Sunday 10 December 2017

PURE - Is this the end of 50 years of dietary advice? It should be.

Several of my Posts have been to expose the absurdity of the diet-cholesterol-heart hypothesis, which has dominated healthy diet advice during more than half a century.

The relationships between diet, cardiovascular disease, and death are topics of major public health importance, and subjects of great controversy.
In European and North American countries, the most enduring and consistent diet advice is to restrict saturated fatty acids, by replacing animal fats with vegetable oils and complex carbohydrates
During the past fifty years there has been little questioning of the theory; the advice to reduce dietary cholesterol and fats continues unchecked. However there have been many studies that have have shown that the diet component of the theory is not sustainable, but the results of these studies have failed to make an impact on popular belief.

The view of a growing number of scientists is that advice to restrict saturated fatty acids is “largely based on selective emphasis on some observational and clinical data, despite the existence of several randomised trials and observational studies that do not support these conclusions”

The PURE study

A large study was recently published in The Lancet. It is known as the Prospective Urban Rural Epidemiology (PURE) study. It investigated the health outcomes of 135,335 individuals aged 35–70 years of age, followed for an average of 7.4 years.

The study was undertaken in 18 countries. These included 3 high-income (Canada, Sweden, and United Arab Emirates), 11 middle-income (Argentina, Brazil, Chile, China, Colombia, Iran, Malaysia, occupied Palestinian territory, Poland, South Africa, and Turkey) and 4 low-income countries (Bangladesh, India, Pakistan, and Zimbabwe). 

Dietary patterns were recorded in detail. The subjects were divided into five groups (quintiles) for diet category, Quintile 1 being the lowest 20% of specific intake, and Quintile 5 the highest 20% intake.

The study documented 5796 deaths and 4784 major cardiovascular disease events.  The main morbidity/mortality categories were total deaths, cardiovascular (CVD) deaths, major CVD events, myocardial infarction (heart attack, MI), and stroke.


The study was complex in that a great deal of data were recorded and presented in the Lancet paper. I cannot present all the data in this review, but I will concentrate on the two major diet groups of saturated fat and carbohydrate.

The study does not record the absolute consumption of food and its constituents, but just proportions. In other words, if fat intake is reduced then the proportion of carbohydrate inevitably increases, and vice versa. 

Dietary Fats 
higher proportions of fat in the diet are linked to lower death rates
Figure 1. Fat intake association with mortality and morbidity

In the “rainbow” Figure 1, we can see on the horitontal x-axis of the graph the 6 categories of morbidity and mortality. Each category or group needs to examined separately. Within each group are the quintiles of fat intake, the lowest on the left and the highest on the right. Each quintile has its own colour, and the legend is shown at the top.

The vertical y-axis indicates the incidence of deaths or major events, incidence per 1000 person-years.

Let us first look at “total mortality”, the first group.  shows a decline in mortality with increasing fat intake, from 7 events per 1000 person-years in quintile 1 to  4.2 events in quintile 6.

We can also see the same pattern in respect of  “major CVD”, “stroke”, and “non-CVD deaths”. There is no effect on MI and CVD deaths.

It appears that there is no detriment to a high proportion of the diet being saturated fats, and there is a significant advantage in respect of total and non-cardiovascular mortality. This is not what we have been led to expect.

Dietary carbohydrate

Now we will turn to dietary carbohydrate and its relationship to mortality and cardiovascular illness.

This is summarised in Figure 2, which looks like Figure 1 but the results different.

higher proportions of carbohydrate in the diet are linked to higher death rates
Figure 2. Carbohydrate intake association with mortality and morbidity

Within the group of “total mortality” we can see that as the proportion of carbohydrate increases from quintile 1 to 5, the mortality rate increases. 

There is a similar but less significant pattern for major CVD events, stroke and non-CVD deaths.

There are no effects on MI and CVD deaths.

In respect of total mortality, non-cardiovascular deaths and major CVD events, a high proportion of carbohydrates in the diet is not a good thing.


During the past 50 years dierty advice reduce the fat content of our diet has inevitably increased the carohydrate proportion. Therefore advice to reduce fat intake, and therefore increasing proportion from carbohydrate, is likely to have increased deaths and major events, the opposite of the intention of public health advice.

The dietary component of the diet–cholesterol–heart hypothesis has perhaps been quiety side-lined by the cholesterol “experts”. But the cholesterol – heart component continues and despite evidence to the contrary it underpins the pharmacological “treatment of cholesterol”. Cholesterol now seems to be a disease in itself.

In the PURE study a higher proportion of total fat  intake and each type of fat was associated with a lower risk of total mortality .
Higher saturated fat intake was associated with lower risk of stroke. 
Total fat and saturated and unsaturated fats were not significantly associated with risk of myocardial infarction or cardiovascular disease mortality. 
Higher carbohydrate intake was associated with an increased risk of total mortality but not with the risk of cardiovascular disease or cardiovascular disease mortality. 

The authors conclude with this statement:
“Global dietary guidelines should be reconsidered in light of the consistency of findings from the present study, with the conclusions from meta-analyses of other observational studies and the results of recent randomised controlled trials.”

Will we see any change of official diet policy?

Wednesday 1 November 2017

Evolocumab - cholesterol myth and vested interests

There is a new medicine now available for lowering cholesterol and thereby intended to prevent deaths from coronary heart disease (CHD).


A few short-term trials have been published that have demonstrated that evolocumab (evo-locu-mab) lowers the blood level of cholesterol very significantly, beyond the effect of statins. But a demonstration of clinical benefit is much more important, especially as we know, that despite what we are told, cholesterol-lowering is not related to reduction in CHD death rate.

Evolocumab is produced by the pharmaceutical company Amgen (see below). It is a monoclonal antibody that inhibits “proprotein convertase subtilisin–kexin type 9 (PCSK9)” and it thereby lowers low-density lipoprotein (LDL) cholesterol levels in the blood. Metabolic details are not important to us at present. There are now many monoclonal antibody medications, ending in -mab, and used in a variety of clinical settings. They need to be given by injection or infusion and they are expensive. They can be dangerous.

The Clinical trial

A randomised controlled clinical trial (RCT) has now been published in the prestigious New England Journal of Medicine (the FOURIER study). 

The study was of 27,564 patients, aged between 40 and 85 years, with known atherosclerotic cardio-vascular disease, with blood LDL-cholesterol level 1.8 mmol/L (70mg per decilitre) or above, and already receiving statin therapy. The study took place in 49 countries.

The subjects were randomly allocated to receive either evolocumab  (13,784) by injection every two weeks (or every month in higher dose) or placebo (presumably saline) by injection (13,780).

The primary outcome endpoint in the trial was "a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization”. The secondary endpoint was "a composite of cardiovascular death, myocardial infarction, or stroke”. 


There was a large reduction in blood level of cholesterol in the treated group, by 59% compared to those receiving placebo. But did this translate into clinical benefit?

At first sight, “yes”. There was a reduction of endpoints in those receiving evolocumab compared to placebo.

These results represent proportionate reductions of 9.8% and 7.4% respectively. This sounds good, but I have previously criticised clinical trial results for displaying proportionate changes rather than absolute changes, which better represent the real world. 

The absolute reductions of both primary and secondary event rates are 1.5% (11.3 - 9.8% and 7.4 - 5.9%). This means that 67 people (100 / 1.5) would need to be treated for about one year to prevent just one end-point. 67 is therefore the Number Needed to Treat (NNT) to achieve this.


What we are not told in the summary becomes more interesting than what we are told, but the details can be found in the full paper. 

The composite endpoints mix deaths with non-fatal events, and this is a dubious method of analysis. There is in fact a slight excess of deaths in the evolocumab treated group than in the placebo group, but this is hidden within the composite bundle of events.

The strange thing is that the trial was stopped prematurely, when the median duration of treatment was just 22 weeks, and when the subjects recruited later had been in the trial for just a very short time. The initial plan had been to continue the trial for 4 years duration of treatment, and so why had it been stopped so early? The reason given is that at 48 weeks from the onset of the trial the result had shown a benefit from evolocumab – that is in the composite bundle analysis. 

But at 48 weeks (the longest time that a subject had been in the trial) there was a slight excess of deaths in the evolocumab group, deaths from any cause and also deaths from cardiovascular disease.

The excess of deaths was small and when the trial was stopped it had not reached statistical significance. It would require 1000 people to receive the medication for about one year for one excess death to occur. But after 4 years (when the trial was planned to end) it almost certainly would have reached statistical significance. Premature ending of the trial avoided this likely serious and negative conclusion.

Conflicts of Interest

We must ask ourselves: is the trail really objective and honest? The trial results were presented with significant “spin”, that is the political ploy of presenting bad news as good news, in this case as the composite endpoints. The spin was enabled by the process of the "bundle of composite endpoints", in which deaths were lost.

The names of the authors of the paper are shown above. A look at some of their details (showing declared conflicts of interest) will give a clue as to whether they might not be objective. Amgen is the pharmaceutical company  that manufactures evolocumab.

RPG reports grants and personal fees from Amgen, during the conduct of the study; grants and personal fees from Amgen, Daiichi-Sankyo, and Merck; and personal fees from Amarin, American College of Cardiology, Angel Med, Beckman-Coulter, Boehringer Ingelheim, Bristol- Myers Squibb, CVS Caremark, GlaxoSmithKline, Janssen, Lexicon, Portola, Pfizer, Regeneron, Sanofi-Aventis, St Jude, and Stealth Peptides, outside from the submitted work. 

TRP reports grants and personal fees from Amgen, during the conduct of the study; and personal fees from Amgen, Sanofi, Merck, Boehringer-Ingelheim, and The Medicines Company, outside the submitted work. 

GMDF reports grants and personal fees from Amgen, during the conduct of the study; grants and personal fees from Amgen and MSD; grants from Boton Scientific; and fees from LivaNova and Sima Tau, outside the submitted work. 

ZAG reports personal fees from Amgen and Sanofi, during the conduct of the study. 

RC reports grants from Pfizer– International Atherosclerosis Society; and personal fees from MSD, Bayer, Amgen, Boehringer Ingeslheim, Sanofi, AstraZeneca, NovoNordisk, Servier, and Kowa, outside the submitted work. 

IG-B reports personal fees and non-financial support from Amgen and Sanofi; and personal fees from Eli Lilly, Regeneron, and Aegereon, outside the submitted work. 

JL-M reports personal fees and non-financial support from Amgen and Sanofi; personal fees from MSD and Laboratorios Dr Esteve, outside the submitted work. 

FM reports grants, personal fees, and non-financial support from Amgen, MSD, Sanofi, AstraZeneca, and Pfizer, during the conduct of the study. 

BRO reports personal fees from Amgen, during the conduct of the study; participation on a data safety monitoring board for Accera; and grants from Long Term Care Group, Merck, Eli Lilly, TauRx, Janssen, Biogen, Avid, and Hoffman-La Roche, outside the submitted work. 

EK reports grants from Amgen during the conduct of the study; and grants from Amgen and AstraZeneca, outside the submitted work. 

ALP is an employee of and holds stocks in Amgen. RS is an employee of Amgen and, as such, has received salary, bonus, stock or stock options, health insurance, and benefits; and is identified as an inventor on at least one pending patent application owned by Amgen relating to evolocumab. SMW is an employee of Amgen; and has a patent for evolocumab issued to Amgen. 

ACK reports grants and personal fees from Abbott, and Mylan; and personal fees from Amgen, AstraZeneca, and Pfizer, outside the submitted work. 

PSS reports grants and personal fees from Amgen, during the conduct of the study; grants and personal fees from Pfizer, outside the submitted work; and that he is the recipient of a National Institute for Health Research Senior Investigator Award and receives support from the Biomedical Research Centre Award to Imperial College Healthcare NHS Trust. 

MSS reports grants from Abbott Laboratories, Clinical Diagnostics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Roche Diagnostics, Takeda, Novartis, Poxel, Eisai, Genzyme, and Pfizer; grants and personal fees from Amgen, AstraZeneca, Intarcia, Merck, Janssen Research Development, The Medicines Company, and MedImmune; and personal fees from Alnylam, CVS Caremark, Lonis, Cubist, Esperion, and MyoKardia, outside the submitted work. 

J- GP, KT, and FS declare no competing interests. 

The expression “He who pays the piper calls the tune” comes to mind.

We can see the remarkable extent to which academic doctors can be funded by the pharmaceutical industry. This must influence the way which their findings are reported. 

We must also remember that when a pharmaceutical company funds a clinical trial (as in this case) the company will "own" the data and have a veto over the presentation of findings.

The economics of pharmaceutical development

There is a real problem in respect of pharmaceutical development in general and evolocumab in particular.

The development of any pharmaceutical agent today will cost a minimum of $1 billion, and there is always the possibility that the agent might fail because of unforeseen side-effects. The $1 billion needs to be recovered from sales, and the price of the medication will depend on the predicted number of prescriptions. 

Statins provide an example of the ideal. They are taken by millions of well people every day for many years. The huge volume of sales will result in low unit price or vast profits, or both. In 2001 cerivastatin had to be withdrawn because of untoward effects (muscle damage) resulting in a large financial loss to the company (Bayer). 

A contrast would be a new antibiotic, and there are not any. Excluding their animal growth-enhancing use, an antibiotic is given for only a few days for an individual person. The low volume of sales will mean that the price of a tablet or injection will be very high, and this will inevitably inhibit use. The £1 billion development cost is not likely to be recovered from sales. As new antibiotics are considered to be in the public interest, the debate is whether antibiotic development should be funded by pharmaceutical companies or governments.

The economics of evolocumab

The cost of production of a mono-clonal antibody such as evolocumab will be very high. The price was fixed in 2016 at £170.10 for a 140mg pre-filled pen or syringe (excluding VAT). This equates to £4422.60 per year, and £6123.60 for the alternative dose of 420mg each month.

The cost of prevention of one primary event would be £4422.60 x 67 (NNT) x 1 (assuming one year treatment), which  is £296 314 ( $394 035, €338 687). It is a matter of judgement as to whether this sum of money is good value to prevent a non-fatal episode of illness, knowing that death will not be prevented.


A non-fatal stroke is an illness that most people dread as it can lead to long-term disability. It is therefore important to look at stroke prevention within the bundle of “composite end-points”.

The number of deaths from stroke differs very little between the two groups. The number is not actually important if total deaths are effectively the same. Changing the cause of death within a given time-scale is not the objective of medicine.

In respect of non-fatal stroke we see a small advantage from evolocumab. 1.9 - 1.5 = 0.4%, which means that 4 non-fatal strokes can be prevented by 1000 people taking evolocumab for about one year, or 1 non-fatal stroke prevented by 250 people taking evolocumab for one year (NNT = 250).

The economics of this is derived from £4477.6 x 250 x 1, which is £1 119 400 ( $1 489 211, €1 279 474). I would suspect that most people would be of the opinion that spending about a million pounds / dollars / euros to prevent a non-fatal stroke would not be good value for money.

Pharmaceutical company considerations

It would be necessary for about 23,000 people to be treated for ten years to recover the £1 billion development cost. This does not include the costs of marketing. The recovery of all the costs would be required to provide a dividend to shareholders and to fund the development of the next product. The stakes are high and it must be important for economic reasons for evolocumab to be taken into widespread clinical practice.

Clearly it is essential for a trial of clinical effectiveness to be successful and to be published, ideally in a prestigious journal. And so we see the publication in the New England Journal of Medicine. The spin indicates success. Conclusions do not reflect results.


There was no “saving of lives”, no matter how many patients might be treated and no matter how many injections of evolocumab might be given. Prevention (delay) of death is by far the most important outcome measure and other cholesterol-lowering trials have identified this. 

A 59% reduction of cholesterol had no mortality benefit, which is against the predictions of the cholesterol-heart hypothesis. The frequently repeated message is that cholesterol-lowering is associated with an arithmetic reduction of CHD deaths, and this is clearly not true. It is also clear from the WOSCOPS statin trial.

Evolocumab has no effect on mortality, perhaps marginally increasing it. It is the same with ezetimibe – distinct lowering of cholesterol but no effect on mortality. Statins slightly reduce mortality and this effect has no relationship to the quantitative reduction of cholesterol. 

The economics of pharmaceutical development is highly vulnerable.

Will the providers of health care, individuals or pre-payment insurance organisations (whether or not government based) be prepared to fund evolocumab?

Tuesday 3 October 2017

The great deception: cholesterol and dietary fats are not bad for us after all

We have lived for half a century in the age of “dietism", and this generally continues. We have been told what we should be eating, or more often what we should not be eating. We have been told to avoid dietary fats and cholesterol. In particular we have been told that eggs and butter are effectively poisonous (i.e. they cause disease and death in relationship to the amount consumed), and that cholesterol is the cause of coronary heart disease (CHD).

Here is an example of what we have been told that we should not have been eating, on account of eggs and butter:

Smoked salmon with asparagus, topped with poached egg and Hollandaise sauce.
Lay the smoked salmon on two or more plates.
Steam the asparagus tips.
Place two egg yolks in a small mixing dish, and mix lightly with a whisk.
Melt 150g butter in a small pan.
Place 30ml white wine vinegar in another small pan and add a bay leaf and about ten peppercorns. Bring to the boil and reduce to one third of volume.
Slowly add the melted butter to the eggs and mix in (leave any solid residue from the butter in the pan).
Add the reduced vinegar, straining out the bay leaf and peppercorns. Continue stirring.
Add the juice of a lemon, strained to remove pips and pulp, and also a little non-grain mustard.
Place mixing bowl in a pan of water and bring to the boil. Continue stirring and the Hollandaise sauce will thicken.
Poach two or more eggs, one for each plate.
Arrange the asparagus on top of the smoked salmon.
Place a poached egg on top of the asparagus.
Pour the Hollandaise sauce over the egg, and a grind of fresh black pepper.
Enjoy the snack. 
Do not feel guilty about eating eggs and butter!


The faulty dietary advice that we have received has been issued on the basis of the epidemic of coronary heart disease (CHD), which was responsible for large numbers of  premature deaths, perhaps 10 million in the UK. The cause was unknown but it was said to be diet, and the main culprit was said to be cholesterol. The diet-cholesterol-heart hypothesis was first proposed in 1950 and became the official policy of the American Heart Association on 1957. It has persisted since.

But there is doubt about at least the dietary component of the diet-cholesterol-heart hypothesis. Theoretical considerations can be based on false premises, such as cholesterol being produced within the body as a self-destructive process, rather than the reality that LDL-cholesterol is the first line of defence against invading micro-organisms. 

Research, as opposed to dogma, observes events in an objective and structured way. Much good quality research has shown that dietary fats and cholesterol have no influence on CHD deaths, but evidence has been over-ridden by the evangelism of cholesterolism. Dogma so often wins, at least in the short to medium term.

The alleged danger of cholesterol became the basis of a huge industrial tsunami backed by "research" in which conclusions were probably written before the results. The published conclusions so often have little resemblance to the results, with much circumlocution. The manipulation of information and the fraud is described thoroughly and clearly in the manuscript “The Oiling of America", by Mary Enig and Sally Fallon. There has been and still is big money in low or manipulated fat diets. There have been and still are reputations of supposed clinical scientists to be maintained.

The diet-cholesterol-heart hypothesis never made sense to those who read the original papers, but few read original papers and critics were silenced. The tsunami of low cholesterol and low fat diets rolled on.

Cholesterol was clearly regarded as bad. We were advised to consume lean meat, no bacon, skimmed milk, little cheese, no butter, no eggs (or perhaps one a week). The traditional English breakfast was at an end. Margarine instead of butter! Milk that tasted like water! Worst of all, no bacon!


But the tsunami is coming to an end, the dietary advice is becoming uncertain. People are eating more cheese, butter and cream. The popular cookery programmes on the television and recipes in magazines, often based in Italian food, include large amounts of butter, cream and eggs, with chefs apologising to any "diet police" who might be watching the programmes. The English breakfast now appears in hotels around the world. The dietary advice of the past half-century has been wrong, but this is not yet officially acknowledged.

As long ago as 1985 there was strong dissent to the diet-cholesterol-heart hypothesis by a number of scientists. Among them was Dr George V Mann, professor of biochemistry at Vanderbilt University, USA. 
Dr George V Mann 1917–2013
Despite his distinguished academic record, little notice was paid to him at the time. Indeed there was a strong rebuttable to his "intemperate" views by Dr Henry Blackburn, an important anti-cholesterol enthusiast. But we are now close to the end of era of diet-heart, as predicted by George Mann. George Mann will be vindicated.

New information 

Now we see new headlines:

A recent study from Finland looked at 1032 men (age 42–60) between 1984 and 1989. The study concentrated on the carotid arteries in the neck. The thickness of the wall of the arteries can readily be measured by modern ultrasound. The diet–cholesterol–heart hypothesis would predict that the arterial wall would be thicker in response to a high cholesterol diet, and this would lead to a higher risk of CHD. The association would be higher in people with a genetic abnormality (polymorphism) of the apolipoprotein E gene (ApoE4). 

The result of the study was simply that a high cholesterol diet had no influence on the thickness of the arterial wall, even in the genetically high risk individuals.


We can conclude after half a century of false information that:
  • Eggs are not bad for you.
  • Cholesterol does not cause heart attacks.
  • Diet fat advice has been wrong.
At last research is coming into the public domain and starting to eclipse the misinformation of the diet evangelists. 

Perhaps we can now eat for pleasure, but acknowledge the sensible dietary advice of  “Don’t eat too much”.