Should medical science ignore the past?

7 September 2008

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: None declared

Uffe Ravnskov, independent researcher

Magle Stora Kyrkogata 9, 22350 Lund, Sweden

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