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A Family Doctor Looks at Statin ADRs

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by Duane Graveline, MD, MPH

The purpose of this article is to summarize what we doctors have learned about the various effects of statin drugs on the human body. Most of the adverse effects of statins have been revealed only in the past decade, some 10 years after these reductase inhibitors first were marketed. One might infer from this statement that marketing of statins in our society began long before we understood the full effects of these drug on human physiology. 

Strangely enough, the major adverse effect effect of statins was sufficiently well known to Merck, the originator of Mevacor, that Merck applied for two patents to help prevent the inflammatory response to come from excess CoQ10 inhibition. The patents were for a combination statin/CoQ10 pill. The patents were granted in 1990 and simply filed away by Merck. The company did not bring the combination drug to market. The government of Canada got around this concern by recommending to all patients taking statins that they also take CoQ10 and L-carnitine as supplements. 

Well into the past decade, longitudinal studies began to reveal the surprising effectiveness of statins even if cholesterol levels remained elevated. The so-called pleiotrophic effect of statins suggested that mechanisms were involved completely alien to the intended purpose of the drug to inhibit cholesterol synthesis. Subsequently this novel effect has been shown to be inhibition of nuclear factor - kappa B, a transcriptase vital to our anti-inflammatory and immunoregulatory systems, a surprising effect completely unforeseen by drug company biochemists (1).

The mevalonic acid-HMG-CoA reductase step that our statin drugs inhibit is but the first step on the long climb to cholesterol synthesis. Many intermediate steps are required before the ultimate goal of cholesterol synthesis is achieved. In at least two of these steps, five carbon units of the enormous steroid class of drugs, destined to be used for other biosynthetic pathways in the human body such as CoQ10 and dolichols, are involved. Statin drugs, while curtailing cholesterol biosynthesis, must inevitably inhibit the production of these other vital, intermediary products. Interestingly, nuclear factor-kappa B does not involve the mevalonate pathway, and this is the mechanism that appears to explain statins' benefit on CHD risk reduction. None of this was even dreamed of 10 years ago.

So now we begin to understand the varied nature of our adverse reactions. In 2001 Pfrieger announced to the world that the missing link in memory formation for which he had been searching for 20 years had finally been found. It was our arch-enemy, cholesterol. We even had special cells in our brains for the exclusive purpose of manufacturing cholesterol on demand, but we needed to understand much more. 

Why do so many people appear to escape statin's harm completely? Why do the symptoms so often take the form of accelerated old age? Why is fatigue so often present? Why are statin ADRs so selective, often appearing solely as memory loss, emotional change or neuropathy? We now have a hypothesis that seems to fit both our varied clinical presentations as well as Merck's CoQ10 concerns first voiced in 1990. It has to do with the inherent variability of mitochondrial DNA damage, coupled with the strong likelihood of alternative pathways for synthesis of our critical biochemicals.

CoQ10 is intimately involved both in the structure and function of our mitochondrial DNA. It is part of the structure of complex one and two of our electron transport system and it also has a specially important antioxidant role because of its location. The immediate effect of any statin is to reduce the bioavailability of CoQ10, potentially compromising electron transport as well as allowing excess free radical damage to the adjacent mitochondrial DNA.

Dolichol inhibition plays an equally important role, in that these compounds are vital to the process of glycoprotein synthesis. Tens of thousands of specific glycohydrolases are required to identify and correct each day's worth of DNA mutations. The impact of dolichol inhibition is an inability to correct oxidative damage. As a result, mutations build up, mitochondria fail, and ATP falls.

Our mitochondria exist in every cell for the purpose of creating energy in the form of ATP. An inevitable consequence of the metabolism of foodstuff is the production of free radicals. Ordinarily our antioxidant system, of which CoQ10 is a part, neutralizes these free radicals more or less completely. Statins interfere with CoQ10 availability. What results is the inflammation Merck was sufficiently concerned about that it requested two patents from the U.S. Patent Office in 1990. Who knows why it failed to pass on this concern to the medical community who soon would be prescribing statins?

The effect of mitochondrial damage may be mutations so severe as to result in their loss. Some of our tissue cells have only a few mitochondria to meet energy needs; others, such as brain and muscle cells, may have thousands. Gradually, they are consumed, resulting in cell death. When sufficient cells die the tissue dies, be it muscle fiber, nerve, pancreas or liver. The clinical picture is a matter of chance - perhaps  muscle weakness predominates in one person whereas another person may have more nerve cell involvement yielding the clinical picture of neuropathy. Another may also have memory impairment, another fatigue. That is the way of mitochondrial damage.

And why is it that some people seem to be able to take statins with impunity? The answer here is likely to be because of the presence of alternative synthetic pathways. In my 23 years of family practice, often I wondered why if you give ten people the same drug and same dose, about six would react the way the books predicted,.Two would over-react, experiencing an excessive response and the remaining two would under-react, with no response whatsoever. We doctors soon learned we are not all made the same way. It seems that multiple pathways to get from point A to point B may frequently evolve.

Whether statins affect you adversely or not, or what form the ill effects may take, is entirely up to chance. Tens of thousands of serious adverse reports have been filed. FDA warnings are far different today then they were 10 years ago. At that time FDA warned the myopathy rate was 2%. They now admit the myopathy rate is 20% (and in 68% of those people it will be permanent). Transient global amnesia was a medical curiosity then but after a decade of statin use some 2,000 cases of transient global amnesia have been reported to FDA just for Lipitor (with over 6,000 estimated from all statins combined). Still FDA has failed to warn about it specifically. Rhabdomyolysis was specifically included in FDA warnings only in February 2012 with 2,731 cases reported just from Lipitor. (All statins can cause this devastating reaction.) With a case fatality rate of 10% this single statin is causing over 25 deaths annually. Back in 2004, Baycol was taken off the market by Bayer because of the 60 deaths it had caused. The rhabdomyolysis score for Lipitor, Mevacor, Zocor or Crestor is now far higher than the one for Baycol ever was.

Perhaps you can explain it to FDA because I cannot. Also in February 2012, FDA announced that the diabetes rate from statins was from 5-10%. More recent data suggests it is much closer to 20%. Regardless of the figure FDA has, at least, issued a warning. Diabetes can be expected to shorten your life--so how does that affect the risk/benefit ratio of statins? It would seem incumbent on an agency dedicated to public health to be more forthcoming on the serious consequences of the drugs it has approved.

Duane Graveline MD MPH

Author: Lipitor, Thief of Memory and Statin Drugs Side Effects

Dr. Duane E. Graveline was a family doctor, aerospace medical research scientist, USAF flight surgeon and NASA astronaut.  Dr. Graveline interned at the famed Walter Reed Army hospital during the time our space pioneers were just beginning to study the medical effects of space flight. He became a flight surgeon and did space medical research on zero gravity deconditioning. He held a unique position as medical analyst of the Soviet bioastronautics program, NASA flight controller and finally, in 1965, was selected as a NASA scientist astronaut. Dr. Graveline still is affiliated with the space program as consultant to the special cosmic radiation hazards to man of "return to the moon and on to Mars."

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You can listen to Dr. Graveline tell his story on our radio show. 

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For the past 4 years the endocrinologist treating my thyroid levels due to surgical removal, has insisted I take at least three 500 mg fish oil pills at bedtime because I won't go on statins for cholesterol of 270 and high triglycerides of 380, at which time my incontinence started. My thyroid has been gone for over 12 years. She says my failure to treat the triglycerides with statins will land me in the emergency room with pancreatitis soon. My problem is this: When she suggested I up my fish oil to 4 pills, my elbows hurt so bad I couldn't even carry my own purse -- so I cut back to 3, but the bladder spasms I developed about the same time as starting the fish oil just won't quit, making me incontinent. I had a colonoscopy last month for which I had to quit the fish oil for 9 days in advance, and, to my surprise the bladder spasms absolutely stopped after the second day without fish oil, so I'm no longer incontinent. Is there some relationship between fish oil intake and bladder spasms? I would really like to keep taking at least one fish oil daily for the slippery effect it has in the bloodstream to prevent clots. I'm a fairly sedentary, 53 year old female on 200 mcg. levothyroxine, three 500 mg. Metformin daily, and very recently one Tradjenta daily. My endocrinologist said I probably needed bladder surgery to stop the incontinence. I think I'm being lied to. Please advise on the incontinence relationship to fish oil because I'm not having surgery for it but I believe 1 fish oil pill a day would be beneficial. Thanks!

People's pharmacy response: We are not familiar with incontinence as a side effect of fish oil. We will be interested to hear if other readers have had a similar experience to you.

If statins alternatives have similar side effects what's the solution to high cholesterol?

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