Miller and colleagues published electronically in the Annals 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 Miller et al.

The overall conclusion that high-dose vitamin E causes increased mortality could also have been a statistical artifact, 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 Annals 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 behavioral 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 scrutinizing 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 randomized 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 favorable 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 metaanalysis questioning the way in which her study has been used, and how her and her coauthors’ positive findings have been used to demonstrate negative findings in the metaanalysis.

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 randomized 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 metaanalysis, 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 longchain 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 behavioral 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

1. Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HJ, Worthington HV, Durrington PN, Higgins JP, Capps NE, Riemersma RA, Ebrahim SB, Davey Smith G. Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review.
British Medical Journal, 2006; 332 (7544): 752-60.

2. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Metaanalysis: high-dosage vitamin E supplementation may increase all-cause mortality.
Annals of Internal Medicine, 2005; 142(1): 37-46.

3. 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.

4. Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HJ, Worthington HV, Durrington PN, Higgins JP, Capps NE, Riemersma RA, Ebrahim SB, Davey Smith 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].

5. 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.

6. 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.