Management of Statin Side Effects


There are no experts in this new medical challenge of preventing and repairing damage done by statin drugs. The scope of statin associated side effects is extremely broad, reflecting the effect of these drugs on multiple physiologic and biochemical pathways.

To understand the rationale for what I am about to say first requires an understanding of the mechanisms of action of the statin drugs as we currently understand them.

Statins drugs have two primary effects on the human body. The first of these is the effect for which these drugs were designed 20 years ago - reductase inhibition of the mevalonate metabolic pathway thereby achieving inhibition of cholesterol synthesis. The second primary effect of statin drugs is serendipity's gift to us, meaning that they just stumbled on to it - nuclear factor kappa B inhibition (1), whereby it exerts the powerful anti-inflammatory action thought by many to be the reason for its benefit in cardiovascular risk reduction.

Directing our attention first to the consequences of mevalonate metabolic inhibition, Statins gird this entire pathway, resulting not only in inhibition of cholesterol synthesis but also inhibition of CoQ10, dolichol, and seleno-protein synthesis and disruption of normal phosphorylation pathways. This latter effect has been reported by Meske (2) to result in enhanced tau protein formation, the stuff of neurofibrillatory tangles.

With NF-kB inhibition, the resulting anti-inflammatory action appears to be favorable for minimizing the consequences of atheromas but what of the parallel immunomodulatory effects on cancers and infections?

It is now believed by many that the reason for the powerful cognitive effect of statins with the amnesia, confusion, forgetfulness, and disorientation, increase of any pre-existing senility and persistent loss of short-term memory is due to their inhibition of glial cell synthesis of cholesterol. Pfrieger (3) first documented this in 2002 when he demonstrated for the first time the important role of cholesterol in the formation and function of the trillions of synapses connecting our neurons.

Since no other means exists for supplying synaptic cholesterol in human brains, the cognitive effects are obvious and predictable. This is why Muldoon (4) has twice reported, first with Mevacor and again, in 2004, with Zocor, 100% loss of cognitive function in statin users if sensitive enough testing is done.

The importance of CoQ10 and its sensitivity to statins has long been known. This is the reason Canada insisted on warning labels for the need for supplemental CoQ10 to be placed on every statin prescription. For some reason the FDA neglected to do this and one can only wonder why this fundamental need was neglected. Was it because the FDA's entire post-marketing adverse drug reporting function is subsidized by drug companies? The adverse drug reports directly attributable to CoQ10 inhibition by statins includes: those associated with energy production - congestive heart failure and chronic fatigue and those associated with loss of cell wall integrity - hepatitis, myopathy, rhabdomyolysis and neuropathy.

Recently we have learned that the side effects of dolichol inhibition include a broad spectrum of behavioral and affective disorders resulting from impaired neuropeptide synthesis More recently I have learned that this assembly of peptide fragments within the endoplasmic reticulum of every cell in our body is only a small part of dolichol's contribution for it is here that vital sugars are attached to proteins and lipids to give a far broader range of diversity and information transfer than either protein or lipid alone can achieve. No longer do we consider sugars as just simple fuel. The effects of just eight vital sugars is just short of miraculous for this is the very center of cell communication and immunodefence. And this attachment of sugars is completely dependent on dolichol's orchestration.

Additionally, we find that the puzzling association of statin uses with onset of such neurodegenerative diseases as MS, ALS, Parkinson's disease and Alzheimer's might relate to the tendency for formation of tau protein when the normal phosphorylation pathway is statin suppressed. Tau is that protein so prominently deposited in the brains in Alzheimer's patients and also has been observed in other neuro-degenerative diseases.

Selenoprotein suppression (5) is yet another consequence of mevalonate pathway inhibition. Recent study has demonstrated a strong relationship of certain neuro myopathies to this factor, especially those cases of muscle pain with exercise and normal muscle enzymes. I cite this evolving research area only to document the existence of these other means by which statin drugs can cause diverse effects in susceptible individuals.

Directing our attention to management, the obvious inference from our preceding review of relevant biochemistry is that we must be far more restrictive in dosing Statins. With the misguided focus on cholesterol, clinicians have been drawn to higher and higher statin dosing. These higher statin doses lead inexorably to greater mevalonate pathway inhibition with its broad range of side effects. Now we have learned that cholesterol is irrelevant to cardiovascular disease control.

Atherosclerosis, I believe, is an inflammatory process and that statins work because of their anti-inflammatory action. Therefore statins should be dosed on the basis of inflammatory response not cholesterol reduction. In 2003, Hilgendorph (5) revealed that the dose / response characteristics of the various statins were such that his basal dosing gave 60% of the maximum NF-kB inhibition with very little difference at progressively higher doses. This way an anti-inflammatory effect is achieved with minimal immunomodulatory action and negligible mevalonate pathway inhibition. In my opinion to this modest statin should be added robust omega 3 with modest supplementation of CoQ10, B6, B12 and folic acid and buffered baby aspirin.

Directing our attention to those already presenting with statin associated damage, the addition of CoQ10, Acetyl-L-carnitine and selenium should be considered in my opinion for persistent muscle pain and weakness. These recommendations are based upon known mechanisms of action of statin drugs and results of recent research.

References: 1) Shovman.Immunol Res,25(3)2002. 2) Meske. Eur J Neurosci, 17, 2003. 3) Pfrieger. Science, 9 Nov, 2001. 4) Muldoon. Am J Med, 108(7), 2000. 5) Mooseman. Lancet 363, 2004. 6) Hilgendorph. Intnat J Clin Pharm and Therapeut, 41(9), 2003.

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

 


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