Should we lower cholesterol as much as possible?
BMJ 2006; 332 doi: https://doi.org/10.1136/bmj.332.7553.1330 (Published 01 June 2006) Cite this as: BMJ 2006;332:1330
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Daniel Hicks's personal experience and concerns echo my own. Like
him, I suspect that much weakness and increasing disability, particularly
in the elderly, may not be recognised as the unwanted effects of these
drugs - which are in such widespread use on the basis of their too-good-to
-be-true image of efficacy without significant risk.
Competing interests:
None declared
Competing interests: No competing interests
Dear Sir,
“The span of our life is seventy years –
eighty for those who are strong –
but their whole extent is anxiety and trouble,
they are over in a moment and gone.” (1)
Surprisingly little has changed since the time of the psalmist!
The life expectancy of a male at 75 is less than 10 years according
to government statistics. (2) Currently in our practice of 10,100
patients, only 3.43% get beyond 80 years, with 0.44% getting past their
90th birthday.
The British Hypertension Society states that all whose risk is 20% or
over should be started on statins, aspirin and an antihypertensive up to
the age of 80 years. (3) Hence a 75 year old male, life-long non-smoker,
non-diabetic with a BP of 140/90, cholesterol of 5 and an HDL of 1 would
be put on triple therapy, rather than congratulated on his good health!
The Whitehall study found, “After more than 25 years of follow up of
civil servants aged 40-69at entry to the study, employment grade
differences still exist in total mortality and in nearly all specific
causes of death. The main risk factors (cholesterol, smoking, systolic
blood pressure, glucose intolerance and diabetes) could only explain one
third of this gradient.” (4)
Recent articles by Brindle et al on the inaccuracy of the Framingham
score sheds doubt on its usefulness. (5)
A review article in the British Journal of General Practice commented
that the best predictor of cardiac death was age. (6)
So do we use a risk scoring system which gives results with a
confidence interval of 50% either way, depending on local prevalence and
social class – remembering that ethnicity and family history add further
major inaccuracies?
The push to provide primary prevention based on risk scores is surely
flawed. There is also the issue of informed consent. If we accept that the
risk of dying for each human being is 100%, there are only three main
variables of death – where, when and how. The “where” is about geography
and social systems, the “when” and “how” are the areas that medicine tries
to influence. How we die tends to be related to when we die. As a child
the main risks are from congenital inheritance, infection, some cancers
and violence (accidental and non accidental). If a young male dies, it is
most likely to be from violence (accidental, non accidental or self
inflicted), a young woman (thinking globally) from child birth. An elderly
person will die from cardiovascular disease, cancer or “bronchopneumonia”
(a euphemism often used to describe the death of an octogenarian with
senile dementia in residential care). If one reduces the risk of dying
with cardiovascular disease, because the maths must add up, presumerably
more people will die of cancer. Ravenskov et al (7) in their article
suggest that this is true – either as a direct effect of statins
themselves, or because mathematically one has to die from something!How
often do we discuss this with patients in the final decades of their
natural life?
There is a seeming madness in the way Western Medicine is developing.
Increasing polypharmacy in an aging population is a risk laden course of
action, which promises few real benefits.
1) Psalm 90 vs 10
2) http://www.gad.gov.uk/Life_Tables/Notation.htm
3) Williams B. et al. Guidelines for the management of Hypertension:
report of the fourth working party of the British Hypertension Society
2004 – BHS IV. Journal of Human Hypertension (2004) 18, 139-185
4) van Rossum et al (2000) Employment grade differences in cause specific
mortality: a 25 year follow up from the first Whitehall Study quoted in
“Risk Matters In Healthcare” K Mohanna and R Chambers Radcliffe Medical
Press (2001)
5) Brindle P et al. The Accuracy of the Framingham risk-score in different
socio-economic groups: a prospective study. BJGP 2005 Vol 55 Number 520
6) Fahy T, Schroeder K, Cardiology BJGP 2004 Vol 54 Number 506
7) Ravnskov U, Rosch P et al. Should we lower cholesterol as much as
possible? BMJ 2006; 332: 1330-2
Competing interests:
None declared
Competing interests: No competing interests
This is an extremely worrying piece, but I am very glad that the
authors have written it. So one of the largest trials to test out the
side effects of statins excluded 44% of those screened? I think any trial
with such selectivity is practically invalid in terms of extrapolating the
results to an everyday primary care population. In everyday practice we
are not advised to exclude anyone from receiving statins, and the BNF says
‘They should be considered for all patients, including the elderly’, but
the PROSPER trial would appear to have been completely overlooked in the
rush to give everyone statins. No reduction in mortality? What on earth
is going on? Have these drugs really been properly assessed? We are
talking prophylaxis here with a drug that 50% of the population may end up
taking, at a huge cost to society, denying legitimate healthcare costs in
other clinical areas. The burden of proof of safety is far greater than
the use of routine drugs for clinical conditions, but the findings would
appear to be sketchy and certainly inadequate to back up one of the
largest public health measures ever. I personally have always been
dubious that there is anything other than a population link in the
reduction of cholesterol levels having a beneficial effect on
cardiovascular mortality. Sure, the statins may have an effect on LDL,
but who is to say that this is not a co-incidental side effect of the
drugs, and the main effect in reducing cardiovascular mortality is the
well known anti-inflammatory effect? And if it is the anti-inflammatory
effect then it would not be surprising that there is an increase in
cancers.
I personally have been studying depression in primary care for 5
years. When I started out I was flabbergasted to find the manipulation of
trials and suppression of data that the drug companies had universally
applied had totally skewed the outcomes, and that the evidence in favour
of SSRI’s was virtually non existent. This was particularly brought home
to me by the Cochrane meta–analysis which concluded that ‘differences
between antidepressants and active placebo are small’(1), followed by the
release of the 10 year data sets by the FDA for the four commonest anti-
depressants when some researchers concluded that the difference
(drug/placebo) was not clinically significant; indeed ‘medications must be
interfering with responsiveness in at least some others who would fare
better on placebo’(2). I am beginning to get a very bad feeling that
similar things have been going on with statins as with SSRI's, and we are
all dancing to big pharmas tune again here. Please someone, reassure me
that this massive statin intervention has a firmer basis than it appears
to. Someone please reassure me that there are more studies in the elderly
with statins that do show a marked reduction in mortality. If no-one can
reassure us of this, I think we all need to be very worried indeed.
1. Moncrieff J, Wessely S, Hardy R (2002) Active Placebo versus
antidepressants for depression. (Cochrane Review) Cochrane Library, Issue
3,2002
2. Kirsch J, Antonuccio D (2002) Antidepressants versus Placebos:
Meaningful advantages are lacking. Psychiatric Times September 2002 vol
19, issue 9
Competing interests:
None declared
Competing interests: No competing interests
While there is good evidence that statins and other cholesterol-
lowering drugs can be beneficial for a large number of people, my own
personal experiences would suggest that there are many for whom statins
can be injurious.
During my correspondence with people who have "post-polio syndrome",
I have found that many, like myself, have experienced severe myopathic
symptoms when on statin therapy. Additionally, since these symptoms have
been seen to occur when on supplemental CoQ10 and have also been seen to
occur with non-statin cholesterol-lowering medications such as ezetimibe
or cholestyramine, it appears that these symptoms may be due directly to
lowered cholesterol levels, vs inhibited synthesis of CoQ10.
A worrisome factor is that the onset of statin-induced myopathic
symptoms can apparently occur months or even years after the initiation of
statin therapy, and the primary symptoms are slowly increasing muscle pain
that can easily be misdiagnosed (especially in aging patients) as "normal"
overuse pain, fibromyalgia, or some other unrelated disorder. Initially,
a reduction in muscle effort may alleviate the symptoms, resulting in a
lowered level of physical activity and, ironically, increased morbidity
due to loss of cardiovascular fitness.
Yet, most of these adverse effects would be missed in short-term drug
studies, and are likely to be missed by many prescribing physicians,
greatly understating both the frequency and severity of the effects.
Competing interests:
None declared
Competing interests: No competing interests
Ravnskov and colleagues raise some important concerns about the
safety of treating much of the adult population with high-dose statins but
do not review how effective this might be[1]. These issues are important
in England and Wales as in January 2006, the National Institute for Health
and Clinical Excellence (NICE) Technology Appraisal requested that the
National Health Service (NHS) in England and Wales provide statin therapy
to all those with cardiovascular disease and to all with a 20% or more
risk of a cardiovascular event in the next ten years[2]. This guidance
gives no clue as to the proposed intensity of treatment, what dose of
statin should be used or what cholesterol targets people should be treated
to (if any).
The vacuum in this guidance leaves the updated Joint British
Societies’ Guidelines (JBS2) published in December 2005 to fill the
hole[3]. Is this wise? Their targets when using lipid-lowering therapy
are to lower total cholesterol to less than 4mmol/l or a 25% reduction, or
LDL-cholesterol less than 2mmol/l or a 30% reduction, whichever gets the
person to the lowest absolute value. These guidelines are based on
consensus, not evidence. What is apparent is that to achieve such targets
for many will require high dose statin therapy.
Is there evidence? There is emerging evidence to show some additional
benefit compared with standard dose therapy in high risk people with
established coronary disease but at the expense of harm related to
myopathy and liver disorder, as pointed out by Ranskov et al[1]. If more
aggressive therapy is applied to lower risk people, such as the primary
prevention population with greater than 20% ten-year risk of
cardiovascular event, as recommended by JBS2, there is a real worry that
this potential for harm could exceed benefit. This worry is supported by
evidence from the recently published Incremental Decrease in End Points
Through Aggressive Lipid Lowering (IDEAL) study[4] which compared
simvastatin 20mg-40mg daily (the dose was increased if total cholesterol
was greater than 5mmol/l, as in ‘4S’) with atorvastatin 80mg daily in
8,888 patients with a history of myocardial infarction. The primary
endpoint of major coronary event was not significantly reduced by
atorvastatin 80mg daily; HR 0.89 (95% CI 0.78–1.01), P=0.07. The
incidences of adverse events resulting in discontinuation (9.6% vs. 4.2%,
P<0.001) and raised liver enzyme levels (e.g. alanine aminotransferase
>3 times upper limit of normal 0.97% vs. 0.11%, P<0.001) were
significantly greater with atorvastatin than with simvastatin.
Thus, even the IDEAL study does not provide compelling evidence that
high-dose statin treatment should be used ahead of simvastatin (20mg and
40mg), as part of a general management strategy for secondary prevention
of cardiovascular events, let alone in primary prevention. It is also
instructive to look at the mean LDL-cholesterol throughout the study which
was lower in the atorvastatin 80mg group – 2.1mmol/l vs. 2.7mmol/l with
simvastatin; this suggests that even with high dose potent statin therapy
at least 50% of people will not obtain the targets proposed by JBS2.
Does this matter? Even putting aside concerns of safety the costs of
lipid regulating drugs in England was £600 million over the last year, and
this represented 8% of the total primary care drug spend; the single most
expensive prescribing area. The NHS is under immense financial pressure
and the absence of detail from NICE on intensity of therapy suggests it is
failing to do its job in giving guidance on cost-effective interventions.
[1] Ravnskov U, Rosche PJ, Sutter MC and Houston MC. Should we lower
cholesterol as much as possible? BMJ 2006;332:1330-1332.
[2] National Institute for Health and Clinical Excellence. Statins
for the prevention of cardiovascular events. Technology appraisal 94 and
related costing template and report. January 2006. Accessed from
www.nice.org.uk on 4/06/06.
[3] British Cardiac Society, British Hypertension Society, Diabetes
UK, HEART UK, Primary Care Cardiovascular Society, The Stroke Association.
JBS 2: Joint British Societies’ Guidelines on prevention of cardiovascular
disease in clinical practice. Heart 2005;91(Suppl V):v1-v52.
[4] Pedersen TR, Faergeman O, Kastelein JJP, et al. High-dose
atorvastatin vs usual-dose simvastatin for secondary prevention after
myocardial infarction. JAMA 2005:294:2437–45.
Competing interests:
None declared
Competing interests: No competing interests
It is true, like Ravnskov et al state, that any revision of targets
needs to be evidence-based and responsible, taking into account the risks
and benefits of such a measure. However, some of the authors' assertions
are unclear and potentially misleading.
The authors do not explain in what way Q10 lowering is actually
harmful. The Rundek study, one of the few that actually measured Q10
levels, did so in insufficient numbers of patients, and the authors of
that study go at great length to still arrive at a conclusion of
significance despite failing to show anything statistically solid.
In one of the largest studies to date, the Heart Protection Study
(1), no evidence was found for neuropsychiatric and pulmonary side-effects
above placebo level. With regards to cancer, Ravnskov et al disregard
recent evidence that statins seem to protect against several forms of
cancer, not least the very common colorectal cancer (2); instead, they
favour older evidence. The HPS had cancer incidence (including various
subtypes) as an endpoint, and no increased cancer risk was found in that
trial (1).
With respect to the authors' competing interests, it is stated
clearly that three of them dispute the very association between
hypercholesterolaemia and heart disease. A most useful model here is
familial hypercholesterolemia, in which young adults with no other risk
factors may develop accelerated atherosclerosis. With the underlying
biochemical abnormality very well known (LDL receptor defects), these
authors' hypothesis becomes almost completely untenable.
It does seem counterintuitive that a very large proportion of the
population may require pharmacological prophylaxis for cardiovascular
disease. At the same time it is widely aknowledged that dietary patterns
have deteriorated, we are in the middle of an obesity epidemic, and that
dietary measures are generally insufficient to mitigate cardiovascular
risk in both hypercholesterolemia and obesity. With the benefits of
statins documented in several very large studies (4S and Heart Protection
Study for starters), why deny statin treatment on the basis of relatively
inconclusive evidence?
(1) Heart Protection Study Collaborative Group. MRC/BHF Heart
Protection Study of cholesterol lowering with simvastatin in 20,536 high-
risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7
-22. PMID 12114036.
(2) Poynter JN, Gruber SB, Higgins PD, Almog R, Bonner JD, Rennert HS, Low
M, Greenson JK, Rennert G. Statins and the risk of colorectal cancer. N
Engl J Med 2005;352:2184-92. PMID 15917383.
Competing interests:
None declared
Competing interests: No competing interests
The Cholesterol Frenzy Continues
Dr. de Wolff states:
"....It does seem counterintuitive that a very large proportion of
the population may require pharmacological prophylaxis for cardiovascular
disease. At the same time it is widely aknowledged that dietary patterns
have deteriorated..."
If dietary patterns have deteriorated does he think that the intake
of cholesterol has increased significantly?
Since there is no evidence that this is happening what would have
justified White House physician Dr. Paul Dudley White's famous words
about being unable to find patients with CVD to try out his new EKG
machine on? Beef drippings, lard, eggs, butter, fatback....those were the
order of the day a hundred years ago. As to CVD, where were the bodies?
It is becoming increasingly clear to the man on the street that the
"prophylaxis" of Modern Medicine is often nothing more than the transfer
of wealth under false pretenses.
As to Dr. de Wolff's mention of Familial Hypercholesterolaemia, the
University of Leiden in the Netherlands published a study of three
individuals with FH.
They examined the medical histories of over 400 family members of these
individuals. Mortality was unrelated to the cholesterol level, yet it
seemed to be linked to the time during which the individuals lived.Those
who lived during the nineteenth and early twentieth centuries had no
increased mortality when compared to the population. If anything, they
tended to live longer.1
Perhaps a thorough reading of Ravnskov's book would be worthwhile, it
shows clearly why Professor George Mann (principal investigator of the
Framingham Study) called the cholesterol hypothesis "the greatest
scientific deception of our time" 2
References:
1 Sijbrands EJG and others. Mortality over two centuries in large pedigree
with familial hypercholesterolaemia BMJ 322, 1019-1023 2001
2 www.fonteine.com/cholesterol_mythe.html
Competing interests:
None declared
Competing interests: No competing interests