MD, PhD, FMedSci, FRSB, FRCP, FRCPEd

supplements

Many dietary supplements are heavily promoted for the prevention of chronic diseases, including cardiovascular disease (CVD) and cancer. But do they actually work or are they just raising false hopes? The evidence on this subject is confusing and proponents of both camps produce data which seemingly support their claims. In this situation, we need an independent analysis of the totality of the evidence to guide us. And one such review has just become available

The purpose of this article was to systematically review evidence for the use of multivitamins or single nutrients and functionally related nutrient pairs for the primary prevention of CVD and cancer in the general population.

The authors searched 5 databases to identify literature that was published between 2005 and January 29, 2013. They also examined the references from the previous reviews and other relevant articles to identify additional studies. In addition, they searched Web sites of government agencies and other organizations for grey literature. Two investigators independently reviewed identified abstracts and full-text articles against a set of a priori inclusion and quality criteria. One investigator abstracted data into an evidence table and a second investigator checked these data. The researchers then qualitatively and quantitatively synthesized the results for 4 key questions and grouped the included studies by study supplement. Finally, they conducted meta-analyses using Mantel-Haenzel fixed effects models for overall cancer incidence, CVD incidence, and all-cause mortality.

103 articles representing 26 unique studies met the inclusion criteria. Very few studies examined the use of multivitamin supplements. Two trials showed a protective effect against cancer in men; only one of these trials included women and found no effect. No effects of treatment were seen on CVD or all-cause mortality.

Beta-carotene showed a negative effect on lung cancer incidence and mortality among individuals at high risk for lung cancer at baseline (i.e., smokers and asbestos-exposed workers); this effect was persistent even when combined with vitamin A or E. Trials of vitamin E supplementation showed mixed results and altogether had no overall effect on cancer, CVD, or all-cause mortality. Only one of two studies included selenium trials showed a beneficial effect for colorectal and prostate cancer; however, this trial had a small sample size. The few studies addressing folic acid, vitamin C, and vitamin A showed no effect on CVD, cancer, and mortality. Vitamin D and/or calcium supplementation also showed no overall effect on CVD, cancer, and mortality. Harms were infrequently reported and aside from limited paradoxical effects for some supplements, were not considered serious.

The authors’ conclusion are less than encouraging: there are a limited number of trials examining the effects of dietary supplements on the primary prevention of CVD and cancer; the majority showed no effect in healthy populations. Clinical heterogeneity of included studies limits generalizability of results to the general primary care population. Results from trials in at-risk populations discourage additional studies for particular supplements (e.g., beta-carotene); however, future research in general primary care populations and on other supplements is required to address research gaps.

A brand-new RCT provides further information, specifically on the question whether oral multivitamins are effective for the secondary prevention of cardiovascular events. In total, 1708 patients aged 50 years or older who had myocardial infarction (MI) at least 6 weeks earlier with elevated serum creatinine levels were randomly assigned to an oral, 28-component, high-dose multivitamin and multi-mineral mixture or placebo. The primary end point was time to death, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. Median follow-up was 55 months. Patients received treatments for a median of 31 months in the vitamin group and 35 months in the placebo group. 76% and 76% patients in the vitamin and placebo groups completed at least 1 year of oral therapy, and 47% and 50% patients completed at least 3 years. Totals of 46% and 46% patients in both groups discontinued the vitamin regimen, and 17% of patients withdrew from the study.

The primary end point occurred in 27% patients in the vitamin group and 30% in the placebo group. No evidence suggested harm from vitamin therapy in any category of adverse events. The authors of this RCT concluded that high-dose oral multivitamins and multiminerals did not statistically significantly reduce cardiovascular events in patients after MI who received standard medications. However, this conclusion is tempered by the nonadherence rate.

These findings are sobering and in stark contrast to what the multi-billion dollar supplement industry promotes. The misinformation in this area is monumental. Here is what one site advertises for heart disease:

Vitamin C could be helpful, limit dosage to 100 to 500 mg a day.

Vitamin E works better with CoQ10 to reduce inflammation in heart disease. Limit vitamin E to maximum 30 to 200 units a few times a week. Use a natural vitamin E complex rather than synthetic products.

CoQ10 may be helpful in heart disease, especially in combination with vitamin E. I would recommend limiting the dosage of Coenzyme Q10 to 30 mg daily or 50 mg three or four times a week.

B complex vitamins reduce levels of homocysteine. Keep the vitamin B dosages low, perhaps one or two times the RDA. Taking higher amounts may not necessary be a healthier approach.

Curcumin protects rat heart tissue against damage from low oxygen supply, and the protective effect could be attributed to its antioxidant properties. Curcumin is derived from turmeric, which is often used in curries.

Garlic could be an effective treatment for lowering cholesterol and triglyceride levels for patients with a history or risk of cardiovascular disease, especially as a long term strategy.

Terminalia arjuna, an Indian medicinal plant, has been reported to have beneficial effects in patients with ischemic heart disease in a number of small studies. Arjuna has been tested in angina and could help reduce chest pain.
Magnesium is a mineral that could help some individuals. It is reasonable to encourage diets high in magnesium as a potential means to lower the risk of coronary heart disease.

Danshen used in China for heart conditions.

And in the area of cancer, the choice is even more wide and audacious as this web-site for example demonstrates.

So, the picture that emerges from all this seems fairly clear. Despite thousands of claims to the contrary, dietary supplements are useless in preventing cardiovascular diseases or cancer. All they do produce, I am afraid, is rather expensive urine.

Web-sites have become a leading source of information on health matters. This is particularly true in the realm of alternative medicine. Conventional health care professionals often know too little about this subject to advise their patients, and alternative practitioners are usually too biased to be trusted. So many consumers turn to the Internet and hope that it offers information which is reliable. But is it?

American pharmacists published a study evaluating the quality of on-line information on herbal supplements. They conducted a search of 13 common herbals – including black cohosh, echinacea, garlic, ginkgo, ginseng, green tea, kava, saw palmetto, and St John’s wort – and reviewed the top 50 Web sites for each using a Google search. Subsequently, they analysed clinical claims, warnings, and other safety information.

A total of 1179 Web sites were examined in this way. Less than 8% of retail sites provided information regarding potential adverse effects, drug interactions, and other safety information; only 10.5% recommended consultation with a healthcare professional. Less than 3% cited scientific literature to support their claims.

The authors’ conclusions were worrying: Key safety information is still lacking from many online sources of herbal information. Certain nonretail site types may be more reliable, but physicians and other healthcare professionals should be aware of the variable quality of these sites to help patients make more informed decisions.

Having conducted my fair share of similar research (e.g. here or here or here or here), I can only concur with these conclusions. When it comes to health care, the Internet is a scary place! In the realm of alternative medicine, it is dominated by people who seem not to care much about anything other than their profits.

But what can be done to change this situation? How can we protect the public from Internet-charlatans? How can one control the Internet? I wish I knew! But there are nevertheless means of directing consumers to those sites which do offer reliable information. Kite-marking high quality sites might be one way of achieving this. This task would, of course, be huge and difficult, but in the interest of public safety, governments and other official institutions should consider tackling it.

Hypercholesterolemia is an important, independent risk factor for cardiovascular disease, according to a generally accepted wisdom. Measures to normalise elevated blood lipids include diet, exercise and drugs, of which statins are the most widely prescribed. But many people have become somewhat sceptical about the wide-spread use of statins: Traditionally, doctors have viewed statin drugs as the most effective way to lower high LDL cholesterol. But today researchers are starting to believe that statins may not be the magic bullet they’ve always been made out to be. Statins can cause severe adverse effects and some experts have questioned whether they generate more benefit than harm and suggested that ‘BIG PHARMA’ are pushing statins not for the benefit of public health but for maximising profit.

This begs the question: is there an alternative?

This RCT tested the efficacy of a dietary supplement providing 1.8 g/day esterified plant sterols and stanols to improve the fasting lipid profile of men and women with primary hypercholesterolemia. Repeated measures analysis of covariance was used to compare outcomes for sterol/stanol and placebo treatment conditions using the baseline value as a covariate. Thirty subjects were randomized and all of them completed the trial.

Baseline (mean±standard error of the mean) plasma lipid concentrations were: total cholesterol 236.6±4.2 mg/dL (6.11±0.11 mmol/L), high-density lipoprotein (HDL) cholesterol 56.8±3.0 mg/dL (1.47±0.08 mmol/L), LDL cholesterol 151.6±3.3 mg/dL (3.92±0.09 mmol/L), non-HDL cholesterol 179.7±4.6 mg/dL (4.64±0.12 mmol/L), and triglycerides 144.5±14.3 mg/dL (1.63±0.16 mmol/L). Mean placebo-adjusted reductions in plasma lipid levels were significant (P<0.01) for LDL cholesterol (-4.3%), non-HDL cholesterol (-4.1%), and total cholesterol (-3.5%), but not for triglycerides or HDL cholesterol.

The authors conclude that these results support the efficacy of 1.8 g/day esterified plant sterols/stanols in softgel capsules, administered as an adjunct to the National Cholesterol Education Program Therapeutic Lifestyle Changes diet, to augment reductions in atherogenic lipid levels in individuals with hypercholesterolemia.

These findings are encouraging but certainly not rock solid. The study was too small, and the effect sizes were less than impressive. A brand-new systematic review, however, provides much more convincing data.

Its aim was to quantify the LDL-cholesterol-lowering effect of plant sterols/stanols as supplements. Eight eligible clinical trials were identified. Among the trials with a duration between 4 and 6 weeks, plant sterol/stanol dose ranged from 1.0 to 3.0 g/day administrated mainly with the main meals (2 or 3 times/day). Intake of plant sterol/stanol supplements decreased LDL-cholesterol concentrations by 12 mg/dL (0.31 mmol/L) compared with placebo. Further analysis showed no significant difference between the LDL-cholesterol-lowering action of plant sterols/stanols supplements vs foods enriched with plant sterols/stanols. The authors concluded that plant sterol/stanol supplements as part of a healthy diet represent an effective means of delivering LDL-cholesterol-lowering similar to plant sterols/stanols delivered in various food formats.

Crucially, this positive verdict does not stand alone. Another recent review included 5 trials and concluded that a dose-effect relationship of plant stanols in higher doses than currently recommended has been demonstrated by recent clinical studies and a meta-analysis.

Plant sterols seem to be not just effective but also safe: none of the trials published to date reported significant adverse effects. The only concern is the potential decrease in the concentrations of lipid-soluble antioxidants and vitamins, including β-carotene, α-tocopherol, lutein, and α-carotene. It is currently not clear whether these effects are clinically relevant.

The relative merits of phytosterols versus statins are not easy to evaluate. We have hundreds of studies of statins but just a few of sterols. This means our knowledge in this area is incomplete. Statins can cause serious adverse effects but their effects on blood lipids is about one order of magnitude larger that those of sterols. There is plenty of evidence to show that statins lower the risk of cardiovascular disease, while such data are missing for phytosterols.

The choice between statins and plant sterols is thus not easy, particularly considering the often emotional arguments and hype used in the ‘cholesterol-debate’. Phytosterols offer one more alternative therapy for lowering LDL-cholesterol levels. They seem safe and have the added attraction of being ‘natural’ – but the lipid-effects are relatively small, the impact on cardiovascular morbidity and mortality is uncertain, and fairly high doses are required to see any lipid-lowering at all.

For those who know about the subject, this is an old hat, of course. But for many readers of this blog, it might be news: ‘Traditional’ Chinese Medicine (TCM) is not nearly as traditional as it pretends to be. In fact, it is an artefact of recent creation. The man who has been saying that for years is Professor Paul Unschuld, one of the leading sinologist worldwide and an expert who has written many books and journal articles on the subject.

During an interview given in 2004, he defined TCM as “an artificial system of health care ideas and practices generated between 1950 and 1973 by committees in the People’s Republic of China, with the aim of restructuring the vast and heterogenous heritage of Chinese traditional medicine in such a way that it fitted the principles–Marxist Maoist type democracy and modern science and technology on which the future of the PRC was to be built…[the Daoist underpinning for TCM] is incorrect for two reasons.  First . . . TCM is a product of Communist China.  Second, even if we were to apply the term TCM to pre-revolutionary Chinese medicine, the Daoist impact should be considered minimal.”

In a much more recent interview entitled INVENTION FROM THE FAR EAST which he gave to DER SPIEGEL (in German), he explained this in a little more detail (I have tried to translate his words as literally as possible):

What is being offered in our country to patients as TCM is a construct that was created in China on an office desk which has been altered further on its way to the West.

Already at the beginning of the 20th century, reformers and revolutionaries urged that the traditional medicine in China should be abolished and that the western form of medicine should be introduced instead. Traditional thinking was seen as backwards and it was held responsible for the oppressing superiority of the West. The introduction of Western natural sciences, medicine and technology was also thought later, after the foundation of the People’s Republic, to be essential for rendering the country competitive again. Since the traditional Chinese medicine could not be totally abolished then because it offered a living to many citizens, it was reduced to a kernel, which could be brought just about in line with the scientific orientation  of the future communist society. In the 1950s and 60s, an especially appointed commission had been working on this task. The filtrate which they created from the original medical tradition was hence forward to be called TCM vis a vis foreigners.

There is little more to add, I think – perhaps just two brief after-thoughts. TCM is a most lucrative export article for China. So don’t expect Chinese officials to rid TCM of the highly marketable ‘TRADITIONAL’ label. And remember: the appeal to tradition’ argument is a fallacy anyway.

Pyruvate, a ketone and an alpha-keto acid, occurs naturally in the body when glucose is converted into energy. It is part of the Krebs cycle, the complex chain of reactions in which nutrients are metabolised to provide energy. High doses of pyruvate seem to stimulate the breakdown of fat in the body. It is therefore not surprising that pyruvate is used in all sorts of slimming aids; and if the advertising for ‘fat burners’ is to be believed, pyruvate is just the ticket for the desperate slimmer.

One such product advertisement, for instance, claims that sodium pyruvate and potassium pyruvate, which can act as a stimulant for the metabolism, adding to the thermogenesis process. Pyruvates have been found in studies to reduced the storage of fat in the body and convert the food source into calories which are then burned off in the production of heat. In one study, rats were injected with three fat burners, including pyruvates, and the rats given the pyruvates burned the greatest amount of fat by increasing the rat’s resting metabolic rate. With the elevated resting metabolic rate, the body burned more fat in individuals, which makes pyruvate an excellent source for weight maintenance.

So, maybe pyruvate works for rats – but does it really help those of us who would like to lose a few kilos? Some studies seem to say so, but others don’t. What do we conclude? There can only be one solution: we need a systematic review of the totality of the available trial evidence – and you probably guessed it: we have just published such an article.

The objective of our systematic review was to examine the efficacy of pyruvate in reducing body weight. Extensive literature searches identifies 9 RCTs of which 6 were met our inclusion criteria. All had methodological weaknesses. The meta-analysis revealed a statistically significant difference of 0.72 kg in body weight with pyruvate compared to placebo. The magnitude of the effect is small, and its clinical relevance is therefore uncertain. Adverse events included gas, bloating, diarrhoea, and increase in low-density lipoprotein cholesterol.

Our conclusion: The evidence from randomized clinical trials does not convincingly show that pyruvate is efficacious in reducing body weight. Limited evidence exists about the safety of pyruvate. Future trials involving the use of this supplement should be more rigorous and better reported.

Pyruvate supplements are popular; people who want to lose weight are misled into believing that they are effective. Bodybuilders as well as other athletes tend to take them because pyruvate is claimed to reduce body fat and enhance the ability to use energy more efficiently. None of these assumptions is based on sound evidence. Regardless of the evidence, a whole industry is exploiting the gullible and doing very well on it.

As these ‘fat burners’ are by no means cheap, I recommend a more efficient and more economical method for normalising body weight: eat a little less and move a bit more – I know it’s naff, but it works!

Herbal medicine is popular. Consumers seem to be attracted by the notion that they are natural – and if it’s natural, it must be safe!!! But do we really know what is in the product that we might be buying? A recently published analytical study aimed to investigate herbal product integrity and authenticity with the goal of protecting consumers from health risks associated with product substitution and contamination.

The researchers used DNA barcoding to conduct a blind test of the authenticity for (i) 44 herbal   products representing 12 companies and 30 different species of herbs, and (ii) 50 leaf samples collected from 42 herbal species. They also assembled the first   standard reference material (SRM) herbal barcode library from 100 herbal species of   known provenance that were used to identify the unknown herbal products and leaf samples.

DNA barcodes from 91% of the herbal products and all leaf samples could be recovered. 59% of the products tested contained DNA barcodes from plant species not listed on the labels. 48% of the products could be authenticated but one-third of these also contained contaminants and or fillers not listed on the label. Product substitution occurred in 30 of the 44 products tested and only 2 of the 12 companies sold products without any substitution, contamination or fillers. Some of the contaminants we found pose serious health risks to consumers.

Based on these findings, the authors drew the following conclusions: Most of the herbal products tested were of poor quality, including considerable product substitution, contamination and use of fillers. These activities dilute the effectiveness of otherwise useful remedies, lowering the perceived value of all related products because of a lack of consumer confidence in them. We suggest that the herbal industry should embrace DNA barcoding for authenticating herbal products through testing of raw materials used in manufacturing products. The use of an SRM DNA herbal barcode library for testing bulk materials could provide a method for ‘best practices’ in the manufacturing of herbal products. This would provide consumers with safe, high quality herbal products.

These findings are fairly alarming. I have previously blogged about the fact that herbal products are far to often adulterated or contaminated. Now it seems that we have to add to this list of dangers the substitution of the herbal ingredient with a presumably less expensive but potentially toxic herb that should not legally be there at all.

The fish oil (FO) story began when a young Danish doctor noticed that there were no heart attacks in Greenland. Large epidemiological studies were initiated, mechanistic investigations followed, and a huge amount of fascinating data emerged. Today, we know more about FO than most other dietary supplements.

Fish oil contains large amounts of omega-3 fatty acids which are thought to be beneficial in treating hypertriglyceridemia,  preventing heart disease.  In addition, FO is often recommended for a wide variety of other conditions, such as  cancer, depression, and macular degeneration. Perhaps the most compelling evidence exists in the realm of inflammatory diseases; the mechanism of action of FO is well-studied and includes powerful anti-inflammatory properties.

Australian rheumatologists just published a study of FO supplements for patients suffering from rheumatoid arthritis (RA). Specifically, they examined  the effects of high versus low dose FO in early RA employing a ‘treat-to-target’ protocol of combination disease-modifying anti-rheumatic drugs (DMARDs).

Patients with chronic RA <12 months’ who were DMARD-naïve were enrolled and randomised 2:1 to FO at a high dose or plaacebo (low dose FO for masking). These groups were given 5.5 or 0.4 g/day, respectively, of  eicosapentaenoic acid + docosahexaenoic acid. All patients received methotrexate (MTX), sulphasalazine and hydroxychloroquine, and DMARD doses were adjusted according to an algorithm taking disease activity and toxicity into account. DAS28-erythrocyte sedimentation rate, modified Health Assessment Questionnaire (mHAQ) and remission were assessed three monthly. The primary outcome measure was failure of triple DMARD therapy.

The results indicate that, the FO group, failure of triple DMARD therapy was lower (HR=0.28 (95% CI 0.12 to 0.63; p=0.002) unadjusted and 0.24 (95% CI 0.10 to 0.54; p=0.0006) following adjustment for smoking history, shared epitope and baseline anti–cyclic citrullinated peptide. The rate of first American College of Rheumatology (ACR) remission was significantly greater in the FO compared with the control group (HRs=2.17 (95% CI 1.07 to 4.42; p=0.03) unadjusted and 2.09 (95% CI 1.02 to 4.30; p=0.04) adjusted). There were no differences between groups in MTX dose, DAS28 or mHAQ scores, or adverse events.

The authors conclude that FO was associated with benefits additional to those achieved by combination ‘treat-to-target’ DMARDs with similar MTX use. These included reduced triple DMARD failure and a higher rate of ACR remission.

These findings are most encouraging, particularly as they collaborate those of systematic reviews which concluded that evidence is seen for a fairly consistent, but modest, benefit of marine n-3 PUFAs on joint swelling and pain, duration of morning stiffness, global assessments of pain and disease activity, and use of non-steroidal anti-inflammatory drugs and …there is evidence from 6 of 14 randomized controlled trials supporting a favourable effect of n-3 LCP supplementation in decreasing joint inflammation in RA. And you don’t need to buy the supplements either; regularly eating lots of fatty fish like mackerel, sardine or salmon has the same effects.

So, here we have an alternative, ‘natural’, dietary supplement or diet that is supported by reasonably sound evidence for efficacy, that has very few adverse effects (the main one being contamination of the supplement with toxins), that generates a host of potentially useful effects on other organ systems, that is affordable, that has a plausible mechanism of action…. Hold on, I hear some people interrupting me, FO is not an alternative medicine, it is mainstream! Exactly, an alternative medicine that works is called….MEDICINE.

Guest post by Louise Lubetkin

Those who recognize and appreciate a fine example of pseudoscientific baloney when they see one know that there is no richer seam, no more inexhaustible source, than the bustling, huckster-infested street carnival that is alternative medicine. There one can find intellectual swindlers in abundance, all offering outrageously implausible claims with the utmost earnestness and sincerity. But the supreme prize, the Fabergé egg found buried among the bric-a-brac, surely belongs to that most convincing of illusionists, the physician reborn as an ardent advocate of alternative medicine.

Why would any physician, exhaustively trained in the basic sciences that underpin every aspect of medical practice, decide to toss aside the entire canon in favor of a return to blatant mumbo jumbo?

There can be only two possible explanations, and they’re mutually exclusive.

First is the unsavory possibility that the physician who embraces alternative medicine is a cynical charlatan who knows full well that what is being offered is worthless, but sees it as a path to a more lucrative form of practice that is largely paid for out of pocket, in cash, requiring no tedious insurance company paperwork and avoiding the unpleasant possibility of Medicare audits.

And then there is the opposite explanation: the physician has actually become a true believer, in which case the wholesale rejection of his or her scientific training is essential in order to resolve the uneasy tension between what the physician knows to be fundamentally true and what he or she ardently believes and wishes were true. The two are diametrically opposed: one is a system of thinking in which each component has been painstakingly validated, assessed and reassessed over time, and revised where necessary with the emergence of new knowledge. The other is a simply a belief system founded on faith and wishful thinking.

Alternative medicine, particularly in the realm of cancer, has a long history of attracting people who are seduced by simplistic explanations of this dauntingly implacable and hugely complex constellation of diseases and become gripped by a messianic conviction that this is the true path to a cure. Never mind that such explanations have usually been around for a very long time and have been repeatedly debunked in carefully conducted studies. There is usually an element of paranoia involved: they see themselves as martyrs and explain the medical profession’s indifference to this revolutionary truth as a conspiracy designed to maintain a profitable status quo by silencing dissidents, especially when they arise from within the medical profession itself.

Which of these explanations is the correct one in any particular situation is not always easy to discern. Take the case of Nicholas James Gonzalez, M.D., a New York physician turned alternative practitioner whose practice focuses largely on the treatment of advanced cancer by nutritional means.

THE ORIGINS OF GONZALEZ’S TREATMENT

Gonzalez presents himself as a true believer who became a convert to alternative medicine after coming across the work of William Donald Kelley, D.D.S., a Texas orthodontist who had his own Damascene conversion when his doctors told him that he was dying of pancreatic cancer and that there was nothing more that they could do for him. Undeterred, Kelley claimed that he had cured himself by means of a rigorous diet combined with frequent self-administered coffee enemas. After thus miraculously dragging himself (and his enema bucket) back from the banks of the River Styx, Kelley decided to abandon straightening children’s teeth in favor of treating people with advanced cancer – perhaps not the most logical career move, to be sure, but Texas is Texas.

Probably the most famous of Kelley’s patients was the actor Steve McQueen, who, in the advanced stages of mesothelioma, turned to the erstwhile orthodontist in search of a cure. Not surprisingly, McQueen died despite Kelley’s ministrations, an unfortunate turn of events which Kelley rationalized away by claiming that he had in fact successfully cured McQueen, but that the medical establishment had subsequently had McQueen murdered in order to prevent him “blowing the lid off the cancer racket.”

But back to Gonzalez.

Like Kelley before him, Gonzalez bases his treatment on the work of James Beard, a long-dead Scottish embryologist who, more than 100 years ago, put forward the notion that all cancer was caused by wayward cells called trophoblasts. Trophoblasts are the cells which organize around the developing embryo very early in pregnancy, and which ultimately give rise to the placenta. Beard, of course, lived and died long before the advent of electron microscopy, the unraveling of the structure of DNA and a myriad other crucial discoveries that have helped to elucidate the hugely complex phenomenon that is collectively referred to as cancer. While his observations concerning the similarities between the invasiveness of cancer and the ability of the primitive placenta to tunnel its way into the uterine wall were undoubtedly astute, they are inadequate to explain what is now known about the etiology and progression of cancer.

Having observed that the placenta’s invasion of the uterine wall ceased at the very moment that the fetal pancreas became active, he took a leap of faith and postulated that it was the fetal pancreatic enzymes that were responsible for arresting the growth and invasion of the trophoblast layer. Beard went further, suggesting that quite apart from their role in digestion, pancreatic enzymes actually represent the body’s main defense against cancer, and therefore it should be possible to control cancer by administering large quantities of pancreatic enzymes.

This hundred-year-old hypothesis forms the cornerstone of the cancer treatment program devised by Gonzalez. (It should also be mentioned that Gonzalez doesn’t limit himself to the treatment of cancer, but uses the same methodology for treating a range of chronic degenerative diseases, including multiple sclerosis, presumably on the assumption that wayward trophoblasts are responsible for these, also, although it is difficult to imagine exactly how.)

Beard rightly surmised that pancreatic enzymes could not be successfully administered by mouth because the acid environment of the stomach would inactivate them immediately. Furthermore, being proteins themselves, any orally administered pancreatic enzymes would be quickly broken down by the gastric enzyme pepsin. Beard therefore advocated administering the enzymes by hypodermic injection.

In this, and in other ways, Beard seems to have been considerably more circumspect about his theory and its therapeutic implications than his modern day acolytes. It is interesting to note that he conspicuously refrained from making any claim that his method was a cure for cancer. A contemporary account of the public debate over Beard’s theory of cancer origins and treatment, which appeared in 1907 in the New York Times, is available here.

Much has happened since Beard’s day, it’s true, but gastric physiology and the essentials of protein digestion have not changed an iota. Pepsin is still pepsin, and the stomach is still awash in acid. Nevertheless, Gonzalez insists that the oral route is perfectly adequate. This odd departure from otherwise strict historical orthodoxy may have more to do with regulatory issues than pharmacokinetics: the type of enzymes he uses are viewed as dietary supplements by the Food and Drug Administration (FDA) rather than as prescription drugs, and are therefore unregulated.

GONZALEZ’S TREATMENT

In addition to pancreatic enzymes taken by mouth, Gonzalez prescribes a restrictive diet (which, even for those whom be pronounces to be obligate vegetarians, includes raw liver), and a staggering number of nutritional supplements which patients must take at regular intervals throughout the day and night.

The dietary guidelines he issues to his patients contain an amazing array of obviously unsound statements which bespeak not only a total abandonment of logical thinking on the part of their author, but also a casual disregard for objective fact, as though the solid benchmarks of physiology and biochemistry, such as pH, were just another narrative.

And then of course there’s the obligatory detoxification, without which no alternative treatment regimen could possibly be considered complete. But beyond its role as a doctrinal tenet, the notion that the body is inadequate to the task of handling its own waste holds a special utility for the practitioner of alternative cancer treatment. By insisting on regular and vigorous detoxification, the practitioner can reinforce the idea that the treatment regime – in this case, the pancreatic enzyme barrage – is working so well that the patient’s liver and bloodstream are in danger of being overrun by waste products from tumor breakdown. This must be a great boost to a patient in the advanced stages of cancer who is grimly contemplating his umpteenth coffee enema of the week and struggling to swallow another round of 30 supplement pills. However, most self-respecting physicians and patients would surely like to have that comforting assertion about massive tumor destruction confirmed with some kind of objective test such as imaging. And if the liver is really so hobbled by its task that it has to be supported by regular retrograde sluicing with tepid coffee, perhaps a few blood tests of liver function might be in order? It appears that such considerations are purely for pedants and infidels: real believers have no need for such niceties.

And then there are the supplements, in staggering quantities and bewildering combinations:

Five times during your waking hours take:

  • 16 pancreas glandular tissue
  • 1 magnesium citrate 60mg

With two doses of pancreas glandular take

  • 2 chicken collagen type II

During breakfast and dinner (twice daily) take:

  • 1 amino acids
  • 1 Calsym (vitamin D3 and calcium carbonate)
  • 1 thyroid (sic)
  • 1 vitamin E 100 IU

During each meal (3 times daily) take:

  • 1 adrenal glandular
  • 2 vitamin C
  • 1 Atlantic kelp
  • 2 Formula #1 (sic)
  • 1 liver
  • 1 lung
  • 2 magnesium citrate 60mg
  • 1 digest aid
  • 1 multivitamin
  • 1 multimineral
  • 3 pancreas glandular tissue
  • 3 thymus glandular tissue
  • 1 vitamin 400 IU

During lunch only take:

  • 1 beta carotene 25,000
  • 1 copper gluconate
  • 1 potassium citrate
  • 1 vitamin A 10,000 (which incidentally is twice the recommended daily allowance)

At bedtime take:

  • 2 iron
  • 2 magnesium citrate 60mg
  • 4 RNA/DNA (sic)

At 3:30am take:

  • 16 pancreas glandular tissue

The patient following such a program would take 187 supplement pills daily. Regardless of the dosage of active ingredients involved, the sheer volume and weight of excipients that are ingested during any one 24 hour period is surely something to take into account, especially in a patient debilitated by the ravages of advanced cancer. In a regimen that puts such emphasis on detoxification this is a curious departure indeed.

But onward.

THE EVIDENCE

In 1999, Gonzalez published a paper in the journal Nutrition and Cancer (abstract here) claiming that he had achieved significantly increased survival in 11 patients with inoperable pancreatic cancer by treating them with what he described as “an aggressive nutritional therapy with large doses of pancreatic enzymes.”

Now bear in mind that pancreatic cancer is one of the most aggressive and deadly of all malignancies. The majority of people with pancreatic adenocarcinoma, which is by far the commonest form of pancreatic cancer, die within a few months of their diagnosis; only one in five patients survive the first year, and just four percent of patients live five years beyond diagnosis.

So when Gonzalez published his paper asserting that 9 of the 11 patients (81%) whom he had treated with this regimen survived one year, while 5 (45%) survived two years, and the remaining 4 patients were still alive and holding their own at the 3 year mark, people sat up and took notice.

Despite the fact that this was a very small study, and rife with biases (not least, an obvious selection bias: a further 12 patients who were unable to comply fully with the treatment were excluded from the analysis), it was sufficiently positive a report in an otherwise unrelievedly gloomy prognostic landscape that it prompted further investigation. Ultimately a full-fledged phase III clinical trial comparing Gonzalez’ nutritional protocol to the standard chemotherapy regimen in pancreatic cancer patients was sponsored by the National Institutes of Health and was carried out at Columbia University.

Perhaps not surprisingly, the trial turned out to be hugely contentious and very unorthodox. As a means of eliminating experimental bias, clinical trials are typically “blinded” and randomized – i.e., they are carefully designed so that patients are randomly assigned to one group or the other, and neither the patients nor the physicians know which treatment they are receiving. But in this case there was no way that the trial could be randomized or blinded. Patients could choose whether to undergo chemotherapy or to be assigned to the Gonzalez protocol group, so both they and the investigating physicians knew what treatment they were getting from the beginning.

When it became apparent, as it quickly did, that the results were not going to reflect well on his treatment protocol. Gonzalez began clamoring loudly for an investigation, claiming that the clinical trial had been deliberately rigged to discredit him. (Those interested in the background to the clinical trial, including a very thorough discussion of its ethical and scientific implications, can read about it in several installments, titled “The Ethics of CAM Trials” (parts I-V), here.)

The results of the clinical trial were reported in a paper published in October, 2009, in the Journal of Clinical Oncology (article here). To summarize the results, the 32 patients who underwent traditional chemotherapy lived more than three times as long (14 months vs 4.3 months), and had a measurably better quality of life, including less pain than those treated by the Gonzalez protocol – and since pancreatic cancer is notoriously painful, this is a hugely important consideration in any treatment, regardless of whether or not it extends survival.

But perhaps the most extraordinary and disturbing aspect of the paper was this paragraph, in the Methods section, describing the Gonzalez protocol:

“The enzyme treatment included orally ingested proteolytic enzymes, nutritional supplements, detoxification, and an organic diet (unaltered from the pilot study). Patients received three pancreatic enzyme and two magnesium citrate capsules with each meal. The patients also took specified numbers of capsules with magnesium citrate and Papaya Plus every 4 hours on an empty stomach. The dose for patients with stage II disease was 69 enzyme capsules, and the dose for patients with stages III or IV was 81 capsules per day. After day 16, patients had a 5-day rest period and then resumed treatment on day 22. Treatment could be adjusted by the physician and could be increased for cancer progression. A diet that required at least 70% of the food to be raw or minimally cooked was required. All food was organic. Prescribed detoxification procedures included coffee enemas twice each day; skin brushing and cleansing; salt and soda baths; and a liver flush, clean sweep, and purging.”

Excuse me? A liver flush? What is that, exactly? And could someone please explain what is meant by “a clean sweep”? And purging? If it’s not an indelicate question, might we be told exactly what that consists of?

How this extraordinary paragraph found its way into print, unchallenged, in the venerable Journal of Clinical Oncology is unfathomable. Why didn’t the editors, or the authors, for that matter, feel that it might be useful – in fact, essential – to (a) append an explanation of exactly what was meant by these terms, and (b) to include some kind of rationale for their use?

And then, of course, there’s the larger question of how the institutional review board at Columbia managed to sidestep the ethical issues inherent in approving a trial that was set up to compare the apples of standard treatment with the oranges of liver flushes and clean sweeps. If there was genuine clinical equipoise here we’re in deep, deep trouble.

You might think that this study, with its damning result, would be the end of it. But you’d be wrong. Gonzalez has written a book, a paranoid, self-exculpatory monologue, a martyr’s manifesto detailing what he perceives as his deliberate persecution at vast public expense by a pernicious cancer industry mafia whose goal is to silence him forever. (Presumably the hit man who got Steve McQueen was no longer available?)

So what are we to make of Gonzalez? Is he a cynical fraud or does he genuinely believe that coffee enemas, skin brushing and massive doses of supplements are capable of holding back the tsunami of cancer?

At the end of the day it hardly matters: either way, he’s a dangerous man.

Antioxidant vitamins include vitamin E, beta-carotene, and vitamin C. They are often recommended and widely used for preventing major cardiovascular outcomes. However, the effect of antioxidant vitamins on cardiovascular events remains unclear. There is plenty of evidence but the trouble is that it is not always of high quality and confusingly contradictory. Consequently, it is possible to cherry-pick the studies you prefer in order to come up with the answer you like. That this approach is counter-productive should be obvious to every reader of this blog. Only a rigorous systematic review can provide an answer that is as reliable as possible with the data available to date. Chinese researchers have just published such an assessment.

They searched PubMed, EmBase, the Cochrane Central Register of Controlled Trials, and the proceedings of major conferences for relevant investigations. To be eligible, studies had to be randomized, placebo-controlled trials reporting on the effects of antioxidant vitamins on cardiovascular outcomes. The primary outcome measures were major cardiovascular events, myocardial infarction, stroke, cardiac death, total death, and any adverse events.

The searches identified 293 articles of which 15 RCTs reporting data on 188209 participants met the inclusion criteria. In total, these studies reported 12749 major cardiovascular events, 6699 myocardial infarction, 3749 strokes, 14122 total death, and 5980 cardiac deaths. Overall, antioxidant vitamin supplementation, as compared to placebo, had no effect on major cardiovascular events (RR, 1.00; 95% CI, 0.96-1.03), myocardial infarction (RR, 0.98; 95% CI, 0.92-1.04), stroke (RR, 0.99; 95% CI, 0.93-1.05), total death (RR, 1.03; 95% CI, 0.98-1.07), cardiac death (RR, 1.02; 95% CI, 0.97-1.07), revascularization (RR, 1.00; 95% CI, 0.95-1.05), total CHD (RR, 0.96; 95% CI, 0.87-1.05), angina (RR, 0.98; 95% CI, 0.90-1.07), and congestive heart failure (RR, 1.07; 95% CI, 0.96 to 1.19).

The authors’ conclusion from these data could not be clearer: Antioxidant vitamin supplementation has no effect on the incidence of major cardiovascular events, myocardial infarction, stroke, total death, and cardiac death.

Few subjects in the realm of nutrition have attracted as much research during recent years as did antioxidants, and it is hard to think of a disease for which they are not recommended by this expert or another. Cardiovascular disease used to be the flag ship in this fleet of conditions; not so long ago, even the conventional medical wisdom sympathized with the notion that the regular supplementation of our diet with antioxidant vitamins might reduce the risk of cardiovascular disease and mortality.

Today, the pendulum has swung back, and it now seems to be mostly the alternative scene that still swears by antioxidants for that purpose. Nobody doubts that antioxidants have important biological functions, but this excellent meta-analysis quite clearly and fairly convincingly shows that buying antioxidant supplements is a waste of money. It does not promote cardiovascular health, it merely generates very expensive urine.

One of the best-selling supplements in the UK as well as several other countries is evening primrose oil (EPO). It is available via all sorts of outlets (even respectable pharmacies – or is that supposedly respectable?), and is being promoted for a wide range of conditions, including eczema. The NIH website is optimistic about its efficacy: “Evening primrose oil may have modest benefits for eczema.” Our brand-new Cochrane review was aimed at critically assessing the effects of oral EPO or borage oil (BO) on the symptoms of atopic eczema, and it casts considerable doubt on this somewhat uncritical view.

Here is what we did: We searched six databases as well as online trials registers and checked the bibliographies of included studies for further references to relevant trials. We corresponded with trial investigators and pharmaceutical companies to identify unpublished and ongoing trials. We also performed a separate search for adverse effects. All RCTs investigating oral intake of EPO or BO for eczema were included.

Two experts independently applied eligibility criteria, assessed risk of bias, and extracted data. We pooled dichotomous outcomes using risk ratios (RR), and continuous outcomes using the mean difference (MD). Where possible, we pooled study results using random-effects meta-analysis and tested statistical heterogeneity.

And here is what we found: 27 studies with a total of 1596 participants met our inclusion criteria: 19 studies tested EPO, and 8 studies assessed BO. A meta-analysis of results from 7 studies showed that EPO failed to improve global eczema symptoms as reported by participants and doctors. Treatment with BO also failed to improve global eczema symptoms. 67% of the studies had a low risk of bias for random sequence generation; 44%, for allocation concealment; 59%, for blinding; and 37%, for other biases.

Our conclusions were clear: Oral borage oil and evening primrose oil lack effect on eczema; improvement was similar to respective placebos used in trials. Oral BO and EPO are not effective treatments for eczema.

The very wide-spread notion that EPO is effective for eczema and a range of other conditions was originally promoted by the researcher turned entrepreneur, D F Horrobin, who claimed that several human diseases, including eczema, were due to a lack of fatty acid precursors and could thus be effectively treated with EPO. In the 1980s, Horrobin began to sell EPO supplements without having conclusively demonstrated their safety and efficacy; this led to confiscations and felony indictments in the US. As chief executive of Scotia Pharmaceuticals, Horrobin obtained licences for several EPO-preparations which later were withdrawn for lack of efficacy. Charges of mismanagement and fraud led to Horrobin being ousted as CEO by the board of the company. Later, Horrobin published a positive meta-analysis of EPO for eczema where he excluded the negative results of the largest published trial, but included results of 7 of his own unpublished studies. When scientists asked to examine the data, Horrobin’s legal team convinced the journal to refuse the request.

The evidence for EPO is negative not just for eczema. To the best of my knowledge, there is not a single disease or symptom for which it demonstrably works. Our own review of the data concluded ” EPO has not been established as an effective treatment for any condition”

Our new Cochrane review might help to put this long saga to rest. In my view, it is a fascinating tale of a scientist being blinded by creed and ambition. The results of such errors can be dramatic. Horrobin misled all of us: patients, health care professionals, scientists, regulators, decision makers, businessmen. This caused unnecessary expense and set back research efforts in a multitude of areas. I find the tale also fascinating from other perspectives; for instance, it begs the question why so many ‘respectable’ manufacturers and retailers are still allowed to make money on EPO. Is it not time to debunk the EPO-myth and say it as clearly as possible: EPO helps only those who financially profit from misleading the public?

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