For statin damage crisis skeptics:

[www.spacedoc.com]

Statins and Mitochondrial Mutations
By Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor


When I first wrote of my personal reaction to Lipitor seven years ago, I considered myself to be lucky to have had only transient amnesia episodes, for when it was over, I was back to normal - or so it seemed to me for the next several years. During this time my statin damage research gradually was revealing hundreds of cases of permanent disabling peripheral neuropathy, permanent myopathy and progressive neuro-muscular degeneration and I wondered, for suddenly, in the past two and one-half years, I have grown old, with weakness and easy fatigueability and the posture and gait of an old man.

My exposure to Lipitor had been minimal - a total of three and a half months at 10mg or less. My awareness of possible statin causation came to me slowly as years passed and I read report after report from statin damaged victims. Many of them exactly described my story, with a gap from beginning of drug intake to onset of symptoms often measured in many years. The feeling of weakness and easily fatigueability of legs and low back made me cringe at the idea of exercise. A chair became my preferred refuge. I am now a doddering old man with withered limbs, a stranger in the mirror.

If my transition to this state had been gradual, the natural result of getting old, I might have missed the relationship, but to transition thusly in just a few years was clearly not normal, and hundreds of other people, all statin users, were experiencing the same thing. My rheumatologist considered a possible ALS-like condition. My neurologist said he strongly suspected mitochondrial mutations secondary to statin use. Only muscle biopsy would refine this presumptive diagnosis, but he had been seeing this syndrome for several years and strongly suspected a statin causation. He said that there is no treatment. This ALS-like condition is slowly progressive and eventually disabling.

What about this presumptive mitochondrial mutation etiology? Does this have merit?
Mitochondria are organelles that provide most of the energy our cells need for the work they do. It is in the mitochondria where CoQ10 and the reduced forms of niacin and riboflavin enter into that ingenious process of moving electrons from hydrogen molecules to one side of a mitochondrial leaf while storing the remaining protons on the other side, creating an energy gradient - the magic energy resource of every cell in our bodies. It is here that oxidative phosphorylation takes place to create ATP.

As with any form of DNA, mitochondrial DNA (mtDNA) sequences are susceptible to mutation. In fact, there is evidence that mitochondrial sequences may mutate at rates 3 to 5 times greater than nuclear sequences. This may be because of the front-line position of these tiny warriors in their battle to utilize oxygen without themselves being oxidized. Constantly at risk they ordinarily are well supplied with anti-oxidants.

Enter statin drugs, capable of halving your CoQ10 in just a few weeks through the inevitable process of mevalonate blockade while inhibiting cholesterol synthesis. Gone is the fuel of the mitochondrial engines and gone is one of the most important anti-oxidants, with the ****of inactivation of free radicals. Abruptly the mutation rate increases at the same time the mitochondrial engines are running low on fuel. Is this something to consider as a cause of statin-altered physiology?

Statin associated chronic neuropathy and chronic progressive myopathy may well be examples of this process in action. It seems likely that a side effect of statin drugs in some people is to trigger just this process - mitochondrial mutations of sufficient frequency and severity to express as a chronic, even progressive condition. Indeed, it is known that accumulating mitochondrial mutations contribute significantly to aging. This appears to be what we are seeing in the cases of permanent muscle wasting, weakness and neuropathies seen usually only in advanced age.

Variability of expression may well explain why some people seem extraordinarily sensitive, showing symptoms early, while others show no apparent effect but may well be victims of low-grade, accelerated aging type of presentation, taking years to become evident. This may also help to explain why some people may be on a statin at an unchanged dose for years before abruptly manifesting symptoms.

The Statin Damage Crisis by Dr. Duane Graveline.

Book Description (Publication Date: March 15, 2009)

The purpose in the choice of the title The Statin Damage Crisis is to draw attention to the thousands of statin damaged people who have written to Dr. Graveline about their disabling neuropathies, myopathies and a variety of neurodegenerative conditions such as ALS and Parkinsonism associated with statin use. Although much of the book's content will be familiar to readers of Statin Drugs Side Effects (this was originally planned as a new edition), The Statin Damage Crisis adds much new material that Dr Graveline has learned of in the past two years. Dr Graveline states:

"Early on my NASA doctors told me my amnesia response to statins was nothing but a coincidence, but I persevered to write my first book, Lipitor, Thief of Memory... Then I learned of statin damage to nerves and muscles and profound behavioral and personality changes, demanding I write a second book, Statin Drugs Side Effects... Even this broadly encompassing book was insufficient to describe what I have learned more recently of the truly dark side of statins - their ability to alter the very fabric of our makeup... I had long wondered why muscle and nerve damage seemed permanent and even progressive like my own ALS-like condition. Now I have found that the ultimate effect of statins on CoQ10 and dolichols is to damage the DNA of the mitochondrial life-force within our cells - mitochondrial mutations masquerading as premature old age."


Read reviews at [www.amazon.com]

Erling - thanks for this. It is a reminder to me that the hints of peripheral neuropathy that I've noticed for the past couple of years may not be related to low back issues (as doctors surmise) but most likely, the damaging effects of statins I took for a short time 22 years ago...now catching up with me in spite of my heroics to keep the mitochondria healthy. Maddening.

Jackie

Please show me one shred of scientific evidence to back this position. Anecdotal claims simply do not cut it. What lab actually did the dna analysis?
Statins are definitely not for everyone.

"suddenly, in the past two and one-half years, I have grown old, with weakness and easy fatigueability and the posture and gait of an old man."

"The feeling of weakness and easily fatigueability of legs and low back made me cringe at the idea of exercise. A chair became my preferred refuge. I am now a doddering old man with withered limbs, "

That's exactly what happened to me, but it started maybe 5 years ago, and I have never used statins. Unless maybe the PTB are putting statins in the food?

Frank, do your own research - if you're not interested, I'm certainly not interested in doing it for you. For the basics you can study Mitochondrial DNA in Aging and Disease by Douglas C. Wallace, PhD at [www.nslc.wustl.edu]. Then all you'll have to do is decide for yourself if blocking Co-enzyme Q10 synthesis will increase the rate of damage to the mitochondrial DNA. Hint: you'll find Coenzyme Q [CoQ10] in the inner membrane of the mitochondrion between complexes I -> III, and II -> III.

Erling

Frank - it's really misleading to rely on studies. There have been a lot of reports about the bias in studies and how they are often designed to have the outcomes they want.

In 2007, I posted a review of the book by John Abramson, MD, who was also faculty at Harvard Medical School.... "Overdo$ed America"....

It begins:

Dear Readers~
This is another lengthy post but one that is especially relevant to our group since we read studies and do research.

Caveat lector: let the reader beware.

So often we reference clinical studies published in respected medical journals to support or refute a finding on a health issue, a drug, a supplement, procedure or medical device. Today, this is a risky practice.

The focus of this report is to alert readers as to why we should view studies with a critical eye (perhaps skeptical) and to create awareness about the bias or spin now permeating our most respected medical journal publications as well as the commercialization of clinical trial material to create demand for pharmaceuticals or medical innovations.

Here's the section that that pertains to statins....

CHOLESTEROL & STATINS

Another key motivating factor to write the book concerns cholesterol and the fact that the National Cholesterol Guidelines keep increasing in strictness.

To set the stage about this situation: In year 2000, Americans were twice as likely to be taking a statin – a cholesterol lowering drug as people of equal risk in Europe and of the 25 million people world-wide who were taking a statin, 13 million were in the US. So we were taking twice our share of statins and Americans were getting three times the number of cardiac procedures – angioplasty and bypass procedures –as were the citizens of the other industrialized countries. So twice as many statins; three times as many procedures. You might say that’s evidence of high-quality medicine but the problem is that the death rate for heart disease in the United States ranked 19th among the industrialized countries and we were losing ground to most of them – we were not getting better, we were getting worse.

In response to that, instead of saying wait a minute, time out, maybe we’re approaching heart disease prevention the wrong way and maybe we ought to be looking at the scientific evidence that shows that lifestyle and nutrition are the key factors in heart disease prevention – not cholesterol and giving drugs. But instead of going in that direction, we went in exactly the opposite so that in 2001, the third iteration of the Cholesterol Guidelines recommended taking the number of Americans on statins from 13 million to 36 million…almost tripling the number of Americans on statins in one fell swoop.

And the problem is that most of the people for whom statins were recommended --23 million people- most of those people did not yet have heart disease because we already understood that statins are beneficial for people who do have heart disease (that came out in the 1993 Guideline) so those 13 million people already had statins recommended for them. So the 23 million people for whom statins became recommended in 2001, didn’t have heart disease.

This is such an outrage –the guidelines say recent clinical studies show that statins reduce the risk of heart disease in women who don’t yet have heart disease and they cite 7 studies. But not a single one of those 7 studies shows evidence to substantiate that statement but there is no way any practicing clinician would ever know that. I found that out because I was doing research for Overdo$ed America and I went through all the footnotes and checked them but the good ole boys just weren’t telling the truth. And in fact – that’s section 2 – anyone can get them if you just want to Google NCEP or National Cholesterol Education Program you’ll get this 284 page guideline. Section 2, they make this misrepresentation about the studies that show these drugs are beneficial for women. In section 8 which is the very back of the guidelines they say “Special Considerations for Women” and say… “Clinical studies to show that statins are beneficial are generally lacking for women. So they admit they weren’t telling the truth. And then they go on and say “These recommendations for women are based on extrapolation of data from men.” Women’s blood should be boiling about this issue.

That was 2001. In 1998, we had the HERS study published in JAMA and that showed that women taking combined hormone replacement therapy their bad cholesterol goes down, the good cholesterol goes up and if anything they had more heart disease – not less. It is very clear there is a different relationship between cholesterol and heart disease in women than men and the folks who are writing th4se guidelines knew it.

And the same story for people over 65. They say that recent studies show that aggressive LDL lowering is effective and cite 9 studies to justify that statement and not one of the 9 actually shows it.

(Ref. p 246 of the book) The PROSPER study came out after the 2001 guidelines and is a well-designed study. It’s a drug-company sponsored and it is designed fairly. It looks at the effect of lowering cholesterol with a statin drug in people from age 70 to 82. It’s a fair mix of men and women and a fair mix of people who did and did not have heart disease. What the PROSPER study found is that people age 70 and over who did not already have heart disease, got no benefit from taking a statin.

There was no significant reduction in the risk of heart disease or mortality compared to the people who took a placebo. But they did have a statistically significant higher incidence of cancer. So that in this study of people ages 70 – 82, who took a statin – short study 3.4 years, in that 4th year of the study, for every 70 people taking a statin drug, there was one extra case of cancer.

So you’ve got the majority of people who are taking statins, don’t have heart disease, there is no evidence they are beneficial for people over 70 for people who don’t have heart disease, and there is statistically significant evidence they increase by 25% the risk of cancer.

When there is no randomized control study that shows benefit and we have a drug-company sponsored trial that shows the risk of cancer goes up in an older population, this makes no sense. To be on a national campaign to get people to take more statins in this category, I find sinful. Just plain sinful. Significant evidence of harm and not evidence of benefit.

If you look at the entire mix of these people age 70-82 , it gets even more striking - half already have heart disease and looking at the whole study, there is no reduction in mortality, when these people are treated with a statin. And yet we know from another study done in Europe, if we look at older people who do four healthy habits – exercise routinely, eat a healthy, Mediterranean style diet, don’t smoke and drink in moderation - the people over 65 who do those four things have a 60% lower death rate than the people who don’t do those things. Yet we are spending our time putting them on statins which increases the risk of cancer.

Statin drugs are the most heavily prescribed drugs hands down – no matter what age but – especially for seniors. Is there science to support how and why these are prescribed especially for seniors? Answer – there is some science and it’s really important to look at this. This is an especially important topic. Statins are the biggest drugs used and it’s enormously important example of what’s going on in the United States. We have this huge campaign to lower cholesterol and what has happened is just like a master magician. We have our eye on cholesterol when the real goal is to reduce the risk of heart disease and stroke. What’s happening is that the statin drugs reduce cholesterol very nicely – no question – but there is not a single randomized controlled trial that shows that these drugs are beneficial for women who don’t have heart disease or people over 65. Not a single trial and ¾ of the people who take these drugs don’t have heart disease

Now, there are three groups of people – men under 65, women under 65 and people over 65.
For men, there are shades of gray. Very high risk men get some benefit from statins not as much as they would get from, exercise, nutrition, quitting smoking and controlling stress – but there is some benefit. But for women, there is not a single randomized controlled study on file that shows that women who do not have heart disease or diabetes benefit from taking a cholesterol lowering drug. Not a one. And yet millions of American women are on these drugs.

Similarly, for people over 65, there is not a single randomized, controlled trial that shows that people over 65 who don’t have heart disease or diabetes would benefit from taking a statin drug. In fact, the one study that does address older people – the PROSPER study, published in Lancet in 2002, looked at people over age 70 – an equal mix of men and women – and equal mix of primary and secondary prevention meaning people who did not yet have heart disease and those who already had heart disease – and for the primary prevention patients (who don’t have heart disease), statins were not beneficial – they did not reduce the incidence of cardiovascular disease or death but statins did increase the risk of cancer by 25% in an older population. So to be recommending statins – and we’ve all heard the phrase, statins should be put in the water they are so good – for people over 65 who do not have heart disease when we don’t have a randomized control study that shows it’s beneficial and we have a drug-company-sponsored trial that shows that the risk of cancer goes up by 25% in an older population, it makes no sense.
end of clip

Read the entire post:

<[www.afibbers.org]>

Jackie

William - You are how old? Are you still experiencing this? If so it would appear to be the same effect... the lack of CoQ10 and then all the other nutrients involved in the ATP/mitochondrial energy production. I hope it was a former complaint for you and is not ongoing. Jackie

IIRC I'm a year younger than you, and yes it is still ongoing.

Didn't think I could be short of CoQ10, should be in the raw meat of healthy animals.

William

William... so you're still a kid!! Long ago when I was learning about the merits of CoQ, it was said that dietary intake of liver and salmon provided the best sources but you had to eat a lot of it. Sardines have it but it would take about a kilogram of sardines to get 100 mg ubiquinone.

The body does naturally produce CoQ but that ability declines with age... I believe the decline point begins around age 25..... so 50 years later, we are probably not producing much on our own. Since you have a high protein intake, one would think that might be sufficient, but then to complicate the story is the fact that also as we age, we are less apt to convert the ubiquinone form to the functional form, ubiquinol.

I found this to be true in my case and also found that supplementing with the regular, ubiquinone form of CoQ10 wasn't enough to give me the muscle function I expected and required. I switched to the Ubiquinol form at high doses (400 mg initially) and everything changed. Like turning on a light switch. Downside: Ubiquinol is pricey. Upside: Even with the muscle damage from statins, I can walk briskly and easily on the treadmill for a couple of miles... and better yet, it allows my heart to feel rock-solid.

Kaneka has produced the patented, reliable ubiquinol form that is the one used successfully in studies to reverse cardiomyopathy and heart failure. Here's a clip from their website:

...."Ubiquinone (CoQ10) levels within the body typically begin decreasing as early as age 20, suggesting that it has a close connection with aging. Additionally, the body’s ability to convert these declining levels of CoQ10 into ubiquinol is also diminished with age. Without proper levels of these vital substances, the body produces less energy and lacks a strong defense against oxidative stress*.

Inadequate levels of ubiquinone and ubiquinol in our plasma and tissues may lead to fatigue as well as a number of age-related conditions*. Additionally, ubiquinol levels have been shown to be reduced in individuals with cardiovascular, neurological and liver-related conditions*.

As the body begins losing its natural ability to maintain optimal levels of ubiquinone and ubiquinol, the most efficient way to restore healthy levels of these nutrients is through supplementation*.

For those who are still able to convert ubiquinone to ubiquinol, supplementing with CoQ10 should be sufficient. However, those who are over 40 years old or suspect their ubiquinol production may be diminished due to oxidative stress should consider supplementing with ubiquinol (KanekaQH™) to raise their plasma levels most efficiently*.
[www.kanekaqh.com]

Thru Hans' vitamin link, [www.iherb.com]

Jackie

William,

The link given in Jackie's posting [www.iherb.com] will not take you to the afibbers.org vitamin shop so afibbers.org will not benefit if you order through this link. You need to use this link [www.afibbers.org]

Hans

Hans - when I called up that link, I first went to your afib vitamin shop link and then clicked on your ubiquinol recommendation....but since I wanted the Natural Factors Ubiquinol which is less expensive, I did the search for it from that link. I thought that was the way to do it. Apparently not.

Am I assuming incorrectly that if we go through the Vitamin Shop Icon, that is enough to automatically have the order credited to you?

Jackie

Jackie,

You are correct. If you go into the afibbers.org vitamin shop and THEN search for and buy the Natural Factors ubiquinol I'll get credit. However if you or someone else go directly to the link you posted I will not get credit as it does not take you to the afibbers.org vitamin shop first.

Hans

Ubiquinol ordered from iHerb via afibbers.org vitamin shop.

Ubiquinol (as Kaneka QH® Ubiquinol)
100 mg

PrimaVie® Shilajit fulvic acid complex
100 mg

Other ingredients: sunflower oil, gelatin, glycerin, purified water, yellow beeswax, caramel color.

This product contains NO milk, egg, fish, peanuts, crustacean shellfish (lobster, crab, shrimp), soybeans, tree nuts, wheat, yeast, gluten, corn, or rice. Contains NO sugar and no artificial sweeteners, flavors, colors, or preservatives.

Not good.

William

As early as 1993 a formal study demonstrated ~40% reduction in Coenzyme Q10 following just 3 months of statin use:

[www.ncbi.nlm.nih.gov]

J Clin Pharmacol. 1993 Mar;33(3):226-9.

Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study.

Ghirlanda G, Oradei A, Manto A, Lippa S, Uccioli L, Caputo S, Greco AV, Littarru GP.

Institute of Internal Medicine, Catholic University Medical School, Rome, Italy.

Abstract

Inhibitors of HMG-CoA reductase are new safe and effective cholesterol-lowering agents. Elevation of alanine-amino transferase (ALT) and aspartate-amino transferase (AST) has been described in a few cases and a myopathy with elevation of creatinine kinase (CK) has been reported rarely. The inhibition of HMG-CoA reductase affects also the biosynthesis of ubiquinone (CoQ10). We studied two groups of five healthy volunteers treated with 20 mg/day of pravastatin (Squibb, Italy) or simvastatin (MSD) for a month. Then we treated 30 hypercholesterolemic patients in a double-blind controlled study with pravastatin, simvastatin (20 mg/day), or placebo for 3 months. At the beginning, and 3 months thereafter we measured plasma total cholesterol, CoQ10, ALT, AST, CK, and other parameters (urea, creatinine, uric acid, total bilirubin, gamma GT, total protein). Significant changes in the healthy volunteer group were detected for total cholesterol and CoQ10 levels, which underwent about a 40% reduction after the treatment. The same extent of reduction, compared with placebo was measured in hypercholesterolemic patients treated with pravastatin or simvastatin. Our data show that the treatment with HMG-CoA reductase inhibitors lowers both total cholesterol and CoQ10 plasma levels in normal volunteers and in hypercholesterolemic patients. CoQ10 is essential for the production of energy and also has antioxidative properties. A diminution of CoQ10 availability may be the cause of membrane alteration with consequent cellular damage.

==========

Coenzyme Q10 <[en.wikipedia.org]>

Inhibition by statins and beta blockers:

Coenzyme Q10 shares a biosynthetic pathway with cholesterol. The synthesis of an intermediary precursor of coenzyme Q10, mevalonate, is inhibited by some beta blockers, blood pressure-lowering medication,[23] and statins, a class of cholesterol-lowering drugs.[24] Statins can reduce serum levels of coenzyme Q10 by up to 40%.[25] Some research suggests the logical option of supplementation with coenzyme Q10 as a routine adjunct to any treatment that may reduce endogenous production of coenzyme Q10, based on a balance of likely benefit against very small risk.[26][27].

Intake:

In the developed world, the estimated daily intake of CoQ10 has been determined at 3–6 mg per day, derived primarily from meat.[72]

Video, 2007: Cardiologist Peter Langsjoen discusses the clinical implications of Coenzyme Q10 [www.youtube.com]

This is interesting... you note 1993 as formal studies indicating CoQ reduction with statin use. I was a case study of my own prior to that. My statin use was in 1989 and only after about 2 months taking either pravacol or zocor (one or the other), I experienced profound leg pain and muscle weakness. When I complained to the Internist, he said: Nonsense, there is nothing to indicate that should happen. My response was: Well, that's the only drug I'm taking so I have to think that's the cause. He replied... Well, I'll just change to another type... so I either started with the pravacol and switched to zocor or the reverse. When the pain and fatigue persisted. I just stopped it and never bothered to go back to that doctor.

I was only 53 and from then on, I had far less stamina and muscle power than previously, although I did manage to do everything I was used to doing, although it was much more difficult. I was unable to hop on one foot as a result and I am still unable to do that simple task. I am grateful that I wasn't mentally injured. Poor Dr. Graveline. Criminal, these statin perscriptions.

It's undoubtedly that individual variabilities or uniquenes allow more detrimental consequences in some than in others. When I get into the CoQ10 depletion and all that happens downstream as a result of that, I can't help but wonder if (for me) it wasn't also contributory to my AF onset at age 59. I'll never know for sure, but I would not be at all surprised.

These are good links, Erling. Thanks for archiving them here.

Jackie

==================

An Interview with cardiologist Peter H. Langsjoen, M.D.
September 8, 2011, By Kirkham R. Hamilton, PA-C


Audio: [www.prescription2000.com]

Text: [www.prescription2000.com]

Excerpts:

DR. PETER H. LANGSJOEN: ... we can just refer to [coenzyme Q10] as Q for brevity...

[In early research] heart muscle was the obvious organ to study because it uses a huge amount of energy and therefore requires an adequate and very high concentration of Q.

...when you replenish Q, you can bring about just beautiful changes in heart muscle function that can't be explained in any other way. In other words, you're not changing the the anatomy of valves in the heart, you're not changing the blood flow or the coronary circulation. So you could safely say that the majority of patients with failing hearts have as one of the fundamental problems an energy deficit or a weakening of heart muscle function.

And when CoQ10 came along -- you know it was discovered in 1957 -- there was a decade or so of basic animal work and biochemical work, and then another decade or so of early Japanese work, all of which was favorable. And it showed very simply that CoQ10, which is the co-factor essential for the great majority of cell energy production, was very low in animals, and then later in human studies in the failing heart. And it was low if you measured it in the blood and even more accurately low if you took a biopsy of the heart. So even before my father's first studies, it was pretty clear that you could measure CoQ10. It was low in patients with heart failure, and the worse the heart failure, the lower the level, and we knew even in those early years that it was essential for the production of cell energy. And heart muscle was the obvious organ to study because it uses a huge amount of energy and therefore requires an adequate and very high concentration of Q.

...when you replenish Q, you can bring about just beautiful changes in heart muscle function that can't be explained in any other way. In other words, you're not changing the anatomy of valves in the heart, you're not changing the blood flow or the coronary circulation. So the majority of patients with failing hearts have as one of the fundamental problems an energy deficit or a weakening of heart muscle function.

...as you're probably aware, heart failure is the number one diagnosis in hospitalization over the age of 65. You always have to be careful that as a profession we are not in some way contributing to it, and one convenient villain that comes to mind is the very aggressive use of statins. Statins dramatically deplete both cholesterol and the coenzyme Q, because they block the common pathway for the biosynthesis of both. And our current research right now is looking at the natural history of statin cardiomyopathies. And just in the past 12 months [at our clinic] we have a little less than 100 [new] cases, and we're excluding anyone who might have a weak heart for any other cause. So these are people who have never had a heart attack, who do not have a bad heart valve, who haven't had chemotherapy or some other insult to the heart, so statins come to mind as a possible aggravating factor. It's not recognized by the general cardiology community, but it's worthy of further work for sure.

When we first viewed this, we thought if heart failure patients, let's say on average had a blood Q level of 0.5 micrograms per milliliter, and if normal people were around 1 -- in other words the failing hearts had about half normal blood levels of Q -- if we supplemented with Q and we attained a blood level of 1 or a little higher, that should be sufficient if what we're doing is just correcting a Q deficiency state. But what happened was that wasn't the case at all. We didn't see much improvement in patients unless these levels (in the early studies) were above 2.5. And then later, especially as we started to treat more and more really sick class 4 heart failure patients, we didn't really turn them around or get our best effect until we had blood levels greater than 3.5. But it took a good 15 or more years to figure that out.

...the average dose of Q is now in the 300 to 400 mg range, but it varies quite a bit because we can follow levels now much more easily than we could originally. At first the only lab in the United States doing Q levels was in Austin Texas - a fairly slow turnaround, and it wasn't that easy to get them done - whereas now we do Q levels here in our office. We have a wonderful research lab and so we don't have to guess as much as we used to. Some people absorb Q very well, and on a dose of 100 mg twice a day they may have a Q level of 5.8 and you don't have to change a thing. And then another patient on the same dose may have a much lower level, so you have to increase them.

KIRK HAMILTON: Well, let's assume then that CoQ10 is good for a failing heart, and you're trying to get levels up above 3.5. I measure at Quest Laboratories and I can get it there with varying [dose] amounts. For the average person there are 2 different supplemental forms of Coenzyme Q10, ubiquinone and the newer ubiquinol. In the nutraceutical world when something new comes out they promote it like anything else, you know?

Dr. LANGSJOEN: Right. Right. Well, the standard Q, which is in its oxidized state, is called ubiquinone, and that's what we have over 40 years experience with. It has some advantages, it's very stable so it has a long shelf life. And if you're not in a big hurry, if you're not treating someone who's in active or obvious heart failure, there would be nothing wrong with using any form of Q, including the standard ubiquinone formulations. Wait a few weeks or so and check the level and see if it's adequate. But in my particular situation patients are referred into my cardiology clinic usually because they're pretty sick, and so I don't have a lot of time to fool around with possibly an inadequate blood Q level. So currently in people who are presenting in heart failure I'm using ubiquinol pretty much exclusively, because it's more predictable - it's always better absorbed. Ubiquinol is anywhere from 2 to 4 times better absorbed than ubiquinone. And like I said, some of these people are so sick you need to get them better as soon as you can.

KIRK HAMILTON: Which one of the forms is better as an antioxidant and which form is better for energy production?

Dr. LANGSJOEN: Well, the way to look at that is they're identical, because when you take ubiquinone, the oxidized form, it is very rapidly changed into ubiquinol, the reduced form, even within the intestinal lining cells. So let's say you gave someone ubiquinone, the oxidized state, and you measure their blood levels, 98% at least of what you measure is going to be in its reduced ubiquinol state. So ubiquinol and ubiquinone are essentially identical except for that very first transit across the intestinal wall. The absorption is much better with ubiquinol, after that they're identical. There's no difference, and they're in a constant [reduced/oxidized] cycle. When we use Q as a coenzyme, it's converted to its reduced or ubiquinol state, and in the mitichondria it's in a setting where it's in the presence of a great deal of free radicals with which it reacts [as an antioxidant] and it goes back to its oxidized ubiquinone state -- so it's a continuous cycle.

...if your Q is inadequate, not only are you not producing cell energy at an optimal level, you're not providing a defense for your mitochondrial DNA. So all these offspring, all these future generations [of mtDNA] are more defective with each step. So one of the theories of aging has to do with this progressive mitochondrial DNA damage, and you can get to a point where it's irreversible. If you have a population of mitochondria that are really screwed up, you can't undo that... you're right, mitochondria are the major source of free radical production in our cells.

KIRK HAMILTON: ... let me stay with statin users because it's used like candy. Do you think you could pretty much eliminate the myalgias and things like that that occur? And also, if the average statin person was taking a couple hundred milligrams of CoQ10 and we got the blood levels up, would that also reduce the risk of increasing the likelihood of [heart] failure, since we might be keeping people alive longer?

Dr. LANGSJOEN: We don't know for sure, but I think so. You know, statins are more complicated than just the reduction of Q and cholesterol. But it makes sense to me that if we routinely gave let's say 200 or 300 mg a day of Q to patients on statins, we could expect to decrease the symptoms of fatigue and also the symptoms of muscle pain or weakness, and you can have either or both. There are some statin side effects that you probably won't influence too much, and those would be the central nervous system problems. You know, the brain requires a huge amount of cholesterol, and when it's decreased it doesn't work as well. Many people on statins have an insidious deficit in their mental capacity, and it can be subtle at first, but almost all of them will eventually have a noticeable impairment in short-term memory. Sometimes it's noticed more by family members than by the patient, but I don't think Q would prevent that.

I'm sort of an unusual cardiologist in that I'm not convinced that the benefits of statins come close to outweighing their harm, so I don't advocate them in the first place. But if you're just looking at the big general way medicine is practiced, 99.9% of physicians use statins aggressively, and they believe that the side effects are minimal. I think they're just not seeing that they're not minimal, and they're certainly not uncommon -- but whether you could prevent most of that with Q we don't know. My guess is you could prevent most of the muscle trouble, but I'm not so sure about memory.

Jackie, thanks for your account of personal experience with statin use. A trustworthy anecdote is worth more than any number of spun study results.

In '93 medical reporting might have been a bit cleaner than today - note professor Gian Paolo Littarru being one of the study's authors - but his urgent 2001 plea went absolutely nowhere: (http://www.icqa.org/issues/issue2.html)

LETTER TO FDA REGARDING STATIN ISSUE

Following the recent events regarding serious side-effects related to statins (the Baycol issue) the International Coenzyme Q10 Association released an official statement (see below) which was sent to the Food and Drug Administration. The same letter will be sent to the European Agency for the Evaluation of Medical Products and to the equivalent Japanese agency.

Institute of Biochemistry - University Politecnic of Marche
Via Ranieri - 60131 Ancona-Italy
Phone: +39-071-2204674 Fax: +39-071-2801932
e-mail: [email protected]
Prof. Gian Paolo Littarru

HFD-511
Food and Drug Administration
5600 Fishers Ln.
Rockville MD 20857

Ancona, September 5th 2001

Object:

Biochemical and Potential Clinical Consequences of Inhibiting Coenzyme Q10 Biosynthesis by HMG-CoA Reductase Inhibitors:
A Critical Opinion by the International Coenzyme Q10 Association.

Dear Sirs,

Please accept this letter as a position statement on the growing problem of adverse side effects related to the use of HMG-CoA reductase inhibitors. The International Coenzyme Q10 Association is a group of scientists and medical professionals with a research focus on coenzyme Q10, which plays a crucial role in cellular ATP production. It has been demonstrated that HMG-CoA reductase inhibitors, also known as statins, block the biosynthesis of coenzyme Q10 and of dolichol, besides the well known effect on cholesterol synthesis. Several studies have shown that administration of different kinds of statins can lead to a parallel decrease of coenzyme Q10 and cholesterol in plasma (1- 9, 19). Animal studies have also demonstrated a tissue depletion in the course of statin treatment (10 - 12) which was particularly evident in aged animals (13). We can reasonably hypothesize that in some conditions where other CoQ10 impoverishing situations exist, treatment with statins may seriously impair plasma and possibly tissue levels of coenzyme Q10. A physiological decline in tissue CoQ10 has for instance been implicated in aging (17,18) which would make the elderly more susceptible to statin-induced CoQ10 depletion.

A decrease in tissue coenzyme Q10 may have adverse effects on cellular ATP production, as has been proven in dogs and guinea pigs (12, 13), and may manifest clinically as systolic and diastolic left ventricular dysfunction with symptoms of fatigue and exertional dyspnea. In patients with pre-existing congestive heart failure the addition of statin therapy causes a decrease in blood CoQ10 levels and a decline in myocardial function (1). Although statin therapy has been shown to have benefits, the long-term response in ischemic heart disease may have been blunted due to the CoQ10 depleting effect. Some evidence of this has already appeared in that oral CoQ10 supplementation in diabetic patients receiving HMG-CoA reductase inhibitors reduced cardiothoracic ratio (9).

It is reasonable to suggest that skeletal muscle pathology such as myalgia and rhabdomyolysis is also related to decreases in tissue coenzyme Q10 concentrations. There are some indications of rapid improvement in statin-induced myalgia and fatigue with supplemental CoQ10 (20). In different kinds of muscle disease the beneficial effects of coenzyme Q10 supplementation have been shown to correlate with improvement in oxidative phosphorylation as monitored by NMR techniques (14 - 16). A few cases have already been reported where CoQ10 reverses the condition of cardiac failure in the course of treatment with statins (1).

These observations may relate to two Merck & Co., Inc. patents for combining CoQ10 with statin in the same capsule: US Patent 4929437, issued May 29, 1990 and US Patent 4933165, issued June 12, 1990, both titled "Coenzyme Q10 with HMG-CoA Reductase Inhibitors". It is possible that the recently reported statin-related deaths are the tip of a side effect iceberg and the magnitude of the potential problem cannot be overstated. It is urgently incumbent upon the scientific community, the pharmaceutical industry, and the regulatory bodies, such as the United States Food and Drug Administration, to be certain that we are not inadvertently creating a life-threatening deficiency of an essential co-factor in many millions of patients.

Attached are pertinent supporting publications and abstracts along with copies of the Merck & Co., Inc. statin/CoQ10 combination patents.

This letter has been reviewed by all of the undersigned members of the Scientific Committee of the International Coenzyme Q10 Association who feel that studies are warranted to examine whether the clinical use of statins can be made safer and possibly more effective by the addition of coenzyme Q10.

We should make every effort to investigate the reasons for, and to prevent further developments of, what have already been serious medical consequences.

We would very much appreciate your input and response.

With all due respect,

Gian Paolo Littarru M.D. Prof. Biochemistry
University of Ancona, Italy

Chairman of the International CoQ10 Association

On behalf of:

Flint Beal, M.D. Prof. - Cornell Medical Centre, NY, USA
Fredrick Crane, Ph.D. Prof. - Purdue University, IL, USA
Gustav Dallner, Ph.D. Prof. - Stockholm University, Sweden
Udo Hoppe, M.D. Prof. - Paul Gerson Unna-Skin Research Centre, Germany
Takeo Kishi, Ph. D. Prof. - Kobe Gakui University, Japan
Peter Langsjoen M.D. - Diplomate American Board of Cardiology, TX, USA
Giorgio Lenaz M.D. Ph.D. Prof. - Bologna University, Italy
Svend Aage Mortensen M.D. Prof. - Heart Centre Rigshospital, Copenhagen, Denmark
Tetsuya Nakamura Ph.D. Prof. - Shibaura Institute of Technology, Japan
Etsuo Niki Ph.D. Prof. - Human Stress Signal Research Centre, Japan
Roland Stocker Ph.D. Prof. - Heart Research Institute, Sydney, Australia
Yoshitomo Oka M.D. Ph.D. Prof. - Yamaguchi University School of Medicine, Japan
Yorihiro Yamamoto Ph.D. Prof. - School of Engineering, University of Tokyo, Japan

References:

1. Folkers K., Langsjoen P., Willis R., Richardson P., Xia L., et al. Lovastatin decreases coenzyme Q levels in humans. Proc. Nat Acad. Sci. USA. 87: 8931-8934, 1990.
2. Ghirlanda G., Oradei A., Manto A., Lippa S., Uccioli L. et al. Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double blind, placebo-controlled study. J. Clin. Pharmacol. 3: 226-229, 1993.
3. Bargossi AM, Grossi G, Fiorella PL, Gaddi A, Di Giulio R, Battino M. Exogenous CoQ10 supplementation prevents plasma ubiquinone reduction induced by HMG-CoA reductase inhibitors. Mol Asp Med. 15: s187-93, 1994.
4. Mortensen SA., Leth A., Agner E., Rohde M. Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors. Mol Asp Med. 18: s137-s144, 1997.
5. Kaikkonen J, Nyyssonen K, Tuomainen TP, Ristonmaa U, Salonen JT. Determinants of plasma coenzyme Q10 in humans. FEBS Lett. 443:163-6, 1999.
6. De Pinieux G, Chariot P, Ammi-Said M, Louarn F, Lejone JL, Astier A, Jactot B, Gherardi R. Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio. Br J Clin Pharmacol. 42: 333-7, 1996.
7. De Lorgeril M, Salen P, Bontemps L, Belichard P, Geyssant A, Itti R. Effects of lipid-lowering drugs on left ventricular function and exercise tolerance in dyslipidemic coronary patients. J Cardiovasc Pharmacol. 33: 473-8, 1999.
8. Human JA, Ubbink **, Jerling JJ, Gelport R, Varmaak WJ, Vorster HH, Lagendijk J, Potgieter HC. The effect of Simvastatin on the plasma antioxidant concentrations in patients with hypercholesterolaemia. Clin Chim Acta 263: 67-77, 1997.
9. Miyake Y, Shouzu A, Nishikawa M, Yonemoto T, Shimizu H, Omoto S, Hayakawa T, Inada M. Effect of treatment with 3-hydroxy-3-methylgltaryl coenzyme A reductase inhibitors on serum coenzyme Q10 in diabetic patients. Arzneimittelforschung 49: 324-9, 1999.
10. Willis RA., Folkers K, Tucker JL., Ye CQ, Xia LJ., Tamagawa H. Lovastatin decreases coenzyme Q levels in rats. Proc. Natl. Acad. Sci. USA ; 87: 8928-30, 1990.
11. Loop RA, Anthony M, Willis RA, Folkers K. Effects of ethanol, lovastatin and coenzyme Q10 treatment on antioxidants and TBA reactive material in liver of rats. Mol Asp Med. 15: s195-206, 1994.
12. Satoh K, Yamato A, Nakai T, Hoshi K, Ichihara K. Effects of 3-hydroxy-3-methylgltaryl coenzyme A reductase inhibitors on mitochondrial respiration in ischaemic dog hearts. Br J Pharmacol. 116: 1894-8, 1995.
13. Diebold BA, Bhagavan NV, Guillory RJ. Influences of lovastatin administration on the respiratory burst of leukocyctes and the phosphorylation potential of mitochondria in guinea pigs. Biochim Biophys Acta. 1200: 100-8, 1994.
14. Nishikawa Y, Takahashi M, Yorifuji S, Nakamura Y, Ueno S, Tarui S, Kozuka T, Nishimura T. Long-term coenzyme Q10 therapy for a mitochondrial encephalomyopathy with cytochrome c oxidase deficiency: a 31P NMR study. Neurology 39: 399-403, 1989.
15. Mizuno M, Quistorff B, Theorell H, Theorell M, Chance B. Effects of oral supplementation of coenzyme Q10 in 31P-NMR detected skeletal muscle energy metabolism in middle-aged post-polio subjects and normal volunteers. Mol Asp Med. 18: s291-8, 1997.
16. Barbiroli B, Iotti S, Lodi R. Improved brain and muscle mitochondrial respiration with CoQ. An in vivo study by 31P-MR spectroscopy in patients with mitochondrial cytopathies. Biofactors 9:253-60, 1999.
17. Kalen A., Appelkvist E.L., Dallner G. Age related changes in the lipid composition of rate and human tissue. Lipids, 24: 579-584, 1989.
18. Soderberg M., Edlund C., Kristensson K., Dallner G. Lipid composition of different regions of the human brain during aging. J. Neurochem. 54, 2: 415-423, 1990.
19. Watts GF, Castelluccio C, Rice Evans C, Taub NA, Baum H, Quinn PJ. Plasma coenzyme Q (ubiquinone) concentration in patients treated with simvastatin. J Clin Pharmacol 46: 1055-1057, 1995.
20. Walravens PA, Greene C, Frerman FE, Lovastatin, Isoprenes, and Myopathy Lancet Nov.4; 2 (8671): 1097-1098, 1989.

International CoenzymeQ10 Association - Institute of Biochemistry - University Politecnic of Marche

Via Ranieri 60131 Ancona - Italy - tel: +39 071 2204674 - fax: +39 071 2801932 - e-mail: g.p.littarru@univpm.it
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