Changing the definition of Familial Hypercholesterolaemia

I am grateful to Mike Sheldrick, a reader of this blog for spotting some news, that was not entirely expected by me. For reasons that I will explain later. As you may know two new cholesterol lowering drugs have now launched. Two PCSK9 inhibitors. I call them the ‘dreaded’ PSCK9 inhibitors. I have written about them a few times. There has been surprisingly little noise about them so far, at least in the UK. Not sure about the US or the rest of the world. They are called Repatha and Praluent. Catchy eh!

These drugs have two major problems at present, at least from a money making perspective. They have no outcome data, by which I mean that they have not been shown to reduce the risk of heart attacks, strokes… or anything else for that matter. (They have been launched purely on their ability to lower LDL to violently low levels). They are also extraordinarily expensive. In the UK Praluent will cost between four thousand to eight thousand pounds ($6 – $12K) per year, depending on the dose1.

Which means that the NHS can, if it so wishes, pay eight thousand pounds a year for a drug that does not actually do anything – other than lower a surrogate marker for heart disease. Now, this may not be seen as bargain of the year. I can imagine great battles are going on right now between the pharmaceutical companies and NICE. The organisation that decides if a drug is cost effective, or not.

At present I would think that the response of NICE would be ‘Are you out of your tiny little minds. Why the [[…] insert swear work of choice here], would we fund this?’ At least I would certainly hope this would be their response. Imagine if everyone on statins in the UK, around seven million, changed to PCSK9 inhibitors This would cost £56 billion pounds [$80Bn] a year. A tidy little sum. Half of the entire NHS budget.

So, what to do? You have this amazing cholesterol lowering super-drug that does nothing, and it is enormously, eye-wateringly expensive. Come on, come on. Think!

To be frank, I thought that the primary marketing tactic would be to claim that statins actually have many, many horrible side-effects – that no-one noticed until…. there were new drugs to be launched of course. Which would mean that all those people who were ‘statin intolerant’ would need to take PCSK9 inhibitors instead. To get that horrible, damaging LDL level down. There is no doubt that the attack on statins is currently happening, but there has been more resistance to this than expected.

So, what else can you do? Well, there is one population where cholesterol lowering is seen as absolutely essential. The population is those who have familial hypercholesterolemia (FH). This group has always been considered at such a high risk of dying from heart attacks and strokes, that no clinical trials have even been done. You just do anything, and everything, to get the cholesterol (LDL) levels down, no questions asked. [No evidence of benefit needed either]

At present about one in five hundred people have FH and, when I started thinking about, I realised that this is really a big enough market for PCSK9 inhibitors. Just to do some simple sums. There are sixty-five million people in the UK at present. If one in five hundred has FH, that represents an FH population of 130,000. If every single one of these people goes on the higher dose of one of these drugs, the total sales would be £1Bn/year. In the UK alone. That is a blockbuster in anyone’s eyes.

If we transpose these figures to the US. The total population in the US is three hundred and twenty million. Which means that 640,000 people will have FH. With Praluent selling at $14,000/year, that would be $9Bn/year in sales in the US alone. Worldwide we are talking tens of billions a year. Of course, there are two virtually identical drugs out there, Praluent and Repatha, so divide the market by at least two – and there are more PCSK9 inhibitors in the pipeline.

Reducing this market still further, not everyone will take an injectable medication every two weeks, no way. And so the total market, though still massive, shrinks down ever further. Realistically, you might get a maximum of a quarter of those with FH on your drug. Amgen, for example would have to cope with piddling sales of $10Bn/year worldwide. Which will not do, not at all. More money must be made.

Of course, the simplest thing to do, to get round the problems with market size is simple. Make the market bigger. And the easiest way to do this is to widen the criteria for Familial Hypercholesterolaemia (FH). And lo, it has come about. The American Heart Association has stated that the level of LDL at with FH can be diagnosed is to be lowered:

“More people may be diagnosed with familial hypercholesterolemia (FH) using criteria contained in a new scientific statement published by the American Heart Association. The expanded definition could also mean more patients will be eligible to receive expensive cholesterol-lowering drugs, including the new PCSK9 inhibitor drugs, (Repatha from Amgen and Praluent from Sanofi/Regeneron)….

The new criteria for heterozygous FH sets an LDL level of at least 190 mg/d L (4.9mmol/l) for adults who have a similarly affected first-degree relative, premature coronary artery disease, or a positive genetic test. According to Mann, 3% of the population has LDL levels over 190 mg/dL level, but, she points out, “less than 1% of the population has FH. You could have docs diagnosing people with HeFH or HoFH* solely so that their insurance will cover a medication, such as PCSK9 inhibitors. That could be very confusing for patients.”2

*HeFH = Heterozygous Familial Hypercholesterolaemia (affects 1:500 – high LDL levels)

*HoFH = Homozygous Familial Hypercholesterolaemia (affects 1:1,000,000 – super-high LDL levels)

In one simple stroke, the market for PCSK9 inhibitors in the US has been increased from 640,000 to 1,920,000. Or, in monetary terms, $9Bn to $27Bn. There, that’s more like it. In the UK the market goes up to 400,000, with max PCSK9 sales going from one billion to three billion pounds sterling. A clever little trick.

I must say that I, possibly the most cynical human on the entire planet, never thought they would do this. I discounted as just too brazen. It would just be likely to be laughed out of court. Silly me. No-one is laughing. Experts are rubbing their chins and nodding sagely at the wisdom of this move. New swimming pools all round, is what they are probably thinking.

Do you think that the American Heart Association’s (AHA) decision here may have been affected by commercial sponsorship? This, of course, would be impossible to say – without getting sued senseless for libel.

However, I had a little look around the AHA, and Amgen, also the ‘non-profit’ FH Foundation and Amgen, and suchlike. Here is one statement from the AHA site. ‘Amgen is a proud sponsor of the American Heart Association’s Heart360 Toolkit3. Ho hum Needless to say. Amgen are also ‘proud’ sponsors of various AHA meetings.

In addition, Amgen are also a foundation ‘corporate sponsor’ of the FH foundation4. They are probably very proud of that too. Finding these financial relationships can be a little tricky, as they are usually hidden in the depths of various websites. Perhaps other mike care to improve on this list…. Probably not that hard to do.

Money makes the world go around, the world go around, the world go around.’





How much longer will you live if you take a statin?

How much longer will you live if you take a statin?

About a year ago I submitted a paper to the BMJ entitled ‘Statins in secondary prevention, lives saved or lives extended.’ To be more accurate, I was the lead author of the paper. So I should say ‘we’ submitted a paper. I have to report that the paper was rejected, re-written and rejected again. In the end I couldn’t get it published.

The main aim of the paper was to point out that the most important reason why someone would take a ‘preventative medicine’ of any sort, was to increase their life expectancy. The question ‘how much longer will I live if I take this tablet for, say, five years?’ Seems a reasonable question to ask and, in turn, have answered. Interestingly no patient has ever asked me this question, so I have never had to answer it.

What we have instead is the repeated use of relative risk. Which is often framed in the following type of way: ‘Atorvastatin/Lipitor will reduce the risk of dying of a heart attack by 36%’… and suchlike. Whilst that figure is true, or at least it was true in one study funded and run by Pfizer… who sell atorvastatin, I knew that a figure like that was horribly misleading. It gave the impression of a gigantic reduction in risk. ‘Your risk of dying of heart disease will be reduced by more than a third!’ Surely you would be mad not to take it, wouldn’t you?

However, how does a figure like that pan out in the most important outcome of all. Namely, increase in life expectancy? I had done a few ‘back of a cigarette packet calculations’ on this, and I was getting some pretty unimpressive figures. But to get it absolutely right I contacted a professor of statistics at the Medical Research Council and asked him if he could work out an exact figure, using real mathematics.

We chose the two most positive studies on statins ever done. The Scandinavian Simvastatin Survival Study (4S) and the Heart Protection Study (HPS). These were secondary prevention studies. By which I mean studies done on people who had already had a heart attack or stroke, or suchlike and were at great risk of having a ‘second’ event. So these were very high risk people, where the benefits of statins would be at their greatest.

Looking at the Heart Protection Study (HPS) done in the UK, we used a technique for analysing survival time called RMST (restricted mean survival time). I won’t go into the details. The HPS study lasted for five years, and we calculated that the average increase in survival time was 15.6 days. This was at the end of five years of treatment (with a confidence interval of 5 days either side). For 4S, the figure was 17 days.

Framing this slightly differently, what this meant was that taking a statin for one year, in the highest risk group possible, would increase your life expectancy by around three days. We thought that people should know this. Unfortunately, the BMJ thought otherwise. Such is life.

However, more recently the BMJ did decided to publish another paper entitled: ‘The effect of statins on average survival in randomised trials, an analysis of end point postponement1.’ They used slightly different mathematical techniques, including the ‘quick method.’ To quote:

‘We also calculated all areas in a less technical manner, that is, by drawing one or more triangles by hand on magnified paper prints of the survival curve for each study and then calculating the areas of these triangles by standard arithmetic. This is referred to as the quick method.

I have to admit that’s my kind of maths. Get out the pencils and draw it all out by hand. They also looked at more studies than we did, and aggregated them. Which has benefits and disadvantages. Sometimes you are not comparing like with like. However, the main results of their study, and their conclusions, were as follows:

Results: 6 studies for primary prevention and 5 for secondary prevention with a follow-up between 2.0 and 6.1 years were identified. Death was postponed between −5 and 19 days in primary prevention trials and between −10 and 27 days in secondary prevention trials. The median postponement of death for primary and secondary prevention trials were 3.2 and 4.1 days, respectively.

Conclusions: Statin treatment results in a surprisingly small average gain in overall survival within the trials’ running time. For patients whose life expectancy is limited or who have adverse effects of treatment, withholding statin therapy should be considered

Overall their findings were far less impressive, even, than ours. They calculated, approximately, a single day of increase in life expectancy for each year of taking a statin. Slightly more in secondary prevention, slightly less in primary (people who have not previously had a heart attack or a stroke).

The main take away message I believe, is the following. Statins do not prevent fatal heart attacks and strokes. They can only delay them. They delay them by about one or two days per year of treatment. For those who have read my books you will know that I have regularly suggested we get rid of the concept of ‘preventative medicine’. We need to replace it with the concept of ‘delayative medicine’.

You cannot stop people dying. You can only make them live longer. How much longer is the key question. With statins this question has been answered. You can, to be generous, add a maximum of two days per year to life expectancy.

Which means that if you were to take a statin for thirty years you could expect to live about two months longer. (Possibly three, more likely one). Assuming, and this is a big assumption, that none of the trials done have been in any way biased towards statins. Even though every single one was funded by the pharmaceutical industry. Further assuming that any benefits seen in the trials will continue for the next twenty-five years.

Why, you may ask, has the pharmaceutical industry never chosen to present the results of the statin trials in this way? In truth that is a bit of a silly question. I think anyone with a half functioning brain knows why the pharmaceutical industry has never chosen to present the result of the statin trials in this way. A 36% reduction in fatal heart attacks does sound rather better than, one extra day of life for every year you take a statin – best case scenario in primary prevention… Does it not?

1: Kristensen ML, et al. BMJ Open 2015;5:e007118. doi:10.1136/bmjopen-2014-007118

The longest journey

Whilst on a short break I picked up the Times Newspaper on Friday the ninth of October. There were two headlines. The main one was ‘Fizzy drinks giant pays millions to diet experts.’ On the other side of the page was ‘Revolution for FIfa after Blatter gets red card.’

The fizzy drinks company was, of course, Coca Cola. I wondered why the headline did not say ‘Coca Cola pays millions to diet experts.’ Perhaps that was just a step too far to upsetting a major advertiser. Although I note that the picture of Sepp Blatter had a large Coca -Cola sign above his head. So, somebody at the Times clearly has a sense of humour.

Now I looked at these headlines and I thought, as I find myself doing most of the time nowadays. Corruption, corruption, corruption everywhere. Sepp Blatter is almost heroic in his ability to brush aside allegations against him and his organisation. ‘I knew nothing about anything.’ Seems to be his defence. Well, if he didn’t know anything he’s incompetent, if he did, he is corrupt. I suspect both.

As for Coca Cola. They just pay ‘experts’ large sums of money, and the expected messages flow forth. According to the Times article they set up the European Hydration Institute to promote… hydration. Which sounds quite innocuous and nothing to do with Coca-Cola at all.

However, guess which drinks people should hydrate themselves with. Why…. Let me think. They get a Professor Ron Maughan to state the dehydration was an ‘unrecognised danger’ for drivers. Drivers should regularly stop and buy drinks to ensure they are properly hydrated with drinks such as… Why… let me think.

Of course, by pretending the European Hydration Institute is some sort of independent academic body, such messages are not simply seen as adverts for Coca Cola, Oasis, and suchlike. This arm’s length marketing is a very old trick now. Heart UK is a charity which is dedicated to warning of the dangers of cholesterol. Heart UK ruthlessly promotes cholesterol lowering as the most important function of the medical profession. Of course it is almost entirely funded by pharmaceutical companies who make cholesterol lowering drugs. [I would say entirely funded, but I am not absolutely sure about this].

Various experts give talks on behalf of Heart UK, paid for by Heart UK, then claim they receive no money from the pharmaceutical industry. Which is, of course, technically correct. They do not receive money from the pharmaceutical industry. Heart UK receives money from the pharmaceutical industry, they then pay the expert, and the expert need not even declare a conflict of interest. ‘How dare you say that I take money from the pharmaceutical industry, you dirty knave…. I did this work for a charity. A charity I say.’

This is also how Sir Rory Collins works. He runs the Clinical Trial Service Unit (CTSU) in Oxford. It runs trials that are almost entirely funded by the pharmaceutical industry. Nearly three hundred million pounds sterling ($500m) over the last ten years or so. He states he receives no money from the pharmaceutical industry, and therefore is not biased in any way. Once again…Industry pays CTSU, CTSU pays Sir Rory Collins = no payment from industry and no conflicts of interest. And if you believe that.

Wherever you look. Wherever I look it is the same old story. Experts are inevitably bought and paid for by one company or another. The messages that come out are universally supportive of the company’s products. If you are not sufficiently supportive the companies will go find something else to turn into an ‘expert.’

As the Times reports ‘In 2013 Spanish researchers found that scientific papers on sugary drinks that were sponsored by or had potential conflicts of interest with the food and drink industry, including Coca-Cola were five times more likely to find no link with obesity than similar papers that were independently funded. They recommend “special efforts to preclude funding by parties with vested interests at all levels.’

In truth, I don’t care that much about Fifa and the endemic corruption thereof. If people can be bribed sufficiently to hold a World Cup in Qatar, average summer temperature 50c, the world is not going to come to an end. Although a few footballers might. Obviously, it would be better if the countries with the best bid actually won, but no-one is going to die. Probably.

However, if companies such as Coca-Cola can fund research that distorts science and promotes the consumption of sugary drink, and helps to create millions upon millions of people with type II diabetes then this is very serious stuff indeed. The increase in morbidly and mortality could end up bankrupting health services around the world.

I know that all organisations and companies, if they are not properly policed, will end up travelling the road to corruption. It seems an immutable law of commerce. In a way I don’t blame the companies. They are, by their nature wolves. If I have a thousand sheep in a field and find the wolves circling, I do not say the wolves, ‘now, really, I do not want you to eat the sheep. Do you promise?’

Wolves: ‘Yes, we promise.

Shepherd: ‘Good.’

Next day, shepherd arrives, sheep mostly eaten, wolves fat. Well, what do you expect? Wolves eat sheep. It is what they do. If you want to stop this happening, build a bloody great fence, or buy some guns, or both. Don’t rely on wolves to suddenly start acting like sheepdogs.

No, I don’t blame the companies for being companies. I blame our politicians. It is only they who can create a system of policing and punishment that will stop companies corrupting researchers, or corrupt researchers demanding money from companies. Yes, this is not a one way street. You can’t have corruption if researchers don’t take bribes.

Unfortunately politicians seem perfectly uninterested in corruption in the medical field. Is it because they themselves are being bribed. I am certain that this is part of it. In the UK large numbers of MPs are non-exec directors of private health companies, and the corporate world swirls around and within the political arena far, far, too closely. Before the last election David Cameron stated that lobbying would be next great scandal.

He says nothing of the sort now, yet lobbying and manipulating on behalf of large corporations has become worse and worse. The UK has not yet reached the situation in the US where lobbyists outnumber politicians by about a hundred to one…. Or thereabouts. And when politicians stop being politicians they immediately become lobbyists. But we heading in that direction.

So where are we? A long, long way down the longest road. The road that ends with everyone in any position of power becoming, essentially, a spokesman for large corporations, where there is no-one left who can or will do anything to stop it. Because, sadly, they are all in it together. I write that last sentence and think, oops, have I just become a conspiracy theorist. Then I think. No, I am not a conspiracy theorist, I am simply Winston Smith.

Study 329 – where the hell is the outrage?

To quote from the BMJ ‘No correction, no retraction, no apology, no comment…’

Study 329 was started in 1994 by Smith Kline Beecham, which shortly become part of the larger conglomerate Glaxo Smith Kline (GSK). Study 329 looked at the use of paroxetine, an anti-depressant, in adolescents with depression.

Following this study paroxetine was promoted and marketed heavily by GSK as demonstrating, in the words of GKS marketing materials: ‘REMARKABLE Efficacy and safety’. Over two million prescriptions were then written for children and adolescents in the US.

However, in 2002 the FDA considered study 329 to be a ‘failed trial.’ In 2003 the UK recommended that paroxetine should not be used in children and adolescents with depression because it increased the risk of self-harm and potentially suicidal behaviour.

In 2004 the FDA placed a black box warning on all antidepressants in adolescents and children stating that they increased the risk of suicidal thinking and suicidal behaviour in these groups. In 2012 GSK finally agreed to pay £2Bn for fraudulently promoting paroxetine.

But the story does not end here. A group of researchers, who had been heavily critical of this trial, finally managed to get hold of the raw data and carried out a re-analysis under the restoring invisible and abandoned trials (RIAT) initiative. Yes, this saga has been a long one.

The reanalysis was recently published in the BMJ with sadly predictable results. The primary conclusion was that ‘Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was increase in harms in both groups.’

This is in stark contrast to the original trial results. When it was first published it appeared to demonstrate very clearly that paroxetine was both safe and effective in adolescents with depression. According to GSK it demonstrated ‘.remarkable efficacy and safety’ However, using exactly the same trial data, reanalysed by independent researchers, we now find that paroxetine was both useless and damaging.

So, what has been the consequences for those involved in the initial trial and the writing up thereof? For those who read the BMJ, you will know that I am now quoting verbatim here:

  • Despite subsequent FDA and MHRA warning about increased risks of suicidal thinking and behaviour and GSK receiving a record fine, partly for illegal off-label promotion of the drug, the original report has not been retracted or even had a correction
  • Academic and professional institutions have failed to publically address the many allegations of wrongdoing
  • None of the named authors had intervened to correct the record. An internal enquiry by the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) concluded that no further action was necessary
  • Brown University remains silent over its involvement in the study. It refuses even to confirm or deny whether any investigation took place1

I will add to this that a co-author of study 329, Karen Wagner, named eight times in the 2011 US Department of Justice complaint against GSK, is currently the president elect of the American Academy of Child and Adolescent Psychiatry – whose journal, the JAACAP, is where the original study was published.

Taking stock. What do we have? A study was done, and published, demonstrating that paroxetine was safe and effective. The trial data were heavily promoted, resulting in millions of children and adolescents being prescribed paroxetine.

The reality is that this drug was completely ineffective and increased the risk of suicide (amongst other things). This has all been known for many years. The latest re-analysis simply confirms everyone’s worst fears.

So surely someone, somewhere, got punished? No they did not. Not only that, but the original published study has not even been retracted. It still sits in the medical database. A young and innocent researcher could come across it, and reference it, and use data from it to support a grant application for a study to use antidepressants in children.

If this were not all completely and absolutely one hundred per-cent fact, you might think we have a possible plot line for a dystopian novel here. A story of terrible corruption where large corporations can distort data through one hundred and eighty degrees, and get away with a fine. A world where bent researchers promote research that results in more children committing suicide, and then move on positions of greater power and authority – with no censure from anyone. To become presidents of major medical societies, for example.

Frankly I don’t think I would dare to write a novel with a plot so completely outrageous. Surely someone, somewhere, would be punished for this behaviour. Surely the paper would be retracted. Surely a co-author of such a study would not be in line for a prestigious position. Surely the public would rise up in outrage.

In truth, it seems, nothing is going to happen at all. I must dig out 1984 and read it again, just to depress myself even further.

1: BMJ 2015;351:h4629

A Swiss Investment Bank gets it completely one hundred per cent right

[Yes, that’s right, a Swiss Investment Bank!]

A kind reader of my blog pointed me at a report by Credit Suisse entitled ‘Fat, the New Health Paradigm.’ I suppose I half expected the usual. Saturated fat causes heart disease, cholesterol causes heart disease. ‘We are a respected bank, what the hell did you expect – that we would rock the boat in some way. Don’t be daft.

What seems to have happened is that they actually looked at the evidence in this area and came to the conclusion that the current dietary advice is utter bollocks and is not based on anything at all. I shall start with a few key points from the Introduction:

‘Saturated fat has not been a driver of obesity: fat does not make you fat. At current levels of consumption the most likely culprit behind growing obesity level of the world population is carbohydrates. A second potential factor is solvent-extracted vegetable oils (canola, corn oil, soybean oil, sunflower oil, cottonseed oil). Globally consumption per capita of these oils increased by 214% between 1961 and 2011 and 169% in the U.S. Increased calories intake—if we use the U.S. as an example—played a role, but please note that carbohydrates and vegetable oils accounted for over 90% of the increase in calorie intake in this period.

A proper review of the so called “fat paradoxes” (France, Israel and Japan) suggests that saturated fats are actually healthy and omega-6 fats, at current levels of consumption in the developed world, are not.

The big concern regarding eating cholesterol-rich foods (e.g. eggs) is completely without foundation. There is basically no link between the cholesterol we eat and the level of cholesterol in our blood. This was already known thirty years ago and has been confirmed time and time again. Eating cholesterol rich foods has no negative effect on health in general or on risk of cardiovascular diseases (CVDs), in particular.

Doctors and patients’ focus on “bad” and “good” cholesterol is superficial at best and most likely misleading. The most mentioned factors that doctors use to assess the risk of CVDs—total blood cholesterol (TC) and LDL cholesterol (the “bad” cholesterol)—are poor indicators of CVD risk. In women in particular, TC has zero predictive value if we look at all causes of death. Low blood cholesterol in men could be as bad as very high cholesterol1.’

At one point they go on to say…

Here is our final hypothesis on why health authorities have remained so certain of their position and unwilling to change their view on saturated fats, omega-6 or carbohydrates:

  1. Health authorities advance very slowly and are afraid to change the market’s status quo (not a wise medical posture).

We have known since the 1960-70s that dietary cholesterol has no influence on blood cholesterol. Yet it took more than fifty years for the USDA/USDHHS to lift recommended upper limits of fat consumption. It took close to 20 years in the U.S.—that was quick—to ban transfats. So we should not look at public health authorities as leading indicators of potential health hazards, but rather as lagging behind.

Bureaucracy tends to move slowly, but when the health risks tied to “incorrect” information are so high, one would hope for swift action and the courage to reverse past mistakes. There was no fundamental reason to move from butter to solvent extracted vegetable oils. If we assume that research was the main reason—as it was claimed at that time—the health authorities now have enough information to change their recommendations, or if still in doubt issue no recommendations.

All quite extraordinary. This report is about as scathing as an organisation like Credit Suisse could possibly be. They have stripped apart the evidence on eating fats and saturated fats. They have come to exactly the same conclusions as I, and many others, have done. When they say:

There was no fundamental reason to move from butter to solvent extracted vegetable oils

That means, there was not one single scrap of evidence. Nothing, zip, nada, zero. So when you see various flower-like margarine manufactures promoting their products as super-healthy…. You know it is just the most complete nonsense. Even a Swiss Investment Bank says so.

And what do they have to say on raised cholesterol levels? Well they have many things to say, mainly that it does not cause heart disease. The shortest summary of their conclusions would be the following:

We can draw the following conclusions:

  1. High cholesterol (above 240mg/dl) (this is 6.2mmol/l) is only a marker of higher cardiovascular death for men. Please note that high cholesterol does not cause heart attacks, it is just a marker.
  2. For all other illnesses, higher cholesterol levels pointed to lower death levels. Why? Because cholesterol helps support, or is a marker of, a better immune system.

I know that this report will be ruthlessly attacked and vilified. Mainly on the basis that it was written by a Bank! And what can bankers possibly know of medical research? How very dare they? My own view on this is that, you know, anyone can read medical research, and if you are in possession of a functioning brain you can also work out what that research is saying.

Indeed, in my opinion, the best placed people to review any form of research are those who do not have a dog in the fight. The authors of this report have no reputations to maintain in medical research. They have no reason to support one side or the other. These people represent an investment bank, and all they are interest in doing is advising their ‘customers’ on what is really true, and what is likely to happen. They are a bit like bookmakers. No emotions involved just ‘what are the odds.’

As they say that odds are, as follows

‘The bottom line of these assumptions is that fat consumption per capita is likely to soar by 23% from now until 2030, protein by 12%, and carbohydrates will likely decline by 2%. This implies annual compound growth of 1.3% for fat consumption, compared to 0.9% over the last fifty years. Total demand for fat will be much higher—43% up for fat or 1.9% a year— given the 16% growth in the global population expected over the next fifteen years.’

Pork bellies are a ‘buy.’ How strange to find myself on the same side of an argument as a Swiss Investment Bank. I would have given you bloody good odds on that yesterday.


Tranny fats ha ha ha

[An apology. Some people have objected to the work Tranny, as this is considered offensive to trans-gendered individuals. I was attempting a play on words from Roddy Doyle’s well known book Paddy Clarke ha ha ha. I had not the slightest intention of causing offense in this way, and I apologise if I have done so. I hope the title can be taken in the ‘innocent’ way that it was meant]

Many years ago a man, who they say, had an ego the size of a planet decided that he just knew what caused heart disease. It was cholesterol consumption in the diet that raised blood cholesterol and killed us all. Unfortunately, for him, he did some research that however much cholesterol you ate, it had no effect on the cholesterol level in the blood.

No matter.’ He laughed gaily. ‘What is the point of a good hypothesis if you cannot change it upon a whim?

So he then decided that it was dietary fat that raised cholesterol levels in the blood and caused us all to die of heart disease. Only it wasn’t that one either. So then he thought it was animal fat (wrong again!) and finally settled upon saturated fat.

Then, through a combination of his forceful personality, and a good bit of merciless bullying anyone who disagreed, Ancel Keys promoted his message far and wide, and those in power decided he was right.

This set in chain a whole series of seemingly disconnected phenomena. The first of these was to start telling everyone that they should not be eating saturated fats, assumed to be animal fats, or else they would die. Thus, recommendations about what was healthy to eat became moved away from those horrible, unhealthy fats, and focussed entirely on eating carbohydrates.

At which point the obesity epidemic began- as you would expect. This was closely followed by the epidemic of diabetes – as you would expect. If you know anything about human physiology.

Then it was realised that diabetics, who were more likely to develop heart disease than anyone else really, really, should not eat any sort of fat. Saturated or otherwise. They were all advised to switch to eating carbohydrates. This of course, makes perfect sense. We have a group of people who cannot control their blood sugar levels, so we tell them to eat almost nothing but sugar.

We now spend more on medication for diabetes than any other form of medicine in the world. Why, because no-one can get their blood sugar levels under control any more. Quelle surprise?

In parallel with this nonsense it was decided that we should replace saturated fats with ‘healthy’ polyunsaturated fats and suchlike. Which inevitably included trans-fatty acids. These were first discovered many years ago, when oils were turned into margarine. The margarine was, at first, coloured pink – as it was considered unfit for human consumption, and was only fed to animals.

Gradually trans-fats, which are also polyunsaturated fats, found their way into almost everything anyone ate – including of course margarine (no longer coloured pink, instead with pretty coloured flowers on the tub). MacDonald’s were virtually forced into cooking their fries in vegetable fat, so that no-one would be exposed to the deadly, evil saturated fats. Hey ho, what happens to vegetable fats at high temperatures? Well, they turn into trans-fatty acids, of course. Who knew? Apart from all chemists in the world.

More recently we find that trans-fatty acids are uniquely unhealthy substances that should be banned, and excluded from human consumption. What a surprise, a range of chemical compounds almost unknown to nature may not be healthy….well, who’d a thunk? This morning I was listening to a debate on the radio about whether the UK should ban all trans-fatty acids. [Well, you can’t ban them all, because some are found in natural foodstuffs.]

I just sat and listened, and thought that the entire world of nutrition was bonkers, and remains bonkers. An egocentric megalomaniac called Ancel Keys decided that ‘HE KNEW’ what caused heart disease, and would brook no dissent. His legacy is that we now force carbohydrates into diabetics, and almost everyone else. We also forced manufacturers to stop selling saturated fat and, instead, switch to super-healthy trans-fats. We made MacDonald’s French fries uniquely unhealthy. A perfect and delicious irony. Accuse MacDonald’s of selling unhealthy food, then make them do it.

God knows how many have died prematurely because of this complete and utter nonsense. Tranny fats, ha ha ha.

The Augean Stables – part II

It has become clear that much of medical research is flawed, and so inherently biased that much of it/most of it simply cannot be relied upon. One of the strongest critics of this current situation is a brilliant statistician, Professor John P Ionnadis. His seminal paper on the subject of medical research, which is nearly ten years old now, was entitled ‘Why Most Published Research Findings Are False ‘. I include the abstract here:

‘There is increasing concern that most current published research findings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias1.’

Has his work been contradicted by anyone? The answer would be a resounding… no. In fact, all that has happened over the last ten years is more and more confirmation that medical research has become worse.

This is an incredibly worrying situation, yet very few people seem in the slightest bothered. The status quo remains in status. When new medical studies come out the press continue to regurgitate the findings as though they are unquestioned gospel. Experts have maintained their status as demi-gods, to be fawned upon as though their work is beyond any possible reproach.

Guidelines, the ones that instruct doctors on how to treat various conditions, are still published without any provisos. Guidelines which are based on evidence that… ‘may often be simply accurate measures of the prevailing bias.’ But woe betide any doctor that fails to follow said guidelines, for they may well be struck off the medical register. In the US, you could end up in jail.

All of these things are bad enough, and there are many other problems. However, in this blog, I want to focus on another issue. Namely, what about placebo controlled studies? Just to make it clear, for those who know a great deal about this area, I am not looking at the issue of ‘what the hell is in placebos anyway, cos it sure as hell ain’t inert substances.’ Whilst the fact that you cannot find out what manufacturers actually put in placebos, which should be inert ‘sugar pills’, but most certainly are not, is extremely important, that is an issue for another day.

Today’s issue is as follows. We have reached a situation in medical research where it may never be possible to find out if certain treatments actually work. Sub-header… ‘And in which case we are all doomed.

Here is the context. Once a treatment has been found to be superior to a placebo, it will be deemed unethical ever to carry out a placebo controlled study ever again. That may not mean much to many people, so I shall expand – using a concrete example (yes, statins again).

If placebo controlled studies have shown that statins reduce the risk of heart disease, and for the sake of argument let us accept that this is true, where does this leave us? It leaves us in the position whereby, if anyone wanted to set up a study to try and disprove that statins are no better than placebo, they will never be given permission to do so.

Why not? Well, before you are allowed to carry out a clinical study, you have to present it to an ethics committee. This committee will look at the proposal and decide if it is indeed ‘ethical.’ Exactly what this means is up for debate. However, if you decided to study the speed at which cars need to run into children, to result in a fifty per cent mortality rate, I imagine you would be turned down by the ethics committee.

More prosaically, if you have found that statins reduce the risk of dying of heart disease vs placebo, then you will no longer be allowed to do a placebo controlled statin trial ever again. The reason for this is that you have already ‘proved’ that statins are superior to placebo. So it will argued that any volunteer placed in the placebo arm of your study would be suffering avoidable harm. Bong! Ethics committee says no. We know statins work, so it is unethical not to give them.

The only studies the ethics committees will allow would be statins vs. statins and a new drug. Equally you would not be allowed to study a new drug vs. placebo, at least not for an indication where statins had shown a benefit. Because everyone ‘at risk’ should be on a statin already.

Now, I have some sympathy for pharmaceutical companies in this situation. If statins reduced the risk of heart disease by 50% (made up figure), then any new drug can only provide an incremental benefit over statins – there is only 50% possible benefit left. So you need to study more people, over a longer period, to demonstrate superiority over statins. A higher hurdle than statins had to get over to be approved.

In another way, obviously, I have less sympathy. Let us suggest that all of the statin trials were biased. Let us further suggest that statins do not have any benefit over placebo. Is there any evidence for this? Well, the only major non pharmaceutical funded study on statins vs placebo was ALLHAT-LLP. Which was run by the National Institutes for Health (NIH). It was reported thus:

‘Washington, DC – Surprising results of an unblinded but randomized comparison of pravastatin (Pravachol® – Bristol-Myers Squibb) vs “usual care” in patients with hypertension and moderate hypercholesterolemia enrolled in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT) show that pravastatin did not significantly reduce either all-cause mortality or fatal or nonfatal coronary heart disease (CHD) in these patients.’

So, no benefit at all. This study was immediately attacked by all the ‘experts’ and dismissed as being useless, not enough LDL lowering, not enough difference from standard care blah, blah. Nothing to see here, move along.

However, I find it interesting that the only statin study which was not funded by the pharmaceutical industry was completely negative. You may even believe that this would give people pause for thought. If so, silly you.

Where does this leave us though? Well, as already stated, you can never, ever, do another statin vs placebo study. For it would be unethical to do so. You can never do a cholesterol lowering study on any other drug vs placebo either, for it would be unethical to do so. If the statin trials were all correct and unbiased and without the slightest doubt attached to them….fine. If, however, these trials were simply accurate measures of the prevailing bias then we are completely screwed.

This leaves us in a situation whereby if we test other drugs against statins, we are testing a drug against a drug that we cannot be certain has any benefits at all. So, what can we prove? Nothing. Which means that the very foundations of all future research in this area have been built on a bog.

So, what can we do? Carry on believing that all the research done is correct and above any suspicion of bias and manipulation. If so, fine, but you may have trouble sleeping at night. If not, you are going to have to tear apart all of the research that has been done, and do it again. I think that makes the task of Hercules look pretty easy.



The Augean stables

For many years it was possible to start a clinical trial, on a drug, without telling anyone that you were doing so. Then, if it turned out to be negative you could just slip it under the carpet and never let anyone know you were doing it. This is what happened with many antidepressant trials. Positive, publish. Negative, bury. Unsurprisingly, the results for antidepressant treatment looked pretty damned good.

Another little trick was to keep the primary end-point of the trial secret. To explain. Say you started a study on statins where you most wanted to look at the effect on overall mortality – whether taking statins meant more people were alive at the end of the study, than those taking a placebo. In this case overall mortality would be the ‘primary end-point’.

You could also measure other outcomes, or end-points. For example, you see how many people were admitted to hospital with angina, or how many people needed an angiogram and/or stent. Or how many people suffered a non-fatal heart attack or stroke. You can, in fact, measure many different things. These would usually be called secondary end-points.

Up until fairly recently, if you failed to reach your primary end-point – the term normally used for this sorry state of affairs would be ‘failed to reach statistical significance’ – you didn’t need to let anyone know. You could just say. ‘Oh look, the number of episodes of angina was significantly reduced, as was hospitalisation for chest pain and the rate of non-fatal strokes.’ Success!

Man on Clapham omnibus:          ‘But, but, I thought you said the trial was going to look at overall mortality.’

Pharmaceutical company:           ‘How do you know that, we never told anyone what the primary end-point would be.’

Yes, I know, pharmaceutical companies cannot speak. But you get the general idea.

Now, if you start trawling around your data, you can almost always find something somewhere got better. And if something else got worse, you can just fail to mention it. Essentially, therefore, unregistered clinical trials are not worth the paper that they are written on. Especially, of course, if they never got written on any paper at all.

In the year 2000 the major US group the National Heart, Lung, and Blood Institute (NHLBI) decided that any studies they were going to fund (these are non pharma company studies) must register all end-point/primary outcomes, before the study started. This means that the trial investigators could not manipulate the results post-hoc.

A group of researchers recently looked at 55 large clinical studies funded by the NHLBI between 1970 and 2012 to see if the transparency rules had made any difference. What they found should shake the foundations of medical research…but it almost certainly won’t:

  • 57% of studies (17/30) published before 2000 showed a significant benefit in the primary outcome
  • 8% (2/25 trials published after 2000 showed a significant benefit in the primary outcome

As the researchers said ‘The requirement of prospective registration in is most strongly associated with the trend towards null clinical trials. The prospective declaration of the primary outcome variable required when registering trials may eliminate the possibility of researchers choosing to report on other measures included in a study. Almost half of the trials [published after 2000] might have been able to report a positive result if they had not declared a primary outcome in advance.1

Pharmaceutical companies have been asked to register trials since 2005.

At this point I am going to try and join two thoughts together. Almost every study done on blood pressure lowering, blood sugar lowering and cholesterol lowering was done before the year 2005. I only choose these three areas as they are the three area of maximum drug prescribing in the world. Billions upon billions are spent in these areas, hundreds of millions are ‘treated’.

The evidence used for this mass medication of the Western World is demonstrably, horribly, biased. Had companies been forced to register their trials prior to publication, positive results would have been reduced by at least 49%. Almost certainly far more. You could put this another way around and say that it very likely that only 8% of studies would have been positive.

We do not know which trials would have been positive, or which negative. Yet we have based the entire edifice of drug treatment, of hundreds of millions of people, on unreliable nonsense. The study in PLOS is only the latest demonstration of this fact. The database of medical research – everything until at least 2005 is a gigantic festering mess. It needs to be stripped out and cleansed.

Do you think this is too strong?

Well I shall now quote Dr Marcia Angell, Dr Richard Horton and Dr Richard Smith. Editors of, respectively, the New England Journal of Medicine, the Lancet and the British Medical Journal. The three highest impact factor journals in medical research.

It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgement of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as editor of the New England Journal of Medicine.’ Marcia Angell.

‘The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue. Afflicted by studies with small sample sizes, tiny effects, invalid exploratory analyses, and flagrant conflicts of interest, together with an obsession for pursuing fashionable trends of dubious importance, science has taken a turn towards darkness.’ Richard Horton

‘The poor quality of medical research is widely acknowledged, yet disturbingly the leaders of the medical profession seen only minimally concerned about the problems and make no apparent efforts to find a solution.’ Richard Smith

Who, in a position of power, will finally wake up and realise that the vast database of medical research stinks of bias and manipulation. Who can we call upon to take up the gigantic and painful task of clearing out the Augean stables?


Four legs better

I spend far too much of my life reading about heart disease and heart disease research and suchlike. As a consequence of this I also consider myself something a ‘Kremlin watcher’. I am always on the lookout for the subtle, carefully crafted and coded messages that are allowed to escape into the outside world from the inner enclaves of power in the medical establishment.

Once something interesting appears, I then try to work out what game is afoot. What you have to recognise is that even the most apparently innocent announcement is crammed with hidden meaning:

Statement:                   ‘Comrade Yushkin has been promoted to the Department of Internal Affairs.’

Interpretation:              ‘Comrade Yushkin has made too many enemies and he has been stabbed in the back by those he thought were friends and kicked out of the Politburo. He is now going to languish in a backwater for the rest of his miserable, pointless, political career. So, for those who thought Yushkin was a rising star…tough.’

Try this one for size:

‘Some prominent cardiologists have questioned the 2013 guidelines, but the ACC and AHA have shown little appetite to return to LDL targets. “LDL may or may not correlate to cardiovascular outcomes,” Dr. Kim Allan Williams, president of the ACC, told Reuters last week1.’

This little nugget was part of a news story about the dreaded PCSK-9 inhibitors, carried by the Reuters news agency. These are blockbuster cholesterol lowering drugs that are descending upon humanity.

However, that is a side issue for the moment. I think we need to return to the comment. ‘LDL may or may not correlate to cardiovascular outcomes.’ Nine little words that you could pass over without really noticing they were there. I would, however, suggest you paid them a little more heed.

The American College of Cardiology (ACC) is at the very epicentre of conventional thinking about heart disease. Now the president…. Kim Williams, el Presidenté himself, has made this statement. “LDL may or may not correlate to cardiovascular outcomes,”

You may think, oh well, little slip of the tongue, nothing to see here, move along. Oh no, absolutely not. Whilst I would be amongst the first to criticise and castigate the ‘experts’ in charge of cardiovascular disease research. There is one thing I would never accuse them of, and that is of being careless.

There is no way on earth that this comment would have been made by mistake. It would have been thought about very carefully indeed. Equally, if Kim Allan Williams had thought he was being quoted in error, he would have asked the journalist to obliterate that statement. Before any interview he would almost certainly demand editorial control over copy. I know I always do.

So, what are we looking at here? I believe that what we are looking at here, ladies and gentlemen, is a major repositioning manoeuvre. For year after year we have been told that a raised LDL is the most important causal risk factor for heart disease.

However, when the latest ACC/AHA (American Heart Association) guidelines came out in 2013 there were no longer any targets for LDL lowering. If someone was at high risk for cardiovascular disease suddenly, lo and behold, you just gave a high dose statin. You did not need to measure what happened to the LDL level, you just prescribed the statin and that was that.

In one way this changed nothing at all, in another way it changed everything. What we had here was an admission, though no-one will admit it, that statins reduce the risk of cardiovascular disease through mechanisms other than LDL lowering. This was shortly followed by the AHA admitting that cholesterol in the diet has nothing to do with raising cholesterol and/or causing heart disease.

More recently several papers have come out clearly demonstrating that saturated fat in the diet has nothing to do with cardiovascular disease. In case you missed it, this paper was in the BMJ last week….

‘Russell J. De Souza, ScD, RD, from McMaster University, Hamilton, Ontario, Canada, and colleagues published their synthesis of observational evidence online August 11 in the BMJ.

Consumption of saturated fats is not associated with all-cause mortality, cardiovascular disease, coronary heart disease (CHD), ischemic stroke, or diabetes2.’

Now the president of the ACC is telling us that LDL may or may not correlate to cardiovascular outcomes. You would have to say that the diet-heart/cholesterol hypothesis is beginning to look a little threadbare right now. One might even say it is dead. However, like the biggest, stupidest dinosaurs, it will stumble about crushing people underfoot for several years before it finally crashes to the ground.

When it does, finally, expire we will have found something very interesting has happened. The ‘experts’ who ruthlessly promoted the diet/heart cholesterol hypothesis a.k.a ‘absolute bollocks’ for the last ‘few decades will have moved their position completely. They will no longer be coaching us all to chant ‘four legs good, two legs bad’. We shall have a new slogan:

‘Four legs good, two legs better.’

Those in power will remain in power. Thus endeth today’s lesson.




Turning diabetes upside down

I have written about diabetes quite a few times. Thus far, I must admit, I have kept the discussion relatively conventional. Anyone who has read my previous blogs may not think so, but compared to what I really believe, everything has taken place close to the middle ground. Time, I believe, to start turning diabetes upside down, give it a good shake, and see what it looks like from a completely different angle.

Some of you may have watched Professor Unger’s fascinating YouTube lecture on type II diabetes. If not, here it is. I recommend it1. To keep things as simple as possible, his view is that the key hormone that drives diabetes is glucagon, not insulin. Indeed, by focussing almost entirely on insulin and sugar/glucose, we cannot understand what is going on with type 2 diabetes, as we are only looking at a small part of the picture. In addition, we are looking at it the wrong way round.

He is, of course right. Now, stop, stand on your head…

Ready, here we go. The critical requirement of human metabolism is to ensure that there is a high enough level of glucose to power the brain. Without sufficient glucose the brains shuts down and dies. Not all the cell types in the brain need glucose and all brain cells can also metabolise ketone bodies, to an extent. (Ketone bodies are synthesized in the liver from fatty acids). However, the bottom line is this. If your blood sugar level drops below about 2mmol/l, and stays there, you will enter a hypoglycaemic coma and die.

Which means that it is absolutely critical that this does not ever occur. In order to prevent this happening we have a hormone that keeps blood sugar from dropping this low. It is called Glucagon. It is produced in alpha-cells in the pancreas (right next to where insulin is produced). How does it work? Here is a short, standard, explanation from

Glucagon plays an active role in allowing the body to regulate the utilisation of glucose and fats.

Glucagon is released in response to low blood glucose levels and to events whereby the body needs additional glucose, such as in response to vigorous exercise.

When glucagon is released it can perform the following tasks:

  • Stimulating the liver to break down glycogen to be released into the blood as glucose
  • Activating gluconeogenesis, the conversion of amino acids into glucose
  • Breaking down stored fat (triglycerides) into fatty acids for use as fuel by cell

Of course, this statement from is true. However, I would ask you to review ten of the words again, and think about them for a moment or two. ‘Glucagon is released in response to low blood glucose levels.’

Now, you almost certainly do not recognise it, but here is the crux of the entire blood diabetes/insulin /glucose discussion. Those ten words, innocent thought they may seem, have been driven by upside down thinking, and represent the exact point where things go wrong.

This not deliberate, indeed the concept is so familiar, so unquestioned, that you almost certainly have no idea what I am talking about. At this point you are probably wondering, ‘what the hell is Kendrick on about here?’

Indulge me for a moment whilst I re-frame that statement.

As it stands, we are given to believe that glucagon is the reactive hormone, only produced when blood sugar levels drop. Insulin, on the other hand, is the key hormone, the controller of metabolism and blood sugar levels. Glucagon only activates to increase blood sugar after insulin (or exercise) has caused it to fall too far. Which is why we have these ten words: ‘Glucagon is released in response to low blood glucose levels’

You think this is not important, just playing with words. Then try this alterative statement on, and see how it fits. ‘Glucagon keeps the blood sugar level high enough to ensure that the brain has sufficient glucose to function. If, however, the glucose levels rise too high, the body produces insulin to counteract the effects Glucagon. This brings blood sugar back down.’

In one way, I am saying exactly the same thing as said. Looked at in another way, however, and I have just changed everything. No longer is insulin the key hormone, it is now ‘merely’ the subservient hormone, produced to counter the effects of too much glucagon.

Once you have changed your thinking around this way, it should come as absolutely no surprise to find the following. If you have a mouse, and you destroy its beta-cells (insulin producing dells in the pancreas) it will become diabetic, and die. However if you get rid of the glucagon producing cells as well, the animal will not have a high sugar level and will not be diabetic – despite having no insulin at all. It will also appear to be completely healthy.

In addition, if you give such a mouse, that cannot produce either glucagon, or insulin, a glucose ‘meal’ the blood sugar level will rise, and then fall, in pretty much the same pattern as a ‘normal’ mouse. Ergo, the body does not need insulin to keep blood sugar levels down. There are other mechanisms that the body can use. I am sure that having insulin help to optimize blood sugar control, but it is far from essential.

Of course, this type of experiment has never been done in a human – for obvious reasons. However, I do not think there is any reason to doubt that the results would be pretty much the same. Which means that, crikey, insulin is not required for blood sugar control… If I tell my medical colleagues this they absolutely and completely refused to believe it. However, it is true. They choose not to believe it, because it undermines what they think is true.

In fact they think what almost everyone else things. Which is that the insulin/glucose: glucose/insulin model of diabetes is correct. It certainly appeared to explain what we saw in type I diabetes, whereby you gave insulin to those with high sugar levels [those who could not produce insulin, the underlying cause of type I diabetes] and they were ‘cured. Whilst the discovery of insulin and the treatment of type I diabetes was a medical triumph, it is also where the thinking went wrong.

It blinded everyone to fact that insulin is not the key hormone in glucose metabolism. It is simply there to act as a negative feedback mechanism to control glucagon. Unfortunately, since Banting Best and MacLeod, we have become stuck with the insulin/glucose paradigm.

If the blood sugar rises, whatever the underlying cause, we call it diabetes and drive it down…sigh. The more it rises the harder you drive it down….Sigh. The lower you get the blood sugar down the better…sigh. How do you do this? Mainly by giving drugs that force beta-cells to produce more insulin, or by adding in drugs that work with insulin to lower blood sugar levels, or by injecting additional insulin.

How well does this work? Some of you will have heard of the ACCORD study, others will not. In this study researchers, tried to force blood sugar levels down as far as possible using intensive treatment. They found the following:

‘Until last week, researchers, doctors and every medical professional has believed for decades that if people with diabetes lowered their blood sugars to normal levels, they could not only prevent the complications from diabetes, but also reduce the risk of dying from heart disease. But the Accord Study, (for Action to Control Cardiovascular Risk in Diabetes), a major NIH study of more than 10,000 older and middle-aged people with type 2 diabetes has found that lowering blood sugar actually increased their risk of death.2

There is one other way of lowering blood glucose, by using insulin ‘sensitising’ drugs. In diabetes most doctors look at metformin as the wonder drug. This drug improves ‘insulin sensitivity’ i.e. it helps to reduce insulin resistance. It is the absolute mainstay of type 2 diabetes treatment. Once again, however, it is targeted at purely the insulin/glucose model:

‘Metformin has been the mainstay of treatment for type 2 diabetes since 1998 when the UK Prospective Diabetes Study showed reduced mortality with metformin use compared with diet alone. Recently a French meta-analysis of 13 random controlled trials questioned the central role of metformin in the care of patients with diabetes. In this meta-analysis, in which 9560 patients were given metformin and 3550 were given conventional treatment or placebo, metformin did not significantly affect the primary outcomes of all cause mortality or cardiovascular mortality. The secondary outcomes—myocardial infarction, stroke, heart failure, peripheral vascular disease, leg amputation, and microvascular complications—were also unaffected by treatment with metformin.3

Today we have a virtually unquestioned model of diabetes that is very simple, and easy to understand. It should be simple to understand as it works like this. If the blood sugar goes up, the body produces insulin to lower it. If the blood sugar goes down, the body produces less insulin and the sugar level goes up.

This has meant that, if you find someone had high blood sugar levels, you basically hit them with insulin. I call insulin the ‘glucose hammer’ and, as a wise man once said. ‘If the only tool you have is a hammer, pretty soon everything starts to look like a nail’.

Reducing glucagon…. anybody?




A tale of mice and men

(PCSK9 and diabetes)

I look into my crystal ball and I see…. I see another wave of diabetes. Yes, the great Nostrokendrickos has spoken. Why do I predict this? Well, I see those given PCSK 9 inhibitors developing diabetes. I see the pharmaceutical companies telling us that this was completely unexpected, a paradox, and not clinically relevant anyway. Hold on…. no the vision is fading….it is gone.

Being an old fashioned type of person I have this strange belief that the body does not produce complex enzymes for a laugh. It takes a lot of energy and resources to make enzymes, or any another form of highly structured protein. If there is no need for them, and what they do, the body sighs with relief and stops making them. Then, over the years, evolution gets rid of the enzyme altogether. It’s kind of how evolution works.

So when we do have an enzyme Proprotein convertase subtilisin/kexin type 9 (PCSK9) I think: What is its purpose? Can it simply be there by mistake? To be frank, I am not entirely sure what the purpose of this enzyme is, but I now know that if you do not have it, bad things can happen. Here is a study which looked at what happens to mice with no PCSK9:

‘Proprotein convertase subtilisin/kexin type 9 (PCSK9), a liver-secreted plasma enzyme, restricts hepatic uptake of low-density lipoprotein (LDL) cholesterol by promoting the degradation of LDL receptors (LDLR). PCSK9 and LDLR are also expressed in insulin-producing pancreatic islet b-cells, possibly affecting the function of these cells. Here we show that, compared to control mice, PCSK9-null male mice over 4 months of age carried more LDLR and less insulin in their pancreas; they were hypoinsulinemic, hyperglycemic and glucose-intolerant; their islets exhibited signs of malformation, apoptosis and inflammation. Collectively, these observations suggest that PCSK9 may be necessary for the normal function of pancreatic islets1.’

Sorry, I realise that the language is a bit technical, so here is a quick interpretation.

  • PCSK9 is an enzyme that degrades/destroys LDL receptors, so cells cannot absorb so much LDL (a.k.a. ‘bad’ cholesterol)
  • Without PCSK9, beta-cells in the pancreas (where insulin is made) absorb too much LDL
  • These LDL ‘overfilled’ beta cells were found to be malformed, dying (apoptosis) and inflamed
  • Mice without PCSK9 which had these ‘overfilled’ beta-cells were also glucose intolerant, did not produce enough insulin and were hyperglycaemic a.k.a. there were diabetic

That was mice, what of men? (And, of course women). Well, if we look at people with familial hypercholesterolemia (FH), they have a lack of LDL receptors, or the receptors don’t work so well due to malformations, or both. Therefore, you get less LDL inside cells, including beta-cells. Therefore:

‘In the cross-sectional analysis from the Netherlands, patients with familial hypercholesterolemia were found to have a 51% lower odds of having type 2 diabetes compared with relatives without the cholesterol disorder, and diabetes prevalence varied by gene mutation type…. Hovingh and colleagues hypothesized that this reduced risk occurs because pancreatic beta cells in people with the condition have decreased cholesterol uptake and improved function and survival2.’

Hovingh was almost certainly right.

Now some people will, no doubt, grab hold of this research to tell us that ‘As we told you all along LDL is dangerous and damaging, it even causes diabetes by harming beta-cells.’ I am sort of waiting for an ‘expert’ to tell us this. Maybe they already have. At which point I shall approach them from behind, then hit them repeatedly with a large wet kipper. I shall then announce, with great satisfaction…

‘No, you idiot, what this shows us is that excess LDL inside cells is damaging and dangerous, but that has absolutely nothing whatsoever to do with having a high LDL level in the bloodstream… idiot.’

Anyway, adding this information together with the study on mice, it seems that the basic function of PCSK9 may simply be to ensure that cells do not absorb too much LDL from the bloodstream, thus protecting them from: malformation, inflammation and death. It certainly seems to be true of beta-cells in the pancreas. Is it true for all other cells – who knows, but it is a bit worrying is it not?

What is certainly true is that PCSK9 inhibitors will almost certainly increase the risk of diabetes, to an even greater extent than statins. This seems entirely predictable; in fact I predict it now. I also predict that the increased risk of diabetes will take years to emerge. This will be for various reasons that I would like to go into, but fear libel suits.

However, when this adverse effect does eventually emerge I know that it will greeted with astonishment and surprise by the ‘experts’ and, at least in public, by the pharmaceutical companies marketing these drugs. Although I am perfectly certain that they know all about this research… they always do. They ain’t stupid.

The great Nostrokendrickos has spoken. Put this article in a time capsule, to be opened when PCSK9 inhibitors are found to cause diabetes.


1: Majambu Mbikay, Francine Sirois, Janice Mayne, Gen-Sheng Wang, Andrew Chen, Thilina Dewpur, Annik Prat, Nabil G. Seidah, Michel Chretien  Fraser W. Scott: ‘PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities.’ FEBS Letters 584 (2010) 701–706


P.S. I wonder what other research they are aware of? I think I might go and find out.

Here they come – take cover

Apart from Rosuvastatin/Crestor, all the statins have lost patent protection, and so the world has changed. I probably need to explain a bit about Patent Protection. If a pharmaceutical company discovers a new, potentially beneficial chemical/drug, it can claim patent protection for twenty two years from the date of first registration of that new chemical compound. Then the clock starts ticking.

So you need to get going to do all sorts of testing on your new chemical to make sure that it actually does something considered useful e.g. kill bacteria, or attack cancer cells, or control progression of rheumatoid arthritis. You also need to ensure it doesn’t kill people, using the sort of doses you would give to achieve a clinical effect. You should ensure that it doesn’t react badly with other commonly used drugs, and on and on.

This all takes time, and costs a lot of money. Companies tell you it costs hundreds of millions to get a drug to market, perhaps even a billion, but their figures are always held tightly to their chest. It certainly costs a lot. How much exactly…no idea. As for the amount of time? Probably about eight to ten years from discovery to launch.

After launch, the companies then have around twelve to fifteen years to sell the drug as hard as they can, whilst they have an effective monopoly. During this window of opportunity they can fix the price wherever they like. This is usually bang on what medical systems think they can afford, or just a sneaky bit more. ‘Oh go on, you know you want it.’

However, once patent protection is gone, generic drug manufacturers that have been waiting in the wings like vultures, can make that exact same drug and sell it, in competition with the company that discovered the drug in the first place – or any other company that wants to make it.

Because generic companies have not had to go through the hugely expensive drug development process, their costs are much less, therefore they can afford to sell the drug far cheaper and still make money. At which point the big companies such as Glaxo, or Pfizer lose interest. Their business model requires enormous profits to support their equally enormous overheads. Selling drugs at a 5% margin is not what they do. They have a workforce of tens of thousands to support.

Getting back to the point in hand. Statins are now, effectively, out of patent. They were the most profitable drugs in the history of the pharmaceutical industry. Lipitor/atorvastatin made tens of billion dollars in profit each and every year it was in patent, and turned Pfizer into the biggest drug company in the world. But statins are now cheap as chips.

Various attempts have been made to combine statins with drugs such as ezetimibe and carry on the patents – you get extra protection for combinations. A few billion has been added here and there. However, the seam of gold has effectively been hollowed out.

So what to do? Shrug your shoulders and move on to a different therapeutic area. Or…? Over the years, billions upon billions have been spent making the statin market into something absolutely massive. This market could also be described as the ‘cholesterol lowering market.’ Everyone, or just about everyone, knows their cholesterol level. They have been trained to be terrified of having a high cholesterol level, and they want it brought down. Bell rings, dog salivates.

In parallel with successfully raising the spectre of having a high cholesterol, the level of cholesterol considered ‘high’ has also been inexorably driven down. Years ago a high level was something over 7.5mmol/l (~300mg/dl). In Europe anything about 5.0mmol/l is now consider high. In the US it is 5.2mmol/l, otherwise known as 200mg/dl (the US and the rest of the world use different units of measurement). However, even that has been further lowered. In those at ‘high risk’ the cholesterol level needs to be below 4.0mmol/l.

The average cholesterol level of human is about 5.5mmol/l (very broad brush stroke), which means that we find ourselves in the weird, yet unquestioned situation, where around 85% of the entire population of the world is now considered to have a high cholesterol. Boy that is some market. Almost every one alive, and with a pulse, should be taking a statin. And people almost demand them ‘I must get my cholesterol level down, now!’

As a pharmaceutical company you certainly do not want to walk away from that, the land of milk and honey…and money. A perfectly prepared market, desperate for anything that lowers cholesterol. Even gaining one percent of that market would mean about twelve million people worldwide… in counties rich enough to pay. If your drug costs a thousand pounds, dollars, or Euros a year, that is still twelve billion pounds dollars or Euros each and every year. Twelve billion profit a year. Be still my beating heart.

And to access that market, all you need to do is to find another way of getting cholesterol down. [Using new drugs that can be patented, and sold at a price that makes a whopping profit]. As a quick aside, the HDL ‘good’ cholesterol raising agents all crashed and burned before you ever knew they existed. They raised HDL and also raised the rate of death from heart disease at the same time. Ooops. So maybe HDL isn’t ‘good’ cholesterol after all. Shhhh, let that be our little secret.

So the industry looked around, and studied everything they could, and they have come up with Proprotein convertase subtilisin/kexin type 9 inhibitors. However, you must ensure that you don’t ever call them that, or everyone’s eyes will simply glaze over followed rapidly by sleep. So this moniker has been shortened to PCSK9 inhibitors. Very catchy.

How do they work? Put as simply as I can. Low Density Lipoprotein (LDL) a.k.a. ‘bad’ cholesterol I is removed from the circulation by binding to an LDL receptor, which is then pulled into the cell. The LDL is ‘unpacked’ and the receptor broken down by PSCK9. However, if you block PCSK9, the receptor lives to fight another day. It is sent back out to the surface of the cell, binds to LDL again and pulls it in. With more and more receptors waving about, the LDL is more rapidly removed from the circulation and the ‘cholesterol’ level drops.

It is true that if you give people a PSCK9-inhibor the LDL/cholesterol levels certainly drop very dramatically. Even more so than with statins. Hoorah! LDL levels can reach virtually zero. Hoorah! Drool! Kerching! As you might expect, a number of pharmaceutical companies have decided to develop their own, very slightly different versions, of PCSK9 inhibitors, and they will all be launching shortly. The one hitting Europe and the US first is likely to be Praluent. Made by Sanofi and Regeneron. It will be given a more catchy brand name when it launches. Cholestegon, or something of the sort.

Of course the hype is going to be monstrous. Newspaper front pages will hail these drugs are life savers, super-statins, Governments must fund them, blah, blah, blah. Billions upon billions will be spent marketing them. Well, you have to speculate to accumulate don’t you.

Experts a.k.a. rent-a-quote dancing bears will do their thing…. ‘Roll up, put money in the jar and the bear will sing and dance any tune you like…’ Yes, experts will dance the tune, and sing the songs required of them by the industry….kerching, kerching, kerching, ker-bloody-ching. ‘Why can’t I see my reflection in the mirror any more mummy?’

Papers will appear in journals that will be reproduced, and repackaged, to be presented to doctors; giving all the scientific reasons why PCSK9-inhibitors need to be used. There are, however, one or two little problems to be resolved.

  • Statin hype
  • Cost
  • Injectable
  • No outcome data

Statin hype

Having spent billions convincing everyone that statins are uniquely effective, have no side effects, and also cure cancer, bacterial infections, HIV, the Ebola virus, bad breath, poor conversational ability, and other things too numerous to mention, your main competitor is the ‘wonder’ drug you created in the first place. Which is also now very cheap.

So, dear pharmaceutical companies, you are going to have to attack statins to create some space in the cholesterol lowering world. We can already see this happening, with sad looking ‘experts’ confirming how terribly disappointing it is that some people just cannot tolerate statins…when I say some, I mean about 25%. ‘But I thought you said statins had no adverse effects.’

Expert: ‘I know, that is what I once thought, but it seems…sob…that many patients have difficulties…sob. Sorry, I am very emotional about all this.’

Pharmaceutical company executive whispers:It’s OK, you can have your money now. There there, don’t get so worked up. You can have your swimming pool.’


Statins now cost about thirty pounds a year. PCSK9 inhibitors will be in the region of five to ten thousand – so I have been told. If so, health authorities are going to be very, very, unhappy. They will see budgets spiralling out of control. This could kill these products stone dead in many countries. However, the companies will be very careful to ensure that they will only be looking for them to be used in a very small sub-set of high risk, statin intolerant patients. [And if you believe that, you will surely believe anything].


These drugs impact on processes within the cell nucleus itself, so they are monoclonal antibodies. They cannot be taken orally, as they would be broken down in the stomach/gut, so they have to be injected. Every two weeks or so, you will need to have an injection. This can be painful and also inconvenient. This will limit uptake. Then again, some people believe that if you inject something, it must be more powerful.

No outcome data

Whilst PCSK9 inhibitors definitely lower LDL, there is no data on their effect on cardiovascular mortality, or any other form of mortality either. They are launching purely on their cholesterol lowering ability. A surrogate outcome. This, of course, saves the tiresome and costly requirement of demonstrating that they actually work. But it may make it rather tricky for them to gain full approval without any proof of efficacy. Or maybe not.

Despite the problems listed above these drugs are coming. Will they be a success? Well those working in pharmaceutical companies are not stupid. They would not be spending billions unless they were pretty certain of success.

What will success look like? Well, frankly, I am sure that they would be happy with one percent of the population taking PCSK9 inhibitors. That would be about three million in the US, four million in Europe, five million in the rest of the world – in countries that have enough money to pay. This is a total market of one hundred and twenty billion pounds/dollars a year. Not bad. Three drugs sharing one hundred and twenty billion is forty billion each, per year, for fifteen years. That is $600Bn lifetime drug earnings.

If they were to succeed in squeezing the market up to ten per cent, that would be a market of one thousand two hundred billion a year. Greater than the GNP of almost every country in the world, up to about Canada. My guess is that they will get to about two to three percent. This market will consist of those with very high cholesterol levels who are ‘statin intolerant’. Yes, be ready for the phrase ‘statin intolerant’, it is how those poor unfortunates who cannot take statins due to adverse effects will be described in future.

Speculating wildly, if they did manage to get everyone on a statin to convert to a PSCK9 inhibitor then the entire GNP of nations would be gone. In the UK, twelve million, or so, are ‘eligible’ for statins. Twelve million times ten thousand is one hundred and twenty billion pounds. That is slightly more than the entire budget of the NHS. Money well spent?

You have been warned.

What happens to the carbs – part II

My interest in nutrition began many years ago as part of my over-riding interest in cardiovascular disease. This means that, unlike many other people, I backed into this area with no great interest in the effect of food on health. For most doctors nutrition takes up about an hour of the medical degree course. We are pretty much given to understand that it is of little medical significance. Eat a balanced diet…end of. I also paid nutrition about that much heed.

However, because of the power and influence of the diet/heart hypothesis I felt the need to understand more about this whole area, and how the system of digestion and metabolism actually worked. At first my interest was purely to find out if there was any clear and consistent association between diet and cardiovascular disease (which I shall call heart disease from now on, as it is simplest to do so).

Like many others, before and since, I could not find any such association. Nor could I find any biochemical or physiological reason why saturated fat, in particular, could cause heart disease. That issue, of course, represents a long and winding road that I am not going down here.

However it did not take long before I became side tracked by the very powerful and consistent association between heart disease and diabetes. People with diabetes have far higher rates of heart disease than people who do not. In the case of women with diabetes, the increase in risk hovers around five times the rate of non-diabetics. So it became clear that I would need to understand diabetes, if I was going to fully understand heart disease.

This led me into the looking at the underlying causes of diabetes (type II). At first it seemed blatantly obvious that type II diabetes was primarily due to insulin resistance (it is far less clear now). In its simplest form, insulin resistance means that you need a higher level of insulin to drive down blood sugar levels, because something is ‘resisting’ its effects. Of course, like everything else, it is rather more complex than this, but I will leave it at that for now.

It also became clear that you can have mild/moderate insulin resistance for many years before you develop frank diabetes. Confronted with resistance to its effects, the body simply increases insulin production to keep blood sugar within the normal range. In this state, sometimes called ‘pre-diabetes’ you do not actually have a high blood sugar, especially not in the fasting state. This, of course was when most blood sugar level measurements were taken. Yes guys, look for a metabolic condition when it isn’t actually visible …very sensible.

However, mild to moderate insulin resistance, even if blood sugar levels are not consistently raised, is not benign. It is associated with a whole series of other metabolic abnormalities such as: central obesity, raised VLDL/triglycerides, low HDL, high blood pressure, high levels of blood clotting factors – to name but a few. In addition you can also find higher sugar levels, and higher insulin levels in the post-prandial state (after eating). Most importantly, to my mind, mild to moderate insulin resistance is also associated with a far higher rate of heart disease.

In the early days, ‘pre-diabetes’ came under many different monikers. Just to give you four:

  • Reaven’s syndrome
  • Syndrome X
  • Insulin resistance syndrome
  • Metabolic syndrome

This caused a lot of initial confusion, but once I chased them all down, it because clear that these different names were simply describing the same phenomenon, which is probably best described as insulin resistance syndrome. Although this title carries its own problems.

The next question, of course, is what causes the insulin resistance? The wisdom was, and remains, that it is caused primarily by obesity. This was based on the observation that, as people got fatter, the risk of diabetes increased almost exponentially. One paper I read many years ago stated that younger obese women had around forty times the risk of diabetes, compared to women of normal weight. That is what you call a strong association. Perhaps causation may even be whispered?

In short, if you added together what was clear about diabetes and insulin resistance, you got a model of type II diabetes which looked pretty much like this:

  • You eat too much food
  • You put on weight
  • As you put on weight you become more and more insulin resistant
  • At first you will develop insulin resistance syndrome
  • If you keep putting on weight you will become so insulin resistant that you will develop frank type II diabetes

I call this the ‘blowing up a balloon’ theory of diabetes. As a balloon expands you have to blow harder and harder to overcome the resistance. As you get fatter and fatter you need more and more insulin to force fats into fat cells. As with many things in medicine this is a nice simple story. It is also very easy to understand, and it is tantalisingly close to being correct

As always, however, when presented with a model like this, my immediate reaction is to try and smash it to bits with contradictory evidence. I figure that any theory that can withstand repeated assault is likely to be correct. On the other hand.

I started by looking at the extremes, as I always do. Beginning with the most obese group people on the planet earth, namely Sumo wrestlers. I wanted to know how many of them have diabetes, and it did not take long to discover that, whilst in training, none of them have diabetes.

I then searched for the opposite end of the spectrum. Were there people with no adipose tissue, and how many of them had diabetes? Surprisingly, there is one such group, the least obese people on earth. They are those with Beradinelli-Siep lipodystrophy. This is a genetic abnormality which means that these poor unfortunates have almost no fat cells. How many of them have type II diabetes? Well, all of them actually.

I then looked for the population with the highest rate of diabetes in the world. This happens to be the Pima Indians of North Mexico/Southern US. I have seen figures reporting that over 80% of adult males Pima Indians have type II diabetes. It may even be more. And yes, they are very obese.

However, there are two other very interesting facts about the Pima Indians. First, they have a very low rate of heart disease. Or they did last time I looked. Perhaps most importantly, in their youth, when they are not obese, they produce far more insulin in response to food than ‘normal’ populations. Or, to put this another way, they are hyper-insulinaemic before they are obese, and long before they become diabetic. So their excess insulin production is not a result of becoming fatter. The causal chain is the other way around.

I have found that if you speak to most doctors about these facts, a look of complete incomprehension passes over their faces. ‘That cannot be right.’ Of course if you believe in the ‘blowing up a balloon’ model of diabetes, then the Pima Indians, Sumo Wrestlers and those with Beradinalli-Siep lipodystrophy do not make any sense. However, in science, when observations do not fit your hypothesis, it is the hypothesis that needs to change, not the facts.

Just to summarize these ‘paradoxical’ facts:

  • You do not need any fat cells to develop diabetes/if you have no fat cells there is a 100% probability that you will be diabetic
  • You can be very , very, obese and not have diabetes
  • You can have increased insulin production long before you become obese (and/or insulin resistant). You become obese later

Just to remind you of the current model.

  • You eat too much
  • You get fat
  • As you get fat you become more insulin resistant
  • In order to overcome this resistance you produce more insulin
  • Eventually you cannot produce enough insulin, the system ‘burns out’ and you develop type II diabetes

Where and how can the paradoxical facts be fitted? The answer is that they cannot. Ergo, the model is wrong. However, luckily, there is another model that fits all the facts. One that I prepared earlier:

  • You produce too much insulin
  • This forces your body to store fat
  • You become obese
  • At a certain point insulin resistance develops to block further weight gain
  • This resistance becomes more and more severe until…
  • You become diabetic

This model explains the Pima Indians. Can Sumo wrestlers be fitted into this model? Yes, with a couple of addendums. Sumo Wrestlers eat to become fat, because added mass provides a competitive advantage if you are trying to shove someone else out of a small ring, before they do it to you.

To achieve super-obesity, they wake up, train for two hours, then eat as much as they can of a high carbohydrate, low fat, broth. They then lie about for a few hours allowing the high insulin levels created by the high carbohydrate diet to convert excess sugars to fat, storing this in adipose tissue. Later on they train very hard again, then eat, then sleep. Rpt.

The reason why they do not become diabetic is on this regime is simply because they exercise very, very, hard. They burn up all the sugar/glycogen stores in the liver and muscle whilst exercising, which means that when they eat, the sugar(s) can – at least at first – be easily stored in muscle and liver (so there is no insulin resistance to overcome). However, once these guys stop training, things do not look so good. Diabetes lurks..

Those with Beradinelli-Siep lipodystrophy have the reverse problem to Sumo Wrestlers. Because they have no fat cells there is nowhere to store excess energy to go. If they eat carbohydrate/sugar, the first 1,500 calories can be stored as glycogen – after that there is nowhere left. If the liver converts sugar to fat, there is nowhere for that to go either. So, you get ‘back-pressure’ through the system. It doesn’t matter how high the insulin level gets, if you have nowhere to store energy you have nowhere to store energy. End of.

Whilst those with lipodystrophy cannot tell us much about diabetes and obesity in ‘normal’ people. This condition does make it very clear that diabetes – insulin resistance, high insulin and high sugar levels – is primarily an issue with energy storage and how the body goes about this storage, and the role that insulin plays. If there is somewhere for excess energy to go easily, insulin levels will not go up, and nor will blood sugar levels.

But what of ‘normal’ people. Can normal people be fitted into the updated model of type II diabetes? Well, of course, they can. But you need another step in the new model, the first step. Which means we have a new causal chain, and it looks something like this ‘You eat too much carbohydrate.’ Adding in this step gives us the new model:

  • You eat too much carbohydrate/sugar
  • You produce too much insulin
  • This forces your body to store fat
  • You become obese
  • At a certain point insulin resistance develops to block further weight gain
  • This resistance becomes more and more severe until…
  • You become diabetic

The best thing about this model is that it works. It is not contradicted by Sumo Wrestlers, Pima Indians of those with lipodystrophy. It explains the association between obesity and diabetes, and how insulin resistance develops. It may not be perfect, but it is a bloody site better than the simplistic model we have got. The one that says, if you eat fat, you will get fatter, then diabetic…. Bong! If you are diabetic you should eat carbohydrate and sugar, not fat…Bong!

How long before mainstream medicine rejects this mainstream model? Another fitty years or so, I would guess

What happens to the carbs?

I have found a strange thing happens when I talk to nutritionists about the fate of carbohydrates in the human body. Professors, who shall be nameless, appear unable to admit how basic human physiology works. For example, they may concede a few steps here and there, but they will never, ever, admit to the following chain that I have described below.

1: Carbohydrates, such as fruit and vegetables, bread, pasta… and, of course, less complex sugars – such as the stuff we sprinkle on cornflakes, that we call ‘sugar’, are all turned into simple sugars in the human digestive tract before entering the bloodstream.

2: If you keep eating carbohydrate the resultant simple sugars will, at first, be stored. The human body can pack away around 1,500 calories of sugar. However, once this limit is reached, the liver will turn the rest into fat.

3: The fat that is made in the liver is palmitic acid

4: The next step is that three palmitic acid molecules are attached to a glycerol molecule, to form a triglyceride.

5: These triglycerides will then be packed into Very Low Density Lipoproteins (VLDL) and released into the bloodstream. [Beware of confusion here. For VLDLs are also called triglycerides although, of course, they are not. VLDLs contain triglycerides but they are not the same thing – even if they are called the same thing].

6: When VLDLs reach fat cells (adipose tissue), the triglyceride is stripped out and absorbed into fat cells. Which means that VLDLs gradually shrink.

7: Once a VLDL has lost a large amount of triglyceride it becomes a new, smaller, lipoprotein, which is often referred to as ‘bad cholesterol’ a.k.a. LDL (Low Density Lipoprotein).

8: LDL is taken out of the circulation, primarily, by the liver. Some LDLs are removed from the circulation by other cells around the body that need the cholesterol contained in them.

9: As can be seen, the only source of LDL is VLDL.

Here a couple of quotes from Wikipedia to confirm at least a couple of these steps:

Lipogenesis is the process by which acetyl-CoA is converted to fatty acids. The former is an intermediate stage in metabolism of simple sugars, such as glucose, a source of energy of living organisms. Through lipogenesis and subsequent triglyceride synthesis, the energy can be efficiently stored in the form of fats.

Lipogenesis encompasses both the process of fatty acid synthesis and triglyceride synthesis (where fatty acids are esterified with glycerol to form fats). The products are secreted from the liver in the form of very-low-density lipoproteins (VLDL). VLDL are secreted directly into blood, where they mature and function to deliver the endogenously derived lipids to peripheral tissues.

Excess carbohydrates in the body are converted to palmitic acid. Palmitic acid is the first fatty acid produced during fatty acid synthesis and the precursor to longer fatty acids. As a consequence, palmitic acid is a major body component of animals. In humans, one analysis found it to comprise 21–30% (molar) of human depot fat and it is a major, but highly variable, lipid component of human breast milk.

I am half tempted to leave the blog here and let you think about what all of that means for a while. However, I feel the need to make a couple of other points, in no particular order. First, I would like you to think about this fact. The form of fatty acid that the liver chooses to synthesize from sugar(s) is palmitic acid, a saturated fat. Palmitic acid is also the major component of breast milk.

Yet, despite this, we are told that saturated fats are uniquely unhealthy, and eating them leads to heart disease. Indeed, within to the very same Wikipedia article on palmitic acid we learn that: ‘According to the World Health Organization, evidence is “convincing” that consumption of palmitic acid increases risk of developing cardiovascular diseases.’

It seems that we are being asked to believe that the body naturally synthesizes a substance, palmitic acid, that actively damages our health. Not only that, but mothers choose to synthesize exactly the same form of fatty acid in their breast milk, which then increase the chances of their offspring developing cardiovascular disease.

Now just how likely does this seem…exactly? We have evolved to kill ourselves from heart disease? As Spock may have said, ‘its evolution Jim, but not as we know it.’ You would think that if polyunsaturated fats were healthy, this is what the human body might choose to make. But no, we eat super healthy fruit and vegetables and then our body, in a unique and ironic twist of fate, converts them into death dealing saturated fatty acids.

Not only that, but just to rub salt into the wounds, once the liver has synthesized these death dealing fatty acid molecules it then chooses to pack them into VLDLs which have the cheek to shrink down into LDL a.k.a. ‘cholesterol’ and these also kill us with heart disease (allegedly).

Of course, if you actually eat saturated fat, this gets nowhere near the liver. It is digested, packed into chylomicrons, and these very large lipoproteins enter the bloodstream directly through the thoracic duct. Which is a secret passage from the gut that opens out in one of the veins in your neck. When chylomicrons encounter fat cells, the fats/triglycerides are sucked out, and the chylomicron shrinks down to virtually nothing. Chylomicrons, however, do not convert to LDL and have nothing whatsoever to do with heart disease – even according to those who think saturated fat in the diet is deadly.

Yet, despite this knowledge we are continuously told, in all seriousness, that eating saturated fat raises our LDL levels and causes us to die prematurely of heart disease. [You may have noticed that cholesterol has hardly entered this discussion at any point.] When people ask me why I don’t believe in the diet/heart hypothesis, I tend to shrug and move the conversation on.

However, if I am feeling a bit stroppy I tend to reply that ‘Even if you were to believe that a raised LDL levels causes heart disease, the current diet/heart hypothesis does not, and cannot make any sense from a biological or physiological perspective.’ If you were actually looking for a substance that really could raise LDL/cholesterol levels it would have to be carbohydrates a.k.a. sugars. After all the only source of LDL is VLDL, and it is eating too much sugar that raises VLDL levels.

In short, how can it not be that carbohydrates raise LDL levels? This is what a basic understanding of lipid physiology tells us must be true. Yet, people write papers on this phenomenon in a tone of almost stunned surprise. Here for example is a paper called ‘The Effect of Dietary Carbohydrate on Triglyceride Metabolism in Humans’:

When the content of dietary carbohydrate is elevated above the level typically consumed (>55% of energy), blood concentrations of triglycerides rise. This phenomenon, known as carbohydrate-induced hypertriglyceridemia, is paradoxical because the increase in dietary carbohydrate usually comes at the expense of dietary fat. Thus, when the content of the carbohydrate in the diet is increased, fat in the diet is reduced, but the content of fat (triglycerides) in the blood rises.

This author, writing for the Journal of Nutrition, finds it paradoxical that… increased dietary carbohydrate usually comes at the expense of dietary fat….but the content of fat (triglycerides) in the blood rises. Well, what did they think would happen? That carbohydrates would turn into fairies at the bottom of the garden?

Once the liver and muscles are full of sugar (stored as glycogen – a polymer of glucose) the body can do absolutely nothing else with it, but turn it into fat – through the processes I have described earlier. This is basic, incontrovertible science.

Most people who are interested in the potential benefits of the low carb high fat diet (LCHF), have tended to look at it from the perspective of helping with controlling diabetes, and promoting weight loss. I came at the LCHF diet from my own perspective, which is heart disease.

When you understand the science you find yourself looking at the diet heart hypothesis (fat in the diet raises LDL levels, which causes heart disease) and thinking. This does not make any sense at all. Yet, such is the determination of the nutritional experts to defend their position that they never, ever, talk about ‘what happens to the carbs?’

What happens to the carbs is that they are all turned into saturated fat. This then raises VLDL levels and these, in turn becomes LDL. Yet eating carbs is supposed to be healthy, and eating saturated fat is unhealthy. Go figure.

The world of nutrition is, I am afraid, nuts.

Conflict of interest – not just about money

There is a major spat going on at present around Conflict of Interest. The New England Journal of Medicine (NEJM) appears to be backtracking on the issue, and they are talking about relaxing their rules. The British Medical Journal (BMJ) is very ‘heavy’ on Conflict of Interest (COI) and has been somewhat critical of the NEJM approach – to say the least. See 13th June edition of BMJ.

To give you a flavour, one article in the BMJ has the title ‘Backtracking on conflicts of interest: a very bad idea… A series of articles in the New England Journal of Medicine has questioned whether the conflict of interest movement has gone too far in its campaign to stop the drug industry influencing the medical profession. Here three former NEJM editors respond with dismay.’

My sympathies are almost entirely with the three former editors: Robert Steinbrook, Jerome Kassirer and Marcia Angell. I think bias, and resultant distortion of medical research is a massive problem. So massive that it has become difficult to believe most of the research that is published. I am not alone in my concerns. Here is what Richard Horton (Editor of the Lancet), has to say on the matter:

‘The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue. Afflicted by studies with small sample sizes, tiny effects, invalid exploratory analyses, and flagrant conflicts of interest, together with an obsession for pursuing fashionable trends of dubious importance, science has taken a turn towards darkness.’

A half of medical scientific research may be untrue… think on the implications of that for a moment. However, before you focus all your efforts on trying to expose financial conflicts of interest as the solution to all problems, you need to take several steps back. Here are just two of the elephants in the room:

  • Just because someone is getting paid, does not mean they are saying or doing anything that is biased, or distorted. So, by introducing punitive rules on payment from the industry, you could be punishing everyone who has ever received any money, when many of them have done nothing wrong.
  • It is incredibly simple to set up structures that allow money to be paid to a ‘charity’, or a University Department, that can then be filtered down to an opinion leader who can then state, quite truthfully, that they receive no money from the industry. So, if you are going to look for conflicts, you are going to have a dig considerably deeper than looking for a direct transfer of money from pharmaceutical company to doctor. And that is tricky to enforce.

There is also another major issue here, which no-one seems to have discussed at all. Which is that money is most definitely not the only currency available when it comes to ‘bribes.’

At present, COI is seen in very simple terms. A conflict of interest is that someone (usually an international expert in, say, psychiatry) is paid lots of money by a pharmaceutical company. They then say exactly what the pharmaceutical company has written down on a piece of paper for them to say e.g. ‘This new product depressagon is completely safe, highly effective, has no side-effects, and I believe that depressagon should be use, first line, in anyone with depression. Thank you, where’s my cheque.’ The last three words are usually silent.

The International expert then sits on a guidelines committee for depression, and encourages all the other members of the panel to put depressagon on the list of first line drugs to be used in depression – and any other mental illnesses they can think of. At which point the Acme Pharmaceutical Company Inc. makes twenty billion dollars a year from depressagon. Which means that the one hundred million paid to the offshore account of said expert can be considered money well spent.

Of course, it is never as crude as this. Paying people money to say what you want them to say is considerably more subtle and nuanced. A raised eyebrow here, a small cough in the correct place there, an embarrassed silence round the table… the rules of playing the game are complex and never written down anywhere. In fact, if you have to ask how to take part, you don’t get invited.

However, urbane, crude, or not, there is still an assumption that the currency of COI is money, specifically money that ends up the experts bank account (directly, or indirectly). This is nonsense. There are many other things on offer. The most important of which is…power.

If you can work with the industry to attract several hundred million to your University for research; if you can be the lead investigator in several major international studies, then you will gain prestige, influence and power. The University may create an entire department as your plaything. You can have fifty new staff members, you will be asked to sit on prestigious committees. You can advise Governments on health policy.

Money….money. Who needs that? To quote Kevin Spacey playing Francis Underwood in House of Cards:

‘Such a waste of talent. He choses money over power. In this town, a mistake nearly everyone makes. Money is the Mc-mansion in Sarasota that starts falling apart after 10 years. Power is the old stone building that stands for centuries. I cannot respect someone who doesn’t see the difference.’

Up to now, all discussions about Conflict of Interest have focussed purely on payment in money. As if this is the only reason why someone may, ever, be influenced. When a medical expert states proudly they are not paid by pharmaceutical companies this may or may not be true. Tracking the flow of money into and out of Universities and medical charities is a complex old game.

However, no-one seems to have grasped a very important concept. You don’t have to pay someone money to manipulate them. They can be rewarded, instead, with power and influence. Conflict of Interest is about far more than money, and we should stop pretending otherwise.

You’re killing my patients (again)

Some of you may remember that the Australian Broadcasting Corporation (ABC) ran two programs in 2013 about saturated fat and statins. The messages were that saturated fat does not cause heart disease, and statins have more side effects than were reported in the trials, and could do more harm than good in patients at low risk of heart disease.

Massive outrage ensued, at least in Australia, a faraway country of which we know little. However, the battle is important for us all. For it is about crushing free speech and stomping on any criticism of medical ‘experts.’ Which is a very dangerous thing indeed.

After internal investigation, ABC pulled both programs and apologized profusely. Even though they could find nothing wrong with the programme on saturated fat, and only one of seventeen objections was upheld. And this objection was, in my opinion, a relatively minor issue (see a previous blog on the matter).

Just to refresh your memory. Here is the only point in which the programs were felt to have misrepresented the facts, followed by my comment at the time.

‘The program’s treatment of use of statins in secondary prevention focused solely on mortality benefits in a way that reinforced the view that statins were overprescribed and their benefits exaggerated. The principal relevant perspective that statins have wider benefits for this group was not properly presented. This perspective was necessary to a fair understanding of the pros and cons of statin use in this group.’

My Comment: [Turning this into English. What the committee believe they found was that the second Catalyst program ‘Cholesterol drug war’ did not mention that statins have benefits on non-fatal outcomes e.g. non-fatal heart attack, and non-fatal stroke. By failing to emphasize this point it was judged that the program gave a misleading perspective on the overall benefits of statins (in secondary prevention).]

However, all of this was represented as follows:

ABC takes down Catalyst heart disease episodes after review criticism Controversial TV program on cholesterol-lowering statins found to have breached editorial standards.

‘Two episodes of the TV science program Catalyst will be removed from the ABC’s website after an internal review found the program had breached editorial standards on impartiality.

The controversial Catalyst program on statins and heart disease, The Heart of the Matter, was attacked by health experts even before it aired last year.

The presenter of ABC radio’s Health Report, Norman Swan, warned “people will die” as a result of the TV program’s messages about heart medications.

Swan, whose criticism of the program has been vindicated by the independent Audience and Consumer Affairs Unit report, had said the program made him “really angry” because it might affect Indigenous Australians, who are especially likely to suffer from high cholesterol.’ {P.S. Norman, indigenous Australians have lower cholesterol levels than the surrounding population}.

If this was all you had heard about the matter you would assume that ABC had done a very shoddy job, with sloppy and potentially dangerous reporting. Yet all of this ‘howling villagers with pitchforks’ attack was based on a single issue. It should be emphasised that, at no point did the programs suggest that anyone should stop taking a statin, or that statins should not be used in high risk patients.

But the vicious attacks did not stop here, oh no. Now we have a paper in the Medical Journal of Australia, reported yesterday, as follows:

Today, researchers from the University of Sydney and the Australian National University report on the impact of another Catalyst program. In October 2013, Catalyst broadcast a segment highly critical of statins, a class of drug used for lowering cholesterol.

The program questioned the link between cholesterol and heart disease, and suggested the benefit of statins in preventing cardiovascular disease was exaggerated.

There was extensive criticism of the program, including from the ABC’s own Norman Swan and the ABC later removed the episodes from the Catalyst website after an internal review found that the episodes had breached its impartiality standards.

The new report in the Medical Journal of Australia used Pharmaceutical Benefits Scheme data of 191,000 people and found an immediate fall of some half a million fewer statins dispensed to patients in the eight months following the Catalyst broadcasts.

The authors wrote:

This translated to an estimated 60,897 fewer people taking statins over the eight months examined. If patients continue to avoid statins over the next five years, this could result in between 1,522 and 2,900 preventable, and potentially fatal, heart attacks and strokes.

One of the study authors, Associate Professor Sallie Pearson, Scientific Director of the Centre of Research Excellence in Medicines and Ageing at the University of Sydney, said:

What is particularly concerning is that this drop in use was seen in people who were at high risk of cardiovascular disease – for example, those who were also taking medications for diabetes. Heart attacks and strokes are the main killers of people with diabetes.

Statins are recommended for people at high risk of cardiovascular disease because they have been shown to be effective. Like all medications, they have risks and benefits and should only be used as recommended.

The study authors wrote:

Even though the observed effect was relatively small, the prevalence of statin use in Australia and their established efficacy means that a large number of people are affected, and may suffer unnecessary consequences.

Why would anyone have done such a study? The only possible reason is that it was a deliberate effort to destroy any possibility of anyone ever criticising statins again? The whole thing is appalling and disgraceful.

At no point (to restate this yet again,) did the programs suggest people at high risk (secondary prevention) of heart disease stop taking statins. Yet, as you can see, the main attacked focussed on the fact that there was a reduction in people taking statin, in those at high risk of heart disease. What nonsense. Yesterday I wrote the following in a comment on an Australian website ‘The Conversation.’1

Here is the kind of delicious irony we should all enjoy. To quote Sallie Pearson, one of the study authors. ‘What is particularly concerning is that this drop in use was seen in people who were at high risk of cardiovascular disease – for example, those who were also taking medications for diabetes.’

Oh my God, people with diabetes are giving up statins. Well, as statins increase the risk of diabetes by 46%* then it would not be surprising to find a significant number of people with diabetes giving up statins. After all, it would have been, in many cases, the statins that gave them the diabetes in the first place. So, giving up the statins would probably have ‘cured’ their diabetes. And as we all know, to quote Sallie Pearson again…’Heart attacks and strokes are the main killers of people with diabetes.’ Yes, indeed.

Pursue this line of argument for too long and madness shall surely follow.

*The use of statin treatment could increase risk of type 2 diabetes by 46%, as a result of decreases in insulin sensitivity and insulin secretion, according to researchers from the Institute of Clinical Medicine in University of Eastern Finland.

P.S. When it comes to statins, 75% stop taking them in the first year anyway. So the Catalyst programme would have been but a drop in a very large ocean.

P.P.S. As you will see, most people stop taking statins due to adverse drug effects which, according to the programmes critics, do not really exist.


Statins and cancer

(Ho hum, not again)

A number of people have written to me pointing out an outbreak of mass hysteria in the UK press about statins protecting against cancer. I suspect this hysteria has been repeated around the world. Here are the headlines from the eponymous Daily Mail

Statins slash risk of death by cancer: They slow tumour growth

by up to 50% reveal major studies

Experts say there is ‘overwhelming’ evidence that statins can treat cancer

Study showed they cut death rates for bone cancer patients by 55 per cent

GPs should make patients aware of pills’ new benefits, researchers say

I have been aware of claims that statins protect against cancer for many years. They pop up on a pretty regular basis. I have tended to ignore them on the basis that, anyone who is stupid enough to believe such research, deserves all the statins they can get.

However, such is the overblown hype this time, that I feel the need to rouse myself from my slumber, and explain why this is just complete rubbish. I don’t need to read the original studies to do this. I have read enough of these over the years. I hope this does not sound too arrogant, but I will happily apologise if any single thing I write here proves to be wrong.

Not randomised controlled studies

The studies quoted will not have been randomised and controlled. By which I mean they did not take, say, forty thousand people and split them into two, randomised, groups. One group to take statins the other to take a placebo. Then wait, say, five years to see what difference there was.

These studies will have been observational. By which I mean you look at people taking statins and see what happens to them vs. people who do not take statins. Such studies can show associations between two variables. But they cannot prove causality. (They cannot provide ‘overwhelming’ evidence of anything either). This is basic science, page one, paragraph one.

Just to provide one example of this. In 1987 a major observational study showed that women taking HRT had a more than forty per cent reduction in heart disease. At which point it was recommended that women took HRT to protect themselves against heart disease. This was, in fact, written into the guidelines of the American College of Physicians. To fail to prescribe HRT was considered medical malpractice in the USA.1

Some years later came the Women’s Health Initiative (WHI) study. The first randomised primary prevention trial to use HRT, and 17,000 women were involved.

‘Analysis of hazard ratios showed that after 5.2 years, there was a 29% increase in coronary heart disease risk, including an 18% risk of coronary heart disease mortality and a 32% increase risk of nonfatal myocardial infarction. There was a 20% increase in risk of fatal stroke and 50% increase in the risk of non fatal stroke in women assigned to HRT.2

So, a 42% reduction in heart disease turned into a 18% risk of dying of heart disease. In short, observational studies are hopelessly unreliable and often turn out to be complete nonsense. And there is a specific reason why I know these statins studies will be complete rubbish, which I will get to.

Relative not absolute risk

Once again, in these studies, we run into the distorting use of relative, not absolute risk. A fifty per cent reduction in risk can mean something, or nothing very much. It depends what the underlying risk was in the first place. In my book Doctoring Data I covered the use/misuse of relative risk in some depth.

Let us just say that if your underling risk of dying in the next five years is 50%, reducing that risk by 50% is a big deal. If the risk of dying in the next five years is 0.1%, then reducing that risk by 50% is five hundred times less of a big deal.

As for slowing tumour growth by 50%. Well, that could mean almost anything. Did you reduce tumour growth by 1%, 50% or some other number. And does reducing tumour growth actually reduce the risk of dying? Of course, you will always find some super rare cancer e.g. bone cancer, where death rates are cut by 55%.

I would imagine this meant about three deaths verses seven in bone cancer. Basically, however small the absolute figures can be to get to a relative risk reduction of 55%. I would guess there will be no statistical significance figure attached to this reduction. Many questions, almost none of them well be answered, you will find.

The elephant in the room (raised cholesterol protects against cancer)

Here, however, is the big issue. People with higher cholesterol levels are far less likely to die of cancer. Add this to the fact that people with higher cholesterol levels are far more likely be prescribed statins, and you start off with the most gigantic built in bias that it is possible to find.

In 1992 (before statins were being prescribed to more than a select few) a conference was held to look at low blood cholesterol and associations with mortality3. Going back this far in time is important. After this, statin prescribing makes it very difficult to disentangle those with naturally low, or high, cholesterol levels vs. those who were taking statins.

All the major studies of the time were reviewed, with nearly one million participants. As you can see from my little graph, reproduced from the figures in the paper, as cholesterol levels rise, the risk of cancer falls. For women, if your cholesterol level is below four, the risk of dying of cancer is 38% higher than if your cholesterol level is above 6.2mmol/l. In men we are looking at a 27% greater risk with low cholesterol levels. {See chart)


Thus any observational study on lowering cholesterol with statins starts off with a massive inbuilt bias in the two populations. You are looking at one group of people who have a much lower risk of cancer to start with, then giving them statins, then declaring that statins protect against cancer….. just the most absolute unscientific codswallop.

As final warning. Be careful about lowering cholesterol too far. A very large Japanese study (that you will never have heard of, because it was not very supportive of statins) looked at prescribing statins to over forty seven thousand people over six years. As they found:

‘The patients with an exceptionally low TC (total cholesterol) concentration, the so-called ‘hyper-responders’ to simvastatin, had a higher relative risk of death from malignancy than in the other patient groups.’4

In fact, the rate of death from cancer in those whose cholesterol fell the most dramatically was increased by three hundred and thirty per cent (relative risk, apologies for doing this, but I do not know the absolute risk). The authors added this warning:

‘Further analysis is necessary to elucidate why the hyper-responders had an increased risk of death; their baseline characteristics will be described and discussed in detail in the future. Nevertheless, the health of patients who show a remarkable decrease in TC or LDL-C concentration with low-dose statin therapy should be monitored closely.’

Can I return to my slumbers on this issue now?



1: American College of Phyisicians. Guidelines for Counselling Post-Menopausal Women about Preventative Hormone Therapy. Ann Intern Med. 117:1038-41. (1992)

2: Writing group for the Women’s Health Initiative Investigators. ‘Risks and benefits of oestrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative Randomized controlled Trials’ JAMA (2002)

3: Jabobs et al: Conference on Low Blood Cholesterol and Mortality: Circulation Vol 86, No 3 September 1992

4: Matsuzaki M et al: Large Scale Cohort Study of the Relationship Between Serum Cholesterol Concentration and Coronary Events With Low-Dose Simvastatin Therapy in Japanese Patients With Hypercholesterolemia Primary Prevention Cohort Study of the Japan Lipid Intervention Trial (J-LIT). Circ J 2002; 66: 1087 –1095


The article below was just sent to me be a fellow GP, who shares my concerns about the prescribing of statins to everyone with a pulse. In fact it was he (I am being coy about naming him here) who led the protest against the over-prescribing of statins within the Royal College of General Practice (RCGP). He also led the protest within the General Practice Committee (GPC), which is the part of the British Medical Association (BMA) that negotiates on behalf of General Practitioners. Yes, the structures of medical politics are byzantine indeed.

Anyway, for those who believe that doctors are unthinking drones who stare at computer screens and merely follow the guidelines they see there, tonight you may raise a glass of beer, or wine, or even whisky, to them.

Short warning. Before you read this article, which appeared in PULSE magazine (the most widely read medical magazine for UK GPs) I feel I need to quickly flick through the acronyms.

  • RCGP = Royal College of General Practitioners
  • NICE = the National Institute of Health and Care Excellence (they look at all the evidence in a medical area, then create the guidelines for treatment that doctors are commanded to follow)
  • QOF = Quality Outcome Framework. A system of payments designed to incentivise General Practitioners to meet various targets e.g. lower blood pressure, measure weight, put people on statins.
  • QRISK = A risk calculator, designed to determine your risk of having a heart attack or stroke in the next five or ten years.

‘The RCGP and the GPC have rejected NICE’s plan to introduce QOF indicators that would see practices rewarded for prescribing statins to patients with a QRISK score above 10%, warning the move threatened the ‘credibility of QOF’.

The move comes as NICE advisors on QOF are due to meet early next week to discuss potential new indicators – including two that would reward practices for prescribing statins to patients newly diagnosed with diabetes or hypertension at a 10% estimated 10-year cardiovascular risk level – which will be up for negotiation for next year’s contract if approved.

The GPC said that it was ‘vital for the credibility of QOF’ that indicators have a robust evidence base, make significant difference to patients and are backed for the profession, adding that these proposals ‘fail on all these counts’.

The RCGP warned that the proposals risked ‘the loss of professional confidence in the healthcare targets they are being asked to meet’.

NICE launched the consultation on proposed new QOF indicators earlier in the year, which included another potential new indicator would pay practices to set up a register of patients with a 10-year risk of 10% or higher, alongside the hypertension and diabetes indicators.

The proposals were made in order to reflect updated NICE lipid modification guidelines, which lowered the 10-year cardiovascular risk threshold at which GPs prescribe interventions, including statin therapy, from 20% to 10%.

This was despite opposition from GP leaders and other leading clinicians concerned about the potential for over-medicalisation of healthy people and diversion of resources away from the sick onto the ‘worried well’.1

‘Get in!’ as they say. I am, to put it mildly, delighted.


The dog that did not bark in the night

Some of you may have noticed this study, others may not. The amazing ‘wonderdrug’ trial proving that cholesterol lowering drugs have unparalleled benefits on preventing stroke. Here is just one headline from the Daily Express. A major newspaper in the UK.

Statins slash stroke risk by 30 per cent: Millions more should be given drug, say experts

New research has found that the wonderdrugs – which include statins and fibrates – can slash the risk of suffering a stroke by a third in the elderly. And experts now say there is clear evidence that even among the over-75s – a group not routinely prescribed statins – people can benefit from the life-saving drugs.

It is yet more evidence that the cholesterol-lowering drugs are lifesavers and that their benefits outweigh the potential side effects. Lead researcher Christophe Tzourio, Professor of Epidemiology at the University of Bordeaux and Inserm, said: “A one third reduction in stroke risk, if confirmed, could have an important effect on public health.”1

And so on and so forth.

Colleagues of mine love to wave articles like this at me with a triumphant smirk. ‘Seems you’re wrong about cholesterol lowering after all.’ What do you say to that? Eh..’ I usually ask them if they actually read the study. ‘Primary prevention with lipid lowering drugs and long term risk of vascular events in older people: population based cohort study.’2 I ask them this question, but I know that they’ve not. I find it rare to come across a doctor who would ever deign do such a thing as read a scientific paper.

However, when studies like this come out, I do feel the need to raise my enthusiasm to a sufficient level to have a peek at the paper. In this case it was rather easy. This paper was published in the British Medical Journal (BMJ), and I get it delivered to me every week by post. What a quaint thing, actual physical reading material.

My first problem, before I even started reading this study, is that I knew beforehand that a raised cholesterol level is not a risk factor for stroke. Never has been, not anywhere, not in any study I have read. Whilst you can find studies claiming that a raised cholesterol level (LDL) is a risk factor for heart disease [ and you can find others that show the opposite], I have yet to find any study demonstrating any association between raised cholesterol and stroke.

Here, for example, is a short extract from one massive study, the biggest, which looked at four hundred and fifty thousand people over seven million years of observation. It was published in the Lancet:

‘The associations of blood cholesterol and diastolic blood pressure with subsequent stroke rates were investigated by review of 45 prospective observational cohorts involving 450 000 individuals with 5-30 years of follow-up (mean 16 years, total 7·3 million person-years of observation), during which 13 397 participants were recorded as having had a stroke.

Most of these were fatal strokes in studies that recorded only mortality and not incidence, but about one-quarter were from studies that recorded both fatal and non-fatal strokes. After standardisation for age, there was no association between blood cholesterol and stroke except, perhaps, in those under 45 years of age when screened. This lack of association was not influenced by adjustment for sex, diastolic blood pressure, history of coronary heart disease, or ethnicity (Asian or non-Asian).3 [My bold].

Now, if you are unable to find an association between cholesterol levels and stroke in seven point three million years of observation then, you know what, it just ain’t there. In fact, I challenge anyone reading this blog to provide any evidence that cholesterol levels are associated with overall stroke risk. Gulp, that makes me hostage to fortune.

This is why stroke associations struggle when they talk about cholesterol and stroke. They seem desperate to say that raised cholesterol levels cause stroke, but just can’t. Here is how the National Stroke Association fudges the issue.

‘High cholesterol may raise your risk for stroke by increasing your risk for heart disease, a stroke risk factor.4

Whilst it is, of course, true that having heart disease does increase your risk of stroke, and vice-versa, the rest of this statement reveals a yawning gap in logic [For the sake of this argument, let us assume it is true that a raised cholesterol causes heart disease].

A (raised cholesterol) → B (heart disease) →C (Stroke)

A does not → C

Question. If A does not lead to C, how does A lead to B, then leading to C? I shall ask for this to become a question in the Oxford and Harvard entrance exams.

[BTW, if you can work this one out, then please feel free to let me know how it works. Exactly.]

Anyway. We find a study demonstrating that two cholesterol lowering drugs, in this case statins and fibrates, significantly reduce the risk of stroke. But a raised cholesterol level is not a risk factor for stroke. Which means that there can be no possibility that the benefit seen can have been due to cholesterol lowering? That, my friends, is simple logic. No need for Oxford and Harvard to get involved at all. This could be discussed on entrance to kindergarten.

Now, just to add to my short analysis this study I would like to draw your attention to something not remarked upon by the popular press at all. However, I thought that you may find it interesting. It was the following statement from the paper:

‘We found no association between lipid lowering drug use and coronary heart disease (hazard ratio 1.12, 0.90 to 1.40).’ [For those who hate figures/confidence intervals, sorry, I left them in for those who like them].

This was the dog that did not bark in the night.

In summary, here we have a study showing that cholesterol lowering reduced the risk of stroke, when a raised cholesterol level is not a risk factor for stroke. On the other hand, it failed to show any benefit on reducing the risk of heart disease. Some would consider that a study such as this raises more questions than answers. However, with wearisome inevitability, it has been twisted around to provide further proof that everyone should be taking statins. Sigh.


2:              Alperovitch et al: BMJ 25 May 2015 pp12.

3:              Cholesterol, diastolic blood pressure, and stroke: 13 000 strokes in 450 000 people in 45 prospective cohorts The Lancet Volume 346, Issues 8991–8992, 30 December 1995, Pages 1647–1653


Sorry seems to be the hardest word

I think that the four words ‘I told you so’ should only be thought, and never written down. No-one likes a smart arse. But sometimes it is impossible to resist….just impossible. In this case I have failed. ‘Father forgive me, for I am weak.’ So, here goes…’I told you so.’

Some of you may be aware that the US dietary guidelines are going to be changed. For some reason it is required that the full report is suppressed for about a year. Presumably so that everyone can pile high their defences when the attacks begin. ‘I think you will find that I have always, ahem, supported these ideas.’ Cough, shuffle of papers….cough. ‘Sorry, no time to take questions.’ Exit left.

The entire report, I believe, stretches to about a bazillion pages. However, here are four of the highlights.

  • Cholesterol is to be dropped from the ‘nutrients of concern’ list. [I love that phrase ‘nutrient of concern’].
  • Saturated fat will be… ‘de-emphasized’ from nutrients of concern, given the lack of evidence connecting it with cardiovascular disease.’ [Whatever de-emphasizing may be. Pretending you never said it in the first place, I suppose].
  • There is concern over blanket sodium restriction given the… ‘growing body of research suggesting that the low sodium intake levels recommended by the DGAC (Dietary Guidelines Advisory Committee) are actually associated with increased mortality for healthy individuals.’
  • And…’ The identification and recognition of the specific health risks posed by added sugars represents an important step forward for public health.’

In short. Cholesterol is healthy, saturated fat is healthy, salt is healthy and sugar is unhealthy. I have pulled those four points out of a press release by the Academy of Nutrition and Dietetics, which I reproduce in full, below.

Academy of Nutrition and Dietetics Commends Strong, Evidence-Based Dietary Guidelines Report

The Academy of Nutrition and Dietetics, the world’s largest organization of food and nutrition professionals, commends the 2015 Dietary Guidelines Advisory Committee for drafting a strong, evidence-based Scientific Report outlining recommendations and rational for the forthcoming 2015 Dietary Guidelines for Americans. The Academy supports these recommendations that will improve how and what Americans eat.

“The Academy applauds the evidence-based systematic review of the literature, which is vital to the DGAC’s assessment of the science,” said registered dietitian nutritionist and Academy President Sonja L. Connor. “We commend the Department of Health and Human Services and the Department of Agriculture for their commitment to the Nutrition Evidence Library and their ongoing efforts to strengthen the evidence-based approach for assessing the scientific literature for future dietary recommendations.”

In comments recently submitted to USDA and HHS, the Academy supports the DGAC in its decision to drop dietary cholesterol from the nutrients of concern list and recommends it deemphasize saturated fat from nutrients of concern, given the lack of evidence connecting it with cardiovascular disease.

“Despite some criticism suggesting that changed recommendations illustrate concerns about the validity of the nutrition science upon which the Dietary Guidelines are based, the DGAC should change its recommendations to be consistent with the best available science and to abide by its statutory mandate,” Connor said.

The Academy also expresses concern over blanket sodium restriction recommendations in light of recent evidence of potential harm to the overall population. “There is a distinct and growing lack of scientific consensus on making a single sodium consumption recommendation for all Americans, owing to a growing body of research suggesting that the low sodium intake levels recommended by the DGAC are actually associated with increased mortality for healthy individuals,” Connor said.

The Academy supports an increased focus on reduction of added sugars as a key public health concern. “Among the identified cross-cutting issues, the evidence is strongest that a reduction in the intake of added sugars will improve the health of the American public. The identification and recognition of the specific health risks posed by added sugars represents an important step forward for public health,” Connor said.

In its comments, Academy also emphasizes that enhanced nutrition education is imperative to any effective implementation. “It is critical to ensure that individuals making diet and behavior changes in accordance with the Dietary Guidelines have access to the resources and support necessary to succeed. HHS and USDA must have sufficient resources to commit to improving a number of initiatives,” Connor said.

“The Academy appreciates the opportunity to comment on the Scientific Report and to serve as a resource to HHS and USDA as they finalize the 2015 Dietary Guidelines and develop resources to implement and promote their use,” Connor said.1

In one way, I commend this press release. At least it has made no real attempt to fudge what is now going to be said. These are the facts.

But you know what. Organisations like this have been haranguing the entire population of the world about the dangers of cholesterol, saturated fat, and salt for the last thirty years. Foodstuffs which they now seem happy to admit, cause no harm, indeed they are almost certainly good for you.

At the same time, they have bombarded us with messages to consume sugar(s). They usually call them carbohydrates, which is disingenuous in the extreme. Carbohydrates are all just sugars in disguise. A disguise that the digestive system can strip off in a few minutes.

Yes, all those healthy fruit and vegetables are simply extended chains of simple sugar(s). And once they enter your digestive system, your body cares not whether or not you ate a carrot or a sugar cube. It delivers them into your bloodstream as sugar [primarily glucose and fructose].

Now there have been a number of people, including me, who have been saying for years that cholesterol and saturated fat are perfectly healthy, salt is good for you and sugar (in large amounts) is bad. We have all been dismissed as cranks and idiots who would have caused the deaths of thousands of people, if they had ever dared to listen to what we had to say.

It turns out the cranks and the mavericks were right. The experts were wrong. Completely and utterly wrong. Damagingly wrong. Whilst the words ‘I told you so’ are temptingly easy to say; and saying them should be resisted. There is another, single word, that appears impossible to say.