Meta-analyses Used To Discredit Supplements

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Health

Pharma

Several recent 'studies' on nutrients seem to contradict either what we know from previous research, or what our intelligence tells us should be true. You only have to scan the headlines and pay attention to the "newly found" dangers of this or that natural substance. From St. John's Wort to Kava Kava, from vitamin C to vitamin E, we hear that they are "not effective" or worse - that they may be dangerous.

Nonsense, says Dr Robert Verkerk of the Alliance for Natural Health, those studies are manipulated. There is a new kind of study that is highly regarded these days, the so-called "meta-analysis". It's based on a choose-and-pick approach where older studies are reviewed and analyzed to combine their wisdom. The criteria of inclusion/exclusion of previous studies in the analysis, and the decision of how to give different weights to different results are so rubbery that almost any conclusion becomes possible. One of the more recent studies that attempts to trash nutrients takes on the health benefits of fish oils...

Image credit: Boris Peterka

The fact that the meta-analysis throwing doubt on omega-3 fish oils coincides with the launch of a pharmaceutical version of the same type of fats made by chemical giant Solvay reminds me of the tryptophan disaster of more than a decade ago. The amino acid L-tryptophan was being used as a mood enhancer and remedy for migraine headaches and had people excited - finally something that worked. At the same time as Prozac was launched, a mysterious contamination of one batch of the amino-acid made by Japanese producer Showa Denko caused all tryptophan products sold as supplements to be taken off the market. Strangely, the tryptophan sold as a medicine remained on sale. Much the same happened with melatonin, a strong anti-oxidant and regulator of sleep patterns. Press reports praised the supplement no end. Once the excitement got "too much", the health authorities came down heavy handed and removed melatonin from the market in several European countries.

Examples of such strange coincidences abound, but let's concentrate on the present. Here is Rob Verkerk's analysis of some of the more recent meta-analyses that suddenly found problems with supplements...

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

By Dr Robert Verkerk, Executive & Scientific Director, Alliance for Natural Health

(you can download a PDF version of the article here)

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 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 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 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 mar