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Interview with Dr. Paul Thompson on the Role of Coenzyme Q10 (CoQ10) in Statin-Associated Myopathy

Although serious statin-associated myopathy is rare, muscle-related complaints are generally held to be the most common and clinically significant adverse effects of statin therapy. The mechanism by which statins may affect muscle is unknown, and a number of explanations have been proposed. One theory that has attracted wide interest relates statin-associated muscle complaints to depletion of coenzyme Q10 (CoQ10). The role of CoQ10 in statin-associated myopathy is the subject of a recently published systematic review by Leo Marcoff and APOLLO Steering Committee member Paul D.Thompson.¹ In this interview, Dr. Thompson discusses the prevalence of statin-related muscle complaints, theories about their causation, and the conclusions of his and Dr. Marcoff’s review of the evidence on the role of CoQ10.

Dr. Thompson, concerning statins, we always hear that the most worrisome and, although relatively rare, most frequent adverse effects are muscle-related, whether it is a question of myopathy, myositis, myalgia, or any muscle symptoms. What is the actual incidence of the different myopathic complaints in patients treated with statins, as we understand it to be in 2007?

Dr. Thompson: Of the different complaints that people have while taking statins, myalgia is by far the most frequent. If you look at the pharmaceutical company studies, you will find that the incidence of myalgia is about 3% in most of the studies, and it is about the same for all the commonly available statin medications. Now, those are studies that have been performed by the pharmaceutical companies, and I’m sure that those numbers are reasonable. But the issue is that the patients who are enrolled in these pharmaceutical studies are not like the patients that most of us see. So the estimate “on the street” is that somewhere between 5% and 25% of patients get some sort of myalgia. Twenty-five percent is probably too high but, if you ask me to give you a guesstimate, I would say somewhere between 5% and 10% of patients who take statins get myalgia.

And is this seen consistently across the range of dosages?

Dr. Thompson: No; most experts would say that the frequency of myalgia increases with the dosage. There are some studies—in fact Pfizer has some results from looking at their combined database—indicating that there is no dose-related effect of atorvastatin on myalgia across the dosage scheme. But, quite frankly, I think most people believe that myalgia is dose-dependent.

What is the mechanism of statin-related myopathy as we understand it?

Dr. Thompson: I don’t think we know. Actually, it’s pretty clear we don’t know. Let me give you some of the current theories. There was an idea that maybe it had something to do with reducing cholesterol in the sarcolemma, in other words the membrane of the muscle. Most people don’t believe that because myopathy doesn’t seem to be related to blood cholesterol levels. There is also an idea that when you block the production of cholesterol by blocking 3-hydroxy-3-methylglutaryl coenzyme A reductase, you also block the production of the G proteins Ras, Rac, and Rho. And those G proteins are used for functions such as stabilizing muscle membranes. So another theory is that statin use can reduce these muscle membrane–related functions.

The third possibility is that statin treatment blocks the production of ubiquinone, or coenzyme Q10 (CoQ10). Now, CoQ10 is a mitochondrial transport protein, and it is pretty clear that the blood concentrations of CoQ10 go down with statin treatment. But they go down because CoQ10 is carried in the low-density lipoprotein (LDL) particle and the very-low-density-lipoprotein particle. As you reduce the blood levels of these particles by treating someone with a statin, the blood levels of CoQ10 go down. So one idea is that statin-related muscle complaints are an effect of CoQ10 depletion.

Now, there is a group led by Georgirene Vladutiu that has done muscle biopsies in people who have statin-related myalgia and myopathy.² They find that a fair number of these people have below-normal CoQ10 levels in their muscle [personal communication cited in reference 1].

Now, the question that we’ve had is this: We know that physical exercise increases the number of mitochondria. We know that being sedentary reduces the number of mitochondria. Does the reduction in CoQ10 levels indicate that CoQ10 depletion caused the muscle problem? Or does it reflect the fact that these people with myopathy became less active and lost mitochondria, so that with the loss of mitochondria the CoQ10 level went down? We don’t know that.

There are 2 other theories that we probably ought to mention. One is the idea that statin treatment may increase the amount of fat that gets into the muscle. Statin therapy, which blocks cholesterol production in the liver, also up-regulates LDL receptor activity in the liver. The question is, Does up-regulated LDL receptor activity in muscle, which could bring more fat and cholesterol into the muscle, create a kind of lipid myopathy? This is an idea that’s been advanced by Ira Goldberg at Columbia University.³

The final idea that I’m aware of is that maybe statins, by up-regulating the LDL receptor, bring plant sterols such as campesterol and sitosterol into the muscle, and that causes myopathy. This theory has been advanced by a study in which Päivä and colleagues⁴ showed that in people treated with statins who had some myopathic symptoms, there was an increase in plant sterols in the muscle.

To my knowledge, those are the current theories. Nobody really knows the answer yet, and when the answer is unknown, theories multiply.

Getting back to the supposed association between CoQ10 and statin myopathy, can you tell us about your recently published review?

Dr. Thompson: Basically, we evaluated the literature systematically, using PubMed and searching with a number of key terms that are detailed in the article. We focused primarily on studies in humans. We collected all of those articles and reviewed them systematically to summarize the evidence that is currently available in the CoQ10 literature.

Of course, the reason for the interest in CoQ10 is that CoQ10 supplementation would be a relatively cheap way to help people who have myalgia. In addition, CoQ10 is used for some mitochondrial diseases, so that if statin-related myopathy is a disease of the mitochondria, maybe people could feel better by taking CoQ10.

And on a practical level, it seems as though, whether it’s efficacious or not, people are using it anyway; so it would be useful to know. What did you and your colleagues find regarding statin effects on circulating CoQ10? How many studies did you look at that assessed that?

Dr. Thompson: We looked at 9 observational studies and 6 randomized controlled trials, and the consensus is that statins reduce serum levels of CoQ10. There’s no doubt about the fact that the serum CoQ10 levels go down.

You also looked at the effect of statins on skeletal muscle CoQ10 levels.

Dr. Thompson: From the literature review, we found that there are only 4 studies with muscle biopsies before and after statin treatment. Unfortunately, the evidence about CoQ10 levels in the muscle is a little more problematic, because there is 1 study that found they go up, 1 that found they go down, and 2 that found them to be unaffected by statin treatment. So it’s a mixed bag, and I think we’re still waiting to find out how statins really affect CoQ10 in muscle.

What about studies that look specifically at symptomatic patients?

Dr. Thompson: We were only able to find 2 studies using CoQ10 supplementation, both in abstract form when we wrote this paper, although 1 has subsequently been published.⁵ One says CoQ10 works and the other says CoQ10 does not work. And these studies were quite small; both had fewer than 40 patients.¹ So we’re really waiting for a definitive study that is adequately designed to investigate the question.

How do you explain the differences in these findings?

Dr. Thompson: It could have been due to the dosage of CoQ10. Most of these studies used 200 mg. It could have been due to the small sample size of these trials. We need trials with bigger samples sizes. The second possible explanation is that maybe some people respond and others don’t. For example, CoQ10 is already used to treat some conditions. CoQ10 is used to treat the MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). So it may be that some people respond because they’re genetically different. We wondered whether a lot of the CoQ10 response is not placebo effect, but some people probably are genetically different, and CoQ10 may work in them. Our bottom line was that there’s no conclusive evidence that CoQ10 works, but it may work in some people because of genetic differences. And if you have a patient who needs treatment with a statin and is having trouble with muscle symptoms, there doesn’t seem to be any great risk in using CoQ10, so why not give it a shot? And we suggested a dosage of about 200 mg/d because that’s what’s been used in most of the studies.

On that point, you are assured that CoQ10 supplementation is safe?

Dr. Thompson: Yes—there doesn’t seem to be any reported risk from CoQ10 supplementation, so we think it’s safe. *

In summary, based on your review, what can and can’t be recommended at this time regarding CoQ10 and CoQ10 supplementation?

Dr. Thompson: We certainly don’t recommend the routine use of CoQ10. Since it’s sold over the counter, it’s unregulated, and you have no guarantee that you’re getting a good-quality product. In fact, nobody is really assaying the material, and some people actually said that upon assaying some CoQ10 tablets, they found there was not very much CoQ10 in them. Not many companies make pharmacologic-grade CoQ10. So that’s a problem. The second problem is that it’s expensive, and if we are not sure that it works, we certainly don’t want people to waste their money.

So our bottom line is that there’s no convincing evidence that CoQ10 works. Nevertheless, we are clinicians, and if you have a patient who needs to be treated with a statin and is having trouble with myalgia, it’s something you could try. I would think that of the people who are spending over $100 million a year on CoQ10 supplements, most are probably wasting their money, but some of them, including some who are taking statins, may actually be getting benefit.

Disclaimer

This interview is intended for use by health care professionals for educational purposes only. The information and opinions expressed by the author in this interview represent his own views, which do not necessarily reflect those of the CVspectrum Steering Committee, The FCG Institute for Continuing Education, or the commercial supporters of CVspectrum.org. Printing and posting this interview on CVspectrum.org does not imply endorsement of either the content or the viewpoint expressed by the author.

References

1. Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy. A systematic review. J Am Coll Cardiol. 2007;49:2231-2237.

2. Vladutiu GD, Simmons Z, Isackson PJ, et al. Genetic risk factors associated with lipid-lowering drug–induced myopathies. Muscle Nerve. 2006;34:153-162.

3. Yokoyama M, Seo T, Park T, et al. Effects of lipoprotein lipase and statins on cholesterol uptake into heart and skeletal muscle. J Lipid Res. 2007;48:646-655.

4. Päivä H, Thelen KM, Van Coster R, et al. High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial. Clin Pharmacol Ther. 2005;78:60-68.

5. Caso G, Kelly P, McNurlan MA, Lawson WE. Effect of coenzyme Q10 on myopathic symptoms in patients treated with statins. Am J Cardiol. 2007;99:1409-1412.