Lipid Lowering and Risk of Statin Side Effects

The Molecular Research Institute of Tuft's New England Medical Center reported the results of a large study of the relationship of statin side effects to the magnitude of lipid lowering achieved.

Common sense says that the higher the statin dose with its resulting fall in cholesterol, the greater the side effect problem, right? If you said right, you are wrong and if you said wrong you are wrong. The results of this study proved to be interesting.

It increasingly appears that the benefit of statin drugs on atherosclerosis with its stroke and heart attacks is not due to cholesterol reduction but to the powerful anti-inflammatory effect of statins.

Atherosclerosis is now considered by most to be an inflammatory process. Cholesterol, the former villain, is now felt to be irrelevant and is there in the plaques solely as an innocent bystander to the body's inflammatory response. And one of the concerns about this new anti-inflammatory role of statins is that it is mediated through inhibition of nuclear factor-kappa B, a transcriptase vital not only to our body's inflammatory response but also our entire immunodefence system. To inhibit inflammation therefore must also inhibit the ability to neutralize viruses, bacteria and mutagenic cells.

You cannot have one without the other. It seems that if you lower heart attack death rates by the use of statins, you increase cancer death rates. And that is exactly what Alawi and his group found.

On the other hand, if you are talking other statin side effects such as rhabdomyolysis and hepatitis mediated through reductase inhibition of the mevalonate metabolic pathway - the widely stated mechanism of action of all statin drugs - the risk of these side effects shows no correlation with lower cholesterol reduction and these two conditions tend to occur just as frequently with minimal cholesterol reduction and statin dose as with the cholesterol hyper-responders and today's super dosing. Some of the worst reports of these two side effects occur with very modest cholesterol changes and statin doses.

If one goes to the chart of the mevalonate pathway and finds the reductase step in this long sequence of biochemical reactions, the first thing you note is that the much touted reductase inhibition, common to all statins, is at the very beginning of the mevalonate pathway. The next thing you notice is that several other metabolically vital pathways share the common mevalonate path. So to inhibit cholesterol synthesis must affect everything else as well but not necessarily to the same degree. This gives us a plausible explanation for why a small cholesterol effect might be associated with a large CoQ10 or dolichol effect. It is a matter of different sensitivities of the different paths involved. And likely, this is all a matter of inherent genetic variability.

I would like to extend this discussion to cognitive effects and statin dose and predict that it, too, is independent. In my own case of transient global amnesia two months after Lipitor 10mg daily, a worst case occurred the following year when at my insistence the dose had been reduced to 5mg daily. This dose was miniscule by any standards yet sufficient to wipe out my entire adult life for a horrifying, in retrospect, 12 hours.

Cognitive effects like these appear to be mediated by statin inhibition of glial cell cholesterol manufacture. We have evolved with this glial cell dependency but did not know this until Pfrieger's paper of 2003. If Alawi and his other authors had included this common side effect of statin in their study, I am certain it would have proven to be completely independent of statin dose and have to do with the inherent sensitivity of the brain cholesterol synthesis capability.

It is not every day that a major study offers results so closely documenting what I would suspect from my past seven years of statin side effect study.

Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor

Books From Amazon

The Dark Side of Statins
The Statin Damage Crisis
Cholesterol is Not the Culprit
Statin Drugs Side Effects
Lipitor, Thief of Memory

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