is not uncommon for clinicians to hear from some of their patients that the use
of statins or HMG-CoA reductase inhibitors is associated with myopathy.
Statin-associated myopathy can include myalgia (muscle pains or aches) and
myositis (muscle breakdown).1,2 In addition, these conditions may or may
not be accompanied by elevations in creatine kinase (CK), but when elevated is
associated with muscle breakdown.1,2
no other risk factors for myopathy are present, how do statins cause myopathy
and is it a direct or indirect effect of the statin on the muscle?
Unfortunately, the exact mechanism for statin associated myopathy is not known
and there are conflicting reports in the literature regarding histological
changes of the myocytes. One of the proposed mechanisms that has received
a lot of attention is a statin-induced reduction of ubiquinone (coenzyme Q10)
in myocytes.3-6 Coenzyme Q10 (CoQ10) is known to decrease oxidative
stress through its antioxidant effects and participation in mitochondrial
respiration (electron transport chain that generates the majority of the cell's
ATP during aerobic metabolism).7-10 Early case reports suggested that
CoQ10 supplementation alleviated statin-associated myopathy by preventing
is the mechanism by which statins decrease CoQ10 levels?
Statins are well known to inhibit the rate limiting step of cholesterol
biosynthesis by inhibiting the enzyme HMG-CoA reductase, which is responsible
for converting HMG-CoA to mevalonate.11,12 When a statin is not present,
mevalonate would normally proceed through a series of reactions to eventually
produce farnesyl pyrophosphate (PP). Farnesyl PP can then continue down
one of three pathways that will produce cholesterol, heme A, or geranylgeranyl
PP. Heme A is important because it used for the prosthetic group in
cytochrome aa3 which is also involved in mitochondrial respiration. The
production of geranylgeranyl PP will go on to do several things, one of which
is to produce ubiquinone (CoQ10). Therefore, since statins inhibit
mevalonate, it is plausible that they will also prevent the downstream
production of ubiquinone thereby decreasing the availability of ubiquinone and
heme A needed for the electron transport chain to work effectively to generate
ATP. If the electron transport chain does not function, aerobic
metabolism will decrease resulting in the cytoplasmic shunting of pyruvate to
lactate (lactic acid) in order to replenish the NAD+ needed generate the net 2
ATP available from glycolysis.12 If the net production of 2 ATP is not
sufficient to maintain cellular metabolism, then the myocyte will theoretically
suffer resulting in muscle pains/aches and/or cell death. Cell death would
explain elevated CK concentrations in the circulation. However, while
CoQ10 levels are decreased in the serum as a result of statin therapy, the
concentration in the muscles do not necessarily decrease and thus the above
proposed and commonly discussed mechanism is not the primary contributor of
else might CoQ10 help prevent statin related muscle problems?
As mentioned earlier, CoQ10 appears to decrease oxidative stress, possibly
through its antioxidant effects.7-10 The antioxidant effects of CoQ10 are
actually found in its chemically unstable form, reduced CoQ10 (H2CoQ10) which
is the form most present in human serum.7-10,16 The generation of H2CoQ10
is facilitated by NADPH-CoQ reductase. Upon generation of H2CoQ10, it
directly reduces lipid peroxyl radicals and facilitates the conversion of
alpha-tocopherol radicals back to alpha-tocopherol which allows it to exert its
antioxidant effects again.17,18 Together these two antioxidant effects of
H2CoQ10 can reduce the oxidative stress that may damage mitochondria prior to
any effects on mitochondrial electron transport. Interestingly, statins
have been shown to reduce the NADPH-CoQ reductase activity which, again, is
responsible for converting CoQ10 to the more potent antioxidant, H2CoQ10.10
In an animal study, CoQ10 supplementation increased NADPH-CoQ activity even in
those animals receiving simvastatin.10
it appears that CoQ10 supplementation may possibly confer beneficial effects
through various mechanisms in some patients (e.g., patients with pre-existing
deficiencies in CoQ10).3-6,19 However, in contrast to the reported
benefits, several recent studies have failed to provide a clear answer to this
question or to explain the exact beneficial effect that some patients may
receive from CoQ10 supplementation.19-21 As a result, the National Lipid
Association's Statin Safety Task Force does not recommend the routine use of
coenzyme Q10 supplementation at this time.1 While the evidence is
conflicting regarding its benefits, the use of CoQ10 supplementation does not
appear to result in any major side effects.
- Thompson PD, Clarkson PM, Rosenson RS et al. An assessment of statin
safety by muscle experts. Am J Cardiol 2006;97:69C-76C.
- Law M, Rudnicka AR. Statin safety: a systemic review. Am J Cardiol 2006;97:52C-60C.
K, Langsjoen P, Willis R et al. Lovastatin decreases coenzyme Q levels
in humans. Proc Natl Acad Sci USA 1990;87:8931-4.
- Walravens PA, Greene C, Frerman FE. Lovastatin, isoprenes, and myopathy. Lancet 1989;2:1097-8.
S, Engle AG, Frens D, Mack D. Muscle coenzyme Q deficiency in familial
mitochondrial encephalomyopathy. Proc Natl Acad Sci USA
P, Abadia R, Agnus D et al. Simvastatin-induced rhabdomyolysis
followed by a MELAS syndrome. Am J Med 1993;94:109-10.
- Takahashi T, Shitashige M, Okamoto T et al. A novel ubiquinone reductase activity in rat cytosol. FEBS Lett 1992;314:331-4.
T, Yamaguchi T, Shitashige M et al. Reduction of ubiquinone in
membrane lipids by rat liver cytosol and its involvement in the cellular
defence system against lipid peroxidation. Biochem J
T, Takahashi T, Mizobuchi S et al. Effect of dicumerol, a Nad(P)h:
quinine acceptor oxidoreductase 1 (DT-diaphorase) inhibitor on
ubiquinone redox cycling in cultured rat hepatocytes. Free Rad Res
A, Takahashi T, Kongkachuichai R et al. Protective effects of coenzyme
q(10) on decreased oxidative stress resistance induced by simvastatin.
J Clin Biochem Nutr 2007;40:194-202.
- Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature 1990;343:425-30.
- Lieberman M, Marks AD. Chapter 34: Cholesterol absorption, synthesis, metabolism, and fate. In: Mark's Basic Medical Biochemistry. A Clinical Approach. 3rd ed. Lieberman M, Marks AD eds. Wolters Kluwer & Lippincott Williams & Wilkins. Philadelphia, PA. 2009;635-643.
R, Jokelainen K, Sahi T et al. Decreases in serum ubiquinone
concentrations do not result in reduced levels in muscle tissue during
short-term simvastatin treatment in humans. Clin Pharmacol Ther
R, jokelainen K, Laakso J et al. The effect of simvastatin treatment
on natural antioxidants in low-density lipoproteins and high-energy
phosphates and ubiquinone in skeletal muscle. Am J Cardiol
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;78:60-8.
T, Matsuya T, Fukunaga Y et al. Human serum ubiquinol-10 levels and
relationship to serum lipids. Int J Vitam Nutr Res 1989;59:288-92.
Y, Komuro E, Niki E. Antioxidant activity of ubiquinol in solution and
phosphatidylcholine liposome. J Nutr Sci Vitaminol 1990;36:505-11.
L, Cabrini L, Fiorentini D et al. The antioxidant activity of
ubiquinol-3 in homogenous solution and in liposomes. Chem Phys Lipids
G, Kelly P, McNurlan MA, Lawson WE. Effects of coenzyme q10 on
myopathic symptoms in patients treated with statins. Am J Cardiol
H, Nohara A, Kobayashi J et al. Effects of CoQ10 supplementation on
plasma lipoprotein lipid, CoQ10 and liver and muscle enzyme levels in
hypercholesterolemic patients treated with atorvastatin: a randomized
double-blind study. Atherosclerosis 2007;195:e182-9.
JM, Florkowski CM, Molyneux SL et al. Effect of coenzyme Q(10)
supplementation on simvastatin-induced myalgia. Am J Cardiol