Wednesday, 1 October 2008

Should we lower cholesterol as much as possible?

source: BMJ
Statins are portrayed as harmless drugs that almost everyone would benefit from, but little is known about the side effects at the high doses now being suggested

People at high risk of cardiovascular disease should be treated more aggressively. This is the message from the American National Cholesterol Education Program published last year.1 By aggressively, it means that low density lipoprotein (LDL) cholesterol concentrations should be lowered to less than 1.81 mmol/l. Recently, Getz et al calculated that in Norway, one of the healthiest nations in the world, about 85% of men and more than 20% of the women over age 40 would be classified as high risk using this criterion.2 If followed, the new recommendations might therefore put most of the Western world's adult population on statin therapy. As the risk to benefit ratio for a more drastic lowering of low density lipoprotein cholesterol is unknown we question the wisdom of this advice.

Heart failure
All statins inhibit the synthesis of hydroxymethylglutaryl coenzyme A reductase, an enzyme involved in synthesis of the precursor of cholesterol and other important molecules such as coenzyme Q10, vital for mitochondrial energy production. Thus statins lower plasma Q10 concentrations and worsen cardiac function in patients with heart failure, and oral coenzyme Q10 can improve or prevent this serious complication.8-10 Heart failure has not been reported with statins, possibly because it has been seen to be the result of the primary disease rather than an adverse effect but also because patients with imminent or manifest congestive failure are routinely excluded from statin trials.

Myalgia and rhabdomyolysis
Muscle complaints are claimed to occur in less than 1% of patients taking statins, but this is almost certainly an underestimate. In a study of 22 professional athletes with familial hypercholesterolaemia who were treated with various statins, sixteen discontinued the treatment because of muscle side effects.11 Competitive athletes may be more sensitive to muscle pain and weakness, but even mild symptoms may have a deleterious effect on elderly people and others who already have muscular weakness.

In rare cases, myopathy has led to rhabdomyolysis and death from renal failure. I

Mental and neurological symptoms
Cholesterol is vital for the development and function of the brain. It is therefore unsurprising that reduced concentrations may produce mental and neurological complaints such as severe irritability, aggressive behaviour, suicidal impulses, cognitive impairment, memory loss, global amnesia, polyneuropathy, and erectile dysfunction.13-19 In many cases the symptoms were reversible and re-occurred after re-challenge.

At least five animal experiments have found that the statins are carcinogenic in amounts that produce blood concentrations similar to those achieved by doses commonly administered to patients.20 Nevertheless, the FDA approved them because cell experiments did not convincingly prove that statins were either mutagenic or genotoxic. But carcinogenicity may be due to the effects of statins on cholesterol because numerous cohort studies have found low cholesterol to be a risk factor for cancer. This may take a long time to surface.

Summary points

US recommendations for low density lipoprotein cholesterol concentrations could put most of the Western world's adult population on statins

Doses of statins would have to be more than eight times higher than currently used

Increasing the dose of atorvastatin by eight times does not lower total mortality

Adverse side effects in clinical trials are under-reported

Any reduction in non-fatal events may be outweighed by more numerous and more severe adverse effects

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