The Great Cholesterol Con: The Truth About What Really Causes Heart Disease and How to Avoid It - PDF Free Download (2024)

the G rea t Cholesterol

. Con

~

t Grea the

Cholesterol

Con

THE TRUTH ABOUT WHAT REALLY CAUSES HEART DISEASE AND HOW TO AVOID IT

DR MALCOLM KENDRICK

JOHN BLAKE

Published by John Blake Publishing Ltd, 3 Bramber Court, 2 Bramber Road, London W14 9PB, England www.johnblakepublishing.co.uk This paperback edition first published in 2008 ISBN 978-1-84454-610-7 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or in any form or by any means, without the prior permission in writing of the publisher, nor be otherwise circulated in any form of binding or cover other than that in which it is published and without a similar condition including this condition being imposed on the subsequent publisher. British Library Cataloguing-in-Publication Data: A catalogue record for this book is available from the British Library. Design by www.envydesign.co.uk Printed and bound in Great Britain by Creative Print & Design, Blaina, Wales 3579108642

© Text copyright Dr Malcolm Kendrick 2008 Papers used by John Blake Publishing are natural, recyclable products made from wood grown in sustainable forests.The manufacturing processes conform to the environmental regulations of the country of origin. Every attempt has been made to contact the relevant copyright-holders, but some were unobtainable. We would be grateful if the appropriate people could contact us.

CONTENTS

Introduction

vii

What is heart disease, anyway? 2

What is cholesterol, anyway? (And what's a fat?)

11

3

You cannot have a cholesterol level

25

4

What are statins and how do they work?

39

5

The rise and rise of the cholesterol hypothesis

45

6

Eat whatever you like (Diet has nothing to do with heart disease)

7

57

A raised cholesterol/LDL level does not cause heart disease

79

8

Statins and heart disease

155

9

What causes heart disease?

203

10 The stress hypothesis - does it fit the facts?

237

11 Other forms of stress

253

12 Glossary

267

INTRODUCTION All humans must die ... astatinate, astatinate!' A Dalek

\ A Ie

are bombarded with so much confusing nonsense about

V Vheart disease that it is difficult to know where to start. Each day

that dawns, it seems, heralds a new study that flatly contradicts the last. Omega 3 fish oils are good for you; Omega 3 fish oils are not good for you. Alcohol protects against heart disease; alcohol does not protect against heart disease. Coffee is good for you; coffee is bad for you. Or maybe it was excess milk in the diet, or green-leaf tea, or ... To quote my lovely daughter, 'yeah, whatever: It has reached the point where I feel like shouting, 'Listen guys, I know you need to 'publish or perish; and the more publicity you can achieve the bigger the next research budget, but you're scaring people half to death. No one knows what to do or what to believe any more. And by the way, your study was RUBBISH! Now go away, grow your beard, and do some proper boring research that no one can understand.' But they won't. For it's so much more fun to appear on a news programme, talking earnestly about your discovery of the latest possible cause of heart attacks - a danger that the public absolutely, positively, must be warned about. Afterwards, you will probably be invited to lucrative speaking engagements at international cardiology 1 Adapted from Dr Who and the Daleks (1 96S). Screenplay by Milton Subotsky. Based on the BBCTelevision serial by Terry Nation. Produced by Milton SUbotsky and Max J Rosenberg.

vii

THE GREAT CHOLESTEROL CON conferences. Does a professorship beckon? 'Who, me? I really don't deserve it, but if you must .. 'Somehow, in this ever-changing, ever-confusing world, one idea has stood the test of time. And it is this:

The Diet-Heart Hypothesis (aka The Cholesterol Hypothesis) If you eat too much food containing cholesterol andlor saturated fat, the level of cholesterol in your blood will rise. The excess cholesterol will be deposited in artery walls, causing them to thicken and narrow. In time this will block blood supply to the heart (and other organs) causing a heart attack, or stroke.

Whichever name you use for it, this hypothesis has the advantage of being extra-super straightforward - suitable for children from the age of five upwards, no parental guidance required. But be careful. Perhaps the single greatest prejudice in scientific research - the researcher'S holy grail, if you like - is the belief that, in the end, the simplest solutions are correct. Occam's razor, E=MC', the perfect four base sequence of DNA. But it is as well to remember a warning from history: For every complicated problem there is a solution that is simple, direct, understandable and wrong. HLMencken

And boy, is the cholesterol hypothesis wrong. To adapt a quote from Blackadder, 'It is wronger than a very wrong thing: Yet it has mesmerised scientists, doctors and the general public for years, exuding a siren song that none can resist, dragging us all to our doom on the sharp rocks of illogicality. OK, when you look at the eye-watering profits being generated, it hasn't exactly dragged pharmaceutical companies to their doom - yet.

viii

OR MALCOLM KENDRICK Indeed, once everyone believed that a high cholesterol level was the most important single cause of heart disease, the gold rush was on to discover drugs that could lower cholesterol levels. A highly successful gold rush led by big pharmaceutical companies. Admittedly, at first things didn't go too well. Various substances were discovered in the 1960s and 1970s that, to widespread rejoicing, lowered cholesterol levels. However, when the clinical trials were carried out it was fO!Jnd that more people died when they took the drugs than when they took the placebo. In some cases the cholesterollowering agents very nearly doubled the overall mortality rate. Which did put rather a dampener on proceedings. In 1970, a study by the WHO (the World Health Organization, not the rock group) on clofibrate (a big drug at the time, but now defunct for reasons that will shortly become apparent), measured. blood cholesterol in 30,000 healthy, middle-aged men in Edinburgh, Prague and Budapest. The 10,000 men with the highest blood cholesterol levels were selected for the trial - half to receive clofibrate, half placebo. After five years there had been a total of 128 deaths in the clofibrate group and 87 in the placebo group. Oops. And there were more fatal heart attacks in the clofibrate group too. It was decreed, however, that this problem had nothing whatsoever to do with the cholesterol-lowering ability of clofibrate. Perish the very thought. The drug obviously had some other, nasty, heart-diseasecausing effects - not that anyone was quite sure what these effects were. But because everyone already 'knew' that a high cholesterol level caused heart disease, no one dared suggest that these results might just might - contradict the cholesterol hypothesis. Hey ho, let not the facts spoil a good story. The 1960s, 1970s and 1980s represented a period that could be known as the BS era; the time Before Statins began. (In a nutshell, statins are drugs that lower cholesterol and so, in the eyes of the mainstream medical community, are believed to reduce the risk of heart disease. More on this subject - much more - to follow.) In this period new drugs were found; they lowered cholesterol, but

ix

THE GREAT CHOLESTEROL CON increased mortality and were, frankly, worse than useless. I think it is true to say that the faith of the cholesterol brotherhood was becoming sorely tested. Even the pharmaceutical industry was, with extreme reluctance, heading off in different directions. Just to give one example: I find it amusing to keep a copy of a document produced by pharmaceutical giants Pfizer in 1992. This was a couple of years before 'statinomania' achieved lift-off. The document was called 'Pathologic Triggers: New Insights Into Cardiovascular

Risk~

I

may have the only remaining copy of this document. As such it must be worth .. . ooh, SOp at least. The document begins: Today, most of our attempts to prevent atherosclerosis [disease of the arteries] have centered on the control of hypertension and hyperlipidaemia [raised blood pressure and raised cholesterol, respectively], as well as lifestyle factors. However, recent insights into the pathology of coronary disease have sharpened our focus on the natural history of atheroma [build-up of fatty deposits on the lining of arteries] and its relentless progression to acute cardiac events ...

Curio user and curiouser. What could they mean? In fact, throughout this document Pfizer is carefully preparing the ground for an entirely new concept: that it is not really high blood pressure and high cholesterol levels that cause heart disease - it is something else. But what could this something else be? What indeed. According to 'New Insights into Cardiovascular Risk; heart disease is mainly associated with the formation of abnormal blood clots ... Given the insidious nature of atherosclerosis, it is vital to consider the role of platelets [small blood cells involved in blood clotting] and thrombosis [the formation of blood clots within a blood vessel or the heart] in the process ...

x

OR MALCOLM KENDRICK Today, together with the rest of the industry, they would dismiss such talk of platelets and thrombosis as utter bunk .:.. for today we have statins.lf anyone mentioned platlets now they would be told to pick up their pay cheque on the way past reception. And how were statins discovered - these glorious and magical pills that will turn us all into latter-day Methuselahs, living well into our sixth centuries? Were they discovered by highly trained scientists toiling in research laboratories, deep in the bowels of a major pharmaceutical company? Were they discovered using three-dimensional modelling and a detailed understanding of the inner workings of liver biochemistry? Do they, indeed, represent another glorious vindication of the value of the industry's much-vaunted multi-billion-dollar research and development budget? Ah ... no. As with many of the bestselling drugs, statins were discovered completely by accident. Which takes us to a small valley in northern China. It is a cold place, a lonely place, a place where a small plant clings to existence in a hostile world (all right I'm using a bit of poetic license here ... ) a plant known as red yeast rice. Red yeast rice has to deal with the many predators who find it rather tasty, making its tenuous hold on life even more precarious. But this plucky little plant has a trick up its sleeve. It produces a poison, known as lovastatin, which kills those animals that are foolish enough to eat it. A researcher from the US government discovered this plant, with its poison, and took it away for further study~ 3 • Presumably, lovastatin was a pretty useless poison, at least from the US Army's point of view. Interestingly, however, lovastatin was found to block an enzyme known as HMG-CoA reductase. This enzyme takes effect on the long, long pathway of cholesterol synthesis in the liver. Therefore, in lesser, not terribly poisonous doses, lovastatin blocks cholesterol production, and lowers blood cholesterol levels in human beings. 2 Yg, Li. Zhang, F. Wang, ZT. Hu, ZB. 'Identification and chemical profiling of monacolins in red yeast rice using high-performance liquid chromatography with photodiode array detection and mass spectrometry: J Pharm Biomed Anal, 3 September 2004; 35(5); 1101-12. 3 Thompson, Richard. 'Foundations for blockbuster drugs in federally sponsored research; The FASEB Journal, 2001; 15; 1671-76.

xi

THE GREAT CHOLESTEROL CON Merck - for many years the world's biggest pharmaceutical company - managed to obtain lovastatin from the US Army, file a patent, and the rest - as they say - is history. Mankind had entered 'The age of the

statin~

Cue celestial music - Star Waf! theme music meets

Beethoven's 'Ode to Joy; that sort of thing. And 10 it was written that Merck, clutching the great staff of Mevacor (the brand name of lovastatin) led the chosen opinion leaders to the Holy Land, a land of great bounty, where fruit hung low from the trees. A land of milk and honey where - if you were a cardiologist lucky enough to run a clinical trial on statins - huge extensions and swimming pools miraculously appeared next to your house. And the year of 'statination' was 1987, in which Merck launched lovastatin. And there was a great wailing and gnashing of teeth from other pharmaceutical companies, who had missed a trick. But they rapidly whipped their research bods into action, crying, 'Find me another HMG-CoA enzyme inhibitor, or else you shall be cast into the outer darkness.' Thus, over the years, several .other 'statins' have appeared. Merck tripped over another one called simvastatin (now sold over the counter as Zocor Heart Pro, in the UK). Bristol-Myers Squibb (BMS) stumbled across pravastatin. Fluvastatin landed at the feet of Ciba (now part of Novartis). Warner Lambert found atorvastatin lying in a small basket in the rushes; then sold marketing rights to Pfizer. Worst business decision ever made? Atorvastatin is the world's biggestselling drug, with profits that would make your eyes water. Bayer mixed the wrong chemicals together and discovered cerivastatin* - so powerful that it allegedly killed hundreds of patients and had to be withdrawn (multi-billion-dollar lawsuits pending). Most recently, we have had rosuvastatin (Crestor), synthesized in Japan, sold to AstraZeneca, and marketed with ruthless determination. All of these drugs make billions and billions of dollars of profit for their companies.

*

Yes, I know, it was probably all a bit more scientific than this. Or maybe not. After all, GlaxoSmithKline desperately tried to develop a statin for years, and failed, despite th~ir multi-gazillion-

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63

VI

THE GREAT CHOLESTEROL CON By golly, saturated fat is so deadly that even a future fall in its consumption will lead to a sudden drop in deaths from heart disease in the present! Proof that the space-time continuum is less rigid than we believe and saturated fat can leak through. The most interesting facts to emerge about rationing are: 1: For 12 years, saturated fat consumption was severely restricted. 2: Fruit and fish consumption increased. 3: The rate of heart disease nearly trebled. I know, it's a bit of a paradox, isn't it? And speaking of paradoxes, I would like to introduce you to a few more. The mos.t famous paradox is the French Paradox. The pesky French, you see, eat more saturated fat than we do in the UK. They smoke more, take less exercise, have the same cholesterol/LDL levels, the same HDL levels. They also have the same average blood pressure and the same rate of obesity. And you know what? They have onequarter the rate of heart disease that we do. One-quarter! In fact, the French consume more saturated fat than any other nation in Europe, and they have the lowest rate of heart disease. The only other nation that comes close to their super-low rate of heart disease is Switzerland, and the Swiss have the second highest consumption of saturated fat in Europe. I believe that I know what some of you are thinking right now. They, the French, are protected from heart disease by drinking red wine, eating freshly cooked vegetables (all those antioxidants, you see) and eating garlic. You've read all this time and time again. I have but one word to say this. Balls! As with almost everything in the world of heart disease, people firmly believe in a whole series of 'facts' that they just know to be true, which are not true at all and never have been. Garlic first. This magical substance is supposed to lower cholesterol levels and protect you from heart disease. You can find hundreds of papers in major clinical journals supporting this known 64

OR MALCOLM KENDRICK 'fact: For example, in 1994 a meta-analysis was published by Silagy. He looked at the effects of garlic on blood cholesterol levels, and concluded that:

The mean difference in reduction of total cholesterol between garlic-treated subjects and those receiving placebo (or avoiding garlic in their diet) was -0.77mmolll. These changes represent a 12% reduction with garlic therapy beyond the final levels achieved with placebo alone. Pretty impressive, oui? But what were the sources for this meta-analysis? A systematic review, including meta-analysis, was undertaken of

published and unpublished randomized controlled trials of garlic preparation ofat least four weeks duration. Studies were identified bya search ofMEDLINE and the ALTERNATIVE MEDICINE electronic database from references listed and review articles, and through direct contact with garlic manufacturers. ' ... and through direct contact with garlic manufacturers'! The idea that you are willing to accept data on the effectiveness of garlic from people who make their money from manufacturing garlic capsules is an interesting one. As for the 'alternative medicine electronic databases; you might as well jump· into a tent filled with hemp smoke and wait for the visions to start. However, Silagy, to his eternal credit, went one step further. He eschewed teleoanalysis and actually did a study. A randomised, placebo-controlled study, he did. And guess what:

There were no significant differences between the groups receiving garlic and placebo in the mean concentrations of serum lipids, lipoproteins or Apo A 1 or 8, by analysis either on intention-to-treat or treatment received.

65

THE GREAT CHOLESTEROL CON In 1998, a group at Bonn University in Germany asked the same question. Does garlic in the diet have any impact of lipid levels in the blood? They conciuded: 'We were actually surprised how clearly negative

the results were.' Further commentary on this study came from Dr Ronald Krauss, Chairman of the American Heart Association's nutrition committee and Head of Molecular Medicine at the University of California's lawrence Berkeley National laboratory (another big cheese, in other words): 'This study qualifies as a solid scientific study. It's what people

should be basing their thought processes on, instead of folklore.' So much for garlic, then. I could go on, analysing the supposed beneficial impact of red wine and lightly cooked vegetables. But if you start chasing down every single factor thought to have some impact on heart disease you will disappear up your own fundament, never to return. Instead, I shall make a more general point. The only reason why garlic, red wine and lightly cooked vegetables were thought to protect against heart disease in the first place is the following. The French have all the major risk factors for heart disease and so they should have a rate of heart disease higher than that in the UK But they do not. It is much, much, much lower. In order to keep the diet-heart hypothesis alive in the face of such directly contradictory evidence, a fig-leaf had to be found, and so it was. It was known that the French ate more garlic, drank more red wine and didn't cook their vegetables into a soggy tasteless mush like the ignorant Brits.lo, as if by magic, these three factors appeared (in

The Lancet, no less), as the explanation for the French Paradox. But there is no evidence that any of these three factors are actually protective. NONE. By evidence, I mean a randomised, controlled clinical study. Not epidemiology, meta-analysis, discussions with French wine producers or green-leaf tea growers, or a trawl through the Fortean Times. In reality, the only reason that these three factors appeared was to protect the diet-heart hypothesis. They are what Karl Popper would call 'ad-hoc hypotheses; which are devices that scientists use to explain away apparent contradictions to much-loved hypotheses. Ad-hoc hypotheses work along the following lines. You find a

66

OR MALCOLM KENDRICK population with a low saturated-fat intake (and few other classical risk factors for heart disease) - yet, annoyingly, they still have a very high rate of heart disease. One such population would be Emigrant Asian Indians in the UK. The ad-hoc hypothesis used to explain away their very high rate of heart disease is, as follows. Emigrant Asian Indians are genetically predisposed to develop diabetes, which then leads to heart disease. Alakazoom! The paradox disappears. On the other hand, if you find a population with a high saturated-fat intake, and a low rate of heart disease, e.g. the Inuit, you can always find something they do that explains why they are protected. In their case it was the high consumption of Omega 3 fatty acids from fish. Yes indeedy, this is where that particular substance first found fame, and hasn't it done well since? This particular game has no end. In 1981, a paper was published in

Atherosclerosis (a cracking good read), outlining 246 factors that had been identified in various studies as having an influence in heart disease. Some were protective, some causal, some were both at the same time. If this exercise were done today I can guarantee you would find well over a thousand different factors implicated in some way. Recently, just to take one example, someone suggested that the much lower rate of heart disease in south-west France, compared to north-east France, was because the saturated fat they ate was different. In the south-west they ate more pork fat and less beef fat. So now it is no longer simply saturated fat that is deadly, it is the precise type of saturated fat, in precise proportions. Just how finely can one hypothesis be sliced before it becomes thin air? What this highlights, to me at least, is one simple fact. Once someone decided that saturated fat causes heart disease, then NOTHING will change their minds. There is no evidence that cannot be dismissed in one way or another. And there is also no end to the development of new ad-hoc hypotheses. You can just keep plucking them out ofthe air endlessly - no proofrequired. Genetic predisposition is one of the most commonly used 'explainall' ad-hoc hypotheses, and it is a particular bug-bear of mine. Someone

67

THE GREAT CHOLESTEROL CON I knew quite well had a heart attack recently, aged 36. He was very fit, almost to international level at cycling. He was also extremely thin. His resting pulse was 50 a minute, his blood pressure was 120/70 (bang on normal). His total cholesterol level was 3.0mmolll, which is very low. He was vegetarian and a non-smoker. I know what you're thinking: he deserved it. Steady, he's a nice bloke, actually, if a bit worthy. Now, you can go through all the risk factors tables produced by the American Heart Association, the European Society of Cardiology and the British Heart Foundation - and any other cardiology society you care to mention. According to the lot of them, he had no risk factors. Therefore, he should not have had a heart attack. However, it did emerge that his father had a heart attack aged 50. A-ha! He was genetically susceptible, then! Phew, there's your answer. I beg to differ: if you think about this in any depth, it is a completely idiotic statement to make. If someone is genetically susceptible to heart disease, that susceptibility must operate though some identifiable mechanism. Or does a big finger suddenly appear from the sky and go: 'Pow! Heart attack time, bad luck: Genetically susceptible people don't need high LDL levels, or high blood pressure. They don't need to smoke or eat a high-fat diet. They don't need to be overweight, or have diabetes - or anything, actually. They are felled by a mysterious genetic force, operating in a way that no one can detect. Other people are killed by risk factors. But such factors count for nothing if you are genetically susceptible. I have one word to say to this - and it's a word I've used before in a similar context. Balls. Karl Popper recognised such reasoning. He called it the use of circular logic. His example, was as follows:

Consider the following dialogue: 'Why is the sea so rough today?''Because Neptune is very angry' - 'By what evidence can you support your statement that Neptune is very angry?' - 'Oh, don't you see how very rough the sea is? And is it not always rough when Neptune is angry?' Popper, K. Popper Selections

68

DR MALCOLM KENDRICK I would ask you to consider the following dialogue:

'Why has this man, with no risk fadors for heart disease, had a heart attack?' - 'Because he is genetically susceptible.' - 'By what evidence can you support your statement that he is genetically susceptible?' 'Oh, don't you see that he has had a heart attack, although he has no risk factors? So he must be genetically susceptible: If you are going to suggest that people are genetically susceptible to heart disease, then you also have to attempt to explain the mechanism. Otherwise, you might as well believe in magic. 'Abracadabra, genetics heart attack.' Alternatively, you could accept that the mainstream risk factors are not, actually, risk factors at all - since you can have a heart attack without having any of them. Your choice. As ever, I have drifted off track a bit. But I wanted to highlight the endless games that people play to keep the diet-heart hypothesis alive. There is always a reason why population X and their paradoxical rate of heart disease does not mean that the diet-heart hypothesis is wrong. And once you have 246 factors to throw into the mix, you can complicate matters by a zillion: 'Oh, you didn't measure this, or that ... ' Then, if all else fails, you can just throw in the dreaded word 'multifactorial: End of discussion. End of will to live. However, despite the fact that any paradox discovered is immediately 'ad-hocced' into non-existence, I thought I would introduce you to a couple more paradoxes before leaving this discussion. Firstly, the Israeli Paradox.

Israel has one of the highest dietary polyunsaturated/saturated fat ratios in the world; the consumption of Omega-6 polyunsaturated fatty acids (PUFA) is about 8% higher than in the USA, and 10-12% higher than in most European countries. In fact, Israeli Jews may be regarded as a population-based dietary experiment of the effect of a high Omega-6 PUFA diet. .. Despite such national habits" there is paradoxically a high prevalence of

69

THE GREAT CHOLESTEROL CON cardiovascular diseases, hypertension, non-insulin-dependent diabetes mellitus and obesity.6

I will allow you to guess what the response to this finding was. Go on, you know you can do it. The response was to suggest that Omega 6 polyunsaturated fats are dangerous, at least they are if the proportion of Omega 6 to Omega 3 exceeds a ratio of 4:1 ... or perhaps it was if Jupiter is out of alignment with Venus in the sign of Libra. Here's another pa'radox. After WWII, saturated-fat consumption in Switzerland increased by 20'per cent. Yet during this 25-year period, the rate of heart disease fell. It is now clearly established, of course, that Swiss cows produce cheese high in Omega 3 fatty acids. The researchers observed a trend. Cheeses from the milk of purely grass-fed alpine cows had the best fat profile, followed,by cheeses from silage-fed alpine cows and linseed-supplemented cows. Lowest in Omega 3 fatty acids were the Emmentalers and then the Cheddars. Grass-based alpine cheese contained four times as much of the plant Omega-3 ALA as did the Cheddar, more Omega 3 fats in general, three times as much conjugated linoleic acid, and 20 percent less of the saturated fat palmitic acid. http://www.sciencenews.org/articles/20040724/food.asp

This passage has the advantage of being completely incomprehensible to all but the most dedicated follower of fat biochemistry. However, it clearly suggests something about Omega 3 fatty acids being at higher levels in alpine-fed cows. 'A-ha ... so that's' why the Swiss rate of heart disease fell: he exclaimed, before his brain finally turned to mush. I could go on and on. But I hope you get the general drift that there is actually no end, ever, to the ability of researchers to come up with a 6: Yam, 0, Eliraz, A, Berry, EM, 'Diet and Disease - the Israeli Paradox: Possible Dangers of a high Omega-6 Polyunsaturated Fatty Acid Diet: Isr J Med Sci, November 1996; 32(11): 1134-43,

70

OR MALCOLM KENDRICK reason why every single paradox is not really a paradox at all. And why a high saturated-fat diet really does cause heart disease. I would just ask, how many paradoxes do you need before the only paradox left is the diet-heart hypothesis itself?

Of course, it you wish to believe all of the ad-hoc hypotheses currently in existence, it seems that you are allowed to eat saturated fat and remain healthy. But only if you eat saturated pork fat and cheese from cows eating grass in a high alpine pasture in Switzerland, but make sure it is cheddar and not Emmental - or was that the other way round? Golly, it sure is tricky eating a healthy diet. You need a biochemist on hand, equipped with a mass spectrometer and a three-dimensional crystallography x-ray machine, lest an unhealthy fat were to slip through. 'Hold on, that's an unconjugated linoleic acid molecule, don't move, don't swallow ... I think I can just reach it..: Before I finish let's just run through a couple of the more spectacular studies contradicting the idea that saturated fat causes heart disease. I will then present you with two graphs that might finally persuade you that a diet high in saturated fat has nothing to with heart disease.

1: MALMO: SWEDEN (2005)' • 28,098 middle-aged men and women • Split into four categories (quartiles) from low to high fat/saturated-fat intake • Follow-up; 6.6 years

Findings Saturated fat showed no relationship with cardiovascular disease in men. Among women, cardiovascular mortality showed a downward trend with increasing saturated-fat intake, but the relative risk reductions did not reach statistical significance. (In other words, there was no difference.) 8 Leosdottir, M. Nilsson, PM. Niisson,JA. Mansson, H. Berglund, G.'Oietary fat intake and early mortality patterns - data from The Malmo Diet and Cancer Study:J Intern Meet. August 200S; 258(2): 153-65.

.n

THE GREAT CHOLESTEROL CON

Condusions With our results added to the pool of evidence from large-scale prospective cohort studies on dietary fat, disease and mortality, traditional dietary guidelines concerning fat intake are thus generally not strongly supported.' ,As ever, the conclusion is vague and somewhat apologetic: ' ... traditional dietary guidelines concerning fat intake are thus generally not strongly supported: Come on, chaps, show a bit of a stiff upper lip! According to this study, the traditional dietary guidelines are utter bunk. Shout it loudly from the hilltop5! Climb every mountain, ford every stream! Shoot every Omega 3 cow!

2: WOMEN'S HEALTH INTERVENTION USA (2006) • 48,835 women aged 50 to 79 • Study length: 8.1 years • Major intervention in diet (Le., this was not a passive observational trial. This was a randomised, interventional, controlled clinical study involving almost fifty thousand women. The gold standard.) Those randomised to the intervention group were intensively counselled to reduce their daily fat intake to twenty per cent of calories, to increase their intake of fruits and vegetables to at least five servings daily, and to increase grain consumption to at least six servings daily. By the sixth year, the intervention group was consuming, on average, 29 per cent of calories as fat, compared to 37 per cent in the control group. The corresponding figures for saturated fat were 9.5 per cent and 12.4 per cent, respectively.

Findings Among the study population as a whole, there were no significant differences in CHD or stroke incidence, CHD or stroke mortality, or total mortality. And, in addition, the low-fat diet produced no reduction in the incidence or mortality rates of breast cancer, colorectal cancer, or total cancer either.

72

DR MALCOLM KENDRICK I thought you might find it interesting to read the 'establishment' interpretation of this trial:

The results of this study do not change established recommen- dations on disease prevention. Women should continue to get regular mammograms and screenings for colorectal cancer, and work with their doctors to reduce their risks for heart disease including following a diet low in saturated fat, trans fat and cholesterol,' said National Heart, Lung, and Blood Institute Director Elizabeth G Nabel, MD. (I would have concluded the exact

opposite from the same study!) This study shows that just reducing total fat intake does not go far enough to have an impact on heart disease risk. While the participants' overall change in LDL "bad" cholesterol was small, we saw trends towards greater reductions in cholesterol and heart disease risk in women eating less saturated and trans fat,' said Jacques Rossouw, MD, WHI project officer. ('We saw trends: I must have missed something.) Judy O'Sullivan, a cardiac nurse at the British Heart Foundation, said: 'Numerous studies have confirmed there are huge heart benefits from maintaining a healthy lifestyle which involves a balanced diet and regular physical activity. It is easy to identify a number of important reasons why this study did not agree with previous research.' (Go on then, Judy, identify them.)

(Now for my favourite quote):'There may have been some "disappointment" that the studies didn't always give clear answers,' acknowledges Dr Elizabeth Nabel, heart chief at the National Institutes of Health.'The findings are what they are ... Now we're in a second wave of putting the findings into perspective.'

7J

THE GREAT CHOLESTEROL CON 'Putting the findings into perspective: Perhaps the findings merely represent a 'paradox'; if not, I am sure that plenty of ad-hoc hypotheses will emerge which will sweep this $400-million-dollar trial into the dustbin.

DR KENDRICK'S 14-COUNTRY STUDY I shall now give you twice as much research for your money as Ancel Keys. I looked at the figures gathered by the World Health Organization on saturated-fat consumption and heart-disease rates in various countries throughout Europe. All figures are from 1998, or within two years of 1998 if figures for that exact year were not available. I looked first at the seven countries with the lowest consumption of saturated fat, and compared this to their rate of heart disease. I then took the seven countries with the highest consumption of saturated fat and compared this to their rate of heart disease (see Figs 18 and 19, below and opposite):

Fig 18 Comparison of heart disease deaths vs consumption of saturated fat % calories (Countries with lowest saturated-fat consumption) GEORGIA

TAJIKSTAN

AZERBAIJAN

MOLDOVA

CROATIA

MACEDONIA

UKRAINE

10%

7.5%

5.0%

2.5%

100

200

Saturated Fat Consumption

300

400

500

Death Rate/l00/000lYear

% Calories

74

600

700

800

DR MALCOLM KENDRICK

Fig 19 Comparison of heart disease deaths vs consumption of saturated fat %calories (Countries with highest saturated-fat consumption)

AUSTRIA

FINLAND

BELGIUM

ICELAND

NETHERLANDS

SWITZERLAND

FRANCE

15%

2.5%

10%

7.5%

5.0%

2.5%

Saturated Fat Consumption % Calories

100

200

300

Death Rate/100/000!Year

When I first showed these graphs to another doctor he exclaimed:'My goodness, saturated fat is worse for you than I thought!'To me, this just goes to show that, even when confronted with the facts, people still view them through preconceived prejudices. I then took him through the graphs more slowly, pointing out that he had got it completely the wrong way round. The facts are: • Every single one of the seven countries with the lowest saturatedfat consumption has significantly higher rates of heart disease than every single one of the seven countries with the highest saturatedfat consumption. At which point his immediate response was:'This can't be right, where did you get this rubbish from?' I then showed him the original figures, pointing out that they came

75

THE GREAT CHOLESTEROL CON from the World Health Organization. He then said, 'Well there obviously must be other factors involved: What he would not do, however, was accept that there is no connection between saturated fat consumption and heart disease. Even when confronted with evidence that is, in my view, overwhelming. Far more overwhelming, ironically, than anything Ancel Keys managed to come up with in the first place. Now, of course, I know that there has to be some

r~ason

why every

single country in the top seven of saturated fat consumption has a lower rate of heart disease than every single country in the bottom seven of saturated-fat consumption. Whatever it is, though, it is not going to have anything to do with saturated-fat consumption.

***** I could fill an entire book with studies that have been done contradicting the diet-heart hypothesis. There are even studies showing, quite clearly, that reducing saturated fat is harmful. But I feel that quoting study after study would get somewhat tedious. However, if you are interested in looking into this area in more detail, there are several very good and well-written sources of information where you can read about such trials to your heart's content. Here are three of them: www.thincs.org www.theomnivore.com www.second-opinions.co.uk Just before signing off on this chapter, I need to make an admission. Despite my slagging off all ad-hoc hypotheses, and their feeble use as crutches to support the diet-heart hypothesis, two dietary substances appear to have surfaced that do seem to be consistently beneficial in protecting against heart disease.

76

OR MALCOLM KENDRICK 1: Omega 3 fatty acids. This type of fat appears to have two effects that may be protective. Firstly, it has a reasonably strong anti-coagulant effect, a bit like aspirin. Secondly, it seems to protect against heart arrhythmias. (Omega 3 fatty acids, it should be added, have no effect on LDL levels.) You tend to find Omega 3-type fats in fish. So, although it rather sticks in my craw, I feel I must recommend that Omega 3 fats are probably good for you. 2: Alcohol Moderate alcohol consumption does appear to reduce the risk of dying of heart disease by about twenty per cent,. on average. The type of alcohol is more or less irrelevant (although wine and beer seem better than spirits). However, extremely heavy or binge drinking seems to have the opposite effect. This may be due to the fact that after a very heavy drinking session, the blood-clotting system can 'rebound~ making blood clots more likely to form.

POSTSCRIPT A few of my favourite quotes It had been noted in the Framingham Study that a high saturated fat consumption reduced the rate of strokes. It was

suggest~d

that,

because strokes tend to affect older men, the fatty diet was causing those in the trial to die of heart disease before they could die of a stroke (yes, it's yet another desperate ad-hoc hypothesis). But the researchers discounted this, saying:

This hypothesis, however, depends on the presence of a strong direct association of fat intake with coronary heart disease. Since we found no such association, competing mortality from coronary heart disease is very unlikely to explain our results. It had to be dragged out of them. But after 49 years, which is a pretty long time period for any study, the Framingham Study flatly contradicts the diet-heart hypothesis.

77

THE GREAT CHOLESTEROL CON The overall results do not show a beneficial effect on coronary heart disease or total mortality from this multifactor intervention.

The above quote is from the Multiple Risk Factor Intervention Trial (MRFIT) involving 28 medical centres, 250 researchers and 361,662 men. Cholesterol consumption was cut by 42 per cent, saturated fat consumption by 28 per cent. With no effect on heart disease. As multiple intervention against risk factors for coronary heart disease in middle-aged men at only moderate risk seem to have failed to reduce both morbidity and mortality such interventions become increasingly difficult to justify. This runs counter to the recommendations of many national and international advisory bodies which must now take the recent findings from Finland into consideration. Not to do so may be ethically unacceptable.

This is a quote from Professor Michael Oliver, and follows a study in Finland. In a ten-year follow-up to the initial study (hailed as a success) it found that those people who continued to follow the carefully controlled cholesterol-lowering diet were twice as likely to die of heart disease as those who didn't. Final word goes to American cardiologist EH Ahrens, Jr. Initially a supporter of the low-fat diet, after 25 years of research he concluded that: If the public's diet is going to be decided by popularity polls and with diminishing regard for the scientific evidence, I fear that future generations will be left in ignorance of the real merits, as well as the possible faults in any dietary regimen aimed at prevention of coronary heart disease.

He is much more polite than I.

78

CHAPTER 7

A RAISED CHOLESTEROL/LDL LEVEL DOES NOT CAUSE HEART DISEASE

A

t this point in the book. I move off the edge of the charts and into unexplored lands marked 'Here be dragons: For while it's true

that the bulk of the mainstream still supports the diet part of the dietheart hypothesis, there are many researchers who have long since given up on the idea - including such notables as Professor Michael Oliver. So I am far from being a lonely traveller in that area. But when it comes to attacking the second part of the hypothesis, namely that raised cholesterol levels cause heart disease, I find myself in the wilderness. There are a few others moving around in this landscape, true, but not many. To be frank. a number of them have a tendency to write in green ink and regularly howl at the moon, whereas I only howl at a full moon. I am also fully aware that when I talk about raised cholesterol levels causing heart disease I am in the realm of the 'known fact' - a fact that has apparently been proven beyond the slightest doubt, time and time again. However, despite that fact that hardly anyone else agrees with me, I believe firmly that the cholesterol hypothesis is wrong. By the time you have finished this chapter, I hope to have convinced you of this fact too. Before starting on the demolition job I !'lust admit that, for many years,l too believed that a raised cholesterol level caused heart disease.

79

THE GREAT CHOLESTEROL CON On the face of it the evidence seemed overwhelming, and it also seemed to make sense. The most powerful facts, at least to me, were the following: Fact One:

Atherosclerotic plaques contain a lot of cholesterol, which must have come from the blood. So heart disease had to have something to do with cholesterol-containing lipoproteins.

Fact Two:

People with familial hypercholesterolaemia (FH) die very young from heart disease, sometimes as young as five.

Fact Three: Statins lower cholesterol levels and protect against heart disease. Fact Four: 'Normal' people (without FH) with higher cholesterol levels are more likely to die from heart disease. These facts seemed concrete and inarguable. Every time I opened a journal, or read a paper, they were confirmed. Again and again. But these facts are really only partially true. They are rather like the false-fronted buildings used in Westerns. If you look at them from dead ahead, you see what looks like an entire town laid out in front of you. But if you move sideways, just a little bit, you can see that the supposedly solid buildings are just four-inch-thick plywood with nothing behind them at all. And so it is with the second part of the cholesterol hypothesis 'raised cholesterol/LDL causes C:;HD: Seen from one angle, the facts look solid. But once you decide to quit the 'opinion leader guided tour; you get a completely different view. And so, ladies and gentlemen, it is time for a backstage trip around the cholesterol hypothesis. Gasp as you see the real facts exposed for the first time!

OR MALCOLM KENDRICK Scream as the fearsome Austrian study bares it claws! Prepare to be amazed as the awesome three-headed Honolulu trial eats lDL in front of your very eyes! Roll up, roll up. Only two and thruppence for adults, and children under six are free!

CHOLESTEROL LEVELS AND STROKES I shall start the discussion by moving sideways for a moment to talk about a slightly different manifestation of cardiovascular disease strokes. Why am I talking about strokes instead of heart disease? Well, strokes and heart disease are part of the family known as cardiovascular disease (CVD). People with heart disease are far more likely to get strokes, and vice versa. Strokes also kill very nearly as many people as heart attacks, so this is not some minor problem. A stroke happens when blood supply to a part of the brain is cut off. The brain tissue downstream dies, and the victim will lose some brain function. A small stroke is sometimes known as a transient ischaemic attack (TIA); a big stroke can be fatal, or leave the victim with severe disability. The most common cause of a stroke is the development of a big, nasty atherosclerotic plaque at the base of neck, in the carotid arteries. Clots form over these plaques. The clots can then break off and travel into the brain, where they get jammed into an artery and block the blood flow. Given the fact that both strokes and heart disease are caused by the development of atherosclerotic plaques, you would think, would you not, that if a raised cholesterol level is a risk factor for heart disease, it would also be a risk factor for stroke? But it is not. In · 1995, The Lancet published a massive study that looked at 450,000 people over a period of 16 years who suffered, between them, 13,000 strokes. This represented 7.3 million person-years of observation. Frankly, that's quite long enough for anybody. And the conclusions thereof: There was no association between blood

cholesterol and stroke:

87

THE GREAT CHOLESTEROL CON More recently, a pan-European study known as EUROSTROKE, published in 2002, asked the same question. The result: 'This analysis of the EUROSTROKE project could not disclose an association of total cholesterol with fatal, non-fatal, haemorrhagic or ischaemic stroke:

There are many other studies showing exactly the same thing. So, you have two conditions - stroke and heart disease - that are both fundamentally a form of arterial disease. Yet, raised cholesterol is a risk factor for one, but not the other. Listed below is a slightly shortened list of risk factors for stroke from the American Stroke ·Association: • High blood pressure • Tobacco use • Diabetes • Carotid or other artery disease • Other heart disease - people with coronary heart disease or heart failure have a higher risk of stroke • Physical inactivity and obesity • Excessive alcohol intake • Some illegal drugs - intravenous drug abuse carries a high risk of stroke • Cocaine use has been linked to strokes and heart attacks • Increasing age • Sex (gender) - stroke is more common in men than in women • Prior stroke or heart attack - someone who has had a stroke is at much higher risk of having another one. If you've had a heart attack, you're at higher risk of having a stroke too Given that these are precisely the same risk factors as for heart disease (in fact, some of them are heart disease), where is cholesterol in this list? Even more critical for this discussion, how can lowering cholesterol with statins reduce the risk of stroke (which they do), if a raised cholesterol level isn't a risk factor for stroke? This most certainly does not make sense.

82

DR MALCOLM KENDRICK Actually, it would make perfect sense if you believe that any benefit gained from taking a statin has nothing to do with lowering cholesterol levels. But this explanation cannot be allowed by the medicine world at large, or else the entire cholesterol hypothesis crumbles to the ground. In fact, in its quiet, academic sort of way, this was a crisis! The inner keep of the castle was under fire, the enemy had got in unnoticed through an underground tunnel. No one had expected an attack from this direction. The cholesterol hypothesis had to be protected. But how? How indeed. Tricky, this one. Very tricky. But you know, the cholesterol brotherhood has some very clever boffins on its side. Although, in this area I think we should trust the instincts of Montaigne: I prefer the company of peasants because they have not been educated sufficiently to reason incorrectly. Michel de Montaigne

By the way, I quote others only in order the better to express myself. Michel de Montaigne

Step one to protect the cholesterol hypothesis was to split strokes into two basic types. • Ischaemic • Haemorrhagic An ischaemic stroke is caused when a small blood clot travels into the brain, then gets jammed as the arteries narrow. The bigger the clot, the bigger the artery that gets blocked and the bigger the stroke. Around 75 per cent of strokes are ischaemic. A haemorrhagic stroke happens when an artery in the brain

83

THE GREAT CHOLESTEROL CON bursts. This causes blood to escape into the brain tissue and cause damage. Haemorrhagic strokes are, generally, more deadly than ischaemic strokes. Once you have split strokes into two types, you then state that an increased cholesterol level causes ischaemic strokes. On the other hand, a low cholesterol level does not cause haemorrhagic strokes, it is merely associated with haemorrhagic strokes. (Yet another ad-hoc hypothesis plucked from thin air.) Then - goodness me, this is getting complicated - if you lower cholesterol levels, you will prevent ischaemic strokes, but you will not cause an increase in haemorrhagic strokes. Which is why lowering cholesterol levels with statins can reduce the overall rate of stroke even if a raised cholesterol level is not a risk factor for stroke. Phew! I'm glad we sorted that one out. At which point you can add in the one missing risk factor from the American Stroke Association list. Yes, it's cholesterol. I cut it out of the list - what a naughty boy. But I did it for a reason. Now you can read it with open eyes:

A high level of total cholesterol in the blood (240 mg/dL or higher [about 6 mmol/I]) is a major risk factor for heart disease, which raises your risk of stroke. Recent studies show that high levels of LDL ['bad] cholesterol (greater than 700 mg/dL [about 3 mmol/I]) and triglycerides (blood fats, 750 mg/dL or higher [about 4.5 mmol/I]) increase the risk of stroke in people with previous coronary heart disease, ischemic stroke or transient ischemic attack (TIA). http://www.americanheart.org/presenter.jhtml?identifier=4776 This is so carefully crafted that if you read it without prior knowledge you would think it said that increased cholesterol levels· increase the risk of stroke. But it doesn't. What it says - if you read it very carefully is that a high cholesterol level is a major risk for heart disease - and heart disease, in turn, increases your risk of stroke. Hmmmm! This is teleoanalysis again:

84

DR MALCOLM KENDRICK • A (a raised cholesterol level) leads to B (heart disease). • B (heart disease) causes C (stroke). • A isn't a risk factor for C in any study. • But A acting through B causes C. • Thus, A does cause C - huzzah! Faultless logic. The American Stroke Association then goes on to state that raised LDL levels increase the risk of stroke - in people who already have heart disease, or who have already suffered a stroke. Now, I could chase myself round in circles trying to dissect the logic in that passage. But I will just make one point. What this passage does not say is that raised cholesterol is a risk factor for stroke. Why not? Because that would be a lie. And the powers that be do not lie - they just ensure that the truth lies sleeping atop a very high tower, guarded by fierce beasties with awfully sharp teeth. As a general point, I will just say that it is a damn sight easier to create ad-hoc hypotheses, and pluck conjectures from the sky, than it is to disprove them. Usually, by the time you have managed to do so, everyone's eyes have glazed over. Or the whole argument has become so complex that you forget where you started. But I am going to hunt this one down, because I believe it is kind of critical. What I am going to show you is that a low cholesterol level ,is actually associated with a massive increase in death from stroke, and may even be a cause. Let's start with a helpful little passage: Epidemiological data are generally consistent with the animal experiments, they indicate that diets which are very low in fat increase the occurrence of some forms of stroke. Societies with a low intake of fat and animal protein, such as traditional Japan, tend to have high rates of haemorrhagic stroke. An elevated risk of stroke is found among segments of the Japanese population with low levels of serum cholesterol, particularly among those with high blood pressure. In a large, screened population of men in the USA, those with

85

THE GREAT CHOLESTEROL CON the lowest serum cholesterol levels had an elevated risk of haemorrhagic stroke. http://www.fao.org/docrepIV4700EIV4700EOi.htm

This suggests that a low cholesterol level may actually cause haemorrhagic stroke. Is this effect powerful enough overcome the theoretical benefits of low cholesterol in preventing ischaemic stroke? To answer this question, we need to move to Japan, land of the rising sun and the falling stroke. While the Japanese have always had a low rate of heart disease, they used to have the highest rate of strokes in the world. At one time their rate of stroke was 30 times their rate of heart attacks. In fact, death from stroke represented such a huge health problem that, in the not-too-distant past, the Japanese were being actively encouraged to raise their fat intake to prevent so many of them dying of strokes. This was probably good advice, as confirmed by a 15-year Japanese study published in Stroke in 2004: The risk of death from [cerebral] infarction [AKA stroke] was reduced by 64% in the high cholesterol consumption group, compared with the low cholesterol consumption group ... Animal protein was not significantly associated with [cerebral] infarction after adjustment for animal fat and cholesterol ... This study suggests that in Japan, where animal product intake is lower than in Western countries, a high consumption of animal fat and cholesterol was associated with a reduced risk of cerebral infarction death.

Compare and contrast this hugely positive result with the miserable failure in any trial to show that reducing saturated fat in the diet prevents heart disease. I know that I am supposed to have moved on from discussing the diet-heart hypothesis, but hey! This is just too good to resist! A high consumption of saturated fat reduces the stroke rate by 64 per cent. Reducing saturated fat in the diet reduces the risk of heart disease by 0 per cent.

86

DR MALCOLM KENDRICK Perhaps as a result of the advice. to increase fat consumption, or perhaps as a result of enemy infiltration by fast food restaurants, in the last 50 years fat, and saturated fat, consumption has gone up in Japan, as have cholesterol levels. (See table below.)

Changes in Japanese diet, 1958-99 1958

1999

Total Calories

2,837

2,202

Carbohydrate intake % calories

84

62

Protein intake % calories

11

18

Fat intake % calories

5

20

Virtually a doubling of protein intake, and a quadrupling of fat intake. Oh my God, what happened to the cholesterol levels? They went up by 20 per cent: Cholesterol levels 1958 = 3.9mmolll Cholesterol levels 1999

=4.9mmol/l

The poor devils, they must have started to drop like flies from heart disease. Ah, no.

Fig. 20 CHD mortality in Japanese men, 1965-95 60 50 0 0

g ~

40 30

a.

~

a:

20 10 0

And just look what has happened to the rate of stroke:

87

THE GREAT CHOLESTEROL CON

Fig.21 Death rates from stroke in Japanese men (aged 60-69), 1950-95 1500

-y--- - - - - - - - - - - - - - - - - - - - - - ,

o

~

1000

o

~

500

a:

1950

1955

1960

1965

1970

1975

1980

1985

1990

1995

Good golly, Miss Molly! I think we have another paradox on our hands. A double paradox, no less. If a raised cholesterol level does actually cause ischaemic stroke, and 75 per cent of strokes are ischaemic, then a 20 per cent rise in cholesterol levels across the board ought to - really ought to - increase the rate of stroke. (Note: this graph does not distinguish between the two types of stroke.) Instead, between 1965 and 1995 the rate of stroke fell from 1,334 to 226 (per 1OO,OOO/year). This is a 5.9-fold reduction. Five point nine. You know, that's very nearly six. And if you are wondering why I chose the age group 60-69, it wasn't because this particular age make my case stronger. It just seemed a reasonable age to look at. Had I chosen men aged 55-59, the rate of stroke fell from 463 to 81 (per 1OO,OOO/year).lf I had chosen 75-79, the rate of stroke fel) from 3,470 to 851 (per 1OO,OOO/year). These figures represent pretty much the same proportional drop. And it is gigantic. In fact, it is the greatest fall in death rates I have ever seen for any disease in any population - ever. So what does this prove? Well, it doesn't prove anything, because epidemiological data can only suggest a connection, or a lack of a connection. However, in Japan, as cholesterol levels went up, death rates from two of the main cardiovascular diseases fell dramatically. Ergo, these data very strongly suggest a causal connection between raised cholesterol levels and cardiovascular disease is [ (Insert adverb of your choice into the brackets above.)

88

1unlikely.

DR MALCOLM KENDRICK You can splutter all you like about paradoxes, and that one country 'does not prove anything: Japan may be just one country, but it is a country of 115 million people. So, in reality, it is 115 million inscrutable paradoxes. I think if I did a clinical trial on 115 million people, most scientists would consider that to be adequately 'powered' to disprove the null hypothesis (don't worry, just a bit of statistical jargon). My takeaway point in this section on strokes is as follows. According to mainstream thinking, ischaemic strokes are caused by raised cholesterol levels, and ischaemic strokes represent 75 per cent of all strokes. However, over the last 50 years, cholesterol levels have risen by 20 per cent in Japan, and the rate of stroke has fallen off the edge of a cliff - dropping 600 per cent. And the rate of heart disease has also fallen dramatically. Gentlemen, try to fit those pieces of a jigsaw puzzle together. (Here's a hint. Some of the pieces may, currently, be upside down.)

CHOLESTEROULDL AND TOTAL MORTALITY Having looked at stroke, and the evidence that the greatest risk factor for stroke is a low cholesterol level, not a high cholesterol level, I think that it is time to introduce the concept of 'total mortality: You see, it is actually possible to die of things other than heart disease, although to hear a cardiologist speak you would sometimes think not. They are utterly obsessed with cardiovascular deaths. Benefits in this area are trumpeted to the very skies. Yet overall mortality is often overlooked; in some trials these data isn't even published at all. Speaking personally, I think that total mortality data are by far the most important thing. I'm not that bothered about exactly how people die. Nor, I suspect, are most people. It's the dying bit we are all trying to prevent, or avoid. Indeed, to be perfectly honest, a massive heart attack seems preferable to dying slowly of cancer. Maybe you think not. It's probably a matter of personal taste. So I think it is interesting to look rather more closely at the association between cholesterol levels and total mortality. That is, mortality from everything. Heart disease, cancer, respiratory diseases, digestive diseases - the works.

89

THE GREAT CHOLESTEROL CON Time, then, to look at the Conference on Low Blood Cholesterol and Mortality, which gathered together the data from 523,737. men and 124,814 women, and reported back in 1992. I think you should probably go and make yourself a cup of coffee at this point, because I do not think you are going to believe the data that I am about to present. So steady yourself. Firstly, the overall mortality data from women:

Fig. 22 Risk of death at various cholesterol levels in the next five years - women 1.15 1.1

"'a:"

1.05

">

.~

-.; a:

0.95 0.9 0.85

< 4.0mmoll

4-5mmolll

5-6mmol/l

>6.0mmolll

I think that's pretty clear, it is not? The healthiest cholesterol level is somewhere around about 5.5mmolil. I know that this data is on total cholesterol, not LDL. But I can assure you that the two things are tightly bound. In study after study, total cholesterol was as good a predictor of death as LDL alone - if not better. And a higher total cholesterol level means, 99 per cent of the time, a higher LDL level. Now, someone like me might look at that data and wonder why the current recommendations are that we should all strive to get the cholesterol level below 5.0mmolll. Indeed, the most recent guidelines recommend that we should be aiming to get below 4.0mmol/l. To be frank, one look at the diagram on female mortality

should tell you everything you need to know about that idea. (Top tip: look to the left and upwards on the graph.) Anyway, on to men and total mortality:

90

DR MALCOLM KENDRICK

Fig.23 Risk of death at various cholesterol levels in the next five years - men

1.2,-----------------------, 1.15

'"a:

1.1

'"

1.05

>

.~

-.; a:

0.95 0.9

+--------.------.-------,-------/ 6.0mmol/l

Not quite the same pattern as with women, more of aU-shaped curve_ But it's still hardly a graph that suggests cholesterol is a deadly killer, as the highest mortality rate is to be found at the lowest cholesterol level. Just for the heck of it, below is a graph showing the rate of noncancer, non-cardiovascular mortality in women. This one just keeps going down as cholesterol levels go up:

Fig. 24 Risk of non-cancer non-cardiovascular death at various cholesterol levels in the next five years - women 1.6 1.4 1.2

'"a: >

'"

0.8

-.;

0.6

~

.~

a:

0.4 0.2 0 < 4.0mmoll

4 -5 mmolll

5 -6mmolll

>6.0mmolll

But you shouldn't worry about low cholesterol levels. Why not? Because no one at the conference did: Most participants considered it to be likely that many of the statistical associations of low or lowered TC (total cholesterol) level are explainable by confounding in one form or another. The conference focused on the apparent existence and nature of these

97

THE GREAT CHOLESTEROL CON associations and on the need to understand their source, rather than on any pertinence of the finding for public health policy. Dr Yusuf, who was a major player at the conference, noted that the excess of non-cardiac deaths was: '... of borderline statistical significance, was spread over a number of causes, and was not related to the strength of the intervention: Yusuf interpreted these findings as 'biologically implausible and probably due to chance: And thus was any association between low cholesterol levels and increased rate of death airily waved away. No need for the public to worry their pretty little heads about such matters. But you know, perhaps the public should worry their pretty little heads. Because a key finding from the Framingham Study was the following.

There is a direct association between falling cholesterol levels over the first 14 years {of the study] and mortality over the following 18 years (11 % overall and 14% CVD death rate increase per 1mg/dl per year drop in cholesterol levels). Yes, you did just read that. Those people whose cholesterol levels fell, were at a greatly increased risk of dying - and at an even greater risk of dying of cardiovascular disease. I shall expand on these figures a bit. The figures on total mortality show an 11 per cent overall increase of death for each 1mg/dl drop in cholesterol levels, which doesn't sound that bad. But remember that mg/dl are titchy little US units. To convert into the magnificent jumbo-sized units used in the UK - mmol/I - you need to multiply by 39. So, a quick translation of the Framingham results gives the following: a 1mmol/I fall in cholesterol levels is equal to a (39 x 11 per cent) increase in the risk of total mortality. Which is 429 per cent. To put this into a real-life context, if your total cholesterol were to fall from 5 to 4 mmol/I, your risk of dying would increase by more than 400 per cent. Not only that, but your risk of dying of a cardiovascular disease would increase by 39 x 14 per cent = 546 per cent.

92

DR MALCOLM KENDRICK This might seem so incredible that you may not believe that you read it. But I can assure you that it is there, in black and white, in the Journal of the American Medical Association, 24 April 1987, pages 2176 to 2180: 'Cholesterol and mortality. 30 years of follow-up from the Framingham Study: I hope you recognise by now that I make up nothing. All facts and data that I use come from peer-reviewed, high-impact journals that can be found by looking in the database, www.pubmed.org - a fantastic resource that is absolutely free. The interpretation of those facts, however - that's a completely different matter. A few statistical models here, a bit of meta-analysis there, just a sprinkling of confounding variables, a few 'probably due to chances' thrown into the mix and, bibbity, bobbity, boo! A circle turns into a square, and cholesterol turns into a deadly killer. But it is time to return the main point of this particular story, which is that a low cholesterol level, especially after the age of 50, significantly increases your risk of dying. One massive long-lasting study that looked specifically at cholesterol levels and mortality in older people, was carried out in Honolulu and published in August 2001 in The Lancet. And the findings thereof:

Our data accord with previous findings of increased mortality in elderly people with low serum cholesterol, and show that long term persistence of low cholesterol concentration actually increases the risk of death. Thus, the earlier that patients start to have lower cholesterol concentrations, the greater the risk of death. Their interpretation:

We have been unable to explain our results. These data cast doubt on the scientific justification for lowering cholesterol to very low concentrations.

93

THE GREAT CHOLESTEROL CON This study, by the way, was immediately attacked from all sides. I think my favourite attack included the word 'irresponsible: Things have come to a pretty pass when publishing a well-designed medical study in The Lancet is considered irresponsible. I mean, people might learn the truth and then there is no way of knowing what will happen. Panicking in the streets, law and order breaking down, the playing of loud and licentious music, egg yolks and meat pies consumed in public places ... But you know, it is not onlY'in the elderly that a low-cholesterol diet is associated with a higher mortality rate. The Austrians carried out a study of 149,650 men and women, looking at cholesterol levels and cardiovascular and all-cause mortality. It was entitled: 'Why Eve is not Adam: prospective follow-up in 149,650 women and men of cholesterol and other risk factors related to cardiovascular and allcause mortality: This study lasted 15 year.s and looked at nearly 70,000 men, and more than 80,000 women ranging from 20 to 95 years of age who underwent, between them, more than 450,000 examinations. This was a huge study. One of the biggest and longest ever. And I am willing to bet a large sum of money that you have never heard of it. One of the reasons for this is that it ended up being published in the

Journal ofWomens Health. Not that I have anything against this journal - how could I? I had never heard of it before tracking down this study. But why was this not published in the 8MJ, or The Lancet or the New

England Journal of Medicine? It was of huge public-health significance, yet it ended up in a journal with a relatively low 'impact' factor and was thus, effectively, buried. However, what this study confirmed is that a low cholesterol level after the age of 50 (and under 50, if you are a man) is significantly associated with all-cause mortality:

In men, across the entire age range .. . and in women from the age of 50 onward only, low cholesterol was significantly associated

with all-cause mortality, showing significant associations with death through cancer, liver diseases, and mental diseases.

94

DR MALCOLM KENDRICK You can't get dearer than that. If you have a low cholesterol level, you are at a much greater risk of death. Perhaps you would prefer a British study? This from the 8MJ in 1995:

Low serum cholesterol concentrations «4.Bmmol/l), present in 5% of the men, were associated with the highest mortality from aI/

causes, largely due to a significant increased in cancer deaths. Or perhaps you would like a Finnish study? This was a report produced 25 years into the Seven Countries Study, published in the American

Journal of Epidemiology in 1992: During the first ten years offol/ow-up: .. men with high cholesterol levels had lower aI/-cause mortality... because of their low cancer mortality and residual mortality. What about a study in the very old? The oldest old - those over 85. The following was published in The Lancet in 1998:

Each 1mmol/I increase in total cholesterol corresponded to a 15% decrease in mortality. Or how about this one from France, published in The Lancet in 1989? A small study, admittedly, but quite amazing nonetheless. Ninety-two women living in a nursing home, most of whom died over the next five years. The lowest mortality rate was at an average cholesterol level of 7.0mmol/l, and the highest mortality rate was at an average cholesterol level of 4.0mmol/l. At this level, the mortality rate was 5.2 times higher than at 7.0mmolil. You probably thought that anyone with a cholesterol level of seven had died fifty years earlier of a heart attack. Not so. Enough already, I hear you cry. OK, enough already. I shall merely summarise the data on overall mortality:

9S

THE GREAT CHOLESTEROL CON • Under the age of 50, your cholesterol level doesn't really make much difference to your risk of dying. However, if your cholesterol level starts falling, watch out. You are at a terrible risk - a 429 per cent increased risk of death per 1mmol/l cholesterol drop, according to the Framingham Study. • After the age of 50, a low cholesterol level is associated with a significantly' greater overall mortality. The older you get, the more dangerous it is to have a low cholesterol leveL Does this mean that a low cholesterol level is, itself, deadly? No, I don't think so. I do not believe that a low or a high cholesterol/LDL level actually causes anything except, perhaps, haemorrhagic stroke - if the level is very low. I think it is mainly a disease 'marker' of a kind. Although, in general, it seems much more dangerous to have a low level than a high level. Of course, I am not the only person in the world to have noticed that low cholesterol levels are associated with increased mortality. The mainstream research community also picked up on this one. Perhaps, to be more accurate,l should say the mainstream research community has failed to sweep this fact under the carpet. {Or maybe they have, since no one I speak to is ever aware of this fact.) What is their explanation? It is as follows. A falling, or low cholesterol level, is a sign of an underlying disease. Thus it is not the low cholesterol level that kills you, it is the underlying disease. It is true that certain diseases - e.g. advanced cancer - can create a low cholesterollevei. as can liver diseases such as chronic Hepatitis B. This makes it likely that some people with low cholesterol levels are suffering from a serious underlying disease. Therefore, this is one adhoc hypothesis with which I am in a certain amount of agreement. The leading proponent of this hypothesis is a researcher called Carlos Iribarren. I think he was the first to propose the idea that a low cholesterol level indicates underlying disease, and he bangs on about it regularly. Whether it was his original idea or not, the rest of the

96

DR MALCOLM KENDRICK scientific community fell upon this concept gratefully, and now repeat it as their new mantra. Thus, everyone can reassure themselves with the knowledge that a raised cholesterol really, truly, is deadly. Even when it's low - perhaps especially when it's low. Time to quote from one of Iribarren's studies, published in the Journal of the American Medical Association (JAMA). This study was

designed to prove that a low cholesterol level was not an independent risk factor for death. The conclusion of the study:

We conclude that the excess mortality at low TC [total cholesterol] levels can be partially explained by confounding with other determinants of death and by pre-existing disease at baseline ... In our study TC level was not associated with increased cancer or aI/cause mortality in the absence of smoking, high alcohol consumption, and hypertension.

So there you go. Once you add in smoking, high alcohol consumption and high blood pressure, you find that low cholesterol levels disappear as a risk factor. Now, I was explaining that, according to mainstream researchers, a low cholesterol level is not a risk factor for dying, because it is, in turn, caused by an underlying disease, and it's the underlying disease that kills you - not the low cholesterol level. Maybe in some cases this is true. However, I find the idea that cancer can cause a low cholesterol level - before the cancer can even be detected - somewhat bizarre. An early stage cancer is smaller than a grain of rice - far smaller. The possibility that 0.1 g, or thereabouts, of tumour mass can have a discernible effect on cholesterol levels seems utterly bizarre. How could it? Of course, when you have advanced cancer, this knackers the entire metabolic system. But can cancer do this five or ten years before diagnosis? I think I will go as far as to say that this is impossible. In fact, I don't need to rely on such theoretical arguments, because this ad-hoc hypothesis has actually been disproved. The Framingham

97

THE GREAT CHOLESTEROL CON research team had also noted a high mortality rate in over-50s who had low cholesterol levels. They too wondered if the low cholesterol levels were caused by an underlying illness: Similar results from several modified analyses make low cholesterol levels due to a severe illness an unlikely explanation for our results.

Sorry about that tortured passage, but I do try to use the exact words of the researchers, rather than put my words in their mouths. (For some reason, people seem to find this more believable.) However, I shall translate. Those with low cholesterol levels did not have a severe underlying illness. They just had

long~term

low cholesterol levels

followed by a much higher mortality rate. And however many 'modified analyses' were used, they just couldn't sweep this association under the carpet without leaving a big bump sticking up in the middle. The Honolulu researchers also looked carefully at their findings in the light of the Iribarren ad-hoc hypothesis: Iribarren and colleagues suggested that a decline in serum cholesterol might occur over a decade before diagnosis of a disease [yeah, right - my words], and such long-term morbidity could be attributable to chronic subclinical infections with Hepatitis B, or to chronic respiratory diseases. . .. our data suggest that those individuals with a low serum cholesterol maintained over a twenty-year period will have the worst outlook for all cause mortality. Our present analysis suggest that this [Iribarren's] hypothesis is implausible and is unlikely to account for the adverse effects of low cholesterol levels over twenty years.

This is as close as one set of researchers will ever come to telling another set of researchers that they are talking complete bollocks. At least in public, anyway. 98

OR MALCOLM KENDRICK Just to ram home the point, the Austrian researchers also analysed their data to see if underlying diseases caused the low cholesterol levels: For the first time, we demonstrate that the low cholesterol effect occurs even among younger respondents, contradicting the previous assessments among cohorts of older people that this is a proxy or marker for frailty occurring with age.

In a way, it's a shame. I rather like Iribarren's hypothesis in a kind of lastdesperate-throw-of-the-dice kind of a way. Low cholesterol levels are caused by early stage diseases, so early that you can't actually detect them. So how do we know they are there? Well we can't, obviously ... duh! They're undetectable, stupid. But we know they must be there, otherwise these people wouldn't have low cholesterol levels. Yes, it's the good old circular argument again.

Q: 'Why have these people got low cholesterol levels?' A: 'Because of an underlying disease.' Q: 'How do you know they have an underlying disease?'

A: 'Well, just look at the low cholesterol levels. They couldn't have such a low level if they did not have an underlying disease.' What I find perhaps most amusing about this area is' the 'clash of the mighty ad-hoc hypotheses~ On one hand we have Iribarren explaining that a low cholesterol level is caused by underlying diseases. So a low cholesterol level is a sign of being completely knackered. On the other hand, we have another group of researchers - led by the mighty Law and Wald, quelle surprise - explaining that 'primitive' peoples have very, very low levels of blood cholesterol, and this is exceedingly healthy. 'You cannot have a cholesterol level that is too low. Statinate, statinate!' So a low cholesterol level in the West is a sign of desperate illness, but a low cholesterol level among primitive peoples is a sign of glowing health - something we should all aspire to achieve. Go figure,

99

THE GREAT CHOLESTEROL CON as they say. I say, go look at the life expectancy of primitive peoples and then tell me how healthy a low cholesterol level might be.'Oh, but they have such a high mortality rate because they die of things other than heart disease.' (Well they would, wouldn't they - see everything written above.) Maybe all groups of researchers should get together and try to put together a story that doesn't keep contradicting itself all the time. Fat chance. To be honest, I don't think that they are even aware that they are arguing directly against each other in their attempts to defend the cholesterol hypothesis. One lot are digging a hole, and the others are frantically filling it in again. Still, it's probably good for the GOP. Moving on from Iribarren, and all the other desperate ad-hoc hypotheses that I really don't have time to mention, the simple fact is this: a low cholesterol level increases the risk of death in men and women. This is one fact that has never been contradicted by any study. It is also a fact that is so well hidden that no one I have ever spoken to is aware of it. Indeed, when I mention it, no one actually believes me. It is also rather important. The fact that a low cholesterol level is unhealthy may even make you think about your cholesterol level in a whole new way. Is it around 5.5mmolll and above? Good. Below 4.0mmolll? Watch out.

WOMEN AND HEART DISEASE Now it is time to look directly at cholesterol levels and heart disease. I will start by looking at women and heart disease, an area of research that may otherwise be referred to as 'The case of the mysterious disappearing fact' starring female sex hormones, the ever-popular menopause, evil LOL and our plucky hero HOL. Along with a full supporting cast of ad-hoc hypotheses - as always. It has been recognised for many years that women, generally, suffer much less heart disease than men - especially younger women. The difference is normally about 300 per cent. This is despite the fact that women have higher average cholesterol levels. The widest gap I found

100

OR MALCOLM KENDRICK was in New Zealand in the 1970s. Here, women aged 45-55 had onetenth the mortalitY rate of men. Now that's what I call a gap. Women, therefore, present a problem for the cholesterol hypothesis. Higher cholesterol levels than men, but much lower rates of heart disease. This must mean that ... Eager schoolboy: 'Sir, sir. .. it must mean that raised cholesterol levels don't cause heart disease: Teacher:'You stupid boy. We know that raised cholesterol levels cause heart disease. Anybody else?' Teacher's pet:'lt means that women must be protected against a high cholesterol level, sir: (Smug grin.) Teacher:'Well done, Snodgrass, that is the correct answer: At this point it is worth presenting some data. These data come, once again, from 1992 and the 'Report of the Conference on low Blood Cholesterol: Mortality Associations; published in Circulation. The researchers looked at all available data on women from 11 major studies or trials, representing 124,818 women. Their conclusions: Many findings for women were discrepant from those for men. Of particular importance in women was considered to be the essentially flat relation of total cholesterol to total mortality, total cardiovascular, and total cancer mortality.

See graph oveleaf (Fig. 25).

Yes, it's the female paradox. Don't worry, you see this is not actually a paradox. (,Phew, for a minute there you had me worried:) Women, you see, are protected against a raised cholesterol level by their sex hormones. Ad-hoc hypothesis no. 8,396,249. For many years, I too, believed that women were protected by their sex hormones. Everyone said it, everyone believed it. After all,

707

THE GREAT CHOLESTEROL CON

Fig.2S Risk of cardiovascular death at different cholesterol levels - women 1.0 0.98 0.97 0.96

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Yet, if we look at heart-disease rates (ages 35-74 per 1OO,OOO/year), every ten years since 1968, when statistics first started, they are as follows:

114

DR MALCOLM KENDRICK Year

CHD rate British Women

CHD rate French Men

1968

175

152

1978

180

154

1988

156

118

1998

97

85

Quelle horreur! French men have a lower rate of death from heart disease than British women, and ·always have done, despite having higher cholesterol levels and a greater burden of other 'risk factors: What does this mean? What indeed. If you want a more spectacular example of the lack of female protection, we can look at Russian women and British men:

Rate of smoking

Russian women 10%

27%

British men

Average cholesterol

5.4mmol/l

6.0mmol/l

Average systolic BP

132

134

Saturated-fat

8.2% of calories

13.6% of calories

267/100,0001year

229/100,001year

levels

consumption Death rate from heart disease (200) As you can see, British men smoke almost three times as much as Russian women, they have 10 per cent higher cholesterol levels, slightly higher blood pressure and eat 40 per cent more saturated fat. And yet their heart disease rate is 14 per cent lower. At this point I think I should highlight the fact that French men have far more risk factors than Russian women, and 300 per cent less heart disease. What the HDL is going on? You may feel that it is unscientific for me to make comparisons between different countries (although I would be interested to hear your reasoning). If so, I shall look within the same countries. In Brazil, in 1989, women suffered a higher rate of heart disease

775

THE GREAT CHOLESTEROL CON than men. Admittedly, this was the only year when women had a higher rate. However, in general, the difference between men and women in Brazil is, and remains, tiny. Below are their respective risk factors: Risk Factor

Brazilian Men

Brazilian women

% with hypertension

19

27

Average cholesterol level

4.92 mmol/l

5.10 mmol/l

%whosmoke

24

18

% who are obese

48

39

OK, so their risk factors are pretty similar. But then again, risk factors for men and women are pretty similar in most countries. Yet, on average, women have one-third the rate of heart disease. In fact in the UK it is one-third, in France it is one-quarter. In New Zealand, at one point, it was one-tenth. In Brazil there is no difference. But I am not going to stop here, because there are countries where women suffer more heart disease than men. For example, an Indian study in Delhi in 1993 showed that: • The overall incidence of CHD was 19.7 per 1,000 • Men: 17.3 per 1,000 • Women: 21.0 per 1,000 In New Zealand in the 1970s, it was found that Maori women had more than twice the rate of heart disease of men, as revealed in a study in the

New Zealand Medical Journal: This paper reports the prevalence of coronary heart disease (CHO) and its relationship with several standard risk factors in samples of New Zealand Maoris ... The prevalence rates of CHO are: 76.1 percent, and 7.3 percent in Maori females and males respectively. Confused yet? If so, I would like to state that this is really not my fault.

716

DR MALCOLM KENDRICK I think everything is quite simple, it's the endless ad-hoc hypotheses developed to protect the cholesterol hypothesis that have created this current unholy mess of sex hormones, HDl, ApoA-l Milano and their like. In the end, to cut through the confusion, you have to take this argument down to basics. Women are either protected against a high cholesterol level or they are not. If women are protected against a high cholesterol level, how can you explain the fact that there are populations where women have lower cholesterol levels than men,

yet suffer more heart disease? Where is the protection here? Where's it gone? On the other hand, if women are not protected against a high cholesterol level, why do they have much less heart disease than men - in most countries - when they have higher cholesterol levels? Run these arguments any way you like, and they keep breaking down as logic snaps under the strain. In fact, there is only one conclusion that can be drawn from this unholy mess: cholesterol levels have no effect on heart disease rates in women. No other explanation fits the facts, but this explanation fits perfectly without the need for any ad-hoc hypothesis. Or, indeed, any other explanation at all. Remove cholesterol from the equation and all confusion disappears. Simple, isn't it? You might then ask, well, why do women generally get much less heart disease than men? That, of course, is the $64,000 question, and one that I shall answer in due course.

RAISED CHOLESTEROL LEVELS AND HEART DISEASE IN MEN At this point, things are beginning to thin out somewhat. A raised cholesterol level doesn't cause strokes, but a low cholesterol level may well do. A raised cholesterol level doesn't increase overall mortality, but a low cholesterol level does. A raised cholesterol level does not cause heart disease in women. What's left? Does a raised cholesterol level cause heart disease in men?

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THE GREAT CHOLESTEROL CON Here are two facts with which I fully agree. 1: In men under the age of 50, a raised cholesterol level is associated with an increased risk of heart disease. (Note that I didn't say 'caused; I said 'associated:) 2: Within countries/populations, a higher cholesterol level in men is associated with a higher rate of heart disease. Does this mean that a high blood-cholesterol level causes heart disease in men? I dinnae think so, laddie. You see, there is far, far too much directly contradictory evidence out there. Time, I think, to introduce you to Australian Aboriginal men for the first time. This group has one of the highest - possibly the highest rates of heart disease in the world. They have a rate that currently stands at 1,100 per 1OO,OOO/year. This is about four times the rate in the UK, and more than ten times the rate in France. (It is a stunning 50 times the rate in French women.) The average blood-cholesterol level in Aboriginal men is 4.9mmol/l, contrasting with 6.1 mmolll in the UK. Their average blood pressure is 125/77 - considerably lower than men in the UK. Their average HDL level is 1.1 mmol/I, which is 0.2mmol/llower than the UK. Their average body mass index (BMI) is 23.2, which makes them considerably less obese than British men. The only conventional risk factor where they truly lead the way is smoking, which stands at just over 80 per cent. (Slightly higher than the rate in Japan where, incidentally, the rate of heart disease is 20 times lower. That's right, 20 times.) The main reason for bringing up the Australian Aboriginals is to compare and contrast their rate of heart disease, and average cholesterol levels, with countries from the MONICA study discussed previously. This study has been going on for ages now. It was set up by the WHO to look at heart disease rates and risk factors around the world.

778

DR MALCOLM KENDRICK I am a big fan of the MONICA study, by the way. It generates huge volumes of data that can be relied upon to be accurate and objective. $0 three cheers to the WHO. The interpretation of their data may often

be exceedingly dodgy, but the data themselves are trustworthy. MONICA is where I found the data on saturated fat consumption across Europe. For years, MONICA can remain silent then, every so often, it bestirs itself and out plops a golden egg. One of the latest golden eggs came from its review of cholesterol levels across Europe. I related these data to its published death rates from heart disease. And to this list I have added in the Australian Aboriginals and drawn a graph (Fig.26):

Fig.26 Comparison between heart-disease rates in men aged 35-74 and average cholesterol levels in 15 populations ~ Average Cholesterol "Levels . - + - - Death Rates

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800

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of the adult population. Something that I have not really brought up, but perhaps I should, is the following question. If statins reduce death from cardiovascular diseases, yet there is no impact on overall mortality, this means that people taking statins must die at a higher rate from other causes. So what are these other causes? Well, it's a good question. But I am afraid that I have no clear-cut answers. In most statin trials there is usually a great echoing silence on the point. In the Heart Protection Study, as you may recall, the researchers didn't even bother to publish the overall mortality data in women, let alone list exactly what people died of. This type of thing makes it rather difficult to get a handle on what people who are taking statins die of instead of heart disease. The data just ain't there. This area is made even more opaque by the reaction of the mainstream researchers to overall mortality data. A recent statin study called 'Treat to New Targets (TNT)~ failed - once again - to show any benefit on total mortality. According to head researcher of the TNT study, Dr John laRosa, 'We need to make the assumption that mortality has been proven, that LDL lowering does in fact lower total mortality rates: We need to the make the assumption? Why does a researcher need to make assumptions - especially when all the evidence seems to me to point the other way? Dr Roger Blumenthal, from Johns Hopkins University Medical Center, in Baltimore, Maryland, said that the TNT mortality finding was

'unfortunate' and 'a bit

surprising~

but that the increase in non-

cardiovascular mortality was 'likely due to chance: Blumenthal went on 168

DR MALCOLM KENDRICK to claim that, 'The totality of evidence does not suggest that lowering LDL cholesterol to very low levels is associated with non-cardiovascular mortality: If there were fewer cardiovascular deaths in the TNT trial, yet

no difference in overall mortality, I would have thought that there is only one conclusion that can be drawn: there were more noncardiovascular deaths. At this point, hopefully, you are beginning to realise that statins may not be quite as super-wonderful as you may have thought. You may also be wondering how it is that, despite their almost complete lack of any real benefit - i.e. actually saving lives - statins have been hyped to the very skies. There is a very simple reason for this. It's called money. Rosuvastatin «(restor) was launched a couple of years ago, or so. In the first year of its launch, $1 billion was spent on sales and marketing. To quote Dr Evil from Austin Powers: 'One ... beellion ... dollars: And this, remember, was only the budget for one of the six statins on the market. One .... beellion .... dollars, it must be said, buys a hell of a lot of publicity. At the same time, you could pay journalists to attend international meetings, and provide them with PR company-generated press packs highlighting the wonders of your drug. Positive findings can then be hyped relentlessly, and the health editors of newspapers wined and dined. Ghost authors can then be found to write up the findings of trials, ensuring that the correct marketing spin is applied to the data. Opinion leaders lend their imprimatur to the papers at the end of this process - along with an eye-watering invoice, naturally. Nowadays, the entire world of clinical trials is controlled to a quite extraordinary degree. To quote Dr Marcia Angell, who used to edit the New England Journal of Medicine (which is one of the top five most

influential medical journals in the world - possibly even number one): It used to be that drug companies simply gave grants to academic medical centres for the use of their clinical researchers

to do a study and that was it. It was at arm's length. The researcher did a study and he or she published the results,

769

THE GREAT CHOLESTEROL CON

whatever those results would be. Now, it's very, very different. The drug companies increasingly design the studies. They keep the data. They don't even let the researchers see the data. They analyse the data, they decide whether they're going to even publish the data at the end of it. They sign contracts with researchers and with academic medical centres saying that they don't get to publish their work unless they get permission from the drug company. So, you can see that the distortion starts even before publication. It starts in determining what's going to be published and what isn't going to be published. This is no longer arm's length. It's treating the researchers and the academic medical centres as though they were hired guns or technicians or something. They just do the work. And the drug company will decide what the data show, what the conclusions are and whether it will even be published. In short, the medical profession is increasingly working closely with pharmaceutical companies.

.

If you have no role in major pharmaceutical-sponsored clinical trials then you do not speak at major meetings, you do not publish 'prestige' papers in high-impact journals, you do not bring in money to your university department. You have little to offer at major international conferences. You live in Backwatersville, man. A Dr John Kastelein from Amsterdam was utterly outraged that anyone should have objected to the last set of NCEP guidelines because of potential conflicts. He felt that the whole conflict-ofinterest issue was being over-hyped. In his words:

Idon't believe a word about the conflict of interest because there is no single opinion leader in the-world who has not done any work for a pharmaceutical company in terms of research or trials. He is supported in his stance by Harvard Medical School Associate Professor Daniel Simon. In his view it's a mistake to tune out the views

770

OR MALCOLM KENDRICK of those with potential conflicts of interest because the pharmaceutical industry is driving medical advances. Most unconflicted researchers 'are not truly expert: He says. In an attempt to get some handle on potential conflicts of interest, several of the most prestigious medical journals banded together to demand that those involved in clinical trials, or writing editorials, reveal their connections to the pharmaceutical industry. This is a process known as 'disclosure: To my mind, there are some major problems with disclosure. The first is that if you do not 'disclose; absolutely nothing happens - at all. This may not be a victimless crime, but it most certainly is a 'punishmentless' crime. If you are rumbled, you can just do a Bill Clinton: 'But what is disclosure, exactly. Oh, I misunderstood ... sorry. You mean being paid vast sums of money by a pharmaceutical company should be disclosed? Gosh. Who would have thought? Golly, I'll try to remember in the future .. . promise: Entering the debate, the NCEP have said:

The members of experts panels charged with developing guidelines are selected for their scientific and medical expertise, their stature and track record in the field, and their integrity. Individuals who are most expert in a subject area are the ones most suitable to serve on a guideline panel for assessing the science and developing clinical recommendations. They are also often the very people whose advice is sought by industry. Most guideline panels therefore include experts who interact with industry ... I especially liked the bit about integrity, though. How did they measure this? Did they buy a new Acme integrityometer, only £29.99 from Argos? Or did they get all the panel members to eat beans and go up and down in a lift, checking that whoever broke wind owned up each time? Panel members selected for their 'stature and track record in the field, and their integrity; is otherwise known as Eminence Based Medicine (EBM).

77J

THE GREAT CHOLESTEROL CON Eric Topol, just to give one more example, maintains that he has severed his ties with the industry in 2004. Here's a little something on the matter from his website www.theheart.org: Topol is unique in that he extricated all ties with industry in 2004. 'I do not believe that my historical relationship with companies with financial interests in this area is influencing patient care today. I have never ordered a commercial test for aspirin or Plavix resistance for any patient and never advocated the use ofsuch tests for clinical care,' he writes, adding that it was not mentioned that he published the only article in a peer-reviewedjournal warning physicians of the unanticipated patential conflicts ofinterest in relationships with the investment industry. 'I have taken a very hard stance on the troubles of the academia-industry megacomplex, have repeatedly challenged industry when there was any question of potential public-health harm, and have tried to set an example ofdissociation from industry while still performing important research to advance heart-disease prevention and therapy. It is ironic that an article that purports to unveil bias among physicians besmirches me: Again, I will have to leave it up to you to sit on the internet for an afternoon and read the facts that my publisher is reluctant to publish. If you do so virtually you will find links between all prominent cardiologists and the pharmaceutical industry. I know that all opinion leaders would be shocked and outraged if you were to suggest to them that they were in any way influenced by the money that they earn from the industry. They consider themselves paragons of virtue. On this issue, however, I defer to the great Robbie Burns:

o wad some Power the giftie gie us, To see oursels as ithers see us! It wad frae mony a blunder free us.

772

DR MALCOLM KENDRICK

THE DAMAGE THAT STATINS CAN DO Moving on from their complete lack of any benefits - for the vast majority of the population - the next thing to mention is the serious damage that statins are already doing to the NHS budget. Currently, they are the most expensive single item of drug expenditure. While the figures keep on changing, in the very near future, if it has not already happened, statins will cost the NHS over £1 billion per year. But this is only the costs of the drugs themselves. There are many additional costs: • Yearly cholesterol tests • Six-month review by a Gp, or nurse • Payment to GPs for getting blood cholesterol levels down through the Quality Outcome Framework system Just to tease out one figure in more detail. If we consider that ten million people, at the very least, are supposed to be on statins and they are given a six-month check-up, this amounts to twenty million consultations per year. An average consultation, adding in blood tests, doctor's time, payment for QoF payment etc., is at least £50, absolute . minimum. So this is an extra £1 billion, on top of the £1 billion spent on the statins. Two billion pounds a year is a not inconsiderable sum of money. What else could you do with the money? Well, you could employ around 70,000 extra nurses a year to start with, which isn't bad going. Or build two brand, spanking new university-sized hospitals, fully equipped, each year. Take your pick. But you know. A billion here, two billion there - it's only money, after all. What I am more interested in looking at here is the potential physical harm that statins can do - apart from possibly causing horribly deformed babies, of course. At this point, I should state that I do not think that statins are hugely dangerous. In most of the trials statins, have done nothing at all to improve overall mortality, but they don't seem to have increased the

173

THE GREAT CHOLESTEROL CON death rate. So putting someone on a statin is unlikely to actually kill them. Having said this, of course, statins may kill. Cerivastatin, the drug withdrawn by Bayer, was implicated in the deaths of at least 100 people before it got withdrawn. Data from the FDA show that simvastatin was established as a direct cause of death in 416 people between 1997 and 2004. All statins have been linked directly to people dying. How many exactly? Who knows? How could you know? Vioxx, the arthritis drug, was estimated to have been linked to more than 100,000 deaths in the USA in two years. And no one noticed! The fatal effects of Vioxx were only picked up coincidentally as part of a major trial to see if this drug could protect against bowel cancer. The impact on mortality was noted, and highlighted, by a rather heroic employee of the Food and Drugs Administration (FDA), Dr David Graham. For his efforts in. protecting the safety of the public he was smeared in the press and ruthlessly attacked. Luckily, a certain Senator Charles Grassley got involved in the case. He wrote a letter to Lester Crawford, the acting commissioner at the FDA at the time. I reprint some sections of it here, because it is an absolute cracker. A symphony in restrained rage:

As Chairman of the Committee on Finance, I have made it clear to you that I expect that Dr David Graham's right as a federal employee will be fully respected by the Food and Drug Administration. Last Wednesday, November 24, 2004, I requested that the Office of Inspector General (DIG), Department of Health and Human Services conduct a complete and thorough investigation into the facts, events, persons, policies, regulations and laws relating to allegations that a number of management level employees at the FDA may have acted 'to discredit an outspoken agency safety office who was challenging the FDA's drug safety policies.' I referred to the attached article from the Washington Post entitled, 'Attempt to Discredit Whistle-Blower Alleged.'...

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DR MALCOLM KENDRICK I'd like to reiterate what I have repeatedly stated in writing and have verbally communicated to your agency, namely that this Committee takes its responsibility to protect witnesses and particularly government witnesses very seriously, and that holds particularly true for Dr Graham.'... I understand that retaliatory action against dissident employees can come under many guises. Therefore, I also request that you address allegations that administrative action may be taken against Dr Graham, including that he may be terminated or transferred against his wishes to a job other than conducting scientific research. Please advise me whether there is any truth to these allegations and, if so, explain what actions are being taken to transfer Dr Graham from his present position and duties at FDA ... On at least 6 separate occasions - 3 by letter and 3 in meetings with FDA staff - I have requested that FDA employees be advised that they may come to Congress and speak freely without fear of reprisal. Do you believe that FDA employees are free to speak to members ofCongress without advising FDA's Office of Legislation? If so, when are you going to act on this request?

Ouch! This sorry saga highlights that fact that a drug could potentially kill hundreds of thousands of people without anyone actually noticing. You may think that this must be impossible. There have to be agencies out there monitoring this sort of thing on a day-to-day basis, combing through the statistics with a fine-tooth comb? Not so - and anyway, how could they? Drug safety is supposed to be fully established in the clinical trial process. Once a drug is out there in the community it could wipe out thousands, unnoticed - witness Vioxx. In addition to the difficulty of expecting an individual doctor to spot patterns of increased mortality, the majority of people taking statins are usually taking other drugs at the same time. So how can anyone

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THE GREAT CHOLESTEROL CON know which drug did what? And what's more, very few doctors report adverse events at all. In short, although it seems unlikely that statins are killing thousands of people, it's as well to remain vigilant. After all, it could take a long time for serious effects to emerge - much longer than any of the statin trials have lasted. Five years may seem sufficient to pick up on serious effects, but if you ran a five-year clinical study on the effects of smoking, you would see no impact on lung cancer - at all. Statins, potentially, are going to be taken for 30,40,50 years. Are they safe over this time period? Only time will tell. Moving on to more immediate effects. The primary way that statins kill people is through a side effect known as rhabdomyolysis, which is breakdown of skeletal muscle. Basically, your muscles dissolve away, the waste products from this process destroy the kidneys and you can then die from kidney failure. This, I hasten to add, is not common. According to one report, in the USA over two and a half years there were only 871 reports of rhabdomyolysis with statins, 38 of which were fatal. How many more cases went unreported is unknown, although several studies have calculated that adverse event reporting underestimates the true number of events by about 95 per cent. Even so, this is not an epidemic by any means. The major problem with statins though, is not that they kill a few hundred people here and there, it is that they create a huge burden of insidious side effects, most of which go unnoticed, or are dismissed. You feel tired? Well, you are getting older, after all. Muscle pains? Hell, we all get them. Even when you suffer a complete belterof a side effect, most doctors refuse to believe this could possibly have anything to do with the statin you are taking. Let me introduce you to a doctor in the USA called Duane Graveline. He is a family doctor, but he also trained as an astronaut with NASA, and works closely with airline pilots to assess their fitness to fly. Some years ago, he was found to have a raised cholesterol level and was put on a statin. He had no problem with this, as he fully believed in the cholesterol hypothesis and the benefits of statins.

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DR MALCOLM KENDRICK However, he then suffered a highly disturbing episode of memory loss, so he stopped taking the statin. He had no further problems for the next year, so his doctor persuaded him start a statin again, and he did so. Shortly after this, he suffered a much worse episode of memory loss, during which he regressed into his teenage years, unable to recall training as a doctor at all. After regaining his memory he was very shaken by the whole episode and binned the statins for good. The doctors treating him made the diagnosis of transient global amnesia, cause unknown. They totally refused to accept the possibility that the statin could be the cause, and neither would anyone else. Feeling like a lonely voice in the wilderness, Dr Graveline then published a letter on a website called People's Pharmacy asking if anyone else taking statins had suffered the same thing. He was immediately inundated by hundreds of cases from distraught patients and relatives. They described a full array of cognitive side effects from amnesia and severe memory loss to confusion and disorientation- all associated with statins, mostly with atorvastatin (Lipitor). The response of the mainstream medical community, however, could be paraphrased thus: 'You don't know what you're talking about. Statins are safe and have very few side effects: Here is one letter that was written to Dr Graveline and is reproduced in his book Lipitor, Thief of Memory: About six weeks ago, my doctor doubled my Lipitor from 20 milligrams to 40 milligrams. For about the past four weeks I have experienced progressive memory loss. I couldn't remember my brother's phone number. I couldn't find my baby's plate of food after preparing it. I couldn't remember recent trips. I couldn't remember to attend a meeting. I couldn't remember a restaurant I ate in and numerous other similar episodes. This is totally out of character for me. I have called my doctor and am awaiting his return call. For your information I am 39 years old and have been on Lipitor about four years.

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THE GREAT CHOLESTEROL CON Will this be memory loss be ignored by the doctor? Probably. Will this be filed as an adverse event? Almost certainly not. This effect will be considered trivial. However, I think that the 'mental' problems associated with statins are far from trivial. As early as the 1960s it was recognised that the people taking cholesterol-lowering drugs tended to die more frequently from violent deaths: accidents, suicide, shootings and the like. This was universally dismissed as a coincidental finding (no matter how many times it cropped up), mainly because no one was able to see how a low cholesterol level could possibly be linked to violent deaths. I read one post-hoc analysis of a cholesterol-lowering trial in which the authors were so determined to prove that the low cholesterol levels could have nothing to do with dying in a car crash that they pushed the analytical boundaries into another dimension. Their argument was that several of those who died while on statins were actually pedestrians, not drivers. So the statin couldn't be to blame for the crash. Hal Just try picking the logic out of that statement. Anyway, thirty years ago, even twenty years ago, even five years ago, no one knew that cholesterol had anything to do with brain function. This despite that fact that the brain contains over 25 per cent of the total amount of cholesterol in the body, and over 2 per c~nt of the total weight of the brain is cholesterol (presumably it was thought to be hanging about in the brain by accident?). However, it has more recently been discovered that if you want the brain to function, this requires cholesterol. A group of researchers, led by Dr Frank pfrieger, was looking into the function of glial cells in the brain. It was known that these 'support' cells had a critical role in the function of synapses (the connections between neurons). Glial cells, it was also known, released_a substance that allowed synapses to form, and function. Without this substance your brain would be almost entirely useless. And what was this fantastic, miracle substance? .Isolated neurons in the laboratory survived and grew, but showed only a few of the electrical signals generated by synapses. But

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DR MALCOLM KENDRICK when exposed to substances secreted by glial cells they produced strong signs of synaptic activity. The identity of the glial ingredient which triggered synapse formation has remained a mystery until now. But research published in the journal Science suggests that cholesterol is the magic ingredient. Yes, the magic ingredient was good old 'deadly' cholesterol. Without cholesterol, the chemical scourge of mankind, your brain cannot form synapses, and you can't think properly, or remember anything. Or remember anything. Maybe it was a tad premature to write off cognitive side effects as a mere coincidence? Especially when it is clear ho",,:, taking a statin might, just might, cause memory loss, even global amnesia. In fact, it is hard to

see how it would not. It might also be possible to see how you

would be more likely to die in a car crash - either as a driver or pedestrian - if your brain isn't functioning properly. 'Now, do I look left, or right?' But what about the link between cholesterol lowering, violence, and suicide? Well, in addition to cholesterol's critical function in synapse formation, it has now been found that a low cholesterol level leads to reduced serotonin levels in the brain. A low serotonin level is one of the key brain abnormalities involved in depression. This is why the most commonly used anti-depressants are designed to boost serotonin levels. They are known as Selective Serotonin Re-Uptake Inhibitors (SSRls). Prozac is the most famous of this group of drugs. low serotonin has also been linked to violence and aggression. And this is far from a theoretical finding. A group of researchers led by Jian Zhang looked at the association between a low cholesterol level and a history of school suspension. They concluded that:

\

Among non-African-American children, low total cholesterol is associated with school suspension or expulsion and that low total cholesterol may be a risk factor for aggression or a risk marker for other biologic variables that predispose to aggression.

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THE GREAT CHOLESTEROL CON ... the results of the current study are consistent with the majority of previous studies examining the associations between low serum cholesterol and various forms of aggression in adults. With few exceptions significant associations have been observed from cross-sectional studies, cohort samples, general population studies, psychiatric patients and criminals, and controlled dietary studies conducted in nonhuman primates. In particular, low total cholesterol has been associated with the onset of conduct disorder during childhood among male criminals.

Added to this, the Royal College of Psychiatry published a paper looking at the role of cholesterol in depression and self harm. It was entitled 'Low cholesterol may indicate risk of suicide: Here I take a few sections from the press release: Lower cholesterol levels were related to higher levels of selfreported impulsivity. The finding of a lower average cholesterol in the DSH (Depression and Self Harm) group confirms other published studies. The authors hypothesise that the increased death rates in populations with low cholesterol may be the result of increased suicide and accident rates associated with increased tendencies to impulsivity. It may be that low cholesterol in some way influences the function of the central nervous system, or acts as a marker for factors governing a predisposition to death by trauma and suicide. It is thought that cholesterol may influence serotonin, a neurotransmitter in the brain, low levels of which are associated not only with depression and suicide, but also with aggression and impulsivity. The latter are often involved before accidents, acts of violence to self and others and attempted or completed suicide.

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OR MALCOLM KENDRICK And so, gentle reader, our scientific knowledge has now advanced to the point where it can no longer be written off as a 'coincidence' that people on cholesterol-lowering drugs are more likely to die violent deaths of one sort or another. A clear causal chain now exists, with every link in place. As a little postscript to this section I would like to quote Frank Pfrieger again: 'A defective cholesterol metabolism in the brain may

impair its development and function: So it may also not be a coincidence that you can get serious neurological abnormalities in babies whose mothers were taking statins while pregnant. How widespread are all of these problems? Who knows? If they exist they will be, almost without exception, underreported. A bit of memory loss here, a lapse into depression there - well, everyone is depressed nowadays, aren't they? Feelings of anger and aggression, a bit of road rage, some muscle pains. Which patient is going to report such symptoms to their GP? And even i~ they do, how seriously is the GP going to take it? Remember that Dr Graveline suffered a fullblown episode of global amnesia and he was still hounded to re-start his statins. What are the other problems with statins? For the sake of brevity, I shall run through them at relatively high speed.

Polyneuropathy Polyneuropathy, also known as peripheral neuropathy, is characterised by the following: • Facial weakness • Difficulty in walking • Difficulty using the arms, hands, or feet • Sensation changes (usually of the arms and hands or legs and feet), such as pain, burning, tingling, numbness or decreased sensation • Difficulty swallowing • Speech impairment • Loss of muscle function or feeling in the muscles

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THE GREAT CHOLESTEROL CON • Pain in the joints • Hoarseness or changing of voice • Fatigue Researchers who studied half a million people in Denmark found that those who took statins were significantly more likely to develop polyneuropathy. Just how significantly was highlighted by a study published by the American Academy of Neurology. The researchers found that patients treated with statins for two or more years had a

26.4~fold increase in the risk of definite idiopathic (caused by a drug) polyneuropathy. That is a 2,640 per cent increase in risk. In general, polyneuropathy is irreversible. Muscle damage

Although rhabdomyolysis itself is rare, muscle pains and muscle weakness are relatively common with statin use. It is very difficult to get a handle on how common this is. The mainstream view is that about one per cent of people taking statins will suffer muscle pain, or weakness. However, I have seen much higher figures. Dr James K Liao, director of vascular medicine research at Brigham & Women's Hospital in Boston and a big supporter of statins, believes muscle pains are much more common, occurring in 15 per cent to 20 per cent of his patients. In this world, as with much else, seek and ye shall find. A research group in Austria decided to analyse 111 people with FH who had been put on statins, and complained of no side effects whatsoever. But the researchers wanted to know if there were signs of muscle injury anyway. They used a test that is not widely availabie, but is the gold standard for detecting 'oxidative' damage. (They measured 8-epiprostaglandin PGF2alpha, if you really want to know.) To their surprise, they found that 11 of the subjects had significant biochemical signs of oxidative damage to their muscles. These fmdings indicate that in the absence of other clinically observable adverse effects, in some of the patients, for an as yet

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OR MALCOLM KENDRICK unknown reason, statin therapy may be associated with increased oxidation injury. Is this clinically important? Who knows? Maybe not for everyone. But this same group of Austrian researchers discovered that statin-related muscle problems are much more likely to occur in those who do a lot of exercise. They looked at a group of professional athletes with FH and found that only 20 per cent of them could tolerate using statins without suffering serious muscle pain and weakness. Apart from athletes, I am certain that the burden of muscle problems is generally underestimated because such problems tend to creep up slowly. My father in-law takes statins - don't worry, he wouldn't dream of listening to me. (Although maybe he will after reading this damned book ... ) After his statin dose was increased last year he was unable to walk more than a hundred yards without having to sit down and rest. He was persuaded to reduce the dose, and he can now walk for over a mile, easily. Of course neither he nor his doctor believe that his muscle weakness and pain was in any way related to the increased statin dose. After all, he is approaching eighty, he has hac! a heart attack, he was already slowing down. So what do you expect? We are all remarkably good at dismissing the symptoms of others. Personally, I believe that a very high percentage of people on statins will suffer some symptoms of muscle ache; most of them they won't report the symptoms, and the doctor won't ask. Doctors are not generally very keen on discovering problems with the drugs that they prescribe.

Liver damage This is reasonably common, although in the main riot serious. Mostly it takes the form of raised liver-enzyme levels in the bloodstream. These tend to go away when you stop taking the statin. There have been cases of liver failure while on statins, but these are relatively rare.

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THE GREAT CHOLESTEROL CON Cancer

This is probably the biggest long-term worry as far as I am concerned. To quote a study from the Journal of the American Medical Association published in 1996: All members of the two most popular classes of lipid-lowering drugs (the fibrates and the statins) cause cancer in rodents, in some cases at levels of animal exposure close to those prescribed to humans ... Extrapolation of this evidence of carcinogenesis from rodents to humans is an uncertain process. Longer-term clinical trials and careful postmarketing surveil/ance during the next several decades are needed to determine whether cholesterol-lowering drugs cause cancer in humans. Ih the meantime, the results of experiments in animals and humans suggest that lipid-lowering drug treatment, especially with the fibrates and statins, should be avoided except in patients at high short-term risk of coronary heart disease.

The pharmaceutical companies have attempted to stomp on this fear by setting up studies that appear to show that statins, rather than causing cancer, actually prevent it. Attack, as they say, is the best form of defence. You may have seen some of the headlines, such as: New research shows that the popular cholesterol-lowering drugs called statins may slash a person's chance of developing breast, prostate, and lung tumors in half.

I plucked the above headline from a major medical website called WebMD. So what's actually wrong with this 'new research'? let's put it this way: • People with low cholesterol levels are at a much greater risk of dying of cancer. • People with low cholesterol levels don't get put on statins (yet).

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OR MALCOLM KENDRICK However, • People with high cholesterol levels are less likely to die of cancer. • People with high cholesterol levels do get put on statins. Therefore, if you find a group of people taking statins, and match them against a group of people not taking statins, hey presto! It is very likely you will see less cancer in those taking statins, because they were protected against cancer in the first place. Luckily, it doesn't actually take long to stomp such headlines into the ground. In the major statin trials, the people taking the statins and those taking the placebo are allocated at random, so on average both groups should have identical cholesterol levels. And guess what? When a meta-analysis of the statin trials was done, and published in JAMA, looking for any effect on cancer:

In our current meta-analysis, statins did not reduce the incidence of cancer or cancer death, No reductions were noted for cancers of the breast, colon, gastrointestinal tract, prostate, respiratory tract, or skin (melanoma) when statins were used... the patients in our meta-analysis were primarily treated with simvastatin and pravastatin. As such, we evaluated pravastatin alone and simvastatin alone on cancer incidence and death and found no impact. In short, the headlines about statins preventing cancer are complete and utter guff, as usual. They reflect marketing spin, pure and simple. But they do their job, the message gets out there: statins don't cause cancer, they actually protect against cancer. Goodness me, is there nothing these drugs can't do? So, while there is no evidence that statins protect against cancer, is there any evidence that they may increase the risk of cancer? There is some, but it is fragmented. A massive (and never-remarked-upon) statin trial in Japan, the J-LlT study, found a small proportion of patients 185

THE GREAT CHOLESTEROL CON who were 'hyper-responders' to simvastatin, i.e. their LDL levels fell dramatically when given the drug. In this group there was a significant increase in deaths from cancer. In addition to this, in the PROSPER study - one of the few statin trials specifically carried out on older people (for whom cancer risk is increased) - there were 24 more cases of cancer in the statin arm than the placebo arm. This, by the way, more than cancelled out all cardiovascular benefits. In the CARE study there were 12 cases of breast cancer in the statin arm against one in the placebo arm. None of this is definitive proof that statins cause cancer, by any manner of means. But to my mind, it is something that needs to be carefully monitored. After all, we already have a few disturbing facts at our disposal: • Statins cause cancer in animals. • There is some evidence that cancer deaths are increased in the statin trials, especially in those who are 'hyper-responders' to statins. • A low cholesterol level is associated with a high risk of death from cancer. • It can take many, many years for cancer-causing agents to reveal themselves. I think that this is more than enough evidence to warrant a high degree of suspicion. So is anyone studying this in any meaningful way? You must be joking. It would be like asking British American Tobacco to fund a study into nicotine addiction.

Heart failure There are actually a myriad of other statin-related side effects. But you would expect to see this in any drug that was being taken by millions of people. A couple that seem to turn up more regularly than others are acute pancreatitis and severe dizziness. However, there is one potentially very worrying side effect that I would like to draw your attention to, heart failure.

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OR MALCOLM KENDRICK In the late 1980s, when Merck were first readying themselves to launch their two statins - lovastatin (Mevacor) followed by simvastatin (Zocor) - they applied for a patent in which their statins would be combined with a substance known as coenzyme Q10. A substance that, for the sake of brevity, I will call Q10 from now on. Q10 is found in all cells, everywhere in the body, which is why it is sometimes called ubiquinone (because is it ubiquitous). It is found in particularly high concentrations in high-energy cells such as muscles, and especially cardiac muscle cells, where it plays a key role in the production of AlP. Alp, as you may remember from biology, is to a cell, what fuel is to a car. Conversion of AlP to ADP releases the energy that cells need to work. When AlP runs out, the cell dies. Which means that a reduction in AlP production could be a rather serious matter. Especially in heart muscle, the muscle that can never rest.Jndeed, both animal and human studies have shown that reduced Q10 levels can lead to left- and right-sided ventricular dysfunction (heart failure to you and me). So where is all this going, you may ask. Well, at this point I shall draw another strand into the discussion. You see, Q1 0 and cholesterol share a biosynthetic pathway. They both originate from Acetyl CoA, and if you block HMG CoA reductase you not only reduce cholesterol synthesis, you also reduce Q10 synthesis. The two pathways do not split until after this point. If low Q10 levels can lead to heart failure, and statins block the production of Q1 0, then statins could cause heart failure. Thus, adding Q10 to a statin makes perfect sense, does it not? In the end, though, Merck never acted on their patents (patent 4929437, issued 29 May 1990 and US Patent 4933165, issued 12 June 1990, both entitled 'Coenzyme Q10 with HMG-CoA Reductase Inhibitors1. Why not? Well, this is the sort of 'commercially sensitive' information that Merck have not published. I note, however, that: • Combination pills are more expensive to make, and it takes longer to get approval from the authorities to launch them.

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THE GREAT CHOLESTEROL CON • Adding Ql 0 to a statin might be an admission that statins are not totally innocent, cuddly and safe - could they be if they required a built-in 'antidote'? • Other statins coming to the market were not going to add Ql0 to their statin . .• The risk of causing heart failure in humans by lowering Ql0 levels had not been definitively proven. Having said this, Merck may have been worried enough by something they had seen to fill in two separate patents for a combination pill, a most unusual move. Their research remains unpublished, so I can only speculate on what it showed. As a little aside, it may be pertinent to this discussion to point out that Merck also make ·(or should that be made) Vioxx. While they claimed that the increased risk of heart attacks came as a complete surprise to them when this finding first 'appeared' in late 2004, during the course of three lawsuits against Merck, it was alleged they deliberately witheld data on the cardiavascular dangers of the drug. You can read about this on the Forbes website: http://www.forbes.com/markets/200S/12/08/merck-vioxx-study 1208markets 14.html Moving on. In addition to the possibility that statins could cause heart failure by blocking Ql0 synthesis, a study published in the 3 December 2003 edition of the Journal of the American College of Cardiology reported a strong relationship between lower cholesterol

levels and increased mortality in patients with heart failure. The study was conducted in the Royal Brompton Chronic Heart Failure Clinic in London. The researchers measured cholesterol levels in over 400 patients with varying degrees of heart failure and followed their outcomes. They found that people with cholesterol levels below S.Ommol/1 have a two- to three-fold increased risk of dying compared to those whose cholesterol levels were higher. In fact, it has been noted in many studies that heart-failure patients seem to have 'reverse

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DR MALCOLM KENDRICK epidemiology: By this, I mean that having a high cholesterol level and being obese and having a high blood pressure are associated with prolonged survival. Bringing all of the strands together, it seems that there are two interrelated mechanisms by which statins could cause heart failure. Firstly, by blocking Q10, thus lowering the heart-muscle energy production; secondly, by lowering cholesterol levels. The 'Coenzyme Q1 0 Association' (yes, there is one) were worried enough about this to have written to the FDA expressing their concern. I believe that they are awaiting a reply - I would advise them not to hold their breath. There are also cardiologists out there who believe that the current sharp rise in heart failure across the western world is a direct result of the use of statins. Theoretically, at least, they have a strong point. However, I don't believe that the data yet exists to prove the case one way or the other. Once again, though, there is enough evidence out there to warrant close attention and monitoring. A final thought: • Several studies have shown that a low cholesterol level is a major risk factor for people with heart failure. • Statins significantly reduce the risk of death once you have heart failure. So, in this case, statins must be working through

non cholesterol-

lowering effects. And finally - the damage that statins can do Leaving aside physical side effects and the eye-watering cost, the everincreasing use of statins will have, I believe, a major negative impact on society as a whole. To give just one example of the potential scale of the impact, a couple of years ago a group of researchers in Norway looked at the latest guidelines on CHD prevention published by the European Society 189

THE GREAT CHOLESTEROL CON of Cardiology. They wanted to see what the full implementation of these guidelines would mean for the Norwegian population - a population which, as the authors point out - has an average life expectancy of 79 - making it one of the longest lived in the history of mankind. The European guidelines defined a blood pressure of 140/90, and a cholesterol level of 5.0mmo/l, as thresholds for intervention. (Intervention means, in 99 per cent of cases, drug treatment.) Using these two levels, the Norwegian researchers then drew a graph showing what percentage of the population would be in the 'at risk' category for high cholesterol and/or a raised blood pressure (see below):

Fig. 28 Drug treatment levels per age group Cholesteral; 5mmoVI and not already included below ----

Blood pressure; 140/90 andlor on antihypertensive treatment

100~----------------------------~~~~~=r~~ 90

ii

80

oS

~

70

~'" '"c

60

ii

50

5i

~

40

"0

:~ ~

30

'0 ~

20 10

o+---~--~--~--~--~--~--~--~--~--~--~~ 20 2S 30 3S 40 45 50 55 60 65 70 75

Age (Years)

As you can see, by the age of 25, 50 per cent of the population is 'at risk' from their high cholesterol levels. By the age of 50 this has gone up to 90 per cent. And if you in add raised blood pressure, thereis hardly anyone left who does not require 'intervention~

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DR MALCOLM KENDRICK What's implied here is that the majority of Norwegians are so unhealthy that they need drug treatment. And, although no one has done it yet, if you applied these latest European guidelines to the UK, you would find an even higher percentage requiring life-long drug treatment. In my view, this is about as far from the concept of health as it is possible to get. We are in grave danger of converting the vast majority of adults in the country from 'healthy; to 'diseased; and worried to boot. And the only solution for your 'disease'? Take a statin for the rest of your life, and never stop. Can it really be true that 90 per cent of the population need life-long medication? This is bonkers. It is Brave New World, it is a combination of all dystopian nightmares of the future come to life. Health, it would seem, is no longer an absence of disease, but an absence of taking the correct medication. First, do no harm? I don't think so.

Statins don't work by lowering LOL levels At this point, grudgingly, I will admit that statins do reduce the risk of dying of heart disease in certain populations. 5tatins definitely reduce overall mortality in men with existing heart disease. So, if you are a man with known heart disease, it may be a good idea to take a statin. (There, I said it - and it did hurt, thanks for asking.) However, before looking at how they actually do this,l think you ought to know in a bit more detail what the figures are. Here I include a chart copied from Uffe Ravnskov, who wrote the book The Cholesterol Myths, and with whom I communicate regularly. He looked at overall mortality rates from the six biggest statin trials at the time and brought together four different figures related to overall mortality. • The relative risk reduction • The absolute risk reduction • The chances of being alive at the end of the trial on placebo • The chances of being alive at the end of the trial on a statin

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THE GREAT CHOLESTEROL CON

Risk reduction (total mortality) in six dinical statin trials Relative risk

Absolute risk

Chance of surviving on placebo

Chance of surviving on statin

45 W05COP5 CARE AFCAP5fTexCAP5 LIPID

-29% -21% -8% +3.9% -21%

-3.3% -0.9% -0.78% +0.09% -3.1%

EXCEL

+150%

+0.3%

88.5% 95.9% 90.57% 97.7% 85.9% 99.8%

91.8% 96.8% 91.35% 97.6% 89.0% 99.5%

These figures represent a mixture of primary and secondary prevention. The reason for using them is to give you an idea of the general scale of risk reductions found in the statin trials. Let's concentrate on three of them in a little more detail: 45, W05COP5 and EXCEL The 45 trial remains the most positive of all the statin trials. In this study, there was a 3.3 per cent absolute risk reduction in total mortality over five years, which equates to a 0.66 per cent reduction in overall mortality each year. This was purely a secondary prevention trial. WOC50P5 was a mixed primary/secondary prevention study. However, average cholesterol levels in this trial were 7.0mmol/l, which puts everyone in the study into a 'high risk' category. In W05COP5 there was a 0.9 per cent reduction in overall mortality over five years - which represents a 0.18 per cent reduction in overall mortality per year. Just to present the other side of the story, in the EXCEL trial, which was entirely a primary prevention study, there was a 0.3 per cent increase in overall mortality over five years. Once agai~, perhaps these figures are not quite as spectacular as you would imagine, given the hype that surrounds statins. Before moving on from the statistics, I would like to tackle the use of the term 'saving lives~ You may remember the press release that accompanied the HPS study:

If now, as a result, an extra 70 million high-risk people were to go

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OR MALCOLM KENDRICK onto statin treatment, this would save about 50,000 lives a year that's a thousand each week. leaving aside the point that this 50,000 figure actually equates to one life 'saved' for every 200 people taking the statin - 10 million is an awful lot of people to use as your denominator - the concept of saving lives, suggesting, as it does, that each of the 50,000 whose lives have been saved will go on to live out a full and healthy life, is not best chosen. In reality, taking a statin can only delay death, not prevent it. By how much? Well, if one in two hundred more people are alive after one year of taking statins, this means that if you wait another two-hundredths of a year (plus another little bit) the statin group will have caught up on the 'placebo' group in total number of deaths. This represents an increased life expectancy of slightly under two days. So, rather than stating that fifty thousand lives would be saved every year by taking statins, it would be considerably more accurate to state that if ten million people (at very high risk of heart disease) took a statin for a year they would all live - on average - two days longer. And if all ten million took a statin for two hundred years, they would all live - on average - an extra year. If we assume that most people would take a statin for thirty years, maximum, this would lead to an average increase in lifespan of approximately two months. Which doesn't sound quite as dramatic as saving fifty thousand lives a year, or a thousand a week - or however else you choose to hype up your figures. But there you go, ifhappens to be considerably more accurate. Also remember that this benefit would only be seen in men with pre-existing heart disease. Women and men without pre-existing heart disease would live not a day longer. They would just have the dubious pleasure of thirty years of paying for drugs, worry and side effects. Perhaps you think that I am also manipulating statistics in a way to make my point. Maybe. But an increase in average survival time is how all results are presented in cancer trials. This is one reason why, I think,

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THE GREAT CHOLESTEROL CON cancer trials tend to look rather unimpressive when stacked up against the highly dramatic 'life-saving' cardiovascular studies*. Anyway, moving back to the main point of this section. In secondary prevention studies (in men) it seems that statins do lower cardiovascular mortality, and by enough to wipe out any increase in other causes of death. But do they do it by lowering LDL levels, or do they do it through other mechanisms? This is not, actually, an easy question to answer with absolute certainty. Maybe by now you feel it doesn't much matter any more given that you have just been made aware of the minute benefits that statins offer, even in the highest risk groups. However, I think it is important to look at this issue for two reasons: • If I can prove that statins do not work by lowering LDL levels, then the entire 'cholesterol hypothesis' totally disintegrates. • Currently, the combined might of the pharmaceutical industry plus opinion leaders are pressing hard for ever-greater LDL lowering and they are deliberately blurring the distinction between primary and secondary prevention. I think that this must be resisted, as it will lead to more and more people being put on very high doses of very potent statins, which would be a complete disaster. But where to start? Where indeed. When the first statin trials came out, it's true that they did seem to provide definitive proof that statins worked by lowering LDL levels. After all, they did exactly what they were supposed to: lower LDL and protect against CHD. But it didn't take long before whole series of anomalies emerged which suggested that statins might be working through other mechanisms rather than by LDL lowering. The non-lipid actions are * Actually, it is an increase in 'median' survival that is used. However, while the difference between average and median can be technically imP9rtant, in most cases the two things are virtually the same. The reason why 'median' increase in survival is not used in cardiology is that it would take a hell of a long time for 50 per cent ofthe people to.die. Not unfortunately usually a problem in cancer trials.

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OR MALCOLM KENDRICK now bundled under the heading 'pleiotropic' effects (see Glossary for full explanation of this term). And so a debate has emerged. A rather one-sided debate, given the scale of the respective budgets supporting either faction. But it is a debate nonetheless. Do statins protect by lowering LDL, or in other ways? In ·the 'statins don't work by lowering LDL levels' corner are the following facts. This is only a small selection: • Statins protect against dying of heart failure, despite the fact that a high LDL level is associated with increased survival in this condition. • The beneficial effects of statins have been seen within weeks, days, even hours of taking a statin. And this finding does not remotely fit with the hypothesis that raised LDL creates gradual plaque buildup over years and years9. • Statins protect against strokes, but a raised cholesterol level is not a risk factor for stroke. • Statins provide the same degree of protection no matter if the LDL level is high, average, or low (HPS study). • Some studies, such as CARE, showed that the greatest degrees of LDL lowering were associated with a rise in deaths from heart disease. While some of us may say, 'Who cares? If they work, they work: if you have spent a lifetime, and built your glittering reputation, 'proving' that raised LDL causes heart disease, you are not going to allow facts like these to remain standing. Equally, if you are trying to sell a statin-based drug entirely on the awesome power of its LDL-Iowering properties, you are not going to take kindly to an alternative explanation jamming up the works. And so, a series of studies were set up designed to prove, for good and all, that the more you lower LDL, the greater the prote.c tion against heart disease. 91n 45, no benefits were seen until 18 months. Which is very odd, considering th.t.1I othertrials have shown much more rapid effects. What were Mereck doing?

us

THE GREAT CHOLESTEROL CON The major studies were PROVE-IT, TNT, A to Z, REVERSAL, ASTEROID and IDEAL. No, there will not be a test at the end of this chapter to remember which was which, or what was what. Or which proved what, why or how. After all, even the acronyms themselves are impossible to remember. And a bit bonkers too - witness ASTEROID (A Study To Evaluate the effect of Rosuvastatin On Intravascular UltrasoundDerived Coronary Atheroma Burden). Wheee! Let's look firstly at the IDEAL study - the biggest. After it ended, Scott Grundy - who, it must be said, is a statinoholic - wrote an article entitled 'The clinical implications of IDEAL: in the context of Recent Intensive Statin Therapy Trials'for Medscape.1 quote: We now have very clear evidence that patients with established CAD [heart disease} will benefit from intensive LDL -Cholesterol [LDL -C}-Iowering therapy.

In short, case closed: statins work by lowering LDL levels, now will you all please shut up? This, I have to say, I find an extremely interesting interpretation, given the results themselves. The IDEAL study - it should be pointed out - was very big. Twice the size of 4S, with 8,888 patients, no less. Patients were either put on 20mg or 40mg of simvastatin (the doses used in 4S), or 80mg of atorvastatin (Lipitor). LDL was lowered by 33 per cent in the simvastatin group and 42 per cent in the atorvastatin group. The result: 'No statistically significant differences were seen in all-cause mortality, cardiovascular mortality, or non-cardiovascular mortality: (In fact, cardiovascular

mortality was very slightly higher in the atorvastatin group.) Despite this, according to the study's author, we now have very clear evidence that patients with established heart disease will benefit from more intensive LDUcholesterol lowering ... This is an interpretation that flatly contradicts the results of the study itself. Although, to be perfectly frank, I see a trend of analysis of trials that bears no relation to my interpretation ofthese trials. Maybe he misunderstood the key findings that 'No statistically

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DR MALCOLM KENDRICK significant differences were seen in all-cause mortality, cardiovascular mortqlity, or non-cardiovascular mortality'? Maybe this wasn't quite

clear cut enough for him? Perhaps, he just missed the word 'No' at the start of the sentence? Easy to do that, I find. And what of ASTEROID? You may remember that this study was hyped to the very skies, appearing as a major news item on the BBC, no less, under the headlines 'Drug can reverse heart disease' - with pretty pictures of disappearing plaques, just to make the point. Not everyone was that impressed. Dr Graham Jackson, a UK cardiologist, wrote an editorial on the matter in the International Journal . of Clinical Practice. I quote a selection of his views on ASTEROID: As a marketing exercise it was brilliant. As an educational exercise it exploited sensationalism. And as a scientific exercise it was another own goal for the pharmaceutical industry (AstraZeneca provided a press release which went largely uncriticised and could be seen as part of a direct-to-the-public advertising campaign) ... So what was so stunning about ASTEROID? Nothing really...

The study was headed by Dr Steven Nissen. Of the ASTEROID trial itself, Dr Nissen stated that he had never seen regression of atherosclerotic plaques in his entire career before this. This sounds similar to his reaction to the ApoA-l Milano trial two years previously: 'We really didn't think it was going to work,' Nissen told WebMD. 'Nobody was more shocked than I was when the statisticians handed me the data ... It is unprecedented. Nobody has even seen this kind of plaque regression. It really is an epiphany.' In relation to

another intensive LDL-Iowering trial that he was in charge of, the . REVERSAL trial: The results were strikil?g,' Dr Nissen said, 'demonstrating a complete halting of coronary disease progression in the atorvastatin-treated patients and continued progression of disease in the pravastatintreated group.'

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THE GREAT CHOLESTEROL CON Dr Steven Nissen, it should be mentioned, was also the lead investigator in the most positive study on intensive LDL lowering that measured clinical end-points, rather than measuring plaque size with an ultrasound probe. It was called Treating to New Targets (TNT). They say that lightning never strikes twice in the same place. Yet there have only been four major studies on intensive LDL lowering that have been positive, and Steve Nissen has been in charge of three of them. In fact, if you removed the Steven Nissen-controlled trials, the evidence on intensive LDL lowering would be almost entirely negative. The only major positive study not run by Steven Nissen was PROVEIT. Ironically, this study was set up by Bristol-Myers Squibb to prove that intensive LDL lowering had no added benefit to moderate LDL lowering. It seemed the ultimate own goal, as it appeared to end up proving the opposite. But did it? Firstly, the bare bones of the trial itself. In PROVE-IT, the investigators took 4,162 patients who had been in hospital following an MI, or unstable angina (almost, but not quite an MI). They then split the group in half and gave one half pravastatin (made by Bristol-Myers Squibb), and the other half a much higher dose of atorvastatin (made by Pfizer). As expected, LDL level, or 'bad cholesterol' level, was reduced to a greater extent in the atorvastatin group. • LDL in the treated pravastatin group: average 95 mg/dl (range 79-113) • LDL in the treated atorvastatin group: average 62 mg/dl (range 50-79) In short, in the atorvastatin group there was a 32 per cent greater reduction in LDL levels, and there was also a 16 per cent greater reduction in - well - almost everything you can think of: all-cause mortality, MI, unstable angina, hospital readmission, interventional procedures - you name it. It was all quite wonderful. In absolute terms,

a somewhat less

wonderful 0.5 per cent reduction in overall mortality per year. My interpretation? Actually, I don't have one. You see, the researchers

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DR MALCOLM KENDRICK gave two different groups of patients two different doses of two different drugs. They then decided that all benefits seen were due to greater LDL lowering. How can they draw this conclusion? The answer is that they cannot. It's impossible to do so, unless you know that the two drugs are absolutely identical in all of their actions, other than the impact they have on LDL lowering. If, for example, atorvastatin has non-LDL lowering benefits on CHD that pravastatin does not, this would be the reason for the difference. But how can anyone know. this has never been tested. Ironically, the possibility that atorvastatin is better at preventing CHD than pravastatin, no matter what the LDL level, is supported by Dr Steven Nissen. In the REVERSAL study, which also used low dose pravastatin and high dose atorvastatin, he found the following:

Surprisingly, despite attaining a low LOL level on pravastatin, these patients showed highly significant progression for percent atheroma volume and percent obstructive volume... At any LOL level, progression was less on atorvastatin than on pravastatin. When I started this study, I believed that any reduction in progression wouldjust be due to lower LOL levels, but now I'm not so sure. This analysis suggests that it may be more than just LOL it seems to be the drug as well... Yes, this is a post-hoc analysis and should be considered hypothesis generating, but I would say it is a robust finding. Goodness me, of all people. This finding actually highlights the hopeless weakness at the heart of all the intensive LDL-Iowering trials. They have almost all used different doses of different drugs. This is not a scientific technique that I would recommend if you ever want to actually prove anything, ever. Even if they had used different doses of the same drug, you would not be able to say that it is the LDL lowering that created any benefit. It could have been another dose-dependent 'direct' drug effect that you haven't even measured, or don't even know exists.

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THE GREAT CHOLESTEROL CON Having said this, there has been one, and only one, major study done in which different doses of the same statin were used - the A to Z trial, using simvastatin. Guess what? Despite major differences in the lDl levels attained, there were no benefits seen from taking the higher dose of simvastatin on cardiovascular - or overall - mortality. This was despite the fact that the 'low-dose' group weren't actually given a statin for the first four months of the study. Bonkers. Frankly, the intensive lDl-lowering studies have not actually proved anything at all - except, perhaps, that simvastatin and atorvastatin are superior in reducing the risk of CHD than pravastatin for - as yet unknown reasons. And anyone who argues differently needs to be given a copy of How to do Scientific Studies - for Five-Year-Olds. Rule one: If you have more than one uncontrolled variable in your study you can't prove anything. Rule two: If you think you have proved something in a study with more than one uncontrolled variable, Rule one shall apply.

Summary At this point I shall attempt to draw all the strands on the use of statins together. First the positive data: • If you are a man with pre-existing heart disease, statins reduce your risk of dying of anything by a maximum of 0.66 per cent per year. (This figure is based on the most positive data from the most positive study - 4S. Study run by Merck, primary data analysis carried out by Merck e~ployee.) • If you are a man without pre-existing heart disease, statins can reduce your risk of dying of cardiovascular disease - by a small amount. • If you are a woman at very high risk of heart disease, statins reduce the risk of dying of cardiovascular disease (that is, strokes and heart disease).

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OR MALCOLM KENDRICK Then the less positive data: • If you are a woman, no matter what your level of risk, statins will not increase your life expectancy by one day. Deaths from cardiovascular disease reduced; deaths from other causes increased. • If you are a man without heart disease, statins will not increase your life expectancy by one day. Then the negative data: • Statins, cholesterol tests and GP appointments and screening are costing the NHS alone billions of pounds a year. • Statins cause muscle pains and muscle weakness in up to 20 per cent of people who take them. • Statins cause rhabdomyolysis, which can be fatal. • One type of statin, simvastatin, over a period of six years, caused 416 deaths in the USA alone. • Statins cause polyneuropathy. • Statins cause memory loss, depression, confusion, irritability and dizziness. • Stains cause major birth defects. Finally, a couple of worrying, though unproved, possibilities: • Statins may increase cancer risk, • Statins may cause heart failure. It is also, as yet, not remotely proven that statins protect against heart disease by lowering LDL levels. The current hyping of the intensive LDL-Iowering trials has been driven purely by the pharmaceutical industry. They claim to have proved beyond doubt that the more the LDL is lowered, the greater the protection against heart disease, and they have tried to use this 'fact' to press for ever-greater cholesterol lowering in the entire population.

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, CHAPTER 9

WHAT CAUSES HEART DISEASE?

M

y interest in heart disease was first piqued, many moons ago, by the knowledge that the French had a very low rate of heart

disease, despite having the entire raft of conventional risk factors. Over the years, I have found far more outstanding paradoxes than the French, but at tliat time they stuck out like a sore thumb, a mute reproach to the conventional theories about heart disease. A reproach that people have continually tried, and failed, to explain. To be frank. I found the mainstream excuses about the protective effects of eating garlic, drinking red wine and lightly cooking their vegetables to be utter bunk. It was obvious that these factors had only emerged to keep the cholesterol hypothesis alive and sweep the French paradox under the carpet. But what else, I thought, could explain the low rate of heart disease in France? As I'm from Scotland - where the heart disease rate at the time I became interested was the highest in the world - my mind turned to the way that the French eat, and the importance of food and eating, in their culture. In Scotland, eating is seen as somewhat akin to filling up your car with petrol. A waste of ten minutes, but it is something that has to be done before going out and 'getting 'pi shed' on a Saturday night. As for cooking, my memory of a traditional Scots recipe is, as follows:

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THE GREAT CHOLESTEROL CON Step one: Place a three-pound lump of beef in a saucepan with a carrot and an onion and boil for eight hours. Step two: Eat with boiled potatoes. And as everyone knows, the Scots love a fry-up.· Even a fried-up Mars bar: Step one: Take a frozen Mars bar and cover in batter. Place in deep-fat fryer for two minutes. Step two: Eat with chips while walking home in the rain. When I was growing up in Scotland, there used to be a substance called zinc ointment - maybe there still is. If you have never heard of it, thank the Lord. It was used as a cream substitute in things like chocolate eclairs. The Scots felt that cream tasted far too delicious to besmirch their puritanical souls. Therefore, it should be replaced with an off-white substance of little taste, although such taste as it had was distinctly bitter and unpleasant. I suspect it was constructed entirely from E-numbers in a petrochemical plant. A few years back, I took my wife to watch Dunfermline Athletic play football. During the match, she made the extremely rash decision to buy a mutton pie. I did warn her, but she wouldnae listen, she just wouldnae. A mutton pie washed down with Bovril, no less. However, it is the mutton pie itself that is a true specialite de la Scottish cuisine. A pastry coating that the British Army has since discovered can prevent uranium-depleted shells from piercing tank armour. And if you do manage to get through this defensive barrier without breaking your teeth, you will discover a small piece of gristle, surrounded by half a pint of grey, liquid fat. The fat usually spurts out, covering all clothing within a ten-foot radius, and it cannot be removed by any form of washing powder yet created. As a general observation, therefore, it can be said that food and eating, are not given quite the same status in Scotland as in France. For

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DR MALCOLM KENDRICK the French, food is a central part of life. Mealtimes are a major social occasion. People spend a long ti":le buying food, preparing meals and then eating. In Scotland they don't, or at least they certainly didn't. This, to me, marked a very obvious difference between the two countries. Could this attitude to food and eating somehow be the reason for . the difference in heart-disease rates between the two countries? And if so, how? Was it something to do with being relaxed while trying to digest food, rather than shovelling it down as fast as possible? With this thought in mind, I began what turned into a 25-year journey of discovery. It has to be said that I have taken many wrong turns along the way. There were several years when I thought that heart disease did not actually have a cause, or causes at all, so often did I find myself in another blind alleyway. Eventually, everything did come together in a way that makes sense and is actually supported by the facts. The primary cause of heart disease, I finally discovered, is ... stress. Well, hey, like haven't about ten million people been saying this for the last fifty years? Indeed they have. However, there is a major problem here, which is that the word 'stress' doesn't really mean anything at all. Or perhaps it means too many things. Or perhaps it just means different things to different people. So how can anyone say that stress causes heart disease, when there is little agreement as to what stress actually means? It's a good question. In order to answer it, I have to attempt to define rather more clearly what I mean by stress.

WHAT IS STRESS? I suppose many people think of stress as a form of time pressure. Busy, busy, busy, so much to do, so little time to do it. Others think of stress as a type of constant grinding worry, like money problems, or having an oppressive boss at work. Stress can also be seen as a transient state - for instance, moving house, or getting married, or even getting up on a Monday morning. Many people believe that stress is good for us, and without it we

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THE GREAT CHOLESTEROL CON would just lounge about doing nothing at all - certainly true in my case. This lack of any clear definition, or even agreement about fundamental principles, such as whether stress per se is healthy, or unhealthy, does make it tricky to measure it in any repeatable way. And without a measurement the medical profession tends to lose interest rapidly. With a cholesterol test, you know exactly what you're getting. It's 5.9, or 6.2, or 3.8, or 2.79. Once you have your figure, you can then give drugs and watch the figure change in front of your very eyes. Then you can draw graphs, do an audit, write papers ... and all sorts of things. Proper science, no less. The sort that gets published in proper journals and leads to proper promotions. But with things like stress, no such measurements exist. We are in the world of the subjective experience, where we have to rely on personal testimony and suchlike. It is not a place where many medical researchers like to venture.

An Eastern Tale (As told to me) A stranger was passing through a village one day when he spotted a wise man scrabbling about in the dust. 'What are you doing?' asked the stranger. 'I am looking for my key,' replied the wise man. '1 shall help,' the stranger exclaimed, and immediately set about the search. He looked under leaves, he sifted in the dust, he looked everywhere. After about two hours there was still no sign of the key. 'Are you sure you lost It out here?' the by now very dusty and thirsty stranger asked.'Oh, no,' the wise man replied. '1 lost it In my house.' Understandably, the stranger was somewhat irrltated.'Then why are we looking out here?' he demanded. The wise man smiled.'Because,' he said 'out here the light is so much better for looking.'

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OR MALCOLM KENDRICK I have to admit that I too, enjoy looking where the light is so much better. But sometimes you have to bite the bullet and accept that this doesn't actually happen to be where the answers lie. And with stress, and heart disease, you must search in a world where some of the answers cannot be directly seen. You can only know they are there by the effects that they have on things around them. Just to give one example, from a study published in the BMJ in 2001 entitled 'The Hound of the Baskervilles effect: natural experiment on the influence of psychological stress on timing of death':

In Mandarin, Cantonese, and Japanese, the words 'death' and 'four' are pronounced nearly identically, and consequently the number 4 evokes discomfort and apprehension in many Chinese and Japanese people. Because of this, the number 4 is avoided in floor and room numbers in some Chinese and Japanese hospitals, and in some Chinese and Japanese restaurant telephone numbers. In addition, the mainland Chinese airforce avoids the number 4, but uses other numbers, to designate its military aircraft, apparently because of the superstitious association between 'four' and 'death: The study by Phillips and his co-authors finds that cardiac deaths peak on the fourth of the month for Americans of Chinese and Japanese descent, and that this pattern is not seen among whites. The study used computerized US death certificates to examine more than 200,000 Chinese and Japanese deaths, and 47,000,000 white deaths, from 7973 to 7998. On one hand we have a real and scientifically measurable effect, which is that Chinese and Japanese die more often on the fourth day of the month - and you can't argue with that, it's a fact. On the other hand, we have something much more difficult to deal with, which is that the reason for this increased risk of death appears to be that the Chinese and Japanese consider the number four to be unlucky. But has anyone worked out how to measure the physiological effect of 'unluckiness'? Can we invent a drug to protect against the damage

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THE GREAT CHOLESTEROL CON cause by the number four? I tend to doubt it. Yet the deadly effect of 'four' exists, nonetheless. So what do we do? Simply ignore this finding, because it is considered virtually impossible to analyse in the reductionist way so beloved of medical science? Or do we bite the bullet and accept that, for some people, the number four can cause deadly stress? Even if we must also accept that it is very tricky to get a handle on what it is about this number that creates stress? I suggest the latter. However, the mainstream has tended to the former approach, i.e. ignoring. Just to give one example ofthis tendency, a huge study was carried out in 52 countries looking at 29,000 people in order to establish the similarities, or differences, between risk factors across a wide range of different populations. This was the INTERHEART study.'o As part of INTERHEART, they measured psychosocial stress hallelujah! Annika Rosengren, Professor of Cardiology at Goteborg University, Sweden - who led the stress aspect of the research - noted that people's psychosocial wellbeing,judged by simple measures, was significant:

'Collectively these [measures] were responsible for about one third ofthe risk of the population studies,'she said. 'Persistent severe stress makes it two and a half times more likely that an individual will have a heart attack compared with someone who is not stressed.' She said stress and depression together increased the risk threefold. The public thinks stress is very important in their heart attack. My patients often say they think it was due to stress, but previous studies have shown contrary effects of stress. But the INTERHEART study shows definitively that stress is one of the most important factors in heart attack in all ethnic groups and in all countries.' http://www.telegraph.co.uklnewslmain.jhtml?xml=lnewsI20041 09102Iwstres02.xml&sSheet=lportaI12004109102Iixportal.html 10 Yusuf 5, Hawken 5, Ounpuu 5, on behalf of the INTERHEART Study Investigators. 'Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): casecontrol study: The Lancet, 2004; 364:937-952.

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OR MALCOLM KENDRICK Most interesting, and surely something worth pursuing further? However, the mainstream response to this was best encapsulated, in the same article, by Professor Sir Charles George, Medical Director of the British Heart Foundation. He did say that the results 'suggested' that stress might have more of a role as a cause of heart attacks than many people had previously thought. (Don't you just love the use of

that word 'suggested'n However, he went on to caution that the findings were the result of 'self-reported' stress that had not been confirmed by chemical measures - of hormones in saliva, for example. In short, you didn't really measure it in the approved scientific manner, therefore it doesn't really exist. In such a casually dismissive fashion is the evidence about perceived stress swept under the carpet, time and time again. Of course, stress is not a simple concept, and measuring it is even more difficult. However, if you are willing to accept proof, and facts, that are less rigid than p < 0.005 (CI 0.63 - 84), then good. After all, as Albert Einstein was wont to say:

Not everything that can be measured, matters, and not everything that matters can be measured. [One of several different versions of this saying attributed to him.] This does not mean that I am simply going to claim that stress is the main cause of heart disease and 'leave it at that. Indeed, I intend to use a great deal of evidence to make the case for - or should that be against - stress. Just because you can't accurately measure everything does not mean that you should give up, or try to use good scientific research wherever possible. At this point, therefore, having thrown enough caveats into the air to sink a battleship, I will take the plunge and attempt to show you exactly how stress causes heart disease. Before I can do this, though, I have to dismantle stress into its component parts. Firstly, we'll need to separate out the things that cause stress - the 'stressors' - from the 'stress response; i.e. the physiological effects that

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THE GREAT CHOLESTEROL CON stressors create. Of course, not all stressors will create a stress response. For example, the number four will have no effect on most people in the West-whereas the number thirteen might. After separating cause and effect, a further split is necessary because there are two basic stress responses: healthy and unhealthy. As a further subdivision, I need to make the distinction between the two types of stressor: physical and psychological. To try and make this a bit clearer, I have created a list of the type of stressors I am talking about, and the likely effects that they have. 1: Examples of physical stressors that create a healthy response: • Exercise • Competitive sport • Massage • Sauna • Moderate alcohol consumption • • • •

Singing Bungee jumping Rock climbing Roller-coaster rides

2: Examples of psychological stressors that create a healthy stress response: • Your football team winning • Passing an exam • Clinching a successful business deal • Organising an enjoyable social evening • A tight sales deadline - but not too tight • Giving a well-received lecture • A busy shift in Accident and Emergency with no one dying • Being Prime Minister

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DR MALCOLM KENDRICK 3: Examples of physical stressors that create an unhealthy stress response: • Excessive, intense, forced exercise in adverse conditions, e.g. working deep below the ground in a coal mine in Russia • Extreme environmental change/rapid alteration in temperature • Being a fighter-jet pilot • Rheumatoid arthritis • Cocaine use • Smoking • Eating under pressure • Major trauma/surgery • Spinal cord injury • Steroid use • Disease of the hormonal system - Cushing's disease (too much cortisol) - Phaechromocytoma (too much adrenaline) - Diabetes (too much blood sugar) - Acromegaly (too much growth hormone) 4: Examples of psychological stressors that create an unhealthy stress response: • Bullying boss • Suffering racism • Being 'dislocated' from the surrounding population/culture • Money worries, long-term debt • Low status in social hierarchy • Poor social network • Non-supportive, unloving or abusive spouse • Football team losing • Getting caught in an earthquake (though this is a physical stressor too) • Getting up on Monday morning • Forced emigration/social dislocation • The number four

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\

THE GREAT CHOLESTEROL CON These are not full lists, by any manner of means - and not all of the things on these lists will create the same response in all people. But I hope that it gives you a clearer idea of the types of 'stressors' that I am talking about. My next trick is to explain exactly how an unhealthy stress response (whatever causes it) goes on to cause heart disease.

HOW AN UNHEALTHY STRESS RESPONSE CAUSES HEART DISEASE In order to explain how this happens, I need to introduce you to the neurohormonal system. This hugely complex system consists of two basic parts: the 'hormonal' part and the 'nervous system' part. While I have provisionally called this the 'stress system; the term is actually horribly inaccurate. Because the system involved in stress is precisely the same system that is involved in relaxation - only in reverse. In fact, for every hormone in the neurohormonal system that fires you up, there is another one that calms you down; and for every set of nerve fibres that revs you up, there is another network that relaxes you. Eastern philosophy would call this whole shebang Yin and Yang, internal balance, which is a pretty good way of looking at it. Because if the neurohormonal system gets seriously out of balance, you are likely to suffer catastrophic metabolic problems, then heart disease ... then cancer, then diabetes, then ... well, too much for me to cover in one book. The hormones involved on the 'stress' side include adrenaline, cortisol, growth hormone and glucagon. On the 'relaxation' side, for the purposes of this discussion, I shall concentrate on insulin. Release of stress hormones is controlled by the hypothalamus and pituitary gland acting in unison. Under a stressful situation - for example, a man pointing a gun at you - the hypothalamus sends alarm messages to the pituitary gland, which then fires off hormonal messengers to the adrenal glands to get them to release adrenaline and cortisol, among other things. This 'three-part' hormonal system, consisting of the hypothalamus, pituitary gland and adrenal glands, is often referred to as the

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DR MA.£COLM KENDRICK Hypothalamic-Pituitary-Adrenal axis, or the HPA-axis for short. The HPAaxis is intimately connected to, and intertwined with, the unconscious or 'autonomic' nervous system.The autonomic nervous system has two basic divisions: the sympathetic and the parasympathetic systems. Neither of these divisions is under your conscious control - unless you are a Zen master, or something of the sort.

Fig. 29 The parasympathetic and sympathetic nervous systems Parasympathetic

Sympathetic Dilates pupil

Stimulates ft ow of saliva

Inhibits ftow of sa liva

Slows heart beat

Constricts bronchi

Accelerates heartbeat Vagus nerve

Dilates bronchi

Inhibits perist alsis and secretion

Sti mulates peristalsis and secretion

Conversion of glycogen to glucose

Stim ulates re lease of bile

Secret ion of adrenaline and noradrenaline

co ntratcts bladder

Chain of sympathetic ganglia

Inhibits bladder contraction

The sympathetic nervous system has a wide range of actions. These include speeding up your heart rate, reducing saliva production and redirecting blood supply to your muscles. It also stimulates the liver to release glucose, thus pushing up blood-sugar levels, and triggers the release of various blood-clotting factors. These are the sort of things

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THE GREAT CHOLESTEROL CON you need when physical danger threatens, which is why this whole process is sometimes called the 'fight or flight' response. On the other hand the parasympathic nervous system has directly .opposing actions. It slows your heart, stimulates insulin production and the release of bile. It also increases the flow of saliva, and directs blood to the guts to aid digestion. Another way to look at this is to say that an activated sympathetic nervous system - working in conjunction with raised 'stress' hormones - represents the 'catabolic' state, a state in which your body is ready to burn up its energy stores, which comes in handy in a fight, or during exercise. You have probably experienced this state after a physical activity such as tennis or squash, when you know you should be hungry but find that when you sit down to eat you have no appetite. The 'stress' hormones are still ruling your metabolism, and are telling you that you are not yet ready to eat. On the other hand, an activated parasympathetic nervous system, working in conjunction with a raised insulin level, represents the 'anabolic'state - a state in which you are ready to eat, digest and store energy - and then have a siesta. In fact, analysing these two metabolic 'states' is where I first began in my quest to understand heart disease. Within our bodies, I knew, we have these two systems that are, essentially, directly antagonistic to each other. Anabolism and catabolism. I reasoned that if you were stressed, and then tried to eat, your metabolism would be thrown into confusion. You would be commanding the neurohormonal system to activate catabolism and anabolism simultaneously. This would mean high levels of adrenaline and cortisol, battling against high levels of insulin. Adipose tissue would be under instructions to both absorb and pump out fats into the bloodstream. At the same time, the liver would be trying to store, and release, glucose. With food inside them, your guts would be automatically switched to 'absorption: But the sympathetic system would be fighting to direct blood away from the guts to the muscles. Wherever you looked, a fight 214

OR MALCOLM KENDRICK for metabolic supremacy would be going on. Perhaps the most important battle would be for control of blood-sugar levels, a battle ending up with 'spikes' of blood sugar - as insulin tried, and most likely failed, to overcome the effects of the stress hormones surging about in the bloodstream. In short, I thought that eating under stress was likely to be pretty damned unhealthy. Equally, taking time over meals, and relaxing while doing so, was likely to be pretty damned healthy. Could this be the reason for the high rate of heart disease in Scotland, and the low rate of heart disease in France? Possibly, probably ... it almost certainly represents part of the answer. More on that later. Now it is time to look at what happens when the 'stress system' breaks down. Actually, from now on, I am going to refer to a breakdown of the stress system as a 'dysfunctional HPA-axis: Sorry about using this jargon, but it is much more accurate and useful. It also moves the discussion away from the slightly woolly concept of stress, to something that can be measured, i.e. HPA-axis function. (Normally this is done by measuring cortisol levels.)

Causes of a dysfunctional HPA-axis Probably the most dramatic dysfunction of the HPA-axis occurs when a tumour develops in the pituitary gland, which then proceeds to pump out far too much in the way of stress hormones. Several types of these tumours can develop. A tumour producing too much growth hormone can lead to gigantism and acromegaly; a tumour producing too much adrenaline can cause a condition known as phaeochromocytoma, etc. However, I am only going to focus on one type: a tumour in the pituitary gland that pumps out too much ACTH (corticotropin). ACTH is a 'precursor' hormone which, in turn, stimulates cortisol secretion from the adrenal glands. So, a tumour in the pituitary gland, (secreting too much ACTH) effectively increases blood cortisol levels. This condition is known as Cushing's disease. Cushing's disease, in turn, has a wide range of different effects -

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THE GREAT CHOLESTEROL CON which are a direct result of the many actions that cortisol has around the body. For example, cortisol: - Triggers the liver to release its stores of glucose. - Stimulates the breakdown of triglyceride stores in adipose tissue, leading to an increase in free fatty acids (FFAs) in the blood. Triglyceride breakdown also releases glycerol, which travels directly to the liver, where it is converted to glucose. - Activates breakdown of muscle protein into amino acids. (The amino acids then travel to the liver, where they are converted into glucose.) -Acts as a direct antagonist to the actions of insulin at most sites in the body. As you might expect, therefore, people with too much cortisol surging about in the system have high blood-sugar levels and a high degree of what is known as 'insulin resistance: In fact, most people with Cushing's disease develop diabetes. Another thing that happens to people with Cushing's disease is that they lose muscle bulk - due to the breakdown of muscle proteins. There is also a redistribution of fat from the periphery (arms and legs) to the trunk, or abdomen. Sometimes this redistribution can be so extreme that it leads to a condition known as 'buffalo' hump. The reason why this happens is because you have two very different types of fat in your body: subcutaneous and visceral. Subcutaneous fat sits just underneath the skin and is found all over the place: arms, legs, neck, even fingers. Sumo wrestlers have lots of this type of fat, and they work hard to build it up. How they do this is a fascinating topic. (Well, at least I find it fascinating, but this is not time to get sidetracked.) Visceral fat, on the other hand, is mainly found around the organs in your abdomen. It is the type of fat that builds up in those who develop the classic 'beer belly: While both types of adipose tissue can each store, and then release, fat, that is the beginning and end of any

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DR MALCOLM KENDRICK similarity. From a metabolic perspective, they are as different as different can be. They are to all intents and purposes different organs. One is fat, the other is 'anti-fat~ I shall tiptoe around this area because it is both enormous, and enormously complex, and I do not want to get bogged down. Suffice to say, for the sake of this discussion, that cortisol stimulates subcutaneous adipose tissue to release fat, thus making it shrink in size. On the other hand, cortisol stimulates visceral fat to do the exact opposite, i.e. absorb and store fats, leading to an increase in visceral fat mass (This is a horrible oversimplification, but for the sake of this argument it will do.) There is another reason for bringing these two types of fat into the discussion at this point, which is that a build-up of visceral fat is now recognised as a major risk factor for heart disease. In fact, many people now believe that visceral fat is the primary underlying abnormality in heart disease, as it is thought to create a wide spectrum of metabolic abnormalities that are closely linked to heart disease. These abnormalities have been brought under the umbrella term 'Syndrome X: Also known, among other things, as: • Metabolic syndrome X • Reaven's syndrome • Metabolic syndrome • Insulin resistance syndrome Whatever you choose to call it (and please will someone make up their minds!), to my mind the current thinking is bonkers. Visceral fat doesn't build up all by itself, just for the hell of it, before going on to create Syndrome X. Something has to cause the build-up of visceral fat in the first place. To argue otherwise is to end up in the mad genetics/magic argument again: 'Visceral fact accumulation just, sort of, happens. We don't know why, so it must be due to genetic susceptibility: (Listen, guys, it doesn't just happen. It is caused by HPA·axis dysfunction and abnormal cortisol levels. Hellooo! have a look at Cushing's disease!)

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THE GREAT CHOLESTEROL CON Anyway, in addition to its effects on raising glucose and insulin levels, and its impact on muscle and fat distribution, a high cortisol level also causes the following abnormalities: • Raised VLDL level • Low HDL level • Raised LDL level • Raised blood pressure • Raised fibrinogen levels (clotting factor) • Raised PAI-l level (clotting factor) • Raised Von Willibrand level (clotting factor) • Raised Lp(a) level (clotting factor) Does anything seem familiar about this list? If not, it will. To round off this topic, I should probably mention that people with Cushing's disease have accelerated atherosclerotic plaque growth, and a gigantically increased risk of heart disease. Strongly reinforcing the fact that it is the raised cortisol level itself that is causing the damage - rather than some other factor - is the evidence from people who take steroids. Steroids, as mentioned before, are among the most widely prescribed of all medications. They are also called 'corticosteroids; because the basic building block of all steroids is cortisol. What this means is that when you take a steroid you are, effectively, giving yourself Cushing's disease. Why would anyone want to do this? Well, one effect of cortisol that I haven't mentioned so far is that it greatly inhibits the immune system. I haven't the faintest idea why cortisol does this. However, because it does, it is used to treat diseases when you want to shut down an overactive immune response. Such 'autoimmune' diseases include rheumatoid arthritis, asthma, eczema and ulcerative colitis. Steroids are also used after a transplant, as they prevent the body from rejecting the organ. In situations like this, steroids are powerful and life-saving drugs. However, if you keep taking them for too long you will end up with the

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DR MALCOLM KENDRICK exact same set of abnormalities found in Cushing's disease: high blood-sugar and insulin levels, low HDL, high VLDU LDL, a whole range of blood-clotting factor abnormalities, and increased visceral fat deposition. In short, the works. What's more, people who take steroids long term are at a greatly increased risk of dying of heart disease. Even fit, young, healthy people. And it can happen very fast. To give one example of the abuse of anabolic steroids (a form of cortisol/corticosteroid that has been altered to create muscle build-up, rather than break it down): Anabolic steroids are frequently abused, thus increasing the risk of cardiovascular disease. We report on a young bodybuilder who presented with ventricular tachycardia as the first manifestation of severe underlying coronary heart disease. Coronary angiogram revealed severe stenotic lesions [narrowings] in the right coronary artery and the left descending coronary artery, and hypokinetic [hibernating] regions corresponding to posterolateral [the back and side] and anterior myocardial infarctions. This young patient had a history without any coronary risk fadors, but with a 2-year abuse of the anabolic steroid stanazolol. Mewis ( (lin (ardiol, February 7996

Here is a young man with no classic risk factors for heart disease. Within two years of abusing steroids, however, he had developed severe occlusion in two major arteries in the heart, and he had also suffered two separate heart attacks (which he didn't actually know had happened). This looks like a fairly clear case of cause and effect to me. Anyway, we have two different 'conditions' where cortisol levels are significantly raised: Cushing's disease and steroid use (or, rather, abuse). In both of them, exactly the same set of abnormalities develop, followed by heart disease. Clearly though, these two 'conditions' represent a very serious form of HPA-axis dysfunction indeed. You would almost certainly expect them to have a major destructive impact on the body. Equally clearly, not everyone who dies

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THE GREAT CHOLESTEROL CON of heart disease has Cushing's disease, or takes steroids. So the next step is to show that other, less obviously severe forms of HPA-axis dysfunction also have the same destructive effect - through the same mechanisms. In order to do this, I want to look at three different initiators of HPA-axis dysfunction: • Depression • Smoking • Spinal-cord injury Depression first. It has long been known that people with depression are at a greatly increased risk of heart disease, but no one seems to be entirely certain why. However, when it has been studied it is clear that in depression you always find HPA-axis abnormalities. There is compelling evidence for the involvement of hypothalamicpituitary-adrenal [HPA-} axis abnormalities in depression. Growing evidence has suggested that the combined dexamethasone [DEX}lcorticotropin-releasing hormone [CRH} test is highly sensitive to detect HPA axis abnormalities. Kunugi H, et al. Neuropsychopharmacology, January 2006; 3 (I left in the stuff about the dexamthasone (DEX)/corticotrophin-releasing

hormone (CRH) test for those who do like to see things properly measured, and refuse to believe in things that cannot be measured.) In addition to the other metabolic problems, depression also leads to a build-up of visceral fat. I popped this observation in to make it clear that visceral-fat build-up is a result of underlying problems with the HPA-axis and raised cortisol levels - it doesn't happen by genetics. Or, indeed, magic. We showed that depressive mood is associated with VAT [visceral adipose tissue}, not with SAT [subcutaneous adipose tissue}, in

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DR MALCOLM KENDRICK overweight premenopausal women. These findings may explain some of the association between depression and coronary heart disease. More studies are needed to elucidate the causal relationship. Lee ES, et aI, Obes Res, February 2005; 13 In fact, I think that depression is an almost perfect model to demonstrate that long-term dysfunctions of the HPA-axis - created purely by psychological stressors - works through exactly the same physical, and measurable, mechanisms as Cushing's disease to cause heart disease. Importantly, if you treat depression, the metabolic abnormalities often disappear - which represents reversibility of effect. I didn't need to choose depression to show that psychological upset causes heart disease. I could have presented research on anxiety, or post-traumatic stress disorder, rather than depression. But I can assure you that research in all of these areas shows exactly the same thing. HPA-axis dysfunction, then metabolic abnormalities, then increased risk of death from heart disease. Once again, it is not a coincidence. This is a direct causal chain from HPA-axis upset to heart disease. Smoking next. Although this may seem to be way out on a limb, it is not, because smoking actually works through exactly the same mechanisms as depression and Cushing's disease, although the effects are more likely due to repeated short-lived HPA-axis dysfunction, rather than chronic problems. Two pieces of evidence. The first is taken from a study that looked at the effect of smoking a cigarette on cortisol and DHEA (dehydroepiandrosterone) levels (DHEA is a steroid hormone made in the adrenal glands in response to stress):

Cortisol and DHEA increased significantly within 20 min (P

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