- Co-enzyme Q10 (CoQ10) is an antioxidant produced by the cholesterol biosynthesis pathway.
- Treatment with statins has been associated with reduced plasma CoQ10 levels, and it has been hypothesised that supplementation with CoQ10 may assist with management of statin-associated muscle symptoms (SAMS).
- Evidence supporting the use of CoQ10 supplements to prevent or treat SAMs in clinical practice is inconsistent.
- If a patient chooses to take a CoQ10 supplement, exercise caution in those taking oral anticoagulants such as warfarin due to potential for interactions.
- Promptly assess suspected SAMS and implement appropriate management strategies to minimise the risk of compromising patient adherence to statins.
With highly effective LDL-C lowering potential, statins are recommended as the first-line lipid-lowering medicine for patients at moderate or high absolute CV risk, in addition to healthy lifestyle changes.1,2
However, despite their efficacy, muscle symptoms are widely perceived to be a common side effect of statins in clinical practice, and this can compromise adherence.3 Although the prevalence of muscle symptoms in patients taking statins is reported to be 7%-29% based on registries and observational studies,3,4 randomised controlled trials have revealed a high background rate of patients reporting muscle symptoms on placebo.5,6 More specifically, a systematic review of 26 randomised controlled trials reported the incidence of muscle symptoms in patients taking statins was 12.7% compared to 12.4% in the placebo group,5 and a double-blinded randomised controlled trial reported incidence of predefined myalgia as 9.4% in patients taking statins compared to 4.6% on placebo.6
While the precise mechanism of statin-associated muscle symptoms is not known, the association between statin treatment and reduced levels of CoQ107 led to the hypothesis that statin-induced CoQ10 deficiency may play a key role in SAMS.8
What is co-enzyme Q10?
CoQ10, also known as ubiquinone or 2-methyl-5, 6-dimethoxy-1, 4-benzoquinone, is an end-product of the cholesterol biosynthesis (mevalonate) pathway.7-9 It acts as an antioxidant, is involved in electron transport in mitochondria, and may play a role in energy transfer in skeletal muscle.7,8
In observational case studies, CoQ10 deficiency has been associated with encephalomyopathy, severe infantile multisystemic disease, cerebellar ataxia, nephrotic syndrome and isolated myopathy.10,11-16
Statin treatment associated with reduction in plasma CoQ10 levels
In addition to the well-known effect of statins on low-density lipoprotein cholesterol (LDL-C) via inhibition of HMG-CoA reductase,17,18 a meta-analysis of 6 RCTs demonstrated that statin treatment is also associated with significant reductions in plasma CoQ10 concentrations.7 This may be due to statin-induced inhibition of farnesyl pyrophosphate production.19 To visualise the cholesterol biosynthesis pathway, see Figure 2 in Deichmann et al, 2010.20
It is also worth noting that, as serum CoQ10 is transported by lipoproteins such as LDL, the reduction in plasma CoQ10 levels after treatment with statins may be at least partly attributed to reduced levels of LDL.9
Is statin treatment associated with reduction in intramuscular CoQ10?
Although reductions in plasma CoQ10 levels have been observed after treatment with statins,7 it is unclear whether this is accompanied by a reduction in intramuscular CoQ10 levels.21 Studies investigating intramuscular CoQ10 levels pre- and post-statin treatment have reported inconsistent (increased or decreased) or non-significant differences.21
Does CoQ10 supplementation improve statin-associated muscle symptoms?
Although CoQ10 deficiency has been associated with various conditions and disorders, the consequences of reduced plasma CoQ10 levels in individuals following statin treatment remain unclear. As CoQ10 deficiency has been associated with myopathies,20 multiple studies have investigated whether CoQ10 supplementation can improve muscle symptoms associated with statin use.22-27
To date, there have been mixed results across trials on the effect of CoQ10 supplementation on muscle symptoms in patients taking statins. Although some small studies have reported a significant reduction in muscle symptoms with CoQ10 supplementation,22-24 others have shown no significant benefit.25-27
However, a 2015 meta-analysis28 concluded there was no significant benefit of CoQ10 on SAMS when considered across these trials, and noted significant interstudy heterogeneity (I2 = 89%, p < 0.001), with methodological limitations, particularly due to small numbers of patients (mostly < 60) in each study.28 These studies used CoQ10 doses of between 100 mg and 400 mg per day, and the authors of the meta-analysis concluded that larger studies using higher doses of CoQ10 may be required to confirm their findings.28
Subsequently, a randomised double-blind crossover study in which patients with confirmed SAMS (n = 38) on simvastatin 20 mg daily received either higher doses of CoQ10 (600 mg/day; n = 20) or placebo (n = 18) for 8 weeks did not report a significant difference in muscle pain.29
What does this mean in practice?
Although Australian guidelines for management of absolute CV risk and hypertension do not provide specific guidance on use of CoQ10,1,30 a European Atherosclerosis Society consensus statement notes that CoQ10 supplementation is not recommended to treat or prevent SAMS.3
However, if a patient chooses to take CoQ10, note that this supplement should be used with caution in those taking oral anticoagulants such as warfarin due to potential for interactions, and international normalised ratio (INR)/prothrombin time (PT) should be monitored.31,32
“While there is limited clinical trial evidence showing CoQ10 supplementation can improve SAMS, a few patients in my experience do report benefit. If all else fails, CoQ10 can be trialled at a dose of at least 100 mg/day for 8 weeks with no guarantee of benefit. If improvement in symptoms is reported, a trial of stopping and restarting CoQ10 therapy could be considered to establish causality.”
Professor Gerald Watts (DSc PhD DM FRACP FRCP)
Consultant physician, Royal Perth Hospital
Winthrop Professor, School of Medicine and Pharmacy, University of Western Australia.
So what are effective management strategies for suspected SAMS?
It is important to promptly assess the signs and symptoms of all patients who present with suspected SAMS. This can help to minimise the risk of compromising adherence to statins, and to differentiate symptoms that may be suggestive of rarer and more severe myopathies.3 This involves using a systematic approach to investigate the nature and characteristics of muscle symptoms, to determine if they are truly statin-related (see the SAMS assessment guide).3,33
If the muscle symptoms are indeed associated with statin use, confirm there is an appropriate indication for statin use before proceeding to trial management strategies as listed in the SAMS management algorithm. Consider strategies such as reducing statin dose, intermittent dosing or switching the type of statin before making a change in cholesterol-lowering medicine, to ensure patients are not left without the benefits of statins for primary or secondary prevention of CVD.2,3,34
- National Vascular Disease Prevention Alliance. Guidelines for the management of absolute cardiovascular disease risk. 2012 (accessed 23 May 2017).
- Cardiovascular Expert Group. Therapeutic Guidelines: Pharmacological management of dyslipidaema. West Melbourne: Australian Therapeutic Guidelines, 2012 (accessed 7 March 2017).
- Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J 2015;36:1012-22.
- Bruckert E, Hayem G, Dejager S, et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients--the PRIMO study. Cardiovasc Drugs Ther 2005;19:403-14.
- Ganga HV, Slim HB, Thompson PD. A systematic review of statin-induced muscle problems in clinical trials. Am Heart J 2014;168:6-15.
- Parker BA, Capizzi JA, Grimaldi AS, et al. Effect of statins on skeletal muscle function. Circulation 2013;127:96-103.
- Banach M, Serban C, Ursoniu S, et al. Statin therapy and plasma coenzyme Q10 concentrations--A systematic review and meta-analysis of placebo-controlled trials. Pharmacol Res 2015;99:329-36.
- Coenzyme Q10 and statin-related myopathy. Drug Ther Bull 2015;53:54-6.
- Bitzur R, Cohen H, Kamari Y, et al. Intolerance to Statins: Mechanisms and Management. Diabetes Care 2013;36:S325-S30
- Quinzii CM, Hirano M. Primary and secondary CoQ(10) deficiencies in humans. Biofactors (Oxford, England) 2011;37:361-5.
- Acosta MJ, Vazquez Fonseca L, Desbats MA, et al. Coenzyme Q biosynthesis in health and disease. Biochim Biophys Acta 2016;1857:1079-85.
- Ogasahara S, Engel AG, Frens D, et al. Muscle coenzyme Q deficiency in familial mitochondrial encephalomyopathy. Proc Natl Acad Sci U S A 1989;86:2379-82.
- Sobreira C, Hirano M, Shanske S, et al. Mitochondrial encephalomyopathy with coenzyme Q10 deficiency. Neurology 1997;48:1238-43.
- Aure K, Benoist JF, Ogier de Baulny H, et al. Progression despite replacement of a myopathic form of coenzyme Q10 defect. Neurology 2004;63:727-9.
- Boitier E, Degoul F, Desguerre I, et al. A case of mitochondrial encephalomyopathy associated with a muscle coenzyme Q10 deficiency. J Neurol Sci 1998;156:41-6.
- Di Giovanni S, Mirabella M, Spinazzola A, et al. Coenzyme Q10 reverses pathological phenotype and reduces apoptosis in familial CoQ10 deficiency. Neurology 2001;57:515-8.
- Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ : British Medical Journal 2003;326:1423
- Australian Medicines Handbook. Statins. Adelaide: AMH Pty Ltd, 2017 (accessed 27 September 2017).
- Saha SP, Whayne TF, Jr. Coenzyme Q-10 in Human Health: Supporting Evidence? South Med J 2016;109:17-21.
- Deichmann R, Lavie C, Andrews S. Coenzyme Q10 and Statin-Induced Mitochondrial Dysfunction. Ochsner J 2010;10:16-21.
- Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J Am Coll Cardiol 2007;49:2231-7.
- Caso G, Kelly P, McNurlan MA, et al. Effect of coenzyme q10 on myopathic symptoms in patients treated with statins. Am J Cardiol 2007;99:1409-12
- Fedacko J, Pella D, Fedackova P, et al. Coenzyme Q(10) and selenium in statin-associated myopathy treatment. Can J Physiol Pharmacol 2013;91:165-70.
- Skarlovnik A, Janic M, Lunder M, et al. Coenzyme Q10 supplementation decreases statin-related mild-to-moderate muscle symptoms: a randomized clinical study. Med Sci Monit 2014;20:2183-8.
- Young JM, Florkowski CM, Molyneux SL, et al. Effect of coenzyme Q(10) supplementation on simvastatin-induced myalgia. Am J Cardiol 2007;100:1400-3.
- Bogsrud MP, Langslet G, Ose L, et al. No effect of combined coenzyme Q10 and selenium supplementation on atorvastatin-induced myopathy. Scand Cardiovasc J 2013;47:80-7
- Bookstaver DA, Burkhalter NA, Hatzigeorgiou C. Effect of coenzyme Q10 supplementation on statin-induced myalgias. Am J Cardiol 2012;110:526-9.
- Banach M, Serban C, Sahebkar A, et al. Effects of coenzyme Q10 on statin-induced myopathy: a meta-analysis of randomized controlled trials. Mayo Clin Proc 2015;90:24-34
- Taylor BA, Lorson L, White CM, et al. A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy. Atherosclerosis 2015;238:329-35.
- National Heart Foundation of Australia. Guideline for the diagnosis and management of hypertension in adults. Melbourne: National Heart Foundation of Australia, 2016 (accessed 13 March 2016).
- eMIMS Cloud. Co-enzyme Q10 capsules (Ubidecarenone) and phenindione. 2017.
- eMIMS Cloud. Co-enzyme Q10 capsules (Ubidecarenone) and warfarin sodium. 2017.
- Rosenson RS, Baker SK, Jacobson TA, et al. An assessment by the Statin Muscle Safety Task Force: 2014 update. J Clin Lipidol 2014;8:S58-71.
- Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J 2016;37:2999-3058