The Fats of Life

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Statins and Mortality

Dr. Neville S. Wilson. – 15 July 2007.

The widely held belief that blood cholesterol levels are potentially harmful and should be lowered in order to prevent heart disease is a product of speculative and persuasive promotion by advocates of what has been called the “cholesterol hypothesis“.

The pharmaceutical industry has supported and exploited this initiative in a highly aggressive and commercially successful marketing strategy and has received tacit support from certain factions of the food industry, who have likewise seized on this  profitable opportunity by demonizing dietary fats and promoting the so-called benefits of low cholesterol foods.

This large scale anti-cholesterol strategy has not only failed to halt the progression of cardiovascular disease but has precipitated  a  trend toward an increase in the consumption of “low-fat” foods, amounting to an increase in dietary  processed carbohydrates, and unprecedented levels of obesity, diabetes and associated morbidity on a  world-wide scale.

The medical profession has, in many cases, unwittingly reinforced this perception by its preoccupation with cholesterol figures and reduction strategies, using complex logarithms to evaluate risk and predict mortality, without giving consideration to the unique circumstances of the individual, and the relevant factors of age, gender, race, and lifestyle, which are important determinants of morbidity and mortality.

The consequences of scare-mongering tactics by the food and drug industry, and high pressure marketing strategies aimed at influencing the prescribing habits of doctors, has created a climate of cholesterol-phobia which is highly manipulative, and not in the best health interests of unsuspecting patients.

STUDIES & MORTALITY:


Collectively, the major clinical trials, involving various strengths of statin drugs in a range of diverse population groups, has not demonstrated all-cause mortality benefits for patients.

Clearly, statins have not been shown to extend lifespan, while at the same time creating  the potential for a range of serious harmful effects in patients using them to lower their cholesterol levels.

In a large clinical trial involving over 10,000 participants randomly assigned to two groups for comparison, those using very high dose statins (Lipitor 80mg.) achieved markedly lower LDL-C levels than those using a much lower dose (Pravastatin 10mg.), and also had 26 fewer deaths in their group.

However, the total number of deaths from causes other than cardiac was GREATER in the high dose group, exceeding those in the low dose group by 31.

Overall mortality was thus not decreased by the aggressive treatment with high dose statins, prompting a cautionary word from an accompanying editorial stating that “further assurances as to the safety of this approach was needed”. (NEJM 2005).

Of further concern was the fact that 85% of the non-cardiac deaths in the high dose group was due to cancer, compared to 75% in the lower dose group.

In another randomized controlled trial (IDEAL) using high and low dose statins, 90% of the participants in both groups  experienced adverse effects of which more than half were serious, yet very little mention was made of these observations by the researchers.

In a 30 year follow up of one of the longest studies ever conducted (Framingham) it was conclusively shown that patients with higher than normal cholesterol levels lived longer than those with lower levels. In fact, “for every 1 mg/dl DECREASE in cholesterol there was a 14% INCREASE in death from cardiovascular causes.  ( JAMA 1987 April 24; 257:2176-2180)

The discovery that statin drugs are able to reduce cholesterol levels in humans, despite their inability to reduce mortality, continues to attract support from self-acclaimed authorities such as the National Cholesterol Education Programme (NCEP), The National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Health (NIH).

Protests from the Centre for Science in the Public Interest to these bodies, seeking an independent and unbiased review of their established cholesterol guidelines, have been met with refusal and a dogged unwillingness to recognise the abundant data which clearly contradicts the dogma espoused by these influential bodies.

Controversy reigns as to who should be targeted for statin therapy, since collectively the statin trials have not shown any benefit in reducing OVERALL mortality.

Lowering blood levels of cholesterol with drugs like statins has not saved lives, OVERALL, and has led to continued efforts and much cost, to try and identify the benefits and /or risks of statin drugs.

BENEFITS VS RISKS:


Although benefits have been reported in select groups of individuals, such as males with histories of established heart disease, and diabetic patients, especially those with peripheral neuropathy (i.e., damage to the nervous system) the potential risks, for a variety of unwanted adverse effects, have been widely documented, and are a source for growing concerns about long term toxicity and harm that are generally underestimated by health professionals.

Some of these adverse effects may be uncommon, but others occur frequently and are often wrongly attributed to ageing or other conditions, and are thus ignored or minimized. (BMJ 2006;332:1330-1332).

In some of the major statin trials subjects who were experiencing unwanted side-effects were exluded from further continuation in the trial, a move guaranteed to produce a favourable statin result for the trial sponsors.

THE STUDIES:

In the TNT Trial, more than 3000 people .were excluded because they did not fulfil the criteria for entry because they had abnormal liver functions, cancer or other diseases, and after commencing the trial with low dose statin, a further 5429 patients were rejected for a variety of reasons, which included adverse events, or unwillingness to continue.

In total, only 54% of the originally selected 18,468 participants were permitted to enter the trial. These participants were therefore healthier than a comparative section of the community using statin drugs, and yet they failed to achieve the advantage of improved lifespan while using the same drugs.

A review of the well-known clinical trials involving statins reveals little evidence for safety and benefit in women, the elderly, children and ethnic groups.

THE RISKS:

Targeting such individuals with statin drugs, a move which appears to be gathering momentum, particularly in the UK, places them clearly at risk for potential adverse effects, and exposes clinicians to the real charge of exploiting a hypothesized interventive protocol that is not evidence based.

The UK proposal to expand screening and extend the range of prescribing statins to the general public is frightening in terms of its potential for turning healthy individuals into hypochondriacs, or at worst, into statin cripples.

Of particular concern is the potential for childbearing women, who may unwittingly receive prescriptions or OTC statins, to conceive children with malformations, not unlike those experienced during the Thalidomide scare in the 1960’s.

There is now a growing body of concerned researchers who openly challenge the “cholesterol hypothesis” on sound scientific grounds, and who have demonstrated the limited, and thus insignificant, benefits reported in the wake of the major statin trials, and who caution against the indiscriminate use of statins based on figures alone.

CHOLESTEROL PROTECTIVE:

The scientific evidence is clear, that cholesterol per se, does not damage or “block arteries”, (as is so simplistically and incorrectly stated by health columnists and advertising propaganda), and that in many cases, high levels of cholesterol can be protective, especially in post-menopausal women, and that low levels of cholesterol can be harmful.

Research has shown that LDL-Cholesterol (the so –called “bad cholesterol” ) is able to provide protection against a wide array of infective organisms, by neutralizing the toxins produced by these organisms. LDL-C binds and inactivates 90% of alfatoxin, an extremely toxic chemical produced by the ubiquitous staphylococcal bacterias, and inactivates lipopolysaccharide, another harmful bacterial toxin. (Biol. Chem.258,5899-5904,1983) and (Infect.Immun 58,2375-82,1990)

Many correlations have been shown between low plasma levels of cholesterol and infective diseases. In the MRFIT study, the risk of death due to AIDS was correlated with low levels of cholesterol, a similar finding in patients with high risk for death following post-operative infection, or victims of oedematous chronic heart failure.

Low blood levels of cholesterol have also been shown to correlate closely with neurological effects such as violent or aggressive behaviour, and even depression and suicide, according to Prof. Matthew Muldoon, at the University of Pittsburgh, Pennsylvania.

These events are not likely to be recorded in trials, and are thus unlikely to be detected and reported, but there is a large body of evidence in support of this frightening phenomenon.

The evidence is thus supportive of the view, that despite limited benefits in specific population groups , statins not only fail, in the long-term, to save lives, but may endanger lives through their deprivation of normal healthy body functions such as the manufacture of essential hormones (testosterone, oestrogen, cortisone), the production of digestive bile acids, enhancement of the immune system, the maintenance of healthy nerve myelin sheaths, and the stabilization of cellular membranes.

Statins produce their cholesterol lowering effect by blocking the mevalonate pathway in the liver, but in so-doing they also block the synthesis of other vital products such as Ubiquinone, Dolichols, and Squalene, known for their capacity to maintain efficient cellular function, healthy heart muscle and anti-cancer properties.

Interrupting these potentially life-preserving functions, as statins do, can lead to the wide array of side effects such as muscle pain and weakness (far more common than documented), nerve damage (also common and under diagnosed), dizzy spells, memory loss, pancreatitis, cancer, depression, and mood swings.(Statin Drugs Side Effects by Dr. Duane Graveline, M.D.)

HEART FAILURE ?

Furthermore, lowering blood cholesterol, may, in itself, be harmful in terms of causing heart failure, the so called “cholesterol paradox”.

A recent study reported in the Journal of American Coll. Cardiology supports earlier findings (1998) that low levels of total cholesterol and lipoproteins were associated with impaired survival in patients with heart failure.
However, contradicting these findings is a study from UCLA that heart failure patients may benefit from statin usage.

Several lines of study, nevertheless, show that heart failure can be precipitated by statins since they inhibit the synthesis of coenzyme Q10 which plays a vital role in cellular energy production, particularly in heart muscle cells.

Dr. Julian Whitaker, an authority on coenzyme Q, has warned that the increasing incidence of heart failure witnessed today is likely a consequence of the widespread use of statins and their interference with normal coenzyme Q levels in heart muscle.

STATIN BENEFIT:

Where benefits are linked to statin therapy ( as there have been ) these have been shown to be entirely independent of the cholesterol levels achieved, and are likely due to the anti-inflammatory properties of the statins in use.

Focusing on blood cholesterol levels only, and ignoring other important risk factors and risk markers, is short – sighted , irresponsible and costly, both in terms of national economic burden, and the subsequent emotional, physical, and mental health burden that unsuspecting individuals may have to bear.

LONG-TERM BENEFITS VS RISKS ?

Because statins are intended to be a lifelong treatment, any individual subjected to such intensive and continuous drug usage needs to be assured, on the basis of clear scientific evidence, that the benefits of taking such drugs outweigh the risks.

We cannot safely predict the long term adverse effects of high, or even modest, dosages of statin drugs, and lessons should be learned from the unfortunate experiences of COX-2 inhibitors and HRT therapy, and recent experimental cholesterol-lowering drugs, like Torcedrapid, which caused many unnecessary deaths.

It is the responsibility of physicians to provide patients with the true facts regarding benefit and risk, thereby enabling them to make informed decisions about their own wellness management, and to employ prescribing habits that are based on evidence rather than assumption.

Dr. Neville Wilson

Medical Suite

The Leinster Clinic

Maynooth

15 July, 2007

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Reviewing Our Approach to the Obesity Crisis

(originally published Feb 1st 2011)

The traditional approach to the management of obesity has been the recommendation to “diet and exercise”, and to elicit the support of family doctors with aims to modify unhealthy lifestyle habits.

The limited success of such conventional strategies is clearly apparent in the unabated escalation of global obesity and its wide range of adverse consequences for human health.

It is appropriate, therefore, to review current paradigms in respect of nutritional policy, and to evaluate the content of public health messages according to the principles of emerging evidence.

A review of the relevant literature suggests that conventional dietary theories do not reflect the consensus findings of critical science regarding nutritional requirements for optimal health.

Within this context there is an opportunity for national health bodies to revise the content of public health messages, and to facilitate a paradigm shift in perceptions of “healthy” and “unhealthy” foods, not only for health professionals, but also for the public who are heavily influenced by dietary guidelines and nutritional propaganda.

THE MESSENGERS:

While the co-ordinated efforts of national bodies are to be welcomed and supported, their failure to escape the influence of American dietary policy has long been apparent. There exists now an opportunity to establish national dietary guidelines which are divorced from the political and economic persuasions which gave content to the policies of the American Heart Association (AHA) four decades ago, and which still influence bio-medical models on a global scale. ( 1 )

Ireland has an opportunity to establish independent dietary policies based on emerging nutritional data and local health requirements, and to take a lead in the “war” against unhealthy eating habits, as it did in the war against the unhealthy smoking habits of the past.

The understandable reservations of many GPs to address lifestyle issues with their patients can be circumvented by a renewed confidence rooted in credible research, and the provision of updated resource material for patients which is innovative, science based and user friendly.

THE MESSAGE:

Public health messages should reflect current evidence in respect of dietary impact on health outcomes. Outdated and politically driven information from American sources should be critically evaluated and discarded. (2)

The current “war on obesity” is essentially a “war on fats”, as portrayed ad nauseum in the public media and sections of the medical literature which constantly echo the outdated dogma of the AHA.

Current health messages consistently and incorrectly portray saturated fats as harmful, and fail to distinguish between these healthy fats, and the potentially unhealthy dietary fats, such as transfats, interesterified fats and industrially produced polyunsaturated fats, which predominate in commercially prepared foods and are widely portrayed as “healthy”.

They also fail to distinguish the nutritional differences between simple and complex carbohydrate groups and their variable impact on health within different sub – groups, such as those who are carb-sensitive or have grain allergies.

Similarly, distinctions have not been made between “complete proteins” as found in animal and dairy products, and the “incomplete proteins” derived from nuts, seeds and legumes, and the deficiencies of vegetable proteins.

National Health policies reflect dietary guidelines that have been historically portrayed by the United States Dept. of Agriculture (USDA) and its past Food Pyramids. ( 3)

A review of the critical evidence will show that these guidelines are more likely to contribute to, rather than prevent, the current escalation of obesity and diabetes and their related consequences.

Such diets can hardly be called “prudent”, as defined by the AHA.

PART II

THE PYRAMIDS:

The USDA Food Pyramid was introduced in 1992 and updated in 1995, and its continued incompatibility with clinical evidence prompted a further review and revision in April 2005, and was named “MyPyramid” (4)

MyPyramid, despite its marked improvement over previous pyramids, continues to ignore emerging clinical evidence in respect of healthy dietary requirements for fats, proteins and carbohydrates, and harbours deficiencies which renders it an incomplete, and somewhat limited, food guide for health professionals and the public alike.

The acknowledged distinctions in MyPyramid between simple and complex carbohydrates are to be welcomed, but the distinctive differences between healthy and unhealthy fats are blurred, while all proteins are treated alike, without recognition being given to the nutritional differences between “complete” animal proteins and “incomplete” vegetable proteins.

The anti-fat and anti-cholesterol policies of the AHA continue to dominate the current dietary guidelines, and continue to be embodied within the Pyramid, rendering it an inadequate testimony to the recognised health benefits of saturated fats, which contrast sharply with the ill effects of unsaturated fatty acids.

According to its website, the MyPyramid Education Framework “provides specific recommendations for making food choices that will improve the quality of an average American diet”.

In reality, the poor quality of the American diet and its adverse health outcomes are universally recognised, prompting pertinent questions about the content and quality of the dietary guidelines that are endorsed by all major health bodies in the USA.

Since Irish dietary guidelines are heavily influenced by the USDA model, it is appropriate to evaluate current national guidelines against the backdrop of escalating obesity and diabetes, given the limited success of current interventive strategies.

It is disconcerting to note the repeated mantra of the USDA in its recommendations for “lowered intakes of saturated fats, transfats, and cholesterol, and increased intake of fruits and vegetables, and whole grains to decrease risk for several chronic diseases”.

By their inclusion of saturated fats with unhealthy transfats in their dietary warnings the authors ignore the findings of critical science that have established saturated fats as healthy and capable of conferring multiple health benefits that are clearly absent from all other types of fat.

The guidelines repeatedly recommend “fat free” or “low fat” milk, “low fat” meat, and the use of “vegetable oils rather than tropical oils” because vegetable oils “do not raise LDL (“bad”) cholesterol”.

This misleading statement ignores the fact that saturated fatty acids (SFA), more than any other fats, raise beneficial HDL levels and have greater cardio-protective properties.

Monounsaturated (MUFAS) and polyunsaturated fats (PUFAS) are recommended in place of saturated fats (SFA) while no reference is made to the potential harm arising from excess PUFAS.

The reference to “limited evidence” for the cardiovascular benefits of omega 3 ignores the wealth of evidence that attests their uniquely protective properties at several levels of disease.

AMERICAN HEART ASSOCIATION (AHA) GUIDELINES:

The AHA continues to promote the perception that dietary fat intake, obesity and heart disease are causally linked, and that “low fat” and “fat free” are synonymous with “heart health”. Their policy statements are clearly presented on their official website and uncompromisingly warn of the “dangers” to health presented by dietary saturated fats. ( 5 )

It states, “ eating food that contains saturated fats raises the level of cholesterol in your blood. High levels of blood cholesterol increase your risk of heart disease or stroke. Be aware too, that many foods high in saturated fat are high in cholesterol which raises your blood cholesterol even higher”.

The website then recommends preferable substitutes for saturated fat, such as vegetable oils and vegetable replacements for traditional meat and dairy products. It also recommends the avoidance of tropical oils in favour of vegetable oils.

Numerous lines of critical evidence have not only challenged the substance of these recommendations, but have repeatedly demonstrated their failure to support optimum health.

National dietary guidelines which echo these principles are similarly culpable, and not only distort, or ignore, the findings of science, but instil in the public mind unwarranted fears, and a conscious preference for foods that are labelled “low fat”, yet lack nutritional value, and carry the potential for health impairment.
Such foods invariably contain high levels of polyunsaturated fats, trans fats or vegetable oils, and carry risks for health that are absent from saturated fat consumption. (6)

Tropical oils at worst are atherogenically neutral, and at best can significantly raise HDL levels, lower cholesterol in hypercholesterolaemic people, and confer anti-carcinogenic and anti-microbial benefits, and their exclusion from a diet, partly due to the soybean lobby, is the loss of a highly beneficial functional food.

The continued vilification of these important dietary fats undermines the opportunity for consumers to make, and enjoy, healthy food choices, and their avoidance, as a result of widespread scare-mongering, must be viewed as a contributory factor in the current epidemic of chronic ill health.

The AHA Guidelines derive from the USDA recommended daily allowance (RDA) of carbohydrates (60%), fats (30%) and protein (10%) with recommendations to limit saturated fats to 7% of daily energy requirements.

Clinical outcomes from research trials which have tested these traditional proportions against variable alternatives have demonstrated greater health benefits from those with reduced carbohydrate proportions and increased fat or protein proportions.

These findings must serve to question the wisdom of conventional guidelines, and prompt a willingness to reshape dietary recommendations in accordance with emerging evidence. (7)

Within the current context of contradictory science and failed popular hypotheses, the prevailing dogma that high carbohydrate / low fat diets represent the “prudent diet” is no longer tenable. (8)

PART III

DIETARY POLICY REVISIONS:

The Harvard School of Public Health produced an alternative food guide to the USDA Food Pyramid, and called it “Healthy Eating Pyramid” in an attempt to improve the perceived weaknesses of MyPyramid. (9)

However, this pyramid continues to promote an unwarranted fear of fats, and calls for a preference of lean meat over animal fats, even though acknowledging that “healthy fats” exist, which it places alongside “healthy carbohydrates”.

The Harvard Pyramid does have the merit of recognising that it is the type of fat, rather than the total content of fat, that is important for health, but relegates red meat and butter to its top shelf, recommending them to be used sparingly in the diet, on the grounds that “red meat is high in saturated fat, and is related to increased risks of colon and prostate cancer, as well as diabetes”. (9)

These fears have repeatedly been shown to be unfounded, with experimental evidence showing that it is dietary carbohydrates, rather than fats, which adversely affect insulin resistance and increase the risk of developing diabetes and weight gain and associated disorders. (10)( 11 ) (12 )
( 13) ( 14)

Dr. Walter Willett, of the Harvard School, gives recognition to these findings and acknowledges that high-fat/ low-carbohydrate diets are good for weight loss, and correctly states that “carbohydrates are not an essential part of the human diet”, and that fuel for the brain can be generated through ketones, from proteins and fats, as an alternative to glucose.

While the Harvard School of Public Health perpetuates the dietary dogma of the American Heart Association (AHA), that saturated fats are harmful because “they raise blood cholesterol”, it nevertheless fails to reflect in its literature, the growing awareness that saturated fats improve the anti-atherogenic lipid profile, and enjoys numerous metabolic advantages over carbohydrates and unsaturated fats.

REVIEWING THE EVIDENCE:

The Food and Agriculture Organization of the U.N. (FAO), in conjunction with the World Health Organization (WHO), produced an Expert Consultation Report in 1994 which reflected the policy statements of the AHA that dietary fat consumption was causally linked to obesity, coronary heart disease (CHD) and some cancers.

Experimental evidence from many lines of study now serve to refute the policy statements of the FAO, and call for a review of the claims regarding saturated fat intake. (15)

The outcomes from several prospective and observational studies conclude that there “is no, or small, association between total daily fat intake and obesity, weight gain, CHD and cancer. (16) (17)

Many of these studies show that low-fat / high carbohydrate diets did not favourably affect serum lipids, fasting serum glucose, fasting serum insulin, or blood pressure, compared with high fat intake diets. (18) (19)

Current recommendations to reduce total fat intake to <30% of daily energy were tested against low carbohydrate (<60%), non-energy restricted diets and resulted in LDL-C reductions, but did not improve weight loss after 12 months, and furthermore, caused an increase in triglycerides and reductions in HDL-C. (20)

The conventional view which favours dietary fat restriction has become increasingly untenable in the wake of research outcomes which expose the lack of scientific credibility for such recommendations.

Reductions of total fat to 30% of daily energy appear to compromise the optimal intake of beneficial fatty acids, particularly when substituted with carbohydrates, according to Hu et al (21) and Mozaffarian et al (22)

In 2002 Willett and Leibell reported the lack of evidence for correlations between obesity and fat intake, and stated that “fat consumption within the range of 18% to 40% of energy appears to have little, if any, effect on body fatness. (23)

Their conclusions were, “ in the USA a substantial decline in the percentage of energy from fat during the last 2 decades has corresponded with a massive increase in the prevalence of obesity. Diets high in fat do not appear to be the primary cause of the high prevalence of excess body fat in our society and reductions in fat will not be a solution”

DENYING THE EVIDENCE:

The UK Food Standards Agency (FSA) has launched a “Saturation Fat & Energy Intake Programme” in an attempt to lower consumer fat intake to below 11%, and have called on businesses to set interval targets for developing and promoting reduced fat, milk cheddar cheese and yogurt products. (24)
By so doing they have failed to acknowledge the real culprits and will thus restrict the healthy food sources while promoting those that endanger health.
The European Dairy Association (EDA) hosted an international Conference in Copenhagen on 25 Sept. 2009 at which a consensus report from experts found no health concerns for dairy consumption, and that fears about saturated fat intake were unfounded and not supported by recent scientific studies. (25)

Fact sheets from the Irish Nutrition & Dietetic Industry (INDI) also convey concerns about “elevated cholesterol”, without making reference to the health benefits of raised HDL which can arise from saturated fat intake. They do correctly advise that “not all types of fats raise blood cholesterol” but do not clarify the distinction. (26)

The documented recommendations to limit fats to 33% of intake and saturated fat to one third of these are linked to statements that “saturated fats increase blood cholesterol and should be limited” and that dietary “hydrogenated vegetable oil” indicates the presence of saturated fats in a product. Clearly, this is not factual. Furthermore, polyunsaturated (pufas) and monounsaturated fats (mufas) are recommended as preferences to saturated fats.

The conventional recommendations to choose polyunsaturated fats and monounsaturated fats on the basis that they are “less harmful to our bodies than saturated fats, and are found in most vegetable oils, for example sunflower oil, olive oils and rapeseed oils” do not reflect the evidence from 27 controlled studies showing that unsaturated fats are in fact more detrimental to health than saturated fats, and that increasing levels of unsaturation diminish the beneficial effects of HDL. (27)

In other words, dietary saturated fats yield greater health benefits than do either the MUFAS or the PUFAS, and these findings are supported in a growing number of comparative studies.

PART IV

THE HISTORICAL EVIDENCE:

Historically, the health benefits in respect of obesity and diabetes, for fat consumption compared to carbohydrate consumption, was evident in a comparison of the Kikuyu and Maasai tribes in Africa. (28)

The Kikuyu lived mainly on cereals and had a mortality rate from respiratory disorders 10 times greater than the Masaai whose staple diet was animal meat and blood. The Maasai were found to have normal blood cholesterol levels and did not suffer with obesity or diabetes.

In a Brazilian study the adverse effects of public health recommendations to reduce fat intake resulted in an increase in the prevalence of obesity, from 17% to 24%, in at risk groups who reduced their intake of fat and increased their intake of carbohydrates. (29)

North American Indians consumed high levels of saturated fat for centuries and only experienced an epidemic of obesity, diabetes, heart disease and cancer when they abandoned their pemmican diet, consisting of 50% protein (lean meat) and 50% fat.

The Eskimos, likewise, enjoyed excellent health while consuming seal meat and seal fat in a proportion of 80% fat and 20% protein.

Observations from the Framingham Study show that those who ate the most saturated fat and the most calories, and ate the most cholesterol, were the most physically active. They also weighed the least, and had the lowest levels of serum cholesterol, were the most healthy, and had the lowest risk of heart disease. (30)

Obesity is not caused by saturated fat ingestion, since dietary fat is a source of energy and does not stimulate insulin secretion, which is a natural response to a high carbohydrate intake.

Saturated fatty acids sustain cellular health and are more likely to support weight loss through a thermogenic effect. Medium chain fatty acids (MCL) like lauric acid, utilise more calories than what they produce for their oxidation, resulting in higher metabolism and body weight loss. (31)

Dietary saturated fats confer additional benefits by inducing a state of satiety, thereby diminishing the need for frequent snacks, a common and inevitable consequence of consuming high carbohydrate meals.

FATS AND WEIGHT LOSS:

Saturated fats predominate in animal fat and tropical oils, and to lesser amounts in vegetable oils, and can also be synthesised from excess dietary carbohydrates. The medium chain fats (MCT) are found in coconut oil, palm kernel oil, and butter, while the longer-chain fats (LCT) occur mainly in meat and dairy products.

Studies have shown that amongst their many health benefits saturated fats can increase energy, boost immunity, and optimise healthy digestion and nutrient absorption. Their capacity for weight reduction and cardiovascular protection are becoming increasingly evident in clinical studies.

Since medium- chain fats (C6 –C 10) have a lower caloric value than longer –chain fats (C12-C18) they are readily metabolised and are an efficient source of energy for immediate use by the organs and muscles, and are thus not stored as fat. (32)

Medium – chain fats also enhance thermogenesis, thereby enabling weight loss to occur. ( 33) They have also been shown to promote ketone production, which can be a source of brain energy, in addition to the utilization of glucose. (34)

A subtle shift in the scientific consensus regarding fats and their health benefits has occurred since the earlier attacks by the AMA on Dr. Robert Atkins for his promotion of high fat / low carbohydrate diets. Despite the several criticisms levelled against the structure of the Atkins diets, current evidence favours the principle that high-fat / low-carbohydrate diets confer health benefits which are strikingly absent in high – carbohydrate / low fat diets as promoted by the AHA and AMA.

The recent acknowledgement by Dr. Walter Willett of Harvard Public School, that the “low fat” message has failed the test of time, calls for a renewed policy statement that incorporates saturated fats into current dietary guidelines, and abandons the anti-cholesterol, anti-fat rhetoric that has not only failed to produce health benefits, but may have contributed to the current epidemic of obesity and escalating rates of diabetes. (23)

Experimental evidence from many lines of study now serve to contradict the food policy statements of the AHA and the FAO, judging them to be, not only inaccurate, but unsafe. (35)

Dr. Frank Hu of Harvard recognised this fact in 2007 at which time he stated “the need for a paradigm shift “ with respect to saturated fats. (35)

PART V

GOOD FATS – BAD FATS:

Dietary saturated fats do not cause obesity, because, unlike carbohydrates, they are not stored and are readily converted into energy for bodily requirements.

The hydrogenated and partially hydrogenated oils which now predominate in processed foods are the real culprits. During the process of fabricating artificial “food” trans-fatty acids are yielded, which by contrast to saturated fatty acids, reduce beneficial HDL levels, raise LDL, increase insulin secretion, and decrease the immune potential by an adverse effect on B cell response and T cell proliferation.

The eventual recognition of trans-fats as a health hazard has prompted their mandatory inclusion on food labels as of 2006, but levels below 0.5 grams may be reported as “zero level” in any given product, thereby masking their presence in popular food choices, yet maintaining their potential for toxicity and harm to human health.

An unintended accumulation of trans-fats may thus occur in the body through the ingestion of several products which are inaccurately labelled as “zero levels”.

The many public health statements that collectively include saturated fats and trans fats in their call for restricted consumption are ill conceived and distortions of fact. These 2 fats are distinctly different from one another in their chemical and physical structure, as well as in their biochemical actions and outcomes for health.

Saturated fatty acids are natural fats while trans fats are artificially created fats. Their vast differences should not be blurred by treating them alike.
The former will support health. The latter will destroy it.

TYPES OF FATS:

Saturated fatty acids (SFA) are characterised by the absence of double bonds with all carbon bonds occupied by a hydrogen atom. This renders them stable, resistant to oxidation, and thus less likely to form free radicles when heated, as is the case with unsaturated fats.

These stable fats predominate in animal fats and tropical oils, like coconut oil, and in smaller amounts in vegetable oils. The body can synthesize saturated fatty acids from excess dietary carbohydrates, if required.

The short – chain (SCT) and medium- chain (MCT) fatty acids are rapidly absorbed after being ingested and stored as a source of quick energy. They therefore do not have the propensity for weight gain that commercial vegetable oils have. (36) (37)

They serve a multitude of vital bodily functions and their dietary absence, or restriction, can lead to dire health consequences.

The unsaturated fatty acids are those with one (monounsaturated) or more (polyunsaturated) double bonds, and become increasingly unstable with loss of saturation, and may result in abnormal and unhealthy lipid formation, which does not occur with the ingestion of fats that are fully saturated. (38)

The main monounsaturated fatty acid (MSFA) is oleic acid (C18) and is derived from olive oil, sesame oil and a variety of nuts. The body can synthesize these fats from SFA when required.

Palmitoleic acid (C16) is a MSFA found almost exclusively in animal fats and has strong anti-microbial properties.

Polyunsaturated fatty acids (PUFA) have 2 or more double bonds, are less stable than SFA, and predominate as either linoleic acid (2 double bonds) or linolenic (3 double bonds).

They are not made by the body and are dependent on food sources in equal ratios. The dietary excess of omega 6 with respect to omega 3 has been identified as a significant cause of a wide range of chronic disorders, and their ubiquitous presence in processed foods presents a health hazard for unsuspecting consumers. (39)

Industrially produced PUFAS such as corn, safflower, soy and sunflower oils are highly unstable and should be avoided because of their propensity to form harmful free radicles and endanger health. They are present in the vegetable oils which are propagated as part of the “prudent diet”. (40)

Evidence suggests that modern diets are excessively high in PUFAS (30%) and that safe levels should not exceed 4% of daily caloric intake. (41)

TRANSFATS are not natural. They are produced by bombarding PUFAS with hydrogen (partial hydrogenation) thereby giving them a longer shelf life, thus serving as a preferential source for the many commercially prepared spreads on the market.

According to several recent studies by Roos, Judd, and Mensink, whenever trans-fats replace saturated fats, beneficial HDL levels decrease, with a dose response effect. (42)
Since food labelling regulations do not require levels below 0.5g to be stipulated on any given product, an unintended accumulation of dietary trans-fats may unwittingly occur through the ingestion of several food sources containing 0.49g of “hidden” trans-fats.

Interesterified fats have been present in commercially prepared foods since the 1950s. Like transfats, they are chemically altered oils, artificially manufactured through fractionation, hydrogenation and inter-ester-ification.

While this fat may be trans free, it can contain chemical residues, hexanes and a variety of waste products that are harmful to cellular structures.

Through inter-ester-ification a vegetable oil is combined with stearic acid, and on this basis food labelling is not required to indicate “interestified”, but may in accordance with FDA licensing use the term “high stearate” on a label.

Food products which are labelled as containing a vegetable oil are likely to contain interesterified fats or transfats.

The elimination from the diet of artificially prepared foods, vegetable oils and many alternative spreads to replace butter, should be encouraged by health professionals in efforts to redirect consumers back to natural and health giving foods, such as butter, whole milk, eggs, animal protein and tropical oils.

PART VI

THE OTHER CULPRITS:

Many popular foods and beverages contain unhealthy levels of high-fructose corn syrup (HFCS), which carries serious and unsuspected health risks.

Their ubiquitous presence in a wide variety of commonly consumed processed foods and carbonated beverages represents a hidden risk for diabetes, obesity, and several chronic disorders, yet they are overlooked as a major threat to human health and receive scant attention from health authorities. (43)

Gaby et al have presented the adverse effects of dietary fructose (44) and recent studies have demonstrated the link between HFCS and the metabolic syndrome. (45)

Because fructose is cheaper than sucrose (table sugar) its ready assimilation into a wide array of popular food products has become a common practice in the food industry, and has largely been ignored by the health industry, despite growing evidence of its associations with type 2 diabetes in the USA. (46)

As far back as 1980 the warning signs were apparent that high fructose levels impaired insulin sensitivity and posed a risk for diabetes and obesity. (47)

Compared to table sugar, which comprises sucrose (50%) and fructose (50%), HFCS contains 80% fructose and 20% glucose, and despite having similar amounts of calories to table sugar, its metabolic effects are different. Fructose results in increased triglyceride synthesis and fat storage in the liver because of its rapid rate of metabolism, compared to glucose which can be stored and utilised as energy.

Fructose ingestion, even in moderate amounts (48) can give rise to non-alcoholic fatty liver disease and impair insulin resistance, leading to impaired glucose metabolism and the metabolic syndrome. (49)

In addition to the high fructose intake from several processed foods, added consumption may occur with excessive fruit and vegetable intake, and with the great emphasis placed on these food groups in the dietary guidelines, at the expense of dietary fats, an unsuspectingly high level of fructose may occur.

It is worthy of note, that no scientific evidence supports the recommendation to eat 5 portions of fruit and vegetables daily, however innocuous such recommendations may appear to be. (50)

Fructose, rather than glucose, can precipitate the formation of toxic advanced glycation end products (AGES) by reacting with lipids, and adding to the complications of diabetes by inducing neuropathy and retinopathy, neuro-degenerative disorders, and even ageing. (51)

In the light of these findings policies which promote carbohydrate intake at the expense of saturated fats should be reviewed as a matter of urgency in the interest of public health.

PART VII

CALORIE RESTRICTION – THE EVIDENCE:

Caloric restriction has repeatedly demonstrated retardation of the ageing process and a marked reduction of risk for chronic disease.

Even minimal caloric reductions may confer health benefits and prolong lifespan. These effects were demonstrated in a 20 year study of rhesus monkeys whose caloric intake was reduced by 30% resulting in a 13% mortality rate from age-related causes, compared to 37% in those whose diets were not calorie restricted. (52)

Of note is the observation that while they lost fat weight, they did not lose muscle mass and sustained brain volume and cognitive and motor function.

Markers of ageing were reduced during 6 years of observation in individuals who reduced their caloric intake by 20%. (53)

Caloric restriction has been shown to prolong life span also by preserving cardiac function through increased mitochondrial formation (54)

More recently, nutrients have been identified which mimic caloric restriction and modify genetic expression leading to retardation of the ageing process. Gene regulators called paroxisome proliferator-activated receptors (PPARS) are triggered by calorie restriction, resulting in healthy fat and carbohydrate metabolism and preservation of glycaemic control. (55)

CARBOHYDRATE RESTRICTION:

The assertion that high-fat diets promote weight gain and adverse health outcomes is false, and should be assessed by evidence-based principles.

Accordingly, the benefits of conventional diets, which promote high carbohydrates and restrict fats, should be tested by these same principles.

Carbohydrate restricted diets were the standard treatment for diabetes before the advent of insulin and anti-diabetic medications, and clinical studies have consistently shown that low-carbohydrate diets improve glycaemic control in diabetic patients (56) (57) (58) (59) (60) and induce weight loss for up to 24 months. (61)

The AHA officially recommends a daily intake of 55% carbohydrate energy per day, which may amount to 75% if recommendations are followed.
Such high levels of carbohydrate intake are likely to advance rather than retard the diabetic process.

In a randomised controlled trial (RCT), involving 53 healthy obese females, a low carb diet was compared with a 55% carb diet (AHA type) and produced a weight loss of 8.5 kg compared to 3.9kg, which continued while the weight loss in the high carb group levelled out. The authors described the results as “ a surprising challenge to prevailing dietary practice”. (Brehm 2003)

Carbohydrate restricted diets have been widely tested to evaluate their effects on weight loss and long term health benefits.

In a RCT by Samaha et al comparing the outcome of a low-carb diet (1630 kcal/day) to a low fat diet (1576 kcal/day) the low carb group lost 5.8 kg compared to the low fat group ( 1.6 kg ) which was sustained at 6 months, with a triglyceride reduction of 20% compared to 4% in the low fat group.
(62)

This trial showed that calorie content is not as predictive for weight loss as is carbohydrate restriction.

Compared with a conventional diet a RCT involving 63 obese men on a low-carbohydrate demonstrated greater weight loss (6.8% vs 2.7%) (63)

A low carbohydrate – ketogenic diet, without any restriction of fats, has repeatedly been shown to produce healthy outcomes with improved lipid fractions (64)

In a 12 week study of 60 participants the NCEP diet was compared to a modified low carbohydrate diet (MCL) and found to be less effective for weight loss. (65)

A low carbohydrate, ketogenic diet improved glycaemic control in obese type 2 diabetic patients allowing many to reduce or eliminate their medication.
Compared to a low glycaemic reduced calorie group these patients had greater weight reductions ( 11.1kg vs 6.9kg) and improved their HDL levels by 5.6 times. (66)

These findings correlate with those from earlier investigations into the effects of carbohydrate restricted diets on diabetes and the metabolic syndrome.
(67) (68) (69) (70) (71)

Yancy et al demonstrated that reducing carbohydrates, rather than fats, produced not only greater weight loss ( 12.9% vs 6.7% ) with improved lipid profiles, but also better participant retention, disproving the notion that low carbohydrates diets are not sustainable. (72)

In a Spanish – ketogenic Mediterranean diet, with unlimited calories, the significant reductions in body weight, blood pressure, triacylglycerols and glucose prompted the researchers to dispel notions of the “healthy diet” as embodied in the Food Pyramid, which calls for fat reduction. (73)

In a review of 6 studies involving 594 participants, over a period of 3 to 18 months, researchers found that reducing dietary fats did not confer any significant health benefits (74)

In a high protein (30%) – low carbohydrate (40%) comparative study with low protein ( 15%) – high carbohydrate (55%) 58 obese subjects with hyperinsulinaemia experienced greater benefit, again raising questions about the health benefits of the conventional 55% carbohydrate recommendations.
(75)

And again, in a review of the Cochrane Database greater weight loss was found to occur with low carbohydrate rather than with low fat diets. The authors concluded that “low fat diets do not cause weight loss.” (76)

In a carbohydrate restricted diet, with either a high fat (45%) or high protein (34%) weight loss was similar ( 10.2kg vs 9.7kg ) with slightly greater benefit for the high fat diet, and similar improvements in insulin resistance and lipid profiles. (77)

Nordman et al (2006) reviewed 5 trials involving 447 individuals and concluded that greater weight loss (-3.3 kg ) occurred with low carbohydrate diets than with low fat diets ( -1.0 kg) within 12 months. Cardiovascular risk factors were more favourable with carbohydrate restriction than with fat restriction. (78)

And again, in a recent ( 2009) RCT of 200 overweight subjects a carbohydrate restricted diet led to greater weight loss and greater cardiovascular benefit than a fat restricted diet. (79)

PART VIII

FAT STORAGE AND OBESITY:

Saturated fats do not promote weight gain or obesity as they are readily converted into energy for physiological requirements.

Dietary carbohydrates, however, are transferred into triglycerides and stored in adipocytes as fat under the enzymatic actions of glycerol-3-phosphate dehydrogenase. These adipocytes (fat cells) regulate their size and number by secreting command signals such as leptin, adinopectin and glycerol-3-phosphate dehydrogenase.

Recent advances in the study of adipocytes have identified them as important mediators in many physiological processes that regulate energy metabolism, or cause obesity. Their capacity to differentiate in response to several transcription factors is currently the focus of enquiry into underlying genetic disorders associated with obesity. (80)

No longer are adipocytes considered to be a passive energy storage organ, but an active endocrine organ which secretes bioactive peptides, called adipocytokines, which act through autocrine, panacrine and endocrine systems. (81)

Adipocytes communicate with their environment through sending and receiving signals which determine their biological functions. (82)

Brown fat cells, by contrast to the white fat apidocytes, regulate the physiological requirements of energy by burning calories, and may thus reduce the amount of white fat in the body.

The white fat cells serve as storage cells and may increase in size to accommodate excess dietary triglyceride, but may also increase in number, through the mutation of reserve preadipocytes, under the stimulation of insulin.

It is important, therefore, to restrict the potential for white fat cells to increase in number during childhood, since they will remain present for life.

WEIGHT MANAGEMENT:

Unwanted weight gain may occur through an increase in calorie consumption, or through a decrease in the command signal network, which is a likely cause for age related weight gain.

If the major share of calories derive from an abundance of carbohydrate ingestion, as recommended in conventional food plans, a greater liklihood exists for weight gain and its related problems.

Novel ways of interrupting the command signal network, or of reducing calories, may include any of the following .

a) Caloric Restriction to under 15001800 calories per day significantly improves insulin sensitivity (83) and extends longevity. (84)

b) Carbohydrate Restriction as shown from numerous trials is safe, effective and sustainable, and offers greater health benefits than conventional high carbohydrate diets. (85)

c) Restoring Insulin sensitivity through nutrient intervention, such as chromium, (86) magnesium (87) cocoa polyphenols (88) omega 3 (89)

d) Alpha – glucosidase inhibition with Acarbose.

e) Alpha – amylase inhibitors, such as Phaseolus vulgaris, an extract from the white kidney bean, appears to have the potential to significantly inhibit the absorption of complex carbohydrates (90) and also boosts cholecystokinin (CCK) which improves satiety with a reduced urge to eat. (91)

f) Amylase inhibition with the African mango Irvingia gabonensis, not only reduces body weight, but improves lipid profiles in obese patients. (92) (93)

g) Dietary fibre has been shown to minimise the post-prandial insulin surge and improve weight loss through decreased carbohydrate absorption. (94)

h) Restoring hormonal balance by regulating oestrogen and testosterone levels, thyroid stimulating hormones, and circulating brain
serotonin with L-tryptophan. ( 95)

i) Increased physical activity to improve insulin activity. (96)

j) Boosting resting energy expenditure by enhanced thermogenesis with medium-chain saturated fatty acids. (97)

CONCLUSION:

Conventional dietary recommendations have failed to halt or reverse a trend that continues to impact negatively on human health, while simultaneously stretching health and financial resources beyond redemption.

It is timely to review the content of traditional food guidelines and to align them with the conclusive evidence of critical science, and to offer dietary information that serves, not political agendas, but the best health interests of the nation.

It is fitting that Dr. Sylvan Lee Weinberg, a former President of the American College of Chest Physicians and editor of The American Heart Hospital Journal indicted current dietary policies of low fat/high carbohydrate for their “unintended role in the current epidemics of obesity, lipid abnormalities, type II diabetes, and metabolic syndrome”, and that “this diet can no longer be defended by appeal to the authority of prestigious medical organizations, or by rejecting clinical experience and a growing medical literature suggesting that the much maligned low-carbohydrate, high protein diet may have a salutary effect on the epidemics in question”. (98)

REFERENCES:

1. The Oiling of America – Gary Taubes.
2. J Am Coll Cardiol, 2004, March 4.
3. www.health.gov/dietaryguidelines/dga 2005
4. www.mypyramid.gov/pyramid 2005
5. www.americanheartassociation
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7. Archives of Internal Med vol 165, no 9, May 9, 2005
8. Arch Intern Med 2006, April 24: 166(80:932)
9. www.discovery magazine.com/2003/mar/breakdialogue/article
10. Diabetes Care 2003, 26: 2261-2267
11. Diabetes Care 2004, 53:2375-2382
12. JAMA 1994, 271 : 1421-1428
13. NEJM 1988, 319: 829834
14. Diabetes Care 1989, 12: 94101
15. Annals Nutr Metab 2009; 55:44-55
16. Am J Clinic Nutr, 2003: 78: 719- 727
17. Obesity-Silver Spring 2007; 15: 967976
18. Curr Atherosc Rep 2005; 7:427
19. JAMA 2007, 297: 969-977
20. Arch Intern Med 2006: 166: 285-293
21. J Am Coll Nutr 2001; 20:5.19
22. Eur J Clin Nutr 2009; 63: 522533
23. Am J Med 2002, Dec 30, 113 – Suppl 9b:475-495
24. www.food.gov.uk/multimedia/page/satfatprog.pdg
25. www.euromilk.org
26. www.indi.ie
27. Arterio Thromb 1992 Aug, 12(8): 911-9
28. Am J Epid 1972, 95: 2637
29. J Epid Community Health doi:10.1136/2008
30. Lancet 1983; 1:10621068
31. J of Nutr Sc. Vitaminology 2002
32. J Nutr 1995 Mar; 125(3): 5319
33. J Am Soc Clin Nutr, 1981, 34624
34. Am J Clin Nutr. 1982, 36: 950962
35. J Am. Coll. Cardiol. 2007: 50:2224
36. Int J Obes Relat Metab Disorders, Oct 1998, 22 (10); 947-9
37. Metab Feb 1995, 44 (2) : 273-9
38. Arterio Thromb 1992 Aug 12(8) 91
39. Biomed Pharmacother 2002 Oct, 56 (8)
40. Eat Fat Lose Fat, Mary Enig PhD, P 8-10
41. Lipids, 1985 20:4227
42. www.health.gov/dietaryguidelines/dga2005/report/HTML/D4
43. Am J Clin Nutr 2004, April;79(4):537-43
44. Altern Med Review 2005,Dec 10(4) 294-306
45. Curr Opin Gastroenterol 2008, Mar 24(2): 204-9
46. Am J Clin Nutr 2004, May;79(5):774-9
47. Am J Clin Nutr 1980 Feb; 33(2):273-8
48. J Nutr 1983 Sept:113(9);1819-26
49. Nutr Metab (Lond) 2005 Feb 21:2(1):5
50. Nutr J 2003:2:2
51. Amino Acids 2008 June:35 (1):29-36
52. Science 2009 June 10; 325(5937) 201-4
53. Annal NY Acad Sc 2007 Oct, 1114; 428-33
54. Am J Physiol Endocrinol Metab 2005 April 28(4): E 818-25
55. Arch Cardiol Mex 2007 Oct – Dec: 77 Suppl 4:54-66-76
56. NEJM 1988, 319:829-834
57. Diabetes Care 1989, 12:94-101
58. JAMA, 271: 1421-1428
59. Diabetes Care 2003, 26:2261-2267
60. Diabetes 2004, 53:2375-2382
61. NEJM 2008, 359. 229-241
62. NEJM May 22, 2003 (vol 348, 20742081)
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73. Nutr J. 2008: 7:30
74. Obes Review. 2003 Aug:4(3): 185
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76. Cochrane Database Sys Rev. 2002: (2) CDOO 3640
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81. Clin Endocrinology 2006; 64(4):355-365
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83. Diabetes Care 2006, June:29(6)
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98. J. Am Coll of Cardiology, 2004 March 4.

Dr Neville Wilson is a Doctor in Maynooth

http://www.leinsterclinic.ie

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The Expanding Role of Omega 3

While the health benefits of poly-unsaturated fatty acids (PUFA) omega-3 have been well established for the past three decades, it is only recently, since its appearance as a pharmaceutical agent, that this remarkable fish oil product has received recognition for its
usefulness as a preventive and therapeutic agent in a wide range of clinical disorders.

espite the growing number of clinical studies which clearly demonstrate its multiple health benefi ts, many physicians continue to withhold fish oil from patients, depriving them of a valuable, cost effective, and safe remedy for several conditions that may pose serious and costly risks to their health.
The striking evidence, from well controlled studies, should serve well to encourage health professionals to prescribe, with confidence, this modern healer of many ills, clearly mindful of its efficacy, safety and well tolerability.

An extensive review of the positive healthy benefits of omega-3 prompted Dr Carl Lavie to say, “Physicians are not as familiar with omega-3 studies …as they are with statins…as they should be”, and as a therapeutic agent, omega-3 should be “promoted to clinicians”.

CARDIOVASCULAR BENEFITS

Dr Lavie and his associates reviewed data from 40,000 participants included in retrospective epidemiological studies and large randomised controlled trials, and found compelling evidence for the positive benefits of omega-3, both in primary and secondary prevention of cardiovascular disease, and also for heart failure. The positive effects of omega-3 were observed on total mortality, sudden death, CHD mortality, and cardiovascular mortality.

The first randomised clinical trial (RCT) which demonstrated the benefits of omega-3 was conducted in 1989 at the University
of Wales, known as the Diet and Reinfarction Trial (DART). In this study 2033 men with a history of a previous heart attack
were given a fish diet twice a week, and after 2 years of dietary intervention experienced a 29% reduction in mortality.

A landmark trial, conducted by Italian researchers in 1999, the GISSI-Prevenzione Trial, enrolled 11000 subjects who had previously suffered a heart attack, and gave them 1000mg daily of fish oil in the form of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), together with vitamin E, and reported a dramatic 30% reduction in cardiovascular mortality and a 45% reduction in sudden death at the conclusion of the 4 year study.

Researchers at Harvard University, in 2002, reported that men who had high levels of EPA and DHA in their blood had an 80% lower risk of sudden cardiac death compared to those with low serum levels of these fi sh oils.

More recently, clinical studies have demonstrated that omega 3 lowers serum triglycerides, thereby reducing a signifi cant cardiac risk factor that accompanies the life threatening metabolic syndrome.

Peer reviewed scientific studies demonstrate that omega-3 may alleviate depression, inhibit cancer, boost bone health and reduce the pain of arthritis

PLAQUE AND ARRHYTHMIA REDUCTION

Furthermore, the potential complications of unstable vascular wall plaque have been averted in studies which demonstrate a slowing in the rate of plaque growth,6 and also by altering the unhealthy composition of unstable plaque, thereby reducing its propensity to rupture with tragic consequences.

One of the most dramatic benefi ts of omega-3 is its ability to prevent sudden death by suppressing potentially lethal abnormal cardiac arrhythmias in patients who have a history of heart muscle damage. In contrast to prescription medicines omega-3 reduces mortality in heart disease and arryhthmias without increasing mortality risk, often a consequence of a pharmaceutical
intervention.

The effects of omega-3 were studied in atrial fibrillation, a common heart arryhthmia, in patients recovering from bypass surgery, and recorded as a 54% reduction benefit.

A novel case reporting the successful termination of sustained vetricular tachycardia with 1 gram of omega-3 was reported by clinicians in the Department of Cardiology, Wythenshawe Hospital, UK.

The potential use of omega-3 supplementation as an aid to conventional anti-arrhythmic drugs has been underscored by recent studies that show a suppression of ventricular tachycardia with intra-venous administration of omega-3, 11 and the prevention of fatal arrhythmias in high risk subjects by omega-3 oral supplementation.

The therapeutic benefi t of omega-3 for heart failure patients was tested in a four year study involving 6975 adult patients who were randomised to receive 1 gram of omega-3 daily. Compared with patients receiving placebo, or rosuvastatin 10mg. daily, those receiving omega-3 had a lower death rate and a lower rate of cardio-vascular related hospitalisation than the placebo or statin group.

OTHER BENEFITS

The broad range of health benefi ts linked to dietary omega-3 extend beyond the positive outcomes for high risk cardiac patients, as well as asymptomatic persons with no history of cardiac disease.

Peer reviewed scientifi c studies demonstrate that omega-3 may alleviate depression, inhibit cancer, boost bone health and reduce the pain of arthritis.

Many of these common disorders have been attributed to the excessively high levels of omega-6 in the typical Western diet.

Omega-6 is a polyunsaturated fatty acid which has inflammatory characteristics, and is ubiquitous in processed foods and commercially prepared consumer products. It has been shown that excessive omega-6 promotes the inflammatory processes
that underlie many common chronic ailments, and is a likely cause for the galloping trend of obesity, diabetes and wide-ranging chronic inflammatory disorders afflicting modern society today.

Dietary omega-3 can neutralise these unwantedinflammatory effects and shift the physiological balance from a pro-inflammatory state to an anti-inflammatory state. Simopoulos has shown how improvements in the omega-6/omega-3 ratio can exert beneficial suppressive effects, with various ratios correlating with improved mortality benefits in cardiovascular disease, colorectal cancer, breast cancer, rheumatoid arthritis and asthma Lower ratios of omega 6/omega 3 in the range of 4:1, or lower, are able to reduce the risk of several chronic disorders highly prevalent in Western society, as well as in developing countries.

Similarly, reductions in the ratio of omega 6 to omega-3 have resulted in significant improvement in the mental health of patients, suffering from a wide range of affective disorders. The anti-inflammatory effects of omega-3 have been shown to enhance functionality of the cerebral neuronal membranes in treated patients, promoting neurite growth and effectively reversing the clinical
symptoms of several psychiatric disorders of affect, like schizophrenia, depression and suicidal ideation.

ANTI-CANCER BENEFITS

The expanded use of omega-3 marine oils in preventing and treating certain common cancers has received much attention in recent years and holds much promise for future cancer treatment.

Countries where high consumption of fish is the norm have reportedly lower cancer rates than elsewhere. The potential role of fish oil in cancer protection was tested by researchers as early as 1995.

More recently, evidence has been uncovered for the role omega-3 plays in reprogramming genetic signals during colon cancer initiation.

These findings have been duplicated in studies and reported by other researchers.

17 The protective role of omega-3 may be attributed to its promotion of a healthy balance between omega-6 and omega-3
which limits the inflammatory mechanisms contributing to elevated cancer risk.

Reducing the potential harm caused by pro-inflammatory vegetable oils containing omega-6 was shown in the Singapore Chinese
Healthy Study to reduce breast cancer.

Omega-3 promotes its cancer protecting properties through inhibition of angiogenesis (tumour blood vessel formation) 21 and inhibition of surface receptors on cancer cells that promote cell proliferation. In experimental studies designed to test the ability of omega-3 to suppress cancer growth, scientists discovered a tumour destructing gene (apoptosis) that was expressed by high levels
of omega-3.

Laboratory application of this discovery in experiments with breast cancer cells demonstrated a 25% inhibition of the cancer cells growth by adding EPA and DHA to the cells.23 The benefits of offering supplemental omega-3 to patients receiving chemotherapy for breast cancer were tested by Menendez et al, who successfully demonstrated the enhanced effectiveness of using omega-3 prior to chemotherapy initiation.

The positive immune responses which derive from omega-3 supplementation may also play a supportive role in post-operative healing following cancer surgery. The anti-inflammatory benefits of supplemental omega-3 during and after surgical

A 2002 study reported that men who had high levels of EPA and DHA in their blood had an 80% lower risk of sudden cardiac death compared to those with low serum levels of these fish oils.

recovery are likely to offer exceptional healing benefits for critically ill patients.

The post-operative benefits in respect of healing, enhanced immunity and shorter hospital stays were documented by Ferraras et al (2005) in respect of surgery for gastric cancer,26 and Nilsen et al (1993) in respect of coronary by-pass surgery.

CONCLUSION

A plethora of studies have thus clearly identified the therapeutic merits of omega-3 (PUFA), providing strong supportive evidence that supplemental omega-3 confers a distinct survival advantage at all levels of risks to human health.

REFERENCES

1. J. Am Coll Cardiol, Aug 11, 2009; 54: 585-594.
2. Lancet, 1989 Sept 30;2 (8666) :757-61 (DART).
3. Lancet, 1999 Aug 7 : 354 (9177):447-55 (GISSIPrevenzione).
4. New Eng J Med 2002 April 11, 346; (5) 113-8.
5. Am J Med Sci 2005 Dec; 330 (6): 295-302
6. Cardiovasc Res. 2001 Dec; 52 (3): 361-71
7. Lancet 2003 Feb 8, 361(9356): 477-85.
8. Lancet 1989 Sept 30, 2 (8666): 757-61
9. J Am Coll Cardiol 2005 May 7, 45 (10) 1723-8
10. Europace 2006, 8(5): 330-332: doi:10. 1093.
11. Lancet 2004; 363:1441-2
12. Circulation 2005: 112; 2762-8.
13. Journal Watch 2008: 7 (10).
14. Biomed. Pharmacother. 2002 Oct; 56(8): 365-79.
15. Nature 2006; 440:813-7
16. Int J. Cancer 2003 Nov 1:107 (2):276-82.
17. Cancer Res 2004 Sept 15:64 (18):6797-804.
18. Nutr Cancer 2002, 42 (2):180-5.
19. Br J Cancer 2006 Mar 27:94(6):842-53
20. Br J Cancer 2003 Nov 3:89 99):1686-92.
21. Nutr Cancer 2000:37 (2):119-23.
22. Neoplasia 2006 Feb:8 (2):112-24.
23. Int J Cancer 2005 Nov 10, 117 (3) 340-8.
24. Euro J Cancer Prev. 2005 June:14 (3):263-70.
25. Lipids 2004 Dec; 39(12):1147-61.
26. Clin Nutr 2005 Feb 24, (1):55-65.

Dr Neville Wilson is a Doctor in Maynooth

http://www.leinsterclinic.ie

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How Long Will You Live?

While no one can predict with certainty what the span of your life may be, there is new scientific evidence to support a choice that will increase very significantly your best chance of a long survival. Unsuspecting and unpredicted events are an ever present threat to longevity, and minimising these risks is our best form of insurance.

Recent scientific evidence suggests that risk factors can be massively diminished by adopting simple dietary measures that include a regular and substantial intake of fish oil. (1)

Observational evidence suggests that a dietary intake of 1400mg. to 2000 mg. of eicosapentaenoic acid (EPA) and 1000 mg. to 1500 mg. of docosahexaenoic acid (DHA) will provide sufficient levels of essential fatty acids to support health and protection against heart disease and its unwanted consequences, (2) as well as a host of prevailing chronic ailments.

The widespread scourge of heart disease continues to take its sad and deadly toll, yet 30 years ago this phenomenon was rare, and unknown amongst the Greenland Eskimos, who enjoyed a generous dietary intake of oily fish on a daily basis. Their frequent intake of cold water salmon guaranteed them high levels of EPA and DHA in their blood and body tissues, affording them protection against an array of chronic illnesses that predominate in western society today. (3)

We now know that omega 3 fatty acids, if derived from uncontaminated sources, can reduce or suppress, potentially lethal abnormal cardiac arrhythmias that often follow a heart attack. (4)

These fatty acids can also prevent the unnecessary clotting of blood that can precede a fatal coronary thrombosis, or stabilise a plaque in the arterial wall that is threatening to rupture and obstruct blood supply to the heart muscles. (5)

The omega 3 heart-friendly fatty acids have also been shown to prevent the aggregation of platelets that can increase the potential for clotting, or the formation of thrombi, and are demonstrably safer than aspirin, often prescribed to prevent blood clotting in at-risk patients. (6)

While aspirin has the potential for causing stomach ulcers and internal bleeding, omega 3 presents no such risk, and provides for a safe, and reliable alternative for patients with heart disease. (7)

It is therefore not surprising that in the first randomised controlled trial conducted in 1989, at the University of Wales (DART STUDY), 2033 men with a history of previous heart attack experienced a 29% reduction in mortality. (8) and in the renowned Gissi-Prevenzione Trial, conducted in Italy in 1999, in which 11000 subjects were enrolled, a 30% reduction in mortality and a 45% reduction in sudden death was recorded in this group after 4 years. (9)

Harvard University researchers showed an 80% reduction in risk for sudden cardiac death in their 2002 study. (10)
A plethora of trials and studies have since been conducted that clearly demonstrate the life sustaining and health preserving benefits of omega 3 fatty acids, also known as n-3 fatty acids in the more recently adopted nomenclature.

The anti-inflammatory properties of EPA and DHA serve to counter the inflammatory effects of dietary omega 6 which is ubiquitous in processed foods, and which, in excess, may contribute to a host of chronic inflammatory disorders, which adversely affect mental health, bone health, heart health, joint health and may even promote conditions such as diabetes and cancer. (11)

The anti-cancer benefits of omega 3 have been widely observed and documented. (12) (13)

More recently, the anti-ageing properties of omega 3 were clearly evident in the HEART & SOUL STUDY, conducted in California, in which dietary omega 3 was positively associated with a novel marker of biological ageing. (14)

Chromosomal telomeres are small protective caps at the end of every chromosome, and they shorten with age, causing, ultimately, the demise of the cell . They are thus useful biomarkers of biological ageing.

The subjects in this study, who had high levels of omega 3 in their blood, demonstrated a reversal of telomere shortening, which, in effect, implied a reversal of biological ageing !

Not only were these subjects protected from having a second heart attack, they were biological younger after 5 years, despite their chronological ageing !

Interestingly, the benefits of telomere lengthening were not demonstrated in patients using statin drugs. (15)

So, how long you live, and how well you feel, and how young you become, can definitely be determined by how much omega 3 is in your blood stream, and in the fatty membranes of your seventy three trillion human cells !

REFERENCES:

1. J.Am Coll of Cardiol. 2009,Aug. 11
2. Lancet Aug. 7 1999; 354; 447455
3. The Ultimate Omega 3 Diet . Evelyn Tribole.
4. Lancet 1989, Sept 30, 2 (8666):751-61
5. Lancet 2003, Feb 8.36 (9350) 47785
6. Thromb Vasc Biol. 2004, Sept. 24 (9) 173440
7. The Dangers of Aspirin – The American College of Gastro.
8. Lancet 1989, 7 Sept 30 (8666) 75761 (DART)
9. Lancet 1999, Aug. 7: 354 (9177): 44755
10. NEJM 2002, April 11, (5) 1138
11. Biomed Pharmacother 2002, Oct; 56 (8); 36579
12. Nutr. Cancer 2000 : 37 (2):11923
13. Neoplasia 2006 Feb: 8 (2) :11224
14. JAMA Jan 20, 2010 vol.303, no.3
15. Circulation 2004; 110 (19): 31363142

Dr Neville Wilson is a Doctor in Maynooth

http://www.leinsterclinic.ie

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Is it Justifiable to Medicalise Healthy Persons?

A recent ruling by the FDA (Dec 2009) permitted new criteria for the use of the cholesterol lowering drug, CRESTOR (rosuvastatin), thereby sanctioning its use as a preventative agent for healthy persons who may be judged to be at risk for cardiovascular disease. (1)

Approval of the new criteria broadened the labelling for Crestor, and opened the door for widespread marketing, aimed at targeting persons without a history of heart disease, yet considered to be at risk, if their blood level of C-reactive protein (CRP), a marker of inflammation, was raised.

MARKERS OF RISK:

The recognition that 50% of heart attacks occur in persons who have normal, or low levels of LDL-C, has prompted ongoing research for novel risk markers that could be readily identified and measured. (2)

Several such risk markers have received attention in recent years, amongst which are Lp PLAT2, Lp(a) and CRP, the latter having been recognised as a risk marker in several early studies since 1990.

These studies include AFCAPS/TEX CAPS, the Scotland Coronary Prevention Study, and more recently PROVE-IT-TIMI 22, REVERSAL and PROVE IT. (2005), involving the use of lovastatin, pravastatin and atorvastatin.

These studies suggest a class effect for CRP reduction by the HMG co-enzyme A reductase inhibitors. (statin drugs), rather than an isolated rosuvastatin (Crestor) effect.

JUPITER STUDY:

More recently, the JUPITER study (2008) sought “justification for the use of statins in primary prevention” by measuring the effect of reducing both CRP and LDL-C in an apparantly “healthy population” whose LDL-C levels were below 3.4 mMol/L, but whose high-sensitivity C- reactive protein (hs-CRP) levels were 2.0 mg/L or more. (3)

The study was conducted on 1315 sites in 26 countries, and randomly assigned 17,802 participants to a control group, using 20mg rosuvastatin, and a placebo group, in a 1:1 ratio distribution.

Of the original 19,323 potential participants, 1,521 were excluded from the study for various reasons.

The trial was scheduled for 4 years, but was prematurely terminated at 1.9 years, because of a perceived benefit in the control group.

The trial authors hailed the outcome as a success story for CRP reduction, by declaring a 43% reduction in cardiac events, that included heart attack, stroke, severe angina or cardiac death. (4)

The popular media expanded this declaration of benefit by hyped up reports of a 50% protection benefit for healthy persons against having a heart attack if they took Crestor. (5)

FDA APPROVAL:

The FDA approval for high dose Crestor ignores the findings from several earlier studies involving less expensive and lower dose statins, with similar outcomes of CRP reductions.

The widespread euphoria following the publication of the study results also ignored 2 important facts, ie. that several non-pharmacological strategies are available for lowering CRP, and that unwanted adverse effects, such as recorded in the Crestor arm of the study, can be avoided by the use of such strategies.

REPORTED BENEFITS FROM CRESTOR:

The JUPITER study researchers reported a 43% reduction in cardiac events (the primary end point ) for the Crestor group, compared to a placebo group, prompting the prediction that if 100 persons with elevated CRP levels took 20 mg. of Crestor, 43 could be saved from a cardiac catastrophe.

Some press reports claimed that almost half of all persons taking this drug would be spared a heart attack !

High dose Crestor in this study achieved a marked reduction in LDL, from 108 mg/dl to 55 mg/dl, which is a 50.9% reduction, and a 37% reduction in CRP, from 4.25 mg/L to 2.2 mg/L.

LIMITED BENEFIT FOR CRESTOR:

Despite the high dose of Crestor (20 mg), optimal CRP levels of below 0.55 mg/L (males) and 1.5 mg/L (females) were not achieved and a significant number of subjects in the Crestor group suffered “major cardiovascular events”, while the all-cause mortality was very similar in both groups.

The number of deaths from ALL CAUSES was 198 (2.2%) in the Crestor group, and 247 (2.8%) in the placebo group. (6)

The absence of CARDIOVASCULAR MORTALITY data for JUPITER was noted by several critics, prompting a re-analysis of the data by de Lorgeril et al. (7)

Dr. de Lorgeril and his French colleagues, having reviewed the trial data, reported an estimate of 12 cardiovascular deaths in each group, concluding that the lack of benefit for cardiovascular mortality, and the high rate of non fatal complications, suggested a bias that prompted early termination of the trial, rather than its continuation.

Other critics have suggested that if the trial had been allowed to continue to its planned conclusion, fewer benefits might have been demonstrated. (8)

EARLY TERMINATION OF STUDY – WHY ?

The primary endpoint was broad.

It included morbidity and mortality, ie. fatal and non-fatal cardiovascular events, and it was because of a purported “treatment benefit” in these areas, according to the Independent Data & Safety Monitering Board (IDSMB), that the trial was abruptly and prematurely terminated in March 2008, after 1.9 years of study (9)

Kaul et al charged that the early termination of the study created a “false positive result, an over optimistic result, a less – convincing result, or a missed opportunity to gather essential data on adverse effects. (10)

Kaul also demonstrated that in 2 randomised controlled trials (RCT), namely, OPTIMIST and CHARM, early benefits for the study drugs compared with placebo, actually disappeared at the final evaluation of the study.

The practice of early termination, therefore, allows for a bias that exaggerates benefits and minimises the long term harm of the treatment that is being evaluated.

ACCLAIMED BENEFITS IN QUESTION:

The claim by the study researchers of a 43% risk reduction for the Crestor group needs to be critically evaluated by reviewing the actual figures that emerged in each group.

The 43% figure creates an inflated measure of benefit, since it represents relative risk reduction (RRR) and not absolute risk reduction (ARR).

A relative risk reduction is merely the ratio of the number of events per 100 persons in the experimental group to that of 100 persons in the control group.

Of the 17,802 men and women in the study, the rate of primary endpoint occurrence was 1.36 events per 100 person years of follow up, while in the control (Crestor) group it was 0,77 events.

In other words, if 10,000 study subjects did not take Crestor, 136 of these might be expected to experience a cardiac event in 1 year, and if 10,000 subjects took Crestor for a year 77 subjects would be expected to experience a cardiovascular event.

Using these figures, the researchers calculated a relative risk reduction in the control group of 43%, reported in the media as “almost 50%” risk reduction.

Clearly, this is a gross exaggeration of benefit. Using the same figures, and calculating the absolute difference in outcome rates, the absolute risk reduction appears as a mere 0.59%, the difference between 1.36% and 0.77%.

The absolute difference, or absolute risk reduction therefore of 0.59%, is less than 1%, and thus a small and insignificant benefit.

A reduction of the primary endpoint (myocardial infarction, stroke, arterial revascularization, hospitalization, death) rate of 0.59 events per 100 person years is not convincing at all.

The editorial comment in the NEJM summarised the limited benefit, by the calculation that 120 people would be required to take the drug for 2 years to prevent 1 stroke, heart attack, or death. (11)

Dr. Mark Hlatky, the editor, further remarked, “The benefit shown in this study is tiny, and if Jupiter were repeated, there might be no benefit at all”. (12)

THE VALUE OF CRP ?

Jupiter gives support to the theory that atherosclerosis is an inflammatory disease, and that CRP may serve as one of several markers for inflammation, within the arterial wall, or elsewhere.

Markers more specific for vessel wall inflammation are LpPLAT2 and LP(a).

Since CRP is a mere marker, it should not be a target for chemotherapy. Zacho et al have proposed that the relationship between CRP and ischaemic vascular disease is not causal. (13)

This proposal undermines the rationale for the Jupiter Study.

They further report that “genetic variants associated with lifelong elevations of CRP levels are not associated with an increase in cardiovascular risk”. (14)

If CRP is only a marker for some other unidentified process, then targeting the marker with drugs is unlikely to provide a preventative benefit. Patients with high CRP levels should be targeted with counsel to modify their lifestyle and diet.

Improvements in lifestyle is likely to be reflected by decreasing levels of CRP. It is well known that exercise, vitamin C and omega 3 can lower the risk of morbidity and mortality, and give rise to reductions in CRP levels.

In the CORONA study both LDL-C and CRP was significantly lowered by rosuvastain, to a similar degree as in JUPITER, and yet performed no better than placebo on the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. (15)

After studying the data, Kaul et al concluded that “hs-CRP appears to be an insufficient predictor of risk and treatment response in JUPITER” (16)

BENEFITS FOR ELDERLY QUESTIONED.

A subgroup analysis from JUPITER was presented at the European Society of Cardiology 2009 Congress and declared a treatment benefit for the elderly participants in the study. (17)

These claims, as proposed by lead investigator Dr. Robert Glynn, were challenged by Dr. Rita Redberg (University of California) stating that data for elderly patients are limited, and that the benefits of statins do not outweigh the potential harms of the drug in this healthy patient population.

She noted that in JUPITER, treatment with rusuvastatin did not result in a significant reduction in mortality or cardiovascular mortality in the overall population, or in those aged 70 years and older. (18)

ADVERSE EVENTS UNDER-REPORTED ?

The small difference in the number of deaths from all causes between the control (Crestor) and placebo group raises serious questions about the validity of the proclaimed benefits in the control arm. ( 2.2% vs 2.8%).
In addition, the absence of data for cardiovascular deaths is a further cause for concern about the claims of benefit.

An added concern is the increased incidence of newly diagnosed diabetes in the Crestor group, with 270 (3.0%) cases being reported in the Crestor group and 216 (2.4%) cases in the placebo group.

It is conceivable that, in the long term, these additional 54 cases of diabetes in the Crestor group might negate the slight cardiovascular benefit observed.

The high dose of Crestor (20mg) used in this study may have contributed to the high incidence of adverse effects, since previously higher dosages at 80mg were identified as the cause of rhabdomyolysis and liver failure, (www.astrazeneca-us.com/pi/crestor.pdf) prompting Astra Zeneca to develop a lower dose at 40mg, which unfortunately also gave rise to renal toxicity. (19)

A comparison of the adverse effects reported in the Crestor group vs placebo group are as follows.

Muscle weakness and pain (1421 vs 1375); myopathy (10 vs 9); rhabdomylosis death (1 vs 0); renal disorders (535 vs 480); hepatic disorders (216 vs 186).

The total no. of adverse effects recorded in the Crestor arm was 2173, versus 2041 in the placebo group, an excess of 132 cases.

Earlier this year the outcome of an observational study involving 2,004,692 patients in 368 general medical practices in the UK was reported in the BMJ, showing an association between statin use and increased risk of cataracts, kidney failure, muscle pain, and moderate or serious liver dysfunction, and no benefit for several cancers. (20)

The numbers of serious adverse events recorded in JUPITER was 1352 (Crestor) and 1377 (placebo).

No data was made available for cardiovascular mortality, but de Lorgeril et al reported an estimate of 12 cardiovascular deaths in each group. These researchers judged the early termination of the trial to be linked to the lack of benefit observed for cardiovascular mortality, and also the high rate of non-fatal complications being recorded. (21)

RESULTS AND DISCUSSION:

The results from Jupiter reveal a mix of gains and losses for primary prevention with a high dose statin, but these gains are not without cost.

Since it is likely that these benefits and risks are a class effect, the concerns raised by this study must apply to all other statins, and should not be limited to the actions of Crestor alone, despite its superior potency.

In June 2010 Dr. Kausik Ray and his team reported a review of the all cause mortality in 11 randomised statin trials involving more than 65000 high risk subjects who had no history of cardiovascular disease.

They discovered an absolute difference of 0.3% in the mortality rate for statin therapy (4.1% statins vs 4.4% placebo) and concluded that primary prevention strategies with statins were NOT justified. (22)

Their conclusions were similar to those of French researchers led by Dr. Michel de Lorgeril, who contested the claims of primary prevention benefit by the Jupiter researchers, by referring to procedural and outcome irregularities which preferentially influenced the outcome data. (24)

While JUPITER highlighted the significance of CRP reduction, it offered no new insights, and represents a Crestor study rather than a CRP study.

It has been repeatedly demonstrated that elevated CRP can be reduced by lifestyle modification, without exposure to the morbidity and mortality risks that were clearly evident in the Crestor arm of the study.

ETHICAL CONSIDERATIONS :

1. The involvement of Paul Ridker in an industry funded study,which aimed to promote a product for which he is co-inventor and patent holder (hs-CRP testing), raises inevitable questions of inescapable conflict of personal interest, a major ethical issue which must detract from the relevance and value of the study.

Commercial interests were therefore not divorced from this study.

Furthermore, 9 of the 14 authors (64%) authors of the Jupiter article have financial ties to the sponsor, and the chairman of the IDSMB that halted the trial prematurely has strong links to industry-sponsored lipid lowering trials. (23)

2. The target group for this study was purported to be “apparently
healthy persons”, allowing for extrapolation of treatment principles to “healthy population groups”.

The subjects, however, were not healthy, many having physical conditions determined by poor dietary and lifestyle choices.

The baseline medium BMI was 28.3 (interquartile range 25.3 to 32), and at least 80% of them were overweight or obese.

At baseline 41% had metabolic syndrome, and thus at high risk for morbidity and mortality, with more than half having a Framingham risk score exceeding 10%.

After 1.9 years 270 in the Crestor group, and 216 in the placebo group had become diabetic.

No attempts were made to counsel these subjects about lifestyle options before administering a potentially toxic drug, and no consideration was given to the projected cost of drug treatment.

Prescribing Crestor 20 mg daily to 120 people (NNT 120) for 1 year at a cost of € 100,000 in order to prevent 1 hard cardiovascular event, is a major ethical indictment when a lifestyle and dietary intervention programme would have been much less costly and without adverse events.

The message that immortality can be found in a pill, so widely and so loudly propagated by this trial and its spokespersons, is not only false and futile, but a failure to maintain the highest standards of ethical care which is surely the mandate of all clinicians.

3. The potential for bias in deciding to terminate the trial prematurely raises ethical questions about integrity of purpose in study design and process, the accuracy of interpreting the outcome data, and the validity of treatment recommendations for future populations based on surrogate endpoints for mortality which have the appearance of being selectively determined.

4. The focus of the study was blurred by the premise that CRP is a justifiable surrogate endpoint to predict mortality, and that the use of a potent statin, like Crestor, to achieve this endpoint is justifiable.

This trial was a a study of rouvastatin (Crestor) and not CRP testing, since CRP was not tested against an alternative risk marker, nor against subjects with CRP levels lower than 2 mg/ L.

The extravagant conclusions about the merits of hs- CRP testing are thus not valid.

5. The practice of subjecting these particular participants to drug intervention without first offering them counselling and advice regarding dietary and lifestyle changes is unacceptable medical practice, and therefore unethical.

In the real world patients who present with evidence of the metabolic syndrome would be offered such counselling prior to embarking on a programme of pharmacological intervention.

CONCLUSION:

The JUPITER study was aimed to justify the use of a potent statin in the primary prevention of cardiovascular morbidity and mortality.

This group of persons, assumed to be at undetected risk, comprises 75% of statin users today, and the extravagant claims by the trial authors “is likely to propel many healthy persons without elevated cholesterol levels onto long – term statin treatment”, according to the French researchers, Dr. Michel de Lorgeril and associates.

Dr de Lorgeril and his team concluded their analysis of JUPITER by describing it a flawed study, and “clinically inconsistent” and “extreme and exaggerated” (24)

A similar conclusion was reached by researchers at the University of Cambridge, UK.

Dr. Kausik Ray and his team performed a meta-analysis of 11 randomized controlled trials that assessed the effects on all-cause mortality of statins versus a placebo or control therapies on all-cause mortality.

The meta-analysis (which also included previously unpublished data) involved 65,229 men and women , with approximately 244,000 person-years of follow-up.

In this meta-analysis all-cause mortality was not significantly different between patients taking statins and those taking placebo, or control therapies.
The researchers concluded that “the all-cause mortality reduction of 20% reported in JUPITER is likely to be an extreme and exaggerated finding, as often happens when trials are stopped early” (22)

Justification for the use of statins in Primary prevention has not been established in this study.

A review of data from this and previous studies clearly demonstrates that treating healthy persons with statins confers no health or mortality benefit, and has no place in responsible health policy.

The lack of cost effectiveness in such a strategy further mitigates against its implementation in health care policy.

REFERENCES:

1. www. Astrazeneca-us.com/pi/crestor.pdf
2. Circ 2003;108(19):292-97
3. NEJM 2008, Nov 20; 359 (21): 2195-207
4. Ann Intern Med 2010; 152: 488-496
5. Irish Medical Times 12.11.10)
6. NEJM 2008: 359 (21): 2195-207
7. Arch Intern Med 2010; 170 (12):1032-36 de Lorgeril)
8. The Heart Org. June 28, 2010.www.the heart.org/article/1092925/print.do 6 July 2010)
9. Circ.Cardiovascular Qual Outcomes. 2009;2(3):279-85, 7 July 2010.http://circoutcomes.ahajournals.org/cgi/reprint /2/3/279
10. Arch Intern Med 2010;2010; 170(12) : 1073-77
11. http//articles.latimes.com/2008/nov/10/science/sci-statin 10)
12. www.abcnews.go.com/Health/Heart Disease News/ Story ? id=6707285&page=1)
13. NEJM 2008, Oct 30; 359:1897
14. Journal Watch Cardiol. Oct 29, 2008
15. NEJM 2007; 357(22): 2248-61
16. Arch Intern Med 2010; 170 (12): 1073-77 Kaul S et al.
17. Annals Intern Med 2010 ; 152:488-496
18. www.theheart.org/article/1069313/print.do
19. pharmacoepidemiol Drug Saf. 2008 Oct;17 (10) : 943-52
20. BMJ 2010;340:c2197
21. Arch Intern Med 2010; 170 (12):1032-36 de Lorgeril et al
22. Arch Intern Med 2010; 170 (12): 1024-31
23. Arch Intern Med 2010:170;1, 032-6
24. Arch Intern Med 2010:170;1007-8

Dr Neville Wilson is a Doctor in Maynooth
http://www.leinsterclinic.ie

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The Fluoride Policy

THE DILEMMA:

The Fluoride dilemma is not new and continues to extract comments and recommendations from responsible bodies who question the safety and wisdom of public water fluoridation.
The proponents of fluoridation, on the other hand, continue to promote the image of safety and benefits to dental health, and resist efforts to have current fluoridation policy reversed.
These debates are currently topical in the USA, and a review of current policy in Ireland is timely, given the growing concerns expressed by international bodies as they review previously held positions about policy and practice.

THE DEBATE:

The proponents and antagonists of fluoridation policy have been deadlocked in a 60 year old debate, with both sides challenging the credibility of research evidence on which their respective views are based.
Ireland currently adopts a policy of fluoridation, which reflects the USA practice standards recommended by the US Environmental Protection Agency (EPA) in 1986.

(The USA Public Health Service endorsed the fluoridation of public water in 1950, before one single trial had been completed !)

Recognising that fluoride has the potential for toxicity the EPA established a maximum allowable concentration for fluoride in drinking water of 4mg/L, with a lower level of 2mg/L aimed at the prevention of dental fluorosis, a mottling of tooth enamel, widely considered to be a cosmetic consequence without risks to health, while providing for protection against dental caries.

The USA Public Health Service set a range of 0,7mg/L – 1,2mg/L more than 40 years ago for the prevention of dental fluorosis, at which time Ireland introduced fluoridation, and continues to do so, with recommendations to local authorities not to exceed levels of 0,8g/L in fluoridation.
Current levels are reported to be at 0,6mg/L – 0,8mg/L.

IEB POLICY:

A meeting of the Irish Expert Body (IEB) on fluoridation took place on 27 Feb, 2008 at which a review of EPA standards was conducted, with reference to the potential for adverse effects at levels between 2-4mg/L.

No evaluation of risk/benefit was undertaken at this meeting for levels of fluoride concentration between 0,7 – 1,2mg/L.

Gaps in the body of evidence prevented the EPA from making judgements of risk or safety at the lower levels, and the IEB bases its current policy on presumptions of safety at the current level.

The Expert Body, according to its Action Plan 2005, identified “the lowering of the fluoride level in drinking water to a range of 0.6 to 0.8 ppm, with a target of 0.77 ppm” as its first priority. (This represents a policy amendment from the 1966 regulations.)

The Expert Body’s view is that fluoridation is safe and effective, and that current policy benefits overall health.

A legitimate concern expressed by the IEB is the dental decay rates in the Republic which have reportedly improved with fluoridation, compared to those in Northern Ireland, but which are likely to increase, given a background of high sugar intake with sweets and fizzy drinks among Irish teenager, a dietary pattern for which Ireland ranks 3rd worst out of 35 countries, according to a HBSC survey.

The IEB also bases its policy on assessments of international practice, quoting endorsements by the World Health Organisation (WHO), the Centre for Disease Control and Prevention, the United States Public Health Service, and the FDI World Dental Federation.

Several government sponsored reports from USA, UK and Canada have reviewed critically previously held positions, and UNICEF, the health arm of the UN has expressed concerns about the harmful effects of fluoridation.

Dr. Sean O’Hickey (IMN July,14 2008) makes a 10 point defence of the current Irish practice of fluoridation, with references to safety, evidence, contamination, peer review, constitutionality, UK proposals and WHO endorsement.

Robert Pocock (IMN July, 21 2008) in his rebuttal of Dr. O’Hickey’s arguments, raises the important issues of absent fluoride regulation and the clinical consequences of systemic toxicity.

FLUORIDE TOXICITY:

The US Agency for Toxic Substances and Disease Registry lists fluoride as among the top 20 of 275 substances that pose the most significant threat to human health.

Warnings of fluoride toxicity have generally been dismissed by proponents of fluoridation as the rantings of over-zealous members of fringe groups. Nevertheless, increasing numbers of influential academics are adding their names to an impressive listing of those who call for a reversal of fluoride policy.

The sobering discovery by Dr. Elise Bassin (Harvard School of Dental Medicine) in 2001 calls for a review of the prevailing casual approach to fluoride toxicity.

In her Doctoral thesis she demonstrated clearly that young boys who drank fluoridated water were five times more likely to develop osteosarcoma (bone cancer) than those who did not drink fluoridated water.

Unfortunately, the significant and irrefutable data she produced was suppressed by Dr. Chester Douglas, her doctoral advisor, and not made available to the public.
The true data  only emerged in April, 2006, at which time her findings were validated in a new study.

Dr. Douglas  was ruled to have made an “unintentional” omission, but his strong financial ties to a fluoride toothpaste manufacturer did not go unnoticed !

These events illustrate the degree of powerful political and financial undercurrents that influence scientific enquiry and public health policy, and raises questions about the fluoride industry in the USA and its close relationship with the aluminium industry and toxic waste handling.

In the USA silica-fluoride and sodium fluorosilicate are used in fluoridation, these chemicals being by-products of industrial waste, and may thus contain traces of other contaminants.

The American Medical Association is not prepared to state that no harm will be done to any person by water fluoridation, according to Dr. Flanagan, Assistant Director of Environmental Health, American Medical Association, while the FDA considers fluoride to be an “unapproved drug”.

As such, fluoride used for water fluoridation does not have FDA approval.

The United States Federal government requested an expert opinion concerning risks for neurotoxicity arising from fluoridated water in military supplies. Dr. Mullenix , the neurotoxin expert stated, “hoped for benefit”. fluoride exposures today are out of control…there are no advantages to water fluoridation, The risks today far exceed the benefits…”

Sweden recommended against fluoridation on the grounds of toxicity, as did France, after consultations with the Pasteur Institute.

Since the chemicals utilised for fluoridation are the by-products of aluminium and fertiliser manufacturing, and contain high concentrations of heavy metals such as arsenic, lead and chromium, their carcingenic potential cannot be discounted.

Assurances are required that Irish fluoride sources are not exposed to such hazardous materials.

BONE FRACTURES:

Several studies show increased fracture rates at fluoride concentrations in drinking water of 4mg/L, and an increase in hip fractures in populations exposed to fluoride concentrations above 1,5mg/L.

Of 19 studies since 1990 exploring the relationship between fluoridated water and hip fractures in the elderly 11 show a positive association.

The sources of fluoride ingestion are ubiquitous and may include many commercial foods, beverages, teas, dental products and pesticide residues on non-organic foods.
Processed Soy products, like milk and ice-cream, readily consumed by young children, contain significant amounts of fluoride.

The lifelong ingestion of these products, in addition to water containing fluoride, may give rise to levels that exceed optimum safety and produce unwanted systemic effects.
Fluoride accumulation may occur in critical organs other than bone (skeletal fluorosis), such as thyroid tissue, the pineal gland and reproductive organs.

SYSTEMIC EFFECTS:

A possible link has been demonstrated between fluoride levels and learning disabilities, brain dysfunction and ADD and ADHD.

Fluoride is a haptogen, with similarities to chlorine, bromine and iodine, and when ingested may displace iodine, giving rise to depleted levels in the body with the subsequent development of hypothyroidism.

Cretinism is prevalent in low iodine areas in Xinjiang, China, and Chinese studies reveal lower IQs in children from areas of fluoridation.

It has been estimated that young children, because of their body weight, may accumulate 3-4 times the adult dose when exposed to fluoridated drinking water.

Preparation of formula milks for infants, using fluoridated water, exposes them to additional risks of toxicity, and warnings to this effect have been issued to Hospital Nurseries.
Such alerts should not be necessary if fluoride was non-toxic or absent from drinking water.

MASS MEDICATION:

The argument of “mass medication” has received a response from Dr. O’Hickey,  but the case of “greater common good arising from decreased dental disease” is far from convincing.

The longest survey ever conducted in the USA by the National Institute of Dental Research showed little difference in tooth decay among children in fluoridated and non-fluoridated communities.

A Canadian review by Dr. D. Locker, of the statistical differences in this study concluded, “ the magnitude of fluoridation’s effect is not large in absolute terms, is often not statistically significant and may not be of clinical significance”.

New Zealand studies, where mandatory dental assessments of children aged 12-13 years take place under the National Health Services Plan, show healthier teeth within non-fluoridated communities compared with fluoridated communities.

The mass medication principle is therefore questionable as a philanthropic principle, and also as a moral exercise.

ETHICAL PRINCIPLES:

Where is the physician who will impose a life-long prescription of an untested, potentially toxic substance, without proven clinical benefit, on a patient that he/she has never met, interviewed or examined ?
Such an act would be judged to be unscientific, unscrupulous, unethical and thus unacceptable.

This is one of the major reasons that most European countries have rejected the policy of fluoridation, citing the moral issue of “the problematic nature of compulsory medication” (Germany), or “force-feeding (Finland).

The indiscriminate targeting of vulnerable population groups with a potentially toxic chemical is a practice that demands critical review with reference to professional ethics, to the principles of science, and to high standards of safety, never forgetting the dictum that remains our guiding principle, “First do no harm!”.

It is timely to review the evidence presented to the 2002 Irish Fluoridation Forum.

Ireland is now faced with a challenge to distance itself from USA policy and implement an independent national fluoridation policy that takes account of emerging scientific data and the best health interests of its several population groups.

(This article was sent to the IRISH MEDICAL TIMES in July, 2008 and not published.)

Dr. Neville Wilson,
The Leinster Clinic, Maynooth,  28 July, 2008.

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The Enhance Trial – Its Failure and Concerns

The long awaited results, of what has become a controversial drug trial, were announced recently, generating intense debate in medical circles, evoking widespread media speculation, and eliciting critical comments from the chair of the USA House of Representatives.

 

Controversies arising in the wake of a disappointing outcome for the ENHANCE TRIAL have provoked challenging commentaries from critical observers, and also  defensive responses from the research team, seeking to minimise the impact of the trial’s shortcomings.

 

Numerous concerns have been expressed, arising from anomalies within the trial.   These are considered here, together with their implications for health-care initiatives and primary care providers, and also for prospective users of the drugs in question.

 

The failure of Ezetimibe, an adjunctive cholesterol lowering agent , to produce a favourable result in this trial, has inescapable  implications for  prescribing doctors, for the drug manufacturer, and for the countless numbers of patients for whom  LDL-C lowering drugs have been prescribed.

 

THE OBJECTIVE:

The Ezetimibe / Simvastatin combination was compared to Simvastatin alone, in a randomised trial involving 720 patients with Familial Hypercholesterolaemia (FH).

 

The aim was to show that by reducing atheroma burden, as measured by Carotid Intima Media Thickness (CIMT) , corresponding LDL-C lowering would be a justifiable strategic objective in attempting cardiovascular risk reduction.

 

As such, it was not a clinical outcome study, focusing instead on the progression of atherosclerosis in the carotid artery as a surrogate end point.

 

According to the lead investigator of the study, Dr. John Kastelein, this was the largest study of carotid IMT that has ever been conducted so far, involving 19 different centres of investigation.

 

The trial was commenced in 2002 and came to a conclusion in April 2006.

 

But the outcome was from what the trial researchers were hoping for. The anticipated favourable results were not observed.

 

This striking failure to produce favourable results  provoked contrasting reactions from the trial researchers and from impartial observers.

 

Dr. P. Shah of Cedar Sinai Medical Centre is convinced that the drug will work, “because of its ability to lower LDL-Cholesterol”, he stated.

 

Dr Richard Lang, of Johns Hopkins,  disagrees with this view, stating that there is “no evidence of extra benefit” to be derived from the use of this, or similar, drugs.

 

The fact that LDL-C lowering by the agents used, either in combination, or independently, had no effect on atheroma reduction has been interpreted by many observers as continuing evidence that LDL-C lowering does not confer clinical benefits.

The Enhance trial, in fact, enhances the conclusions from most of the major statin trials that there is no association between the degree of total cholesterol or LDL-C lowering and the CHD survival rate.

 

ATHEROMA BURDEN :

 

The reduction of atheroma burden, as reflected in CIMT reduction, is considered by many investigators to be a reliable prediction of improved outcome for high-risk patients with cardiovascular disease.

 

In the trial Ezetimibe / Simvastatin produced a 58% reduction of LDL-C from baseline, after 2 years, compared with a 41% reduction of LDL-C with Simvastatin alone.

Despite these marked LDL-C reductions, with an increase by 17% of LDL reduction in the combination therapy, there were no beneficial changes observed in CIMT, as measured by intravascular ultrasound (IVUS), thereby calling into question presumptions of clinical benefit for these drugs in particular, and for LDL-C lowering in general.

 

CONCERNS :

 

The trial has attracted intense media attention because of several concerns.

 

  1. The first of these was the delay in announcing the trial results, interpreted by some observers as a deliberate attempt to hide a negative result, and one which prompted the USA House of Representatives to challenge the drug manufacturers, Pfizer and Astra-Zenica, with accusations of impropriety.

 

  1. A second concern, which was also raised by the USA House of Representatives, was that the study was not registered with the ClinicalTrials.gov until after 31 October 2007, 18 months after completion of study.

 

  1. A third issue raising the ire of many observers was an attempt, before releasing any results, to change the end point of the trial, an act viewed by some as “an apparent manipulation of trial data”.

 

  1. A fourth concern was that of drug safety. Reports have emerged documenting liver damage to patients caused by the Ezetimibe / Simvastatin combination. Dr Mark Stolk reported 2 cases of Hepatitis in 2006 of which one was fatal.

Canada and Australia have both issued warnings regarding the risks of Ezetimibe which appear to have been ignored elsewhere.

 

  1. The fifth major concern arising from this trial was its clear failure to demonstrate the anticipated benefits in respect of atheroma reversal.

 

This negative finding has implications at several levels, viz.

 

a)     For patients who currently use these agents in the belief that by so doing they will derive anticipated clinical benefits

b)    For prescribing doctors who continue to focus efforts on LDL-C reduction strategies with little regard for lifestyle modifying strategies.

c)     For the pharmaceutical industry and its insistance on marketing drugs without matching evidence of efficacy or safety.

d)    For the prevailing paradigm that LDL-C is a “bad cholesterol”, a threat to wellness and longevity, and deserving the full weight of pharmacological intervention aimed at maximum suppression .

 

UNDERLYING HYPOTHESIS:

 

These implications bring into  focus the underlying hypothesis that drives the war against cholesterol and shapes the prescribing habits and counselling objectives of many health professionals.

 

The popular perception, that high levels of circulating cholesterol are always harmful, serving as primary instigators for atherosclerotic disease, is not shared by all investigators.

Biological studies contradicting the prevailing paradigm underscore the arguments of those who refute claims that guidelines are evidence-based.

Dr Martin Krumholtz (Yale) speaks of “obscured evidence”” and Dr. Rodney Hayward (Michigan) reports, “current evidence supports ignoring LDL-C altogether”

 

LDL-C vs. OX-LDL :

 

The traditional focus on LDL-C reduction, as a strategy for minimising cardiovascular risk, ignores  the biological evidence that oxidised-LDL (OX-LDL), a modification of circulating LDL-C, is a more potent pro-atherosclerotic stimulus than native LDL-C.

 

Evidence suggests that it is the former, rather that the latter, which imposes it’s deleterious effects on the vessel wall, through a complex cascade of pro-inflammatory processes, giving rise to a thickening of the arterial wall and ultimately plaque formation.

A study by Dr Frans van de Werf (Belguim) showed that LDL-C had no predictive value, but that OX-LDL was predictive of acute coronary syndrome and MI.

 

Several lines of study suggest that pro-oxidant factors alter a healthy endothelium,giving rise to modifications of circulating LDL-C  and subsequent oxidised-LDL formation.

 

These factors have been shown to include cigarette smoking, poor glycaemic control, excessive refined dietary carbohydrate, homocysteine, iron overload, nutritional deficiency, nitric oxide depletion, microbial infection, an imbalance of Omega 6 and Omega 3, and psychological stress.

 

Several studies demonstrate that there is no association between OX-LDL and LDL-C, and that OX-LDL can be reduced by addressing causative factors, while circulating LDL-C remains unchanged .

Alternatively, the latter can be pharmacologically reduced without producing evidence of  clinical benefit.

 

Japanese researchers have demonstrated a strong association between OX-LDL and advanced carotid plaques, and also a propensity for plaque rupture with elevated OX-LDL, rather than with LDL abnormalities.

 

PLAQUE  FORMATION:

 

The traditional perception of cholesterol laden debris accumulating on the vessel wall and progressively occluding the artery lumen to produce stenosis continues to dominate thinking in public and professional circles.

 

Current evidence dispels this notion as simplistic and inaccurate, offering instead a model of complex intra-arterial wall inflammation, as a consequence of repair mechanisms operating in response to  oxidant induced damage.

 

Mounting evidence suggests that plaque formation and clinical outcome are not always correlated, and that coronary arteries with severe stenosis (>70%) do not cause the majority of myocardial infarctions that are documented.

 

Plaque formation may stabilise, or become unstable, leading to fragmentation and embolism, under pro-oxidant conditions.

Japanese researchers show that OX-LDL rather than LDL-C provides the conditions that predispose to plaque rupture and cardiac events.

 

HDL-C BENEFITS:

 

The clinical benefits of HDL-C are well documented and have been explained by Mertens and Holvoet in terms of its antagonistic activity to OX-LDL.

By reversing the stimulating effect of OX-LDL on monocyte infiltration in the inflammatory process, HDL-C exerts a beneficial anti-inflammatory effect, which in turn prevents atherosclerosis.

 

CONCLUSION:

The prevailing notion that circulating levels of cholesterol TC and LDL-C are the primary instigators for atherosclerosis, and that pharmacological reductions of LDL-C will reduce atheroma burden with improved clinical outcome is not supported by the ENHANCE TRIAL.

 

The results are due to be presented at the American College of Cardiology (ACC) in March this year (2008)  for review and analysis and for further commentary.

 

 

Dr. Neville Wilson.

The Leinster Clinic – Medical Suite.

Maynooth.

 

04/02/08.

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The Person Behind the Numbers

The review and revision of Clinical Guidelines for purposes of risk stratifying and risk reduction in cardiovascular disease prevention is an ongoing challenge and current initiatives focus on their implications for primary care providers.

 

The AHA guidelines for 2007 offer a timely and broader spectrum of risk not previously captured by the traditional Framingham algorithm. (1)

 

In the UK (QRISK) and Scotland’s (ASSIGN) new scoring methods were recently advocated and tested against the Framingham equations and judged to be more accurate, by taking account of social deprivation as an additional factor of risk for CVD.

 

And the Fourth European Guidelines on Cardiovascular Disease Prevention in clinical practice is shortly to release its findings and recommendations.

 

The search for an updated and appropriate scoring tool justifies scepticism about the validity and limitations of traditional models and also the need for a critical appraisal of hypotheses underlying such models.

Furthermore, the central issue which demands attention in the clinical setting is the uniqueness of the individual in risk assessment.  The clinical implication is for a focused and global assessment of the  PERSON BEHIND THE NUMBERS  with respect to a broader range of risk factors than previously considered.

 

THE PERSON BEHIND THE NUMBERS

Looking at the “Person behind the numbers” is a familiar slogan widely publicised by a well known manufacturer of a popular cholesterol lowering agent.

 

The slogan is arresting because it embodies a principle that is central to health care and serves as a precept that health professionals dare not ignore, and that is the uniqueness and importance of the individual.  The Person being treated must remain ever central in healthcare delivery and individualising their wellness management must take precedence over blanket prescriptions dictated by statutory guidelines for risk management.

 

However, despite this worthy sentiment, numbers and statistics often predominate, and have increasingly become the focus of promotional guidelines designed to shape the prescribing habits of doctors.

 

Public health messages reflect a perception that morbidity and mortality reducing strategies are best served by aggressive reduction of patient plasma lipid levels with little reference to other vital parameters, and current guidelines are poised to perpetuate this perception and promote its application.

 

Opposing these initiatives are groups of independent researchers worldwide who question the validity of the evidence driving this programme, and warn of the consequences of aggressive and unwarranted lipid lowering strategies.

 

The concerned family doctor is caught between these polarised viewpoints and is burdened with the balancing act of providing evidence-based medical care while protecting his/her patients from the risks of unwanted consequences which can be debilitating and devastating, both for individuals and families, and which generally have been under-estimated and under-reported. (2)

 

It thus becomes an imperative for practitioners, against this background of rapidly changing targets, to make a critical appraisal of all recommendation regarding guidelines and to resist inclinations of blind submission to “recommended guidelines” without an individualised assessment of the patient’s peculiar and unique circumstances.

 

Looking at the “PERSON”  behind the numbers, must take precedence over the figures on the laboratory report, and the age-old question must be asked, “Who is the PERSON having the disease, and not, “What disease does this person have?”

 

THE VULNERABLE PATIENT

 

Guidelines take account of potential risks to health and are driven by the desirable outcomes of reduced morbidity and improved mortality.  They thus provide a working tool for evaluating and stratifying a wide range of risk factors, often modifiable, enabling physicians and patients to thereby engage in mutually agreed strategies aimed at patient wellness and longevity.

 

Guidelines for risk assessment have traditionally focused on lipid levels, hypertension and smoking habits with reference to age and gender, but a wider spread of factors that are potentially unfavourable to health have been ignored in such models, and these deserve appraisal for a realistic assessment of patient vulnerability.

 

Social and domestic circumstances, lifestyle habits, nutritional status, stress burdens, family and genetic histories, as well as age, gender, and ethnicity, in addition to traditional factors, demand assessment if we are to understand the Person before us in the clinical setting, since each of these has the potential for life-threatening consequences.

 

THE FRAMINGHAM MODEL – ITS WEAKNESSES

 

The Framingham studies serve as a reference base for scoring risk and produced figures that were in fact related to all cause mortality and not to cardiac mortality. (This fact is not widely recognised by practitioners ! )

 

Furthermore, the data for those who suffered heart attacks reveal that, contrary to expectation, almost half of these subjects had low plasma cholesterol levels. (3)

 

Also, 30-year follow up survival curves showed that those with higher cholesterol levels actually lived longer, and that mortality rates for males older than 48 years were no different for those with either high or low cholesterol levels.

 

These investigators reported an 11% increase in cardiovascular mortality for every 1% mg/dl decrease in cholesterol levels. (4)

 

The Framingham data clearly reveal, contrary to the generally held view, that low cholesterol levels do not prolong life any longer than high levels.

 

FALSE REPORTING

 

Despite these clear revelations, the National Heart Lung and Blood Institute made the following statement, which clearly contradicts the findings of Framingham: “A 1% reduction of cholesterol corresponds to a 2% reduction in CHD risk.” (5)

 

It should be a source of great concern to practicing physicians, that not infrequently, professional bodies issue proclamations and subsequent press releases that distort, and thereby falsify facts, and project perceptions of benefit which have not been demonstrated.  In so doing, they demolish their own credibility.

 

In the light of these undesirable trends it is quite legitimate to ask why guidelines continue to selectively focus on cholesterol levels as a major risk threat when the evidence is lacking.

 

EXAGGERATED TRIAL CLAIMS

 

t should also be noted that trial summaries usually report data for cholesterol reduction in relative rather than absolute risk percentages, thereby grossly exaggerating the perceived benefits and conveying to the public a distorted message about the dangers of cholesterol.

 

One of many examples is evident in announcements following the LIPID RESEARCH CLINICS CORONOARY PREVENTION TRIAL (LRC-CPPT) designed to test the efficacy of lipid lowering in reducing the rate of CHD. A 24% reduction in CHD and a 19% reduction in non-fatal MI was reported and hailed as “strong evidence for a causal role for these lipids in the pathogenesis of Coronary Heart Disease”. (6)

 

In reality no such “strong evidence” existed.  This “benefit” of cholesterol-lowering was a relative % risk only, and when translated into absolute risk (AR) reduction reflected a mere 0.6% reduction for CHD death and a mere 1.1% reduction for non-fatal MI.

 

This gross manipulation of figures was later acknowledged by Dr. B. Rifkind who had been the study Director. (7)

 

Likewise, the figures for MRFIT trial purported to support the hypothesis that high cholesterol levels caused heart disease, but the data supporting this perception was shown to be inaccurate and carefully produced, and at times purposely falsified, according to Prof. Lars Wenko ( 8)

 

The Framingham revelation is not unique.

 

Numerous studies, including those from Canada, Britain, Finland, and France have produced similar conclusions.  High levels of cholesterol do not decrease mortality, and yet traditional guidelines persist in targeting cholesterol as a major culprit and agent in the development of cardiovascular disease.

 

No evidence has ever been produced implicating cholesterol as a causative agent in cardiovascular or total mortality, and patients need to hear these honest facts from their physicians.

 

It is worth considering that to withhold this fact from patients is to unnecessarily burden them with anxiety and needless stress,  and thereby increase their risk for morbidity . ( ? Negligence )

 

WHO MONICA

 

The WHO MONICA project tracked the rates of cardiovascular death compared to cholesterol levels in several European countries and revealed a clear pattern of inverse relationship between cholesterol levels and cardiovascular death.

 

Countries with the highest average cholesterol levels like Switzerland had the lowest cardiovascular death rate and those with the lowest cholesterol levels, like Russia, and the highest death rate.  These were figures for males aged 35-74 years. (9)

 

The selective targeting of bio-chemical risk factors and exclusion of lifestyle, social and nutritional factors diminishes the power of risk stratification and ignores the real Person behind the numbers.

 

It is thus appropriate for researchers like Drs Abramson and Wright to ask whether lipid lowering guidelines are evidence based.

 

In their response to the 2005 meta-analysis reported by the cholesterol treatment trialists, (CTT) they present results from 8 randomised clinical trials in which no total mortality reduction by cholesterol lowering with statins was evident. (10)

 

With reference to cardiovascular events the “absolute risk reduction (ARR) of 1.5% was so small that 67 people would have to be treated for 5 years to prevent 1 event”, they reported.

 

They acknowledge that only in a select group of high risk males, between the ages of 30 and 69 years, there might be benefits.  They furthermore contend that statins do not reduce CHD events in almost 11,000 women in pooled trials, nor do they reduce CHD events in men and women older than 69 years.

 

BEING HONEST

 

Wright states that physicians should be honest with their patients about the lack of evidence in low risk patients and the low absolute difference in relative risk even in high risk patients requiring primary prevention.

 

He concludes, “if physicians were truly honest with their patients, I think there probably would be very few people being treated for primary prevention with a statin.”

An honest appraisal of the trials that tout benefits for cholesterol lowering provides compelling evidence for a cautious approach to interpreting numbers and their significance  until other factors are taken into account.

 

“Who is the Person, rather than “What are the numbers.”

 

LOWER TARGETS (TNT)

Directives from the NCEP are aimed at lowering lipid targets with aggressive statin therapy in accordance with TNT recommendations. (11)

 

Physicians would better serve the health interests of their patients by a careful appraisal of individualised circumstances and assessment of risk vs. benefit in the light of these proposals.

 

Proponents of the aggressive approach argue that while the cautious lobby disagrees and calls for further assurances of safety before implementing such targets. (12)

 

The conclusion of authors of a study which measured the degree of plaque regression when treated with statins contradicts this notion.  They clearly state “lower is not better.” (13)

 

Dr. Bertram Pitt calls for a cautionary approach after noting that while in TNT 26 fewer CHD deaths were reported in the high dose group (atorvastation 80mg), 32 more deaths occurred in this group, again demonstrating that even with intensive lowering of cholesterol levels, mortality was not improved.

An important question raised by Dr. Pitt was whether LDL-C is the most effective target of lipid lowering strategies.  He suggested that possibly the ratio of apolipoprotein (Apo)B to (Apo)A-1 might be a better indicator of cardiovascular risk. (14)

 

NO MORTALITY BENEFITS

 

A secondary analysis of TNT was undertaken by Wenger at al to assess the efficacy and safety of high dose atorvastation in patients 65 years of age or older.  Her conclusions suggested a clinical benefit with aggressive reductions of LDL-C to less than 2.6 mM/L.

 

However the trend towards increased death from cancer in this group supports concerns about a possible dose related potential for cancer in the elderly.

Concerns for cancer related therapy were also expressed when reviewing the outcomes of PROSPER (24 deaths in the treatment group). (15), CARE (12 cases of breast cancer), J-LIT (12 cancer deaths).

 

Other trials which touted “benefits” from lipid-lowering, and in fact failed to demonstrate mortality benefits, were REVERSAL, EXCEL, ALLHAT, and ASCOT, the latter exaggerating benefits by reporting a 27% reduction in fatal and non-fatal stroke, when in fact the comparative figures were 1.7% (statins) and 2.4% (control) which equates to an absolute difference 0.7%, which is hardly a “significant benefit”. (16)

 

Thus again, there has been no evidence forthcoming for mortality benefits with cholesterol lowering, and the question, “Are the guidelines evidence based?” must again be asked.

 

The fact that nearly 50% of ACS events occur in patients with normal to below normal lipid levels is strong evidence for a non causal role for cholesterol in cardiovascular disease.

Its association with atherosclerosis may be linked to the repair process following intimal injury, together with several other factors which may also be present, thus serving as useful biomarkers.

The measurement of these “non-traditional” bio-markers may provide an alternative and superior model for risk assessment and their incorporation into guidelines makes good sense.

 

BIOMARKERS

 

Circulating “non-traditional” bio-markers are currently being evaluated for their potential to indicate risk for cardiovascular disease.

Noteworthy amongst these are CRP, apolipoprotein B, homocysteine, fibrinogen, insulin and iron, although controversy surrounds their utility value.

More sophisticated emergent bio-markers for optimising risk stratification are myeloperoxidase, lipoprotein a, isoprosteines, small dense LDL, and oxidized LDL. (17)

 

The value of these bio-markers accrues from their capacity to indicate inflammation in the arterial tree which is the underlying mechanism implicated in atherogenesis.

 

INFLAMMATION

The widely held view of CHD occurring as a consequence of vessel occluding deposits of cholesterol “sludge” is no longer scientifically tenable, and should not be propagated by health professionals or medical commentators, since it leads to false perceptions of “cholesterol plugging” and unwarranted public anxiety about cholesterol levels.

 

This false perception is widely propagated in the media and promoted by several lines of “health information”.

 

Cholesterol does not plug arteries, and the recent statement by a visiting academic about “plugging up the works” (18) is unscientific, inaccurate, and misleading, and clearly disappointing !

 

Nor do LDL particles “stick to the arterial wall,” as he suggested.

 

Atheroma occurs not in the vessel lumen, but in the vessel wall, and involves a complex mechanism of inflammatory response to intimal injury, possibly as a consequence of micro-environmental changes linked to factors such as ageing, sepsis, and/or overproduction of reactive oxygen species (ROS).

 

ATHEROMA

 

No evidence exists for the causative involvement of cholesterol in atheroma formation, and its presence in calcified plaque is thought to represent a protective activity.  Reducing cholesterol levels has not been shown to reduce plaque.

 

LOW DENSITY LIPO-PROTEIN ( LDL-C)

 

It has long been known that LDL itself is not a reliable independent risk factor for CHD and that oxidized LDL, which represents altered LDL in the arterial wall, has a stronger association with atherogenesis.

 

Furthermore, “lower is not better”, is the conclusion of the authors in their study on plaque regression, (19) supported by other investigators, declaring that LDL lowering is not beneficial. (20)

 

Neither has intensive LDL lowering conferred benefits for patients with calcified aortic stenosis.  The SALTIRE trial demonstrated a failure of statins to halt the progression of calcified aortic stenosis, and the authors state, “we do not recommend statin therapy for patients with calcified aortic stenosis in the absence of coexisting vascular disease.” (21)

COEXISTING VASCULAR DISEASE

 

A meta-analysis in 2004 by Pierre Amarenco demonstrated the benefits of statins in stroke reduction in patients with documented CHD, and young men with pre-existing cardiovascular disease and diabetes have demonstrated benefit from satin therapy (CARDS).

 

Likewise, patients with previous ischaemic stroke were shown to have a 16% reduction benefit for recurrent stroke and a 35% reduction for a major cardiovascular event with high dose atorvastatin (SPARCL).  The risk/benefit ratio, however, for haemorragic stroke remains a question of debate. (22)

 

Also, in a recent study, statin withdrawal after vascular surgery appeared to be associated with an increased risk for peri-operative cardiac events, suggesting a benefit for extended release fluvastatin in these patients. The benefits of using statins in these groups of patients has been clearly demonstrated. (23), but these benefits are likely to be due to pleiotrophic effects (anti-inflammatory ) and not to cholesterol lowering .

 

THE ROLE OF HDL

 

The beneficial effect of intensive statin therapy on the rate of plaque regression was shown by Nicholls et al in an analysis from 4 previous trials, but no significant differences were found regarding clinical outcome with either the higher or lower dose statin.

The likelihood of atheroma regression resulting from a small increase in HDL (7.5%) is supported by the GREASE Study which demonstrated the clinical benefits of small increases in HDL. (24)

 

THE ROLE OF OXIDIZED LDL

 

Unlike plasma cholesterol and circulating LDL, oxidized LDL (OX-LDL) correlates well with lipoprotein (a) in the presence of acute coronary syndromes (ACS), suggesting thereby a potential role as a plasma marker for risk.

Also, in patients with metabolic syndrome, high levels of OX- LDL were associated with a greater predisposition to atherothrombotic coronary disease.

 

There are numerous research reports demonstrating the harmful effect of oxidized LDL (OX-LDL) on vascular endothelium (eg. Navab, Holvoet), and growing evidence for a causal role in atherosclerosis for reactive oxygen species (ROS).

 

The protective role of anti-oxidants in ROS reduction, despite the disappointing outcome of recent antioxidant trials, is considered by some researchers to provide avenues for future research. (25)

 

The positive effects of  N3 – polyunsaturated oils (Omega –3 ) in this regard have been noted.

 

ANTIOXIDANTS

 

A recent Canadian study evaluated the effect of nutritional intervention on circulating OX-LDL showing a distinct beneficial reduction of OX-LDL without any changes in plasma LDL-C or LDL levels. (26)

 

These findings support earlier observations in the Lyon Diet Heart Study that LDL-C levels were not altered in the reduction in myocardial infarction ( heart attack ) risk in response to a Mediterranean diet, as did the ATTICA study (2004) which demonstrated reductions in OX-LDL but not LDL-C in response to a Mediterranean diet. (27)

 

These findings have implications for non-pharmacological intervention by physicians when reviewing the nutritional status of their patients.

 

NON-PHARMACOLOGICAL STRATEGIES

 

A broader view of individualised risk factors in respect of personal and lifestyle habits, social deprivation, nutritional vulnerability, and emotional stress deserves attention and intervention, before resorting to pharmacological manipulation of biochemical numbers.

 

The under-utilization of N-3 polyunsaturated fatty acids (Omega 3) as a powerful anti-inflammatory nutrient is sadly evident in clinical practice, and could provide a clinically proven strategy for modulating the progression of atherosclerosis and reducing MI mortality by 20%. (29) as well as reducing elevated plasma triglyceride levels.

 

BENEFITS OF CHOLESTEROL

 

Managing risk involves being honest with patients, and the unfounded fear of cholesterol needs to be addressed by physicians when counselling patients, particularly the elderly, where its protective role has been repeatedly demonstrated in trials.

 

Apart from the normal physiological benefits of cholesterol in respect of hormone synthesis (testosterone, oestrogen, cortisone), the synthesis of Vitamin D, the production of digestive bile acids, immune system enhancement, maintenance of healthy nerve myelin sheaths and stabilization of cellular membranes, several trials have demonstrated a strong association between high levels of cholesterol and reduced mortality from bacterial and viral infections.

 

The ability of lipo proteins, especially LDL, to neutralise harmful bacterial endotoxins implicated in a wide range of critical infections is indicative of the immunoprotective effects of cholesterol and contradicts the prevailing paradigm that cholesterol is harmful and is to be feared. (30)

 

LOW CHOLESTEROL LEVELS

 

Low blood levels of cholesterol, on the other hand, have been shown to correlate closely with neurological effects such as violent and aggressive behaviour, mood disturbance, and even depression and suicide.

 

The unnecessary reduction of plasma cholesterol levels has the potential to compromise health and longevity, while higher untreated levels, especially in women and elderly, appear to prolong life with less risk of drug induced adverse events.

 

HEART FAILURE

 

The beneficial effects of higher cholesterol levels in heart failure patients has been demonstrated and explained in terms of lipoprotein modulation of inflammation, while low levels of circulating lipoprotein and cholesterol have been shown to be independent predictors of impaired outcome in heart failure patients, but the association cannot reliably be shown to be causal.

 

FUTURE GUIDELINES

 

The Fourth European Guidelines on Cardiovascular Disease Prevention in Clinical Practice represents an update version of the 2003 Guidelines and will attempt to broaden the base for risk assessment by including lifestyle parameters hitherto ignored.

 

In so doing it is not likely to be “simpler” than previous guidelines (as requested) but more appropriate, and serve better as a means of understanding the “Person behind the numbers.”

 

The Guidelines, therefore, call for more than a mere manipulation of lipid numbers, since they will challenge us to evaluate individual vulnerability, with considered use of appropriate, non-traditional biomarkers, and options for non-pharmacological interventions at appropriate levels of risk.

 

Dr. Neville Wilson

The Leinster Clinic

Maynooth

Co. Kildare

 

August 31, 2007

 

 

 

 

 

 

 

 

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17.            J. Am College of Cardiol. 2006; 47: 19-31

18.            IMT 20/4/07

19.            AMAJ Cardiol. 2003: 92: 334-336

20.            NEJM 2005, 325; 2889

21.            NEJM 2005, 352: 2389-2397, 2440-2443

22.            STROKE 2004; 35: 2902-2909

23.            AMJ Cardiology 2007; July 15: 100(2) 316-321

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25.             Athero. Thromb. & Vasc. Biol. 2005; 25-29

26.            J. Nutr. 135; 410-415

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28.            Eur. J. Med. Res. 2003 aug. 20 (8) 337

29.            Lancet 354; 447-455

30.            QJMed 2003; 90; 927-934

 

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