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”.

Sunday, 17 September 2017

Statins are of no value in the elderly

Most (virtually all) episodes of heart attacks (myocardial infarction, MI) and deaths from coronary heart disease (CHD) occur in people above the age of 70 years. This group is generally regarded as "elderly". Conventional wisdom is that CHD  and its most serious manifestation of MI, is "due to cholesterol". However previous Posts have shown the absurdity of this. 

The Framingham study from the USA was a 30 year follow-up of the population of this town in Masachussets. The objective was to investigate the factors that would be associated with early death, specifically death from CHD. The expectation was that the cholesterol level of the blood would be the major factor, but it was not to be.

The conclusion to the major Framingham paper was:

blood cholesterol level is not important

In young men a high blood level of cholesterol predicted a higher death rate, but this was only minimal in young women. In men and women above the age of 50 years, blood level of cholesterol did not predict death from CHD or from "all causes".

Framingham - no effect of cholesterol on survival
Survival of men in Framingham. Note the survival is identical in all cholesterol groups: blood cholesterol did NOT predict survival.

How remarkable that this conclusion did not penetrate medical consciousness. Despite the fact the great majority of deaths from CHD have been in people above the age of 50 years, reducing blood and dietary levels of cholesterol has continued to dominate medical activity.

Statin medications to achieve cholesterol-lowering were introduced in the late 1980s and the result of the first clinical trial was published in 1995. However it was only in the 21st century that statins came into widespread use. The logic was that reducing the cholesterol level of the blood would lead to a reduction of age-adusted deaths from CHD. 

As things have turned out, the small benefit from statins is not related to cholesterol reduction. Although this is clear from the first published trial, such data has been withheld from the publications of subsequent statin trials, and the published conclusion is denied. 

The 20th century epidemic of CHD was coming to an end at the close of the 20th century and so there could only be a low expectation of statin being of any benefit, irrespective of cholesterol.

And this has been shown to be the case.

New study 

A study from the New York University School of Medicinepublished this year, concerned the effect of pravastatin given to 1467 participants over the age of 75 years compared to 1400 controls of the same age. The study concluded that pravastatin gave no advantage. There was no reduction of either deaths or coroanry events in those receiving pravastatin.

JAMA Intern Med. Published online May 22, 2017. doi:10.1001/jamainternmed.2017.1442 

We have seen in a previous Post that a high level of cholesterol appears to give a survival advantage in the elderly, those above the age of 70 years. This is clear from three studies, Honolulu, New Haven (Connecticut USA), and Paris. So why are the elderly given interventions designed to reduce cholesterol?

There is no reason for well people over the age of 70 years (or indeed of any age) to take statins. If such a person has experienced an MI (heart attack) then there might be a marginal advantage to taking a statin, but in the absence of up-to-date trials the evidence for this is far from strong. Benefit from statins is now less likely than undesirable side-effects. 

Sunday, 6 August 2017

Is being overweight really "killing millions"? Or is it good for us? The obesity paradox.

The Organ Grinder - L S Lowry

Dramatic headlines sell newspapers but might misinform the readers. Risks are generally greatly exaggerated and statistics are far from clear. 

A headline in the UK press on June 13th 2017 stated:

(Between normal weight and obesity is called "overweight", that is excess weight short of obesity. It is this that is apparently "killing millions".)

I must say that I have been unaware of millions being killed by anything at present, certainly not by being a bit overweight and not actually obese.

It goes on:
" Nearly two-thirds of adults in Britain weigh too much " 

Do you know – all these two thirds are going to die, and so are their slim fellow-citizens, whose "virtue" of slimness will not give them immortality. Who says that they "weigh too much"? Is it doing them any harm? On what is the standard based? And when was it established?

Another comment:
" Experts say many people failing to understand risks "

Perhaps the experts fail to understand risks. How is it that so many people are living so much longer? This is not disputed. 

Let us look further at the influence of body weight on survival.


In previous Posts I have referred to the Framingham study in the USA. The study is  based on a small town in Massachusetts and it was initiated in 1948. It has followed 5209 participants aged between 28 and 62 years, recording the development of illness and death during the past 70 years . It is an observational programme that has collected much useful information. 

I have previously drawn attention to the 40 year study of cholesterol levels of the population. The conclusion reached is that “After the age of 50 years there is no increased overall mortality with either high or low serum cholesterol levels.” Despite its profound importance, this finding never entered collective consciousness. It is the cholesterol truth that has been kept away from the public and the media.

Between 1951 and 2011, 1058 participants in Framingham suffered from a stroke. 

Most episodes of stroke are ischaemic, the result of cerebral infarction, the occlusion of blood supply to part of the brain. This is usually due to narrowing of an artery by the process of atherosclerosis. It is occasionally due an embolus from or via the heart. The other cause of stroke is a cerebral haemorrhage, due to the rupture of an artery, usually from an asymptomatic aneurysm. It is difficult to distinguish the two forms of stroke clinically, but CT scanning will show a haemorrhage. The absence of haemorrhage on CT scan leads to the diagnosis of ischaemic stroke. It is this group that is the subject of a study from Framingham published this year.

The purpose of this particular study was to investigate the influence of body weight on the outcome of stroke. The outcome measure was survival at ten years. In addition to following the outcome of those who had suffered stroke, age-matched controls from Framingham were also followed.

BMI (Body Mass Index)

In the initial presentation of data the subjects were divided into two groups based on BMI, the simple measure of obesity. The two groups were those with BMI less than 25 (normal) and those with BMI 25 or greater (overweight or obese).

BMI is a number based on weight and height: weight Kg / height in metres squared. Between 18 and 25 is regarded as “normal”. "Normal" is arbitrary and thus judgmental. We see from the headline above that two-thirds of UK adults being so defined as overweight is not a statistical normality. 

Effect of BMI on survival

Framingham study shows no effect of BMI on ten year survival
Figure 1: Ten year survival based on BMI (Framingham study)

Figure 1 shows the 10 year survival rates of the control groups, who had not had a stroke. They were divided into those with BMI less than 25 and those with BMI 25 or greater. It can be seen clearly that there is no significant difference. The two survival lines are very close together, indistinguishable. This is an important finding from a large and well-constructed study, but the information appears to have been hidden from public scrutiny.

The main purpose of the study was to investigate the outcome after a stroke, and we can see this in Figure 2.
Framingham study show better survival of obese following stroke
Figure 2: Effect of BMI and stroke on survival

In Figure 2 we see the addition of the survival lines for the people who had experienced a stroke. They are divided into two groups depending on BMI. 

It is not surprising that the life expectancy of those who had a stroke was about half that of  those who had not experienced a stroke, the control group. Having had a stroke is clearly a serious risk indicator of an early death.

Figure 3: Effect of BMI on survival after stroke

Figure 3 show just the stroke survivors. Following a stroke there is a significant difference in the 10 year life expectancy, depending on the BMI. Here we encounter what has been recognised in previous studies and called “the obesity paradox”

The life expectancy is much better in the obese group (BMI 25+, green line) compared to their slimmer counterparts (BMI <25, blue line). This is not what conventional wisdom would have led us to believe.

The study also subdivided the  participants into the sub-categories of:
“normal weight” (BMI less than 25), 
“low overweight” (BMI 25 to less than 27.5), 
“high overweight” (BMI 27.5 to less than 30), 
“low obesity”, (BMI 30 to less than 32.5), 
“high obesity” (BMI 32.5 or greater).

Once again we can first look at the control group, those without stroke, and we can see the results in Figure 4. A low column height is a good thing.
Framingham - survival advantage for the "overweight"
Figure 4: Relative risks of death by obesity group (controls, Framingham)

The normal weight group has death rate at 10 years standardised at 1.0. Low overweight has a similar risk of death. The lowest risk of death is with the high overweight group, a relative risk reduction of 0.78. This is a 20% reduction of risk of death at 10 years. 

Low obesity is little different from normal weight, but high obesity gives a survival disadvantage with a relative risk of 1.21 (21% increased risk of death at 10 years).

These results, taken from a sample of the general population of Framingham, are very interesting: despite what we are told in the headlines at the top of this Post, there are advantages in being overweight, but not if BMI is above 32.5.

Survival after stroke

We can now look at the data for those who had experienced a stroke, shown in Figure 5. Again a low column height is a good thing.
Framingham - obesity and survival after a stroke
Figure 5: Risk of death at 10 years and obesity following stroke (Framingham)

The death rate at 10 years for normal weight individuals is standardised as 1.0. We see a survival advantage in those with low overweight, high overweight, and low obesity – that is with people with BMI between 25 and 32.5. With “low obesity” there is a death risk reduction of almost 40%.

If BMI is greater than 32.5 there is a survival disadvantage, with an increase in risk of death at 10 years of just under 20%.

We have been looking at observations. Explanation is something different and I have no intention of making a guess. There is so much about body weight and its controls that we simply do not understand.

In respect of the survival advantage of overweight and mild obesity, there is no explanation in respect of characteristics of the population groups (see Figure  6). 

Figure 6: Characteristics of Framingham obesity study

For example it is the normal weight group that has the highest proportion of severe strokes. This group also has the highest proportion of smokers. The obese group has the highest incidence of diabetes, as would be expected, but surprisingly the lowest incidence of coronary heart disease. 

The lower risk of death in the overweight groups as shown in Figure 5 cannot be explained by the table in Figure 6 or other factors in the fuller analysis of risk factors.

The lesson from this first-class study study is that moderate obesity appears to give  a survival advantage following a stroke. In the control population obesity does not give a survival disadvantage.

Previous study of BMI and survival

It has been shown but not extensively publicised that BMI and measures of adiposity do not in themselves predict cardiovascular disease. This was published in The Lancet, the work being funded by the British Heart Foundation and the UK Medical Research Council.

I have shown in a previous Post further evidence that mild to moderate obesity does not give a survival disadvantage, but some advantage. The details can be seen in Figure 7.

Figure 7: BMI and death rate
The graph lines indicate risk of death based on BMI for two groups, ages 50 years (green line) and 70 years (blue line). As would be expected the death rates were higher in the 70 year-olds. 

But in both age groups the lowest death rates were in those people with BMI between 20 and 30. There was a gradual increase of death rate as the BMI increased to 45, the point of gross obesity, a dangerous condition. However the death rate rose steeply in the other direction with BMI less than 20. 

The best life expectancy was in those considered to be overweight or mildly obese. Our obsession with thinness should come to an end.

Overweight is an advantage after heart surgery

A recent study from the University of Leicester, UK, was led by Professor Gavin Murphy and its results were published in the European Heart Journal.  The study concerned the early mortality following heart surgery, and it has been given particularly detailed coverage by the academic press.

The study was of 401,227 adults, and a review of 557,720 patients from 13 countries. Average age was 59 years and 27% were women.

Being overweight appears to give a survival advantage after heart surgery
Figure 8: Body weight and risk of death after heart surgery

The results can be seen in Figure 8. The risk of death was highest at 8.5% in the underweight group. It was 4.4% in the "normal" weight group but even lower at 2.7% and 2.8% in the overweight and obese groups. It was very surprisingly low at 3.3% in the obese patients who were considered to be at particularly high risk.

There have been attempts to disregard or explain away these findings but this was not the purpose of the study. Explanation must wait. There are of course attempts to find faults that might invalidate the findings, as we expect all categories of excess weight to be dangerous, but such attempts have not been successful. The research was very well controlled and those with low weight appear to be at the greatest risk.


We can conclude that there is much about body weight that we do not understand. Gross obesity is to be avoided, not only because of death rate but also because of serious morbidity, especially musculoskeletal problems and reduced mobility. 

However we cannot conclude that thinness is to be applauded. At the present time we have two concurrent epidemics. The first is that of long life expectancy, a serious social problem. It is a to a major extent the consequence of the end of the epidemic of coronary heart disease. The other epidemic is allegedly that of obesity. Perhaps this so-called "epidemic" is an important factor leading us to be living longer.

BMI between 20 and 30 seems to be about right, and the evidence is clear.


Journal of the American Heart Association doi: 10.1161/JAHA.116.004721

 2011 Mar 26;377(9771):1085-95. doi: 10.1016/S0140-6736(11)60105-0.

New Scientist 2014; Volume 222, Number 2967, Page 44.

Eur Heart J (2017) 38 (23): 1786-1787.