Clinical Review

Hypercholesterolaemia and its management

BMJ 2008; 337 doi: http://dx.doi.org/10.1136/bmj.a993 (Published 21 August 2008) Cite this as: BMJ 2008;337:a993

Should medical science ignore the past?

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
07 September 2008
Uffe Ravnskov
independent researcher
Magle Stora Kyrkogata 9, 22350 Lund, Sweden
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