Effects of Coenzyme Q10 on Statin-Induced Myopathy: An Updated Meta-Analysis of Randomized Controlled Trials

Hua Qu, Ming Guo, Hua Chai, Wen-Ting Wang, Zhu-Ye Gao, Da-Zhuo Shi, Hua Qu, Ming Guo, Hua Chai, Wen-Ting Wang, Zhu-Ye Gao, Da-Zhuo Shi

Abstract

Background Previous studies have demonstrated a possible association between the induction of coenzyme Q10 (CoQ10) after statin treatment and statin-induced myopathy. However, whether CoQ10 supplementation ameliorates statin-induced myopathy remains unclear. Methods and Results PubMed, EMBASE , and Cochrane Library were searched to identify randomized controlled trials investigating the effect of CoQ10 on statin-induced myopathy. We calculated the pooled weighted mean difference ( WMD ) using a fixed-effect model and a random-effect model to assess the effects of CoQ10 supplementation on statin-associated muscle symptoms and plasma creatine kinase. The methodological quality of the studies was determined, according to the Cochrane Handbook. Publication bias was evaluated by a funnel plot, Egger regression test, and the Begg-Mazumdar correlation test. Twelve randomized controlled trials with a total of 575 patients were enrolled; of them, 294 patients were in the CoQ10 supplementation group and 281 were in the placebo group. Compared with placebo, CoQ10 supplementation ameliorated statin-associated muscle symptoms, such as muscle pain ( WMD , -1.60; 95% confidence interval [ CI ], -1.75 to -1.44; P<0.001), muscle weakness ( WMD , -2.28; 95% CI , -2.79 to -1.77; P=0.006), muscle cramp ( WMD , -1.78; 95% CI , -2.31 to -1.24; P<0.001), and muscle tiredness ( WMD , -1.75; 95% CI , -2.31 to -1.19; P<0.001), whereas no reduction in the plasma creatine kinase level was observed after CoQ10 supplementation ( WMD , 0.09; 95% CI , -0.06 to 0.24; P=0.23). Conclusions CoQ10 supplementation ameliorated statin-associated muscle symptoms, implying that CoQ10 supplementation may be a complementary approach to manage statin-induced myopathy.

Keywords: coenzyme Q10; coronary disease; meta‐analysis; statin therapy; statin‐induced myopathy.

Figures

Figure 1
Figure 1
Literature search process and study selection.
Figure 2
Figure 2
Risk of bias summary.
Figure 3
Figure 3
Forest plot for statin‐associated muscle symptoms: coenzyme Q10 vs placebo (fixed‐effect model). CI indicates confidence interval; ID, identification; WMD, weighted mean difference.
Figure 4
Figure 4
Forest plot for statin‐associated muscle symptoms: coenzyme Q10 vs placebo (random‐effect model). CI indicates confidence interval; ID, identification; WMD, weighted mean difference.
Figure 5
Figure 5
Meta‐regression plot. A, Mean change in muscle pain score according to administration doses of coenzyme Q10 (CoQ10). B, Mean change in muscle pain score according to CoQ10 supplementation time. C, Mean change in muscle pain score according to year of publication. D, Mean change in plasma creatine kinase (CK) according to administration doses of CoQ10. E, Mean change in plasma CK level according to CoQ10 supplementation time. F, Mean change in plasma CK level according to year of publication.
Figure 6
Figure 6
Forest plot for plasma creatine kinase: coenzyme Q10 vs placebo (fixed‐effect model). CI indicates confidence interval; ID, identification; WMD, weighted mean difference.
Figure 7
Figure 7
Forest plot for plasma creatine kinase: coenzyme Q10 vs placebo (random‐effect model). CI indicates confidence interval; ID, identification; WMD, weighted mean difference.
Figure 8
Figure 8
Forest plot for plasma creatine kinase on the basis of region (fixed‐effect model). CI indicates confidence interval; ID, identification; WMD, weighted mean difference.
Figure 9
Figure 9
Forest plot for plasma creatine kinase on the basis of region (random‐effect model). CI indicates confidence interval; ID, identification; WMD, weighted mean difference.
Figure 10
Figure 10
Publication bias. A, Funnel plot for muscle pain. B, Begg test for muscle pain. C, Egger test for muscle pain. D, Funnel plot for plasma creatine kinase (CK). E, Begg test for plasma CK. F, Egger test for plasma CK. WMD indicates weighted mean difference.

References

    1. Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen M‐R, Wiklund O, Agewall S, Alegria E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, Wood D, ESC Committee for Practice Guidelines (CPG) 2008‐2010 and 2010‐2012 Committees . ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769–1818.
    1. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol. 2006;97:S52–S60.
    1. Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, Roden M, Stein E, Tokgozo lu L, Nordestgaard BG, Bruckert E, De Backer G, Krauss RM, Laufs U, Santos RD, Hegele RA, Hovingh GK, Leiter LA, Mach F, Marz W, Newman CB, Wiklund O, Jacobson TA, Catapano AL, Chapman MJ, Ginsberg HN; European Atherosclerosis Society Consensus , Stroes E, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, Roden M, Stein E, Tokgozo lu L, Nordestgaard BG, Bruckert E, Krauss RM, Laufs U, Santos RD, Marz W, Newman CB, John Chapman M, Ginsberg HN, John Chapman M, Ginsberg HN, de Backer G, Catapano AL, Hegele RA, Kees Hovingh G, Jacobson TA, Leiter L, Mach F, Wiklund O. Statin‐associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36:1012–1022.
    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.
    1. Langsjoen PH, Langsjoen AM. The clinical use of HMG CoA‐reductase inhibitors and the associated depletion of coenzyme Q10: a review of animal and human publications. Biofactors. 2003;18:101–111.
    1. Banach M, Serban C, Ursoniu S, Rysz J, Muntner P, Toth PP, Jones SR, Rizzo M, Glasser SP, Watts GF, Blumenthal RS, Lip GY, Mikhailidis DP, Sahebkar A. Statin therapy and plasma coenzyme Q10 concentrations: a systematic review and meta‐analysis of placebo‐controlled trials. Pharmacol Res. 2015;99:329–336.
    1. 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.
    1. Fedacko J, Pella D, Fedackova P, Hänninen O, Tuomainen P, Jarcuska P, Lopuchovsky T, Jedlickova L, Merkovska L, Littarru GP. Coenzyme Q10 and selenium in statin‐associated myopathy treatment. Can J Physiol Pharmacol. 2013;91:165–170.
    1. Skarlovnik A, Janić M, Lunder M, Turk M, Šabovič M. Coenzyme Q10 supplementation decreases statin‐related mild‐to‐moderate muscle symptoms: a randomized clinical study. Med Sci Monit. 2014;20:2183–2188.
    1. Tóth Š, Šajty M, Pekárová T, Mughees A, Štefanič P, Katz M, Spišáková K, Pella J, Pella D. Addition of omega‐3 fatty acid and coenzyme Q10 to statin therapy in patients with combined dyslipidemia. J Basic Clin Physiol Pharmacol. 2017;28:327–336.
    1. Taylor BA, Lorson L, White CM, Thompson PD. A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy. Atherosclerosis. 2015;238:329–335.
    1. Young JM, Florkowski CM, Molyneux SL, McEwan RG, Frampton CM, George PM, Scott RS. Effect of coenzyme Q10 supplementation on simvastatin‐induced myalgia. Am J Cardiol. 2007;100:1400–1403.
    1. Bookstaver DA, Burkhalter NA, Hatzigeorgiou C. Effect of coenzyme Q10 supplementation on statin‐induced myalgias. Am J Cardiol. 2012;110:526–529.
    1. Rott D, Leibowitz D, Goldenberg I, Klempfner R. Effect of coenzyme Q 10 supplementation on statin‐induced myalgia, a randomized double‐blind, placebo‐controlled study. J Prev Med Care. 2016;1:16–22.
    1. Bogsrud MP, Langslet G, Ose L, Arnesen KE, Sm Stuen MC, Malt UF, Woldseth B, Retterstol K. No effect of combined coenzyme Q10 and selenium supplementation on atorvastatin‐induced myopathy. Scand Cardiovasc J. 2013;47:80–87.
    1. Banach M, Serban C, Sahebkar A, Ursoniu S, Rysz J, Muntner P, Toth PP, Jones SR, Rizzo M, Glasser SP, Lip GY, Dragan S, Mikhailidis DP. Effects of coenzyme Q10 on statin‐induced myopathy: a meta‐analysis of randomized controlled trials. Mayo Clin Proc. 2015;90:24–34.
    1. Pek SLT, Tavintharan S, Woon K, Lin L, Ong CN, Lim SC, Sum CF. MicroRNAs as biomarkers of hepatotoxicity in a randomized placebo‐controlled study of simvastatin and ubiquinol supplementation. Exp Biol Med. 2016;241:317–330.
    1. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta‐analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.
    1. Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savović J, Schulz KF, Weeks L, Sterne JAC. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.
    1. Rice K, Higgins JPT, Lumley T. A re‐evaluation of fixed effect(s) meta‐analysis. J R Stat Soc Ser A Stat Soc. 2018;181:205–227.
    1. Mabuchi H, Nohara A, Kobayashi J, Kawashiri MA, Katsuda S, Inazu A, Koizumi J. 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;195:182–189.
    1. Deichmann RE, Lavie CJ, Dornelles AC. Impact of coenzyme Q‐10 on parameters of cardiorespiratory fitness and muscle performance in older athletes taking statins. Phys Sportsmed. 2013;40:88–95.
    1. Nanna MG, Navar AM, Wang TY, Mi X, Virani SS, Louie MJ, Lee LV, Goldberg AC, Roger VL, Robinson J, Peterson ED. Statin use and adverse effects among adults >75 years of age: insights from the patient and provider assessment of lipid management (PALM) registry. J Am Heart Assoc. 2018;7:e008546 DOI: 10.1161/JAHA.118.008546.
    1. Ashton E, Windebank E, Skiba M, Reid C, Schneider H, Rosenfeldt F, Tonkin A, Krum H. Why did high‐dose rosuvastatin not improve cardiac remodeling in chronic heart failure? Mechanistic insights from the UNIVERSE study. Int J Cardiol. 2011;146:404–407.
    1. Berthold HK, Naini A, Di Mauro S, Hallikainen M, Gylling H, Krone W, Gouni‐Berthold I. Effect of ezetimibe and/or simvastatin on coenzyme Q10 levels in plasma: a randomised trial. Drug Saf. 2006;29:703–712.
    1. McMurray JJ, Dunselman P, Wedel H, Cleland JG, Lindberg M, Hjalmarson A, Kjekshus J, Waagstein F, Apetrei E, Barrios V, Böhm M, Kamenský G, Komajda M, Mareev V, Wikstrand J. Coenzyme Q10, rosuvastatin, and clinical outcomes in heart failure: a pre‐specified substudy of CORONA (Controlled Rosuvastatin Multinational Study in Heart Failure). J Am Coll Cardiol. 2010;56:1196–1204.
    1. Päivä H, Thelen KM, Van Coster R, Smet J, De Paepe B, Mattila KM, Laakso J, Lehtimäki T, Von Bergmann K, Lütjohann D, Laaksonen R. High‐dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial. Clin Pharmacol Ther. 2005;78:60–68.
    1. Lee B, Tseng Y, Yen C, Lin P. Effects of coenzyme Q10 supplementation (300 mg/day) on antioxidation and anti‐inflammation in coronary artery disease patients during statins therapy: a randomized, placebo‐controlled trial. Nutr J. 2013;12:1.
    1. Choi H‐K, Won E‐K, Choung S‐Y. Effect of coenzyme Q10 supplementation in statin‐treated obese rats. Biomol Ther (Seoul). 2016;24:171–177.
    1. Pasha R, Moon TW. Coenzyme Q10 protects against statin‐induced myotoxicity in zebrafish larvae (Danio rerio). Environ Toxicol Pharmacol. 2017;52:150–160.
    1. Choi SY, Park JS, Roh MS, Kim C‐R, Kim MH, Serebruany V. Inhibition of angiotensin II‐induced cardiac fibrosis by atorvastatin in adiponectin knockout mice. Lipids. 2017;52:415–422.
    1. Liu C‐W, Yang F, Cheng S‐Z, Liu Y, Wan L‐H, Cong H‐L. Rosuvastatin postconditioning protects isolated hearts against ischemia‐reperfusion injury: the role of radical oxygen species, PI3K‐Akt‐GSK‐3β pathway, and mitochondrial permeability transition pore. Cardiovasc Ther. 2017;35:3–9.
    1. Mikashinovich ZI, Belousova ES, Sarkisyan OG. Impairment of energy‐dependent processes in the muscle tissue as a pathogenetic mechanism of statin‐induced myopathy. Bull Exp Biol Med. 2017;162:433–435.
    1. Almukhtar H, Garle MJ, Smith PA, Roberts RE. Effect of simvastatin on vascular tone in porcine coronary artery: potential role of the mitochondria. Toxicol Appl Pharmacol. 2016;305:176–185.
    1. Stránecký V, Neřoldová M, Hodaňová K, Hartmannová H, Piherová L, Zemánková P, Přistoupilová A, Vrablík M, Adámková V, Kmoch S, Jirsa M. Large copy‐number variations in patients with statin‐associated myopathy affecting statin myopathy‐related loci. Physiol Res. 2016;65:1005–1011.
    1. Needham M, Mastaglia FL. Statin myotoxicity: a review of genetic susceptibility factors. Neuromuscul Disord. 2014;24:4–15.
    1. Toma E, Loignon M. Statin‐associated myopathy with normal creatine kinase levels. Ann Intern Med. 2003;138:1007–1008; author reply 1008‐1009.
    1. Mohaupt MG, Karas RH, Babiychuk EB, Sanchez‐Freire V, Monastyrskaya K, Iyer L, Hoppeler H, Breil F, Draeger A. Association between statin‐associated myopathy and skeletal muscle damage. Can Med Assoc J. 2009;181:E11–E18.

Source: PubMed

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