Hypercholesterolaemia and its management
BMJ 2008; 337 doi: https://doi.org/10.1136/bmj.a993 (Published 21 August 2008) Cite this as: BMJ 2008;337:a993
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Dear Sir,
Dr Bhatnagar and colleagues (1) have written a useful review for non-
specialists, covering a large area of work. Whilst we accept the
difficulty of providing an entirely comprehensive account of such a fast
moving field, we would like to comment on the treatment sections of the
article.
The benefits of statins are regarded as a class effect; however,
there are differences between statins in addition to their varying effect
on lipid profile.
Statins vary in their metabolism and this affects their potential for
drug interaction. Simvastatin and atorvastatin are metabolised via the
CYP3A4 pathway. Concurrent therapy with drugs that interfere with CYP3A4
pathway (such as anti retrovirals, cyclosporine, digoxin, diltiazem and
anti fungals) may lead to statin accumulation and an increased propensity
for myopathic side effects. Statins not metabolised via this pathway such
as pravastatin, rosuvastatin and fluvastatin should be considered in these
patients.
Furthermore, whilst the incidence of myositis is now less than 0.5%,
it does appear to be less frequent with hydrophilic statins such as
pravastatin (2,3). This is thought to be secondary to less muscle
penetration (4) making hydrophilic statins a suitable therapeutic option
for patients hindered by myopathic complaints on lipophilic statins such
as simvastatin/ atorvastatin.
With regard to adjunctive therapy such as ezetimibe, despite an
additional absolute 15% reduction in LDL cholesterol, the combination of
simvastatin and ezetimibe has shown neutral results in recent trials (5,
6) thus far.
We await the results of the IMPROVE-IT trial (7), in the interim NICE
suggests it is reasonable to employ the combination to achieve LDL target.
The increase in cancer incidence in the recent SEAS trial is surprising.
However, it would not be the first lipid-altering drug with unexpected
adverse effects. The increase in mortality and blood pressure with
Torcetrapib in phase III studies has lead to Pfizer halting trials and
their development programme for Torcetrapib. In contrast, the safety
profile for statins is known. Ten year follow up from 4S and WOSCOPS
trials have not shown an increased incidence of cancer with statins (8,9).
Thus, until we have the results of IMPROVE -IT, perhaps alternative
statins such as atorvastatin or rosuvastatin, which have more prognostic
and safety data should be employed if target is not achieved with
simvastatin.
Guidelines aim to simplify decision-making, suggesting simvastatin
for all with dose adjustment and adding ezetimibe if necessary. However,
this may not always be optimal for individual patients. The practicing
physician must therefore also be aware of statin subtypes, interactions
and the benefits and pitfalls of new adjunctive therapies.
Dr Sayan Sen MRCP
SpR Cardiology, Barnet & Chase Farm Hospitals NHS Trust
Dr A Pirshahid.
Clinical Fellow, Barnet & Chase Farm Hospitals NHS Trust
Dr A Bakhai FRCP
Consultant Cardiologist, Barnet & Chase Farm Hospitals NHS Trust
1.Hypercholesterolaemia and its management. Deepak Bhatnagar,
Handrean Soran, and Paul N Durrington BMJ 2008;337:a993, doi:
10.1136/bmj.a993
2..Incidence of hospitalized rhabdomyolysis in patients treated with
lipid-lowering drugs. Graham DJ; Staffa JA; Shatin D; Andrade SE; Schech
SD; La Grenade L; Gurwitz JH; Chan KA; Goodman MJ; Platt R JAMA 2004 Dec
1;292(21):2585-90. Epub 2004 Nov 22
3.Safety and tolerability of pravastatin in long-term clinical
trials: prospective Pravastatin Pooling (PPP) Project. Pfeffer MA; Keech
A; Sacks FM; Cobbe SM; Tonkin A; Byington RP; Davis BR; Friedman CP;
Braunwald E. Circulation 2002 May 21;105(20):2341-6
4.Differential sensitivity of C2-C12 striated muscle cells to
lovastatin and pravastatin. Gadbut AP; Caruso AP; Galper JB J Mol Cell
Cardiol 1995 Oct;27(10):2397-402
5. Simvastatin with or without Ezetimibe in Familial
Hypercholesterolemia. J Kastelein MD, F Akdim MD, E Stroes MD, et al New
Engl J Med 2008 358:1431-1443
6. Design and Baseline Characteristics of the Simvastatin and
Ezetimibe in Aortic Stenosis (SEAS) Study. Rossebo AB; Pedersen TR; Allen
C; Boman K; Chambers J; Egstrup K; Gerdts E; Gohlke-Barwolf C; Holme I;
Kesaniemi VA; Malbecq W; Nienaber C; Ray S; Skjaerpe T; Wachtell K;
Willenheimer R Am J Cardiol. 2007 Apr 1;99(7):970-973. Epub 2007 Feb 15
7. IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary
Syndrome:Vytorin (Ezetimibe/Simvastatin) vs Simvastatin. In progress.
Clinicaltrials.gov
8.Mortality and incidence of cancer during 10-year follow-up of the
Scandinavian Simvastatin Survival Study (4S). Strandberg TE; Pyorala K;
Cook TJ; Wilhelmsen L; Faergeman O; Thorgeirsson G; Pedersen TR; Kjekshus
J. Lancet 2004 Aug 28;364(9436):771-7.
9. Long-term follow-up of the West of Scotland Coronary Prevention
Study. Ford I; Murray H; Packard CJ; Shepherd J; Macfarlane PW; Cobbe SM.
N Engl J Med. 2007 Oct 11;357(15):1477-86.
Competing interests:
None declared
Competing interests: No competing interests
20 years ago the normal values of cholesterol was between 4.4 and 8.8
according to my lab’s reference values. Cholesterol is necessary for
survival, brain function, membrane stabilizing, infection protection among
other things. Why should we change the natures own millennii old research?
Why is animal fat dangerous? Didn’t you drink your mother’s milk with
56 E% animal fat during the first months of your life? How can a nutrient
tested for very many generations be bad for you? If animal fat would be
bad for us, all mammals should have been extinct eons ago.
Why does a cow have four stomachs? Because she eats cellulose and
need those four stomachs to break down cellulose to glucose. The glucose
is transformed via acetic acid to fat and protein. So the cow is a very
good converter of carbohydrates to protein and fat. And, the cow collects
all vitamins and minerals she needs to be OK.
If you eat corn, the corn will exit the other way seemingly complete,
you can not digest one single molecule of cellulose. But you can eat meat
from the cow and you don’t need anything more but salt and water. Humans
have been hunters since at least 10 000 generations. We hunters just have
to eat meat, fish, egg and fat to stay healthy.
Also, how did we treat a diabetic 87 years ago? Well, in Sweden we
used fat pork and heavy cream stewed cabbage. The diabetic did not have
any symptoms of his disease, lived as long as any nondiabetic. And we had
more than a hundred years of experience.
Today we order diabetics to eat 60 % of all energy to be
carbohydrates, And then those poor diabetics need a lot of drugs including
insulin to try to keep the blood glucose level down. Why do we need 60 E%
carbohydrates when carbohydrates are nonessential? Protein and fat are
essential, that’s why we need them but we don’t need to eat one single
molecule of carbohydrates.
The world is inverted today. We eat carbohydrates which are
nonessential, we don’t eat fat which is essential, as well as protein.
We’ve better start thinking instead of doing what others tell us to do.
Competing interests:
Senior citizen and can tell the truth without being hit economically
Competing interests: No competing interests
I was encouraged to see that you had published Uffe Ravnskov's letter
and thus put some authoritative balance into the lemming like rush to
lower cholesterol at any price. Repetitive papers continue to appear
singing the praises of attacking the imagined disease of
hypercholesterolemia, all in the same vein, and providing no recent
trials, but turning over old work, in the name of meta analysis.
A paper in the BMJ only a few weeks ago was still singing the praises
of the HPS study, which can so evidently be seen to be flawed, especially
in the way it eliminated reports of early side effects, and the
conclusions were based more on fervent hope than factual figures.This same
BMJ paper quoted the "Keys' Theorem" in relating the consumption of
saturated fat to cholesterol levels. No theorem in any branch of real
science would be given any credence at all if data was selected solely to
fit the hypothesis.
Medical research and guideline preparation would be much better
served if they were not solely the work of blinkered one-specialism
workers, and some criticism of their methods and objectives by other
possible interested branches of medicine such as metabolism and
mitochondrial problems could be seen to have been made and taken into
account.
There are now thousands of damaged statin users in so many countries,
but those who continue to advocate statins appear to acknowledge only the
minimal side effects recorded in trials, where the dangers mentioned in
the Merck patents of 1990 were never put forward as possible outcomes. All
others are said to be just anecdotal My near approach to death's door 5
years ago was just one such, alongside the 80 in MHRA's records who were
not recognised in time and so were not saved.
Long live Drs Ravnskov, Kendrick, McCully and Langsjoen, and thanks
to the late Karl Folkers who brought real scientific methods and true
biological knowledge to lighten up this very murky and worrying scourge of
the population today.
Competing interests:
Statin damaged patient
Competing interests: No competing interests
The body produces cholesterol every day.The amount produced and type,
will depend on the body's requirement to restore, grow and repair cellular
structures within the body at that time, for the given conditions.
We assume that we know better...and 'adjust' nature's millenia of
evolutionary design with man-made chemicals, instead of correcting the
detrimental dietry and life-style habits which precipitated the adverse
health conditions.
Aside from giving us the totally expected dangerous side effects from
going against this situation, we exacerbate the problems by not correcting
the underlying causes.
Are we mad?....or should I not be concerned about the vast sums of
money this Statin market increasingly generates by finding new supposedly
suseptable groups...even children... to prescribe to?
Fortunately, Pandora's Box is now open to all, thanks to the Internet
and the allopathic model of wellness through drugs is feeling very
exposed..
...or maybe you have a convincing body of totally independent reliable
research, indicating a distinct reduction in death rates due to Statin
administration?
I am just amazed that the human race managed to survive thus far
witout the intervention of Big Pharma's wonderous benefits...
Competing interests:
None declared
Competing interests: No competing interests
In
their review about hypercholesterolaemia and its management Dr Bhatnager and his
coworkers declared that they had selected references from reviews if they
provided “a useful, objective, and comprehensive account including extensive
recent references.” By using this
method the authors have missed much important knowledge from the past. Let me
illustrate.
Hypercholesterolaemia was said to be one of the major
causes of atherosclerosis. How come that no association between plasma
cholesterol and degree of atherosclerosis has been found in post-mortem studies
of unselected individuals?1-6 And how come that no angiographic trial
has found exposure-response between degree of cholesterol lowering and outcome.7
A
population was considered to be unhealthy when its average plasma cholesterol
concentration exceeded 5 mmol/l. How come that almost all studies have shown
that high cholesterol is not a risk factor for women?8 And how come
that old people with high cholesterol live longer than old people with low?9-25
The latter is particularly curious because at least in Sweden more than 90% of
all cardiovascular deaths occur in people above 65.
The
optimal cholesterol concentration should be lower in patients with diabetes,.
How come that numerous studies have found that high cholesterol is not a risk
factor for diabetics?26-39
People with familial hypercholesterolaemia were
said to be at a particular high risk. How come that in cohorts of such people,
cholesterol is not associated with the incidence or prevalence of cardiovascular
disease?40-47 And how come that these people’s risk of coronary
heart disease is normal after age fifty, and that their average life span is
similar to other people’s?48
A diet low in saturated fat was said to lower the
risk of cardiovascular disease. How come that no randomised, controlled trial,
where the only intervention was a lowering of cholesterol by dietary means has
succeeded in lowering coronary or total mortality? How come that more than 20
cohort studies have found that patients with coronary heart disease have eaten
the same amount of saturated fat as healthy controls?49,52 How come
that almost all cohort studies have found that stroke patients have eaten less
saturated fat than healthy controls?53-62 And how come that the
concentration of the short-chain fatty acids in the tissues, the most reliable
reflection of saturated fat intake,63-66 are not associated, or even
inversely associated with coronary heart disease and degree of atherosclerosis?67-73
The authors cite a meta-analysis of 14 statin
trials having shown that for each 1 mmol/l lowering of plasma LDL cholesterol,
coronary and stroke events fell by about 21%. These figures were based on mean,
not individual values. Curiously, no clinical or angiographic trial has found
any association between degree of individual cholesterol lowering and outcome?7
There is a likely explanation, however.
If the benefit from the HMG-coenzyme A-inhibitors is
due to their pleiotropic effects only, not to their inhibition of the
cholesterol synthesis, a calculation using mean values should show
exposure-response, also for degree of cholesterol lowering, whether cholesterol
lowering by itself is useful or not. But
even if the lowering of cholesterol is unimportant, there should also have been
exposure-response for cholesterol for individual values because both the
pleiotropic effects and cholesterol lowering are caused by inhibition of the
mevalonate pathway; a more complete blockage should result in stronger
pleiotropic effects and a more pronounced lowering of cholesterol, and vice
versa. As this has not been the case in any trial, the only explanation is that
some of the participants had a heart attack, although their cholesterol was
lowered very much, and/or that some had no cardiovascular symptoms although
their cholesterol was lowered very little, meaning that high cholesterol is
protective. There is also much clinical and epidemiological evidence for that.74
No doubt, statin treatment may be of benefit, but the
effect is grossly overstated. The figure 17% for instance is the relative
percentage; no more than a few percent of those who are taken statins gain
benefit, and only if they are high-risk patients.75 Little, if any
effect has been seen for women and healthy people with normal or high
cholesterol. Add also that the benefit may easily be outweighed by the side
effects, because they are both much more serious and much more frequent than
reported in the statin trials, if reported at all.75
A critical revision of the cholesterol campaign
seems urgent, preferably performed by scientists without links to the drug
industry.
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Competing interests:
None declared
Competing interests: No competing interests
Rapid response:
Cholesterol management: doctors should remember their public health
responsibilities
Editor, Bhatnagar et al's view that cholesterol management should be
based on patients' predicted cardiovascular risk is a pragmatic, cost-
effective solution to the delivery of individual doctor to-patient
clinical care, particularly where drugs are to be prescribed. (1) Doctors
also have public health responsibilities. From the public health
perspective, every person in the country should be helped by the doctors
to minimise their cholesterol, so that in future the mean value for the
population will be below 4 mmol per litre, when we will largely dispense
with pharmaceutical approaches. Doctors need to help to. My viewpoint has
been expressed vigorously in Concepts of Epidemiology (2) and I quote:
“Molecular science will deepen understanding of the interaction between
the environment, lifestyle, and the gene…. The public health dividend from
such knowledge will come from altering the pattern of risk factors in the
whole population. Reducing serum cholesterol from the currently
pathological level of 6 mmol per litre and more in some populations, to a
physiologically normal value of 4 mmol per litre or even less, without
mass medication, requires an understanding of how people and societies
change. … in my 30 years since graduation I have seen professional
perceptions on the level of total cholesterol requiring action drop from
about 7 mmol/l, to about 6 mmol/l and now to 5 mmol/l. My figure of 4
mmol/l still looks radical but it will probably be standard by the next
edition of this book.”
Serum cholesterol is determined by a combination of biochemistry and
what food is grown, processed, purchased, cooked, and eaten. Trade
agreements, agricultural policy, marketing, and economic subsidy are
crucial determinants of costs, availability and consumption. Other
lifestyle factors such as physical activity are also of importance.
Doctors, and not just public health ones, need to get involved in the
greater challenge.
Reference List
(1) Bhatnagar D, Soran H, Durrington PN. Hypercholesterolaemia and
its management. BMJ 2008; 337(aug21_1):a993.
(2) Bhopal RS. Concepts of Epidemiology. 2 ed. Oxford: Oxford
University Press, 2008.
Competing interests:
None declared
Competing interests: No competing interests
Thank-you to the authors for this useful article.
The interesting definition of an abnormal cholesterol could be
developed further to...
A desirable cholesterol level is based on the value at which the CVD
risk is unacceptably high, provided that the risk can be reduced to a
level which is worthwhile to the patient by treatments which are tolerable
and acceptable.
Assuming a 20% risk over 10 years of a significant cardiovascular
event, and a 25% absolute risk reduction if statins are taken for 10 years
(the threshold for statin prescribing for primary prevention);
If 100 people at this level of risk take a statin for 10 years, 80
will not have a cardiovascular event who would not have had one anyway, 15
will have a cardiovascular event who would have had one anyway and 5
patients will not have a cardiovascular event as a result of (all 100)
taking a statin for 10 years.
In other words the annualised NNT is 200 to prevent one cardiovascular
event.
(Please check my calculations and correct me if I am wrong!)
What I would like to ask the authors, because it is something I would
like to tell patients, is by how much is ones life or healthy life
extended by taking a statin. In other words are there survival data for
patients on statins such that we can say not only; Statins reduce your
risk of having a heart attack or stroke by a quarter and on average if 20
people (like you) took a statin for 10 years, 1 less person would have a
heart attack or stroke, but also, if you take a statin for 10 years on
average you will live x months longer or will remain fit and active (by
avoiding a stroke) on average y months longer.
I'd be very grateful if the authors or other readers could point me at
such information.
Best wishes,
David Bossano
Competing interests:
None declared
Competing interests: No competing interests
Dr Epstein is surely right to prescribe caution in the use of
Ezetimibe - but there are other reasons to be cautious about the
prescription of all the cholesterol lowering drugs.
The West Midlands Centre for Adverse Drug Reactions (adr.org.uk),
authors of the Adverse Drug Reaction Bulletin (ADRB) have recently issued
a warning via the FDA concerning a "potentially increased risk of cancer
associated with Simvastatin and Ezetimibe when used in combination
(Vytorin)."
The FDA is apparently investigating a report from the Simvastatin and
Ezetimibe in Aortic Stenosis (SEAS) trial. The SEAS trial "tested whether
lowering LDL-cholesterol with Vytorin would reduce the risk of
cardiovascular events in individuals with aortic stenosis. A lower overall
cardiovascular risk was not found with Vytorin. However, there was an
additional observation that a larger percentage of subjects treated with
Vytorin were diagnosed with and died from all types of cancer combined
when compared to placebo during the 5-year study."
Of course, there is no need to panic. The FDA believes some caution
is required in interpretation of these preliminary results from SEAS
bearing in mind that other large ongoing trials have not shown similar
findings.
The statins are very effective in reducing levels of cholesterol but
their rather modest effect on the cardiovascular end point (death) appears
largely independent of this undoubted fact. I believe there is good reason
to be cautious about the collateral damage suffered in the ‘war on
cholesterol’ and the effect of this damage on all cause end points.
Competing interests:
None declared
Competing interests: No competing interests
Dr Bhatnager et al state a popular belief that combination treatment,
with statin and etetimibe, may be used if cholesterol lowering targets are
not met. We do accept that lowering cholesterol with statins reduces the
risk of vascular events. However, there are still no randomised-controlled
trials that support the benefit of ezetimibe in reducing vascular events.
Until such trials are available, etetimibe should be prescribed with
caution.
Competing interests:
None declared
Competing interests: No competing interests
Re: Statins: A Class Effect?
It is amazing that Sayan Sen et al should quote a figure of less than
0.5% for the incidence of myositis from statin use, when many have
reported that it is nearer 20% in the general situation. The low figure
appears to arise from trial reports, which fail to count these events
fully. The larger figure is also borne out by affected patient reports on
websites where they seek help for the problem, not available from their
doctors, and from personal stories of folk known to me.
I am also surprised that the letter says that the depth of
penetration of the statin into the muscle has a bearing on the severity of
myositis. Merck explained in its 1990 patent applications that reduction
of Q10 production in the mevalonate pathway, in which all statins work, is
the cause, but this fact has not been allowed to trickle down to coal face
clinicians.
Another facet on lowered lipids was put forward this month in the
American Heart Journal by P Tamara et al where 17,000 patients
hospitalised with heart failure, had their lipid profile taken, and their
progress was analysed, covering 2 years. 46% were on statins. Each 10ml
INCREASE in cholesterol level was associated with a 4% DECREASED risk of
in-hospital mortality from heart failure.
Food for thought there, especially by the Heart Czar, who says that
the older generation should have a chance to "share the benefits of statin
therapy" (perhaps a place further up in the queue at the undertakers??)
Competing interests:
Statin damaged patient
Competing interests: No competing interests