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Atorvastatin Decreases the Coenzyme Q10 Level
in the Blood of Patients at Risk for Cardiovascular
Disease and Stroke
Tatjana Rundek, MD; Ali Naini, PhD; Ralph Sacco, MD; Kristen Coates, MS; Salvatore DiMauro, MD Background: Statins (3-hydroxy-3-methylglutaryl co-
Patients: We examined a cohort of 34 subjects eli-
enzyme A reductase inhibitors) are widely used for the gible for statin treatment according to National Cho- treatment of hypercholesterolemia and coronary heart dis- lesterol Education Program: Adult Treatment Panel III ease and for the prevention of stroke. There have been various adverse effects, most commonly affecting muscleand ranging from myalgia to rhabdomyolysis. These ad- Results: The mean ± SD blood concentration of CoQ10
verse effects may be due to a coenzyme Q10 (CoQ10) de- was 1.26 ± 0.47 µg/mL at baseline, and decreased to ficiency because inhibition of cholesterol biosynthesis also 0.62 ± 0.39 µg/mL after 30 days of atorvastatin therapy (PϽ.001). A significant decrease was already detectableafter 14 days of treatment (PϽ.001).
Objective: To measure CoQ10 levels in blood from hy-
percholesterolemic subjects before and after exposure to
Conclusions: Even brief exposure to atorvastatin causes
atorvastatin calcium, 80 mg/d, for 14 and 30 days.
a marked decrease in blood CoQ10 concentration. Wide-spread inhibition of CoQ10 synthesis could explain the Design: Prospective blinded study of the effects of short-
most commonly reported adverse effects of statins, es- term exposure to atorvastatin on blood levels of CoQ10.
pecially exercise intolerance, myalgia, and myoglobin-uria.
Setting: Stroke center at an academic tertiary care hos-
pital.
EVERSINCETHEIRINTRODUC- lectively,becausethebiosyntheticpath-
way of cholesterol is shared by other com- reductase inhibitors) have been widely and successfully used for the treatment of hy- percholesterolemia and coronary artery dis- ease and for the prevention of stroke. New decrease of the CoQ10 level induced by stat- evidence suggests that the effect of statins effects. This hypothesis is especially at- ated by their lipid-lowering properties, but rather by their anti-inflammatory (antiath- erosclerotic) action. These “wonder drugs,” various adverse effects, most commonly in- (Mevacor),8,9 simvastatin (Zocor),10,11 and pravastatin sodium (Pravachol),9,10 do de- uria.1-3 In the case of cerivastatin sodium (Baycol), the adverse effects were so com- tients and control subjects, although the number of subjects studied and the sever- ity of CoQ10 deficiency varied markedly in and consulting from Pfizer Inc.
Pfizer Inc had no involvement different reports. Surprisingly, one ran- verse effects of statins is that they inhibit cholesterol synthesis effectively but not se- and atorvastatin calcium (Lipitor) failed (REPRINTED) ARCH NEUROL / VOL 61, JUNE 2004 2004 American Medical Association. All rights reserved.
amined for changes in liver enzyme levels, renal function, and any severe and nonsevere described adverse effects. In particu- We had a unique opportunity to study the short- lar, subjects were monitored for muscle pain or weakness. Com- term effects of atorvastatin, 80 mg/d, on blood CoQ monly reported, but often transient, adverse effects, such as flatu- in 35 subjects who were eligible for statin treatment ac- lence, constipation, stomach pain, and indigestion, were noted.
cording to the criteria of the National Cholesterol Edu- PROCEDURES
cation Program: Adult Treatment Panel (NCEP ATP) III.13This study was an add-on to a longitudinal B-mode ca- After a 12-hour fast, blood was drawn by phlebotomy, col- rotid ultrasonographic imaging study of the effect of a lected in EDTA-additive tubes, and centrifuged immediately at daily dose of atorvastatin on carotid wall elasticity. The 4°C at 3000 rpm for 20 minutes. The plasma was removed and aim of this corollary study was to test the hypothesis that stored at −80°C. At the end of the study, all plasma samples short-term exposure to atorvastatin, 80 mg/d for 30 days, available after primary analysis of lipid profiles were used for 10 assay (baseline, 34 subjects; 14 days of atorvastatin pared with pretreatment levels. A secondary hypothesis therapy, 32 subjects; and 30 days of atorvastatin therapy, 36 was that this effect might be rapid and already detect- able 2 weeks after the initiation of treatment.
10 was extracted from plasma (a 50-µL sample and 950 µL of ice-cold 1-propanol) by vortex mixing in a mi-crocentrifuge tube for 2 minutes; after centrifugation at 14 000 rpm for 10 minutes at 4°C, 30 µL of clear supernatant was in-jected directly into the high-performance liquid chromato- SUBJECTS
graphic system. High-performance liquid chromatographicanalyses were performed using a reverse-phase isocratic sys- Forty subjects older than 45 years with an elevated low- density lipoprotein cholesterol level, as defined by the NCEPATP III, were included in a longitudinal B-mode carotid ultra- STATISTICAL ANALYSIS
sonographic imaging study aimed at evaluating the possible rapideffect of a single dose of atorvastatin on carotid artery wall elas- Coenzyme Q10 concentrations are expressed as the mean±SD and as interquartile ranges before atorvastatin treatment and To be eligible for atorvastatin treatment according to the 14 and 30 days after the initiation of treatment. An analysis of NCEP ATP III criteria, the subjects had to have the following variance was used to compare CoQ10 levels at baseline and at features: (1) known coronary heart disease (CHD) or CHD the 2 follow-up visits. Absolute and relative CoQ10 changes at equivalent (peripheral artery disease, abdominal aortic aneu- 14 and 30 days were compared by a paired t test. Relative changes rysm, symptomatic carotid artery disease, diabetes mellitus, or were calculated by dividing percentage differences from base- multiple risk factors for CHD conferring a 10-year risk factor line by baseline values, multiplied by 100. Differences were for coronary artery disease of Ͼ20%), (2) 2 or more risk fac- 1-tailed and considered statistically significant at ␣=.05. Data tors for CHD and a low-density lipoprotein cholesterol level for other variables are given as mean ± SD.
of 130 mg/dL or higher (Ն3.36 mmol/L), or (3) no risk factorsor one risk factor and a low-density lipoprotein cholesterol level higher than 160 mg/dL (Ͼ4.14 mmol/L).
The NCEP ATP III–defined risk factors included the fol- lowing: (1) age for men of 45 years or older and for women, We studied 34 subjects (18 men and 16 women) who had 55 years or older; (2) hypertension, a blood pressure of 140/90 plasma CoQ10 levels measured at baseline and 1 month mm Hg or higher, or the need for antihypertensive therapy; (3) after treatment with atorvastatin. Their age was 70 ± 7 a high-density lipoprotein cholesterol level of less than 40 mg/dL years. They included Caribbean Hispanic subjects (22 (Ͻ1.03 mmol/L); (4) cigarette smoking; and (5) family his- [64%]), African American subjects (8 [24%]), and white tory of premature CHD or CHD in first-degree relatives (men, The concentration of CoQ10 at baseline in these 34 Exclusion criteria included active hepatic or renal dys- individuals was 1.26 ± 0.47 µg/mL (range, 0.66-3.04 µg/ function, connective tissue disease, chronic inflammatory dis- mL) (interquartile ranges: quartile 1, 0.66-1.00 µg/mL; ease, malignancy or history of malignancy, any acute illness, quartile 2, 1.01-1.26 µg/mL; quartile 3, 1.27-1.44 µg/ leukocytosis (white blood cell count, Ͼ10ϫ103/µL), throm-bocytosis (platelet count, Ͼ450ϫ103/µL), anemia (hemato- mL; and quartile 4, 1.45-1.84 µg/mL), well in line with crit, Ͻ40%), and corticosteroid therapy. Patients hospitalized our own values in healthy individuals (0.84 ± 0.29 µg/ for acute coronary syndrome within 6 months of the start of mL) and with values in the literature. These values were the study were excluded. Women who were nursing and who not significantly different by age (Ͻ70 vs Ն70 years; were or might become pregnant were not eligible. Patients being P = .46, t test), sex (P = .35, t test), or race (P = .74, analy- treated for hyperlipidemia with a statin were excluded.
The prospective study subjects were screened for eligibil- After 30 days of atorvastatin therapy, the plasma ity based on their risk factor profiles and the NCEP ATP III cri- CoQ10 concentration decreased significantly from base- teria. The conduct of the study was approved by the Western Institutional Review Board. Informed consent was obtained be- 10 level at 30 days, 0.62 ± 0.39 µg/mL; absolute reduction, 0.66 µg/mL; and relative reduction, 52%; fore enrollment at the baseline visit.
All subjects received oral atorvastatin, 80 mg/d, for 30 days.
PϽ.001). A significant (PϽ.001) decrease was also de- The study assessments included a fasting blood test, carotid ul- tected after 14 days of treatment, when the plasma CoQ10 trasonography, and the determination of inflammatory mark- level in 32 subjects had decreased by 49% (Figure). The
ers at baseline (before atorvastatin treatment) and 14 and 30 decreases between baseline and day 30 in total choles- days thereafter. At the 14- and 30-day visits, subjects were ex- terol (220 ± 43 vs 131 ± 31 mg/dL [5.7 ± 1.1 vs 3.4 ± 0.8 (REPRINTED) ARCH NEUROL / VOL 61, JUNE 2004 2004 American Medical Association. All rights reserved.
mmol/L]; PϽ.001), low-density lipoprotein cholesterol (143 ± 39 vs 70 ± 27 mg/dL [3.7 ± 1.0 vs 1.8 ± 0.7 mmol/L]; PϽ.001), and triglycerides (142±71 vs 97±35 mg/dL [1.6±0.8 vs 1.1±0.4 mmol/L]; PϽ.004] were similar (us- The intraindividual CoQ10 change was 0.64±0.28 µg/mL (relative reduction, 49%; PϽ.001) after 30 days of atorvastatin therapy, and 0.67 ± 0.23 µg/mL (relative reduction, 45%; PϽ.001) after 14 days of treatment (Figure). In all subjects and at both follow-up visits, (PϽ.001) lower than at baseline. In 2 subjects, CoQ10 con- centrations were higher on day 30 than on day 14, but still lower than at baseline. One of these 2 subjects stopped taking atorvastatin after 10 days, and the other was non- compliant, taking the pills only occasionally.
Mean ± SD plasma coenzyme Q10 (CoQ10) concentrations at baseline and at 14and 30 days after atorvastatin calcium therapy. The asterisk indicates that the value is significantly different (PϽ.001) from baseline.
Few drugs are as widely used as the statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, that studies were conducted on few or even single individu- effectively decrease blood levels of cholesterol and pro- als, and others on larger series. A double-blind placebo- tect against various cardiovascular diseases related to ath- controlled study10 of healthy volunteers treated for 1 erogenesis. Similarly, few drugs have generated as much month with either pravastatin, 20 mg/d (n = 10), or sim- controversy as the statins2: adverse effects, predomi- vastatin, 20 mg/d (n = 10), for 4 weeks showed similar nantly affecting skeletal muscle,3,15 have been wide- decreases (50% and 54%, respectively) of blood CoQ10 spread and severe enough to force one pharmaceutical levels, whereas 10 individuals receiving placebo showed company to withdraw cerivastatin from the market. How- no change. In another large study,9 45 hypercholester- ever, statins are still widely used and their safety is still olemic patients were randomized in a double-blind trial: debated. The common mechanism of action of these drugs, one group received increasing doses of pravastatin so- inhibition of cholesterol metabolism at the level of meva- dium (20, 40, and 80 mg/d) and a second group re- lonic acid, has the unintended consequence of impair- ceived increasing doses of lovastatin (10, 20, and 40 mg/d) ing the synthesis of other compounds that share meva- for a total of 18 weeks. In both groups, there was a gradual lonate as a precursor, such as dolichols and CoQ10 decrease of blood CoQ10 level: after 18 weeks, the CoQ10 (ubiquinone). In our well-controlled longitudinal study, level was 80% of baseline with pravastatin and 71% of atorvastatin caused a rapid and substantial decrease of plasma CoQ10 concentrations, which was evident 14 days The only study12 with negative results involved 12 after the initiation of therapy and was even more marked healthy subjects: 6 received pravastatin sodium, 20 mg/d, for 4 weeks and 6 received atorvastatin calcium, 10 mg/d, Impaired synthesis of CoQ10 could well explain the for 4 weeks. After a washout period, each group received variety of adverse effects reported because of the central the alternate drug for another 4 weeks. No change in blood role of this compound in energy generation through the CoQ10 level was found at the end of each treatment. This mitochondrial respiratory chain and because of its anti- study is noteworthy because—like ours—it used atorvas- oxidant properties.4 Indirect support for a pathogenic role tatin, although the dose was much lower than that used of CoQ10 deficiency comes from data from patients with by us and the number of subjects was much smaller.
idiopathic—presumably primary—CoQ10 deficiency.
We took advantage of the availability of blood These patients have a mitochondrial encephalomyopa- samples from a large cohort of hypercholesterolemic pa- thy, most commonly presenting as an autosomal reces- tients in whom we studied the short-term (2- and 4-week) sive spinocerebellar atrophy syndrome.16,17 A rarer myo- effects of atorvastatin calcium, 40 mg/d, on carotid ar- pathic variant combines central nervous system signs tery elasticity by B-mode ultrasonography. The results (ataxia, epilepsy, and mental retardation) with a mito- on carotid artery elasticity will be reported elsewhere. This chondrial myopathy dominated by recurrent rhabdomy- was a large and uniform population of patients from whom olysis and myoglobinuria (which is, perhaps not coin- samples of plasma were obtained at baseline and after 2 cidentally, one of the most severe adverse effects of statin and 4 weeks of therapy. All samples were kept frozen un- til the CoQ10 assay to minimize methodological varia- It is, therefore, not surprising that, starting with Folk- tions. Baseline CoQ10 concentrations corresponded to ac- ers et al,18 several groups have studied the effects of stat- cepted normative values, from our own experience and ins on the blood concentration of CoQ10 in humans, in from the literature, and were relatively uniform (Figure).
patients with hypercholesterolemia and in healthy sub- There was a highly significant and marked (about 50%) jects. It is somewhat difficult to compare results be- decrease of the CoQ10 concentration after 2 weeks of ator- cause different studies used different statins, different dos- vastatin administration, which was essentially un- ages, and long- or short-term exposures. In addition, some changed after 4 weeks of treatment. To our knowledge, (REPRINTED) ARCH NEUROL / VOL 61, JUNE 2004 2004 American Medical Association. All rights reserved.
this is the first unequivocal demonstration that atorvas- tatin—like pravastatin and simvastatin10—also reducesblood levels of CoQ10, and to about the same extent.
Our patients did not report severe adverse effects dur- 1. Bliznakov EG, Wilkins DJ. Biochemical and clinical consequences of inhibiting coenzyme Q biosynthesis by lipid-lowering HMG-CoA reductase inhibitors (stat- ing 30 days of exposure to atorvastatin. In particular, there ins): a critical overview. Adv Ther. 1998;15:218-228.
were no complaints of myalgia or weakness. Only one sub- 2. Bliznakov EG. Lipid-lowering drugs (statins), cholesterol, and coenzyme Q10: the ject experienced weakness and tingling in the legs, which Baycol case—a modern Pandora’s box. Biomed Pharmacother. 2002;56:56-59.
disappeared 2 days after reducing the dose of atorvastatin 3. Sinzinger H, Wolfram R, Peskar BA. Muscular side effects of statins. J Cardio- vasc Pharmacol. 2002;40:163-171.
calcium to 40 mg/d (the plasma CoQ10 level was 0.84 µg/mL 4. Crane FL. Biochemical functions of coenzyme Q10. J Am Coll Nutr. 2001;20:591- at baseline, 0.38 µg/mL on day 14, and 0.34 µg/mL on day 30). The most common adverse effects were flatulence and 5. Ogasahara S, Engel AG, Frens D, Mack D. Muscle coenzyme Q deficiency in fa- constipation, which usually resolved within days.
milial mitochondrial encephalomyopathy. Proc Natl Acad Sci U S A. 1989;86: Our study does not address the question of whether 6. Sobreira C, Hirano M, Shanske S, et al. Mitochondrial encephalomyopathy with tissue levels of CoQ10 were also decreased by atorvas- coenzyme Q10 deficiency. Neurology. 1997;48:1238-1243.
tatin. One previous study11 of healthy volunteers treated 7. Di Giovanni S, Mirabella M, Spinazzola A, et al. Coenzyme Q10 reverses patho- with simvastatin, 20 mg/d, for 4 weeks had shown a 30% logical phenotype and reduces apoptosis in familial CoQ10 deficiency. Neurol- 8. Folkers K, Langsjoen P, Willis R, et al. Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci U S A. 1990;87:8931-8934.
tation, our findings raise the possibility of a widespread 9. Mortensen SA, Leth A, Agner E, Rohde M. Dose-related decrease of serum co- inhibition of CoQ10 synthesis in patients treated with ator- enzyme Q10 during treatment with HMG-CoA reductase inhibitors. Mol Aspects vastatin. Given the many patients exposed to relatively Med. 1997;18(suppl):S137-S144.
high doses of this drug and the persistent occurrence of 10. Ghirlanda G, Oradei A, Manto A, et al. Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study.
adverse effects related to statins, it may be reasonable to J Clin Pharmacol. 1993;33:226-229.
add CoQ10 in patients receiving long-term treatment with 11. Laaksonen R, Jokelainen K, Sahi T, et al. Decreases in serum ubiquinone con- statins in general, and atorvastatin in particular. This rec- centrations do not result in reduced levels in muscle tissue during short-term ommendation is strengthened by the general experi- simvastatin treatment in humans. Clin Pharmacol Ther. 1995;57:62-66.
12. Bleske BE, Willis RA, Anthony M, et al. The effect of pravastatin and atorvastatin 10. Am Heart J. 2001;142:e2. Available at: http://www2.us .elsevierhealth.com/scripts/om.dll/serve?retrieve=/pii/S0002870301528100&. Ac-cessed March 12, 2004.
Accepted for publication January 27, 2004. 13. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol Author contributions: Study concept and design (Drs
in Adults. Executive Summary of the Third Report of the National Cholesterol Rundek, Naini, Sacco, and DiMauro); acquisition of data Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treat-ment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001; (Drs Rundek and Sacco and Ms Coates); analysis and in- terpretation of data (Drs Rundek, Naini, Sacco, and 14. Naini A, Lewis VJ, Hirano M, DiMauro S. Primary coenzyme Q10 deficiency and DiMauro and Ms Coates); drafting of the manuscript (Drs the brain. Biofactors. 2003;18:145-152.
Rundek, Naini, and DiMauro); critical revision of the manu- 15. Evans M, Rees A. The myotoxicity of statins. Curr Opin Lipidol. 2002;13:415- script for important intellectual content (Drs Rundek, Naini, 16. Musumeci O, Naini A, Slonim AE, et al. Familial cerebellar ataxia with muscle Sacco, and DiMauro and Ms Coates); statistical expertise coenzyme Q10 deficiency. Neurology. 2001;56:849-855.
(Dr Rundek and Ms Coates); obtained funding (Dr Run- 17. Lamperti C, Naini A, Hirano M, et al. Cerebellar ataxia and coenzyme Q10 defi- dek); administrative, technical, and material support (Ms ciency. Neurology. 2003;60:1206-1208.
Coates); study supervision (Drs Rundek, Naini, Sacco, and 18. Folkers K, Wolaniuk J, Simonsen R, et al. Biochemical rationale and the cardiac response of patients with muscle disease to therapy with coenzyme Q Natl Acad Sci U S A. 1985;82:4513-4516.
This study was supported by an investigator-initiated 19. Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson grant from Pfizer Inc, New York, NY; the Hazel K. God- disease. Arch Neurol. 2002;59:1541-1550.
dess Fund (Dr Rundek); and a grant from the Muscular Dys- 20. Muller T, Buttner T, Gholipour AF, Kuhn W. Coenzyme Q10 supplementation pro- trophy Association, Tucson, Ariz (Dr DiMauro). vides mild symptomatic benefit in patients with Parkinson’s disease. NeurosciLett. 2003;341:201-204.
We thank Luisa Godoy, BS, for her dedication to the 21. Group HS. A randomized, placebo-controlled trial of coenzyme Q10 and rema- patients in the study; and Annette Szumski, MS, for her as- cemide in Huntington’s disease. Neurology. 2001;57:397-404.
sistance with data management and statistical analysis. 22. Matthews RT, Yang L, Browne S, et al. Coenzyme Q10 administration increases Corresponding author and reprints: Salvatore DiMauro, brain mitochondrial concentrations and exerts neuroprotective effects. Proc NatlAcad Sci U S A. 1998;95:8892-8897.
MD, 4-420 Columbia University College of Physicians & 23. Hayes S, Del Bene M, Trojaborg W, et al. Therapeutic trial of coenzyme Q10 (CoQ10) Surgeons, 630 W 168th St, New York, NY 10032 (e-mail: in amyotrophic lateral sclerosis (ALS/MND) [abstract]. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;(suppl 3):119.
(REPRINTED) ARCH NEUROL / VOL 61, JUNE 2004 2004 American Medical Association. All rights reserved.

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