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The effect of coenzyme Q10 in statin myopathy
Abstract
Objectives:
Statins significantly reduce CV morbidity and mortality. Unfortunately, one of the side effects of statins is myopathy, for which statins cannot be administered in sufficient doses or administered at all. The aim of this study was to demonstrate the effect of coenzyme Q10 in patients with statin myopathy.
Design/setting:
Twenty eight patients aged 60.6±10.7 years were monitored (18 women and 10 men) and treated with different types and doses of statin. Muscle weakness and pain was monitored using a scale of one to ten, on which patients expressed the degree of their inconvenience. Examination of muscle problems was performed prior to administration of CQ10 and after 3 and 6 months of dosing. Statistical analysis was performed using Friedman test, Annova and Students t-test.
Results:
Pain decreased on average by 53.8% (p<0.0001), muscle weakness by 44.4% (p<0.0001). The CQ10 levels were increased by more than 194% (from 0,903 μg/ml to 2.66 μg/ml; p<0.0001).
Conclusion:
After a six-month administration of coenzyme Q10, muscle pain and sensitivity statistically significantly decreased.
... Las estatinas reducen significativamente el riesgo cardiovascular (2)(3)(4)(5)(6)(7) , siendo actualmente los fármacos hipolipemiantes más efectivos (4,8,9) . Desafortunadamente, conllevan efectos secundarios de etiología no esclarecida (10)(11)(12) que afectan principalmente al músculo esquelético, produciendo desde miopatías hasta rabdiomiolisis (7,(13)(14)(15)(16)(17) , razón por la que en ocasiones existen dificultades en la adherencia a la terapia con estatina (5,10,13,17) , no pueden administrarse en dosis suficientes o no pueden administrarse en absoluto (3,5,11,(17)(18)(19) . ...
... Las estatinas reducen significativamente el riesgo cardiovascular (2)(3)(4)(5)(6)(7) , siendo actualmente los fármacos hipolipemiantes más efectivos (4,8,9) . Desafortunadamente, conllevan efectos secundarios de etiología no esclarecida (10)(11)(12) que afectan principalmente al músculo esquelético, produciendo desde miopatías hasta rabdiomiolisis (7,(13)(14)(15)(16)(17) , razón por la que en ocasiones existen dificultades en la adherencia a la terapia con estatina (5,10,13,17) , no pueden administrarse en dosis suficientes o no pueden administrarse en absoluto (3,5,11,(17)(18)(19) . ...
... La inhibición de la HMG CoA reductasa es necesaria tanto para la síntesis de colesterol como para la de Coenzima Q 10 (CoQ 10 ), ello implica la reducción de su concentración sérica de ambos productos finales de la ruta del mevalonato (22,23) . De este modo, se sugiere que las estatinas podrían afectar la función mitocondrial en músculo esquelético (2,3,8,15) . Además, la CoQ 10 es un transportador básico en la cadena respiratoria de la mitocondria (2,4,17,(22)(23)(24) . ...
Introducción: La incidencia de eventos cardiovasculares fatales es muy elevada y el tratamiento con estatinas es vital para reducir este riesgo en muchos pacientes, sin embargo, sus efectos adversos sobre el músculo esquelético dificultan la adherencia o la continuación del mismo. Se ha propuesto la suplementación de coenzima Q10 para revertir mialgias asociadas a el empleo de estatinas. Los ensayos clínicos que se realizaron en los últimos 10 años obtuvieron resultados contrapuestos. El objetivo de este trabajo es revisar la evidencia sobre la eficacia del empleo de suplementos de coenzima Q10 en para mitigar las miopatías causadas por las estatinas. Metodología: Se realizó una búsqueda sistemática de la literatura publicada hasta Julio de 2020. Las bases de datos consultadas fueron MEDLINE y SCOPUS. También se consultaron instituciones como la Agencia Española del Medicamento y Productos Sanitarios (AEMPS), la European Medicines Agency (EMA) y la Food and Drug Administration (FDA). Resultados: La etiología de las mialgias asociadas a estatinas sigue siendo desconocida y la evidencia encontrada en los ensayos clínicos y metaanalisis obtuvieron conclusiones dispares. La European Medicine Agency (EMA) solo considera el empleo de suplementos en síndrome de deficiencia primaria de coenzima Q10, mientras en Reino Unido el National Institute for Health and Care Excellence (NICE) y el National Institute of Health (NIH) no recomiendan el empleo de estos suplementos para tratar mialgias asociadas al empleo de estatinas. Conclusiones: El conjunto de los estudios analizados no consiguió una evidencia unánime para poder recomendar este empleo de suplementos de coenzima Q10 de modo confiable. Se necesitan estudios mejor diseñados que aporten reproducibilidad y robustez a futuros ensayos clínicos.
... Coenzima Q10 (CoQ10), conhecida também como ubiquinona é um componente essencial da cadeia respiratória mitocondrial. Possui importantes funções na produção de adenosina trifosfato (ATP), na respiração celular e atua como potente antioxidante [1][2][3][4][5]. ...
... Foram analisados 18 trabalhos científicos envolvendo a suplementação do nutracêutico (ubiquinona ou ubiquinol) para melhora dos seguintes efeitos induzidos por estatinas: miopatias/danos musculares [2,[5][6][7][8][14][15][16][17]; disfunções ventricular/endotelial [6,18,19] e mitocondrial [8,[20][21][22]; hepatotoxicidade [7,8,15,22]; fadiga, dispneia, perda de memória e neuropatia periférica [6]; cardiomiopatia induzida por estatinas [13]; sensibilidade a insulina [23]; também, foi estudado o efeito da CoQ10 na melhora de parâmetros de performance física (aptidão cardiorrespiratória e/ou desempenho muscular) [16,24]; assim como de marcadores inflamatórios e níveis de enzimas antioxidantes em usuários de estatinas [25]. ...
... É bem consolidado que a suplementação de CoQ10, mesmo em curto prazo, eleva significativamente os níveis de ubiquinona plasmática [5,7,8,13,[16][17][18][19][20][21][22][23][24][25]. Como demonstrado por Diemen et al., que em apenas quatro semanas de suplementação, com a dosagem de 300 mg/dia já obtiveram esse resultado, ou ainda, como Zlatohlavek et al., que alcançaram o significativo aumento de 194% nos níveis séricos de CoQ10 com 60 mg/dia de ubiquinol (duas doses de 30 mg/dia) em seis meses de suplementação. ...
Coenzyme Q10 (CoQ10), also known as ubiquinone, is an essential component of the mitochondrial respiratory chain. One of the causes of its deficiency is the chronic use of statins, a class of widely prescribed anti-cholesterolemic drugs. Its reduction can cause undesirable side effects, such as dyspnea, hepatic alterations, muscular and/or gastrointestinal symptoms, rhabdomyolysis, peripheral neuropathies, type 2 Diabetes Mellitus, among others. This literature review aimed to understand whether CoQ10 supplementation reduces the side effects caused by the use of statins, to describe them, and to indicate the safe and effective dose for the success of this nutritional strategy. This is a systematic review of the literature, which was searched in the MEDLINE/PubMed database, of studies published between 2004 and 09/2020, using the descriptors and combination Ubiquinone AND Anticholesteremic Agents and Ubiquinone AND Cholesterol. A total of 462 articles were identified, and after reading the title, abstract, and applying the exclusion criteria, 18 scientific papers were included for analysis. The studies presented varied populations and methodologies, and the methods for evaluating the results were also heterogeneous, mainly due to the variety of side effects studied. Of the 18 studies, ten (66.6%) found some benefit from supplementation. It was evidenced that the usual dose of supplementation (between 100 and 300 mg) was able to bring benefits regarding the following parameters: diastolic, endothelial, and mitochondrial function, fatigue, myopathies, dyspnea, memory loss, peripheral neuropathy, lipid profile, antioxidant and anti-inflammatory activity, and hepatotoxicity evidenced after 30 days of supplementation, and also a reduction in cardiovascular risk.
... Several clinical studies confirmed the beneficial effect of CoQ 10 to reduce pain and weakness of skeletal muscle induced by statins. Different types and different daily doses of CoQ 10 (30 to 200 mg per day when taking statins) are used to reduce muscle pain [41][42][43][44][45]. Authors recommended 200 mg CoQ 10 daily in patients with statin-induced myopathy [40]. ...
... Patients with statin-induced myopathy and pain used various types of statins, in various daily doses. Supplementation with 2x30 mg ubiquinol (reduced coenzyme CoQ 10 ) for 6 months significantly decreased skeletal muscle pain [42]. Administration of statins reduces metabolism and viability of skleletal muscle cells. ...
Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) decrease LDL-cholesterol, triacylglycerols, coenzyme Q10 (CoQ10) concentrations and isoprenoids synthesis. Benefits of statins include vasodilatatory, antiarrhythmic, antitrombotic and antiinflammatory effects (pleiotropic), stimulation of endogenous antioxidants function and reduction of oxidative stress. Decreased CoQ10 concentration is an important reason for the occurrence of adverse effects, as statin-induced myopathy. In hypercholesterolemic rats treated with atorvastatin (dose 80 mg/(kg body weight)/day) for four weeks, we documented dysfunction of myocardium and liver mitochondrial oxidative phosphorylation, and a decrease in mitochondrial CoQ9-OX and CoQ10-OX concentrations. Reduction of CoQ10 concentrations and dysfunction of skeletal muscle mitochondrial respiration and ATP production brought about by statin use can be referred to as "statin-induced mitochondrial myopathy". From our experience and that of several other authors, targeting reduction of the statin-induced mitochondrial myopathy is appropriate at daily doses of 60 mg-100 to 200 mg CoQ10, in particular for patients with muscle pain, general weakness, increased activity of creatine kinase and transaminases, in cardiovascular diseases, impairment of memory, and sexual dysfunction.
... Direct evidence for a CoQ10-induced compensation of mitochondrial function was reported by Rosenfeldt et al. [133] in patients undergoing heart surgery, which resulted in increased CoQ10 levels in serum, atrial trabeculae, and isolated mitochondria compared with patients receiving placebo, with an improvement in mitochondrial respiration, as adenosine diphosphate/oxygen ratio, and a decrease in mitochondrial MDA content. [76,196]; metabolic syndrome [185][186][187]; statin-induced myalgias [188][189][190][191][192]; bronchial asthma [193]; ...
... Controversial results were reported from clinical trials aimed at testing CoQ10 in counteracting various dysmetabolic conditions [185][186][187], statin-induced myalgias [188][189][190][191][192], bronchial asthma [193], pre-eclampsia [194], cutaneous infections [195], psoriasis [76,196], cataract surgery [197], and idiopathic infertility [198]. ...
An extensive number of pathologies are associated with mitochondrial dysfunction (MDF) and oxidative stress (OS). Thus, mitochondrial cofactors termed "mitochondrial nutrients" (MN), such as α-lipoic acid (ALA), Coenzyme Q10 (CoQ10), and l-carnitine (CARN) (or its derivatives) have been tested in a number of clinical trials, and this review is focused on the use of MN-based clinical trials. The papers reporting on MN-based clinical trials were retrieved in MedLine up to July 2014, and evaluated for the following endpoints: (a) treated diseases; (b) dosages, number of enrolled patients and duration of treatment; (c) trial success for each MN or MN combinations as reported by authors. The reports satisfying the above endpoints included total numbers of trials and frequencies of randomized, controlled studies, i.e., 81 trials testing ALA, 107 reports testing CoQ10, and 74 reports testing CARN, while only 7 reports were retrieved testing double MN associations, while no report was found testing a triple MN combination. A total of 28 reports tested MN associations with "classical" antioxidants, such as antioxidant nutrients or drugs. Combinations of MN showed better outcomes than individual MN, suggesting forthcoming clinical studies. The criteria in study design and monitoring MN-based clinical trials are discussed.
... Coenzyme Q10 (CoQ10) is a producing center of the cell known as the mitochondria and has an effect on electron transport and energy production (ATP). CoQ10 has also an antioxidant effect on mitochondria and cell membranes and protects lipids from oxidation and thereby stabilizes biological membranes, so it is essential for the health of all human tissue and organs (7,8). Antioxidants are substances that scavenge oxidants (free radicals), compounds that alter cell membrane, tamper with DNA and even cause cell death. ...
... Blood concentration of vitamin C and other antioxidant decrease due to the accelerated consumption in the blood (19). CoQ10 (Ubiquinole) is one of the key substances in the myocardial energetic metabolism and also important for cell membrane stability, and with CoQ10 deficiency, myocytes could be prone to damage in the form of myopathy or myositis or even rhabdomyolysis (20) so it is essential for the health of all human tissue and organs (7,8). Protective effect of CoQ10 against cardiovascular and neurodegenerative diseases is well established (9). ...
Introduction: Indomethacin increases generation of mitochondrial reactive oxygen species (ROS) which have a crucial role in the indomethacin-induced gastric ulcer. Coenzyme Q10 has an antioxidant activity on mitochondria and cell membranes and protects lipids from oxidation and is essential for stabilizing biological membranes. Superoxide dismutase (SOD) acts as one of the defense mechanisms against free radicals. When the generation of ROS overwhelms, the antioxidant defense, lipid peroxiation of cell membrane occurs and cause cell damage.
Materials and Methods: Male adult Wistar rats were divided into A and B groups. The rats in group A were then further divided into three subgroups of 6 animals each and received one of the following treatments: Animals in the first subgroup received saline. Animals in the second subgroup received saline and indomethacin. Animals in the third subgroup received vitamin C and indomethacin. The rats in group B were also further divided into 3 subgroups of 6 rats each and treated with one of the following treatments: Animals in first subgroup received 1% Tween 80 as vehicle. Animals In second subgroup received 1% Tween 80 and indomethacin. Animals in third subgroup received CoQ10 and indomethacin. Four hours after the last treatment, animals were killed by an overdose of ether and 2 ml blood was drawn from left ventricle into syringe containing EDTA (1mg/ml) and the stomachs removed were cut and gastric mucosal lesions were examined). Ulcer indexes were determined and SOD activity measured in plasma
Results: Pre-treatment with both vitamin C and coenzyme Q10 was associated with attenuation of ulcer index and increased SOD activity compared with animals treated with indomethacin alone (P<0.001).
Conclusion: This effect of CoQ10 may be due to its electron donating property that inhibits the decrease in SOD activity in gastric tissue (replenishment of endogenous SOD) and inhibiting lipid peroxidation.
... Examination of muscle problems was performed before administration of CoQ10 and after three and six months of dosing. Statistical analysis of facts and figures concluded the effectiveness of CoQ10 supplementation in significantly improving muscle pain caused by statins [26]. ...
... Humans or animals fed with non-vegetarian diet will have higher CoQ10 intake and its absorption varies with the amount and uptake increases with increase in fat content. The absorption of reduced form is more than that of the oxidized CoQ10, and with its large molecular weight, about 60% of intake is excreted through the feces [23]. The yeast fermentation technique, which involves with inclusion of B vitamins in their culture, is the major form of industrial CoQ10 synthesis. ...
... It is worth mentioning that the inhibition of HMG-CoA reductase blocks the synthesis of mevalonate, a precursor of farnesyl pyrophosphate that, in addition to being a substrate of cholesterol, is also the substrate for ubiquinone, also known as coenzyme Q synthesis [48]. Therefore, integrating coenzyme Q with supplements can be a strategy for reducing muscle pain mediated by statins [49,50]. Our study adds knowledge for clinical practice, but it also has some limitations. ...
Background:
Matrix metalloproteinases (MMPs) are involved in vascular wall degradation, and drugs able to modulate MMP activity can be used to prevent or treat aneurysmal disease. In this study, we evaluated the effects of statins on MMP-2, MMP-9, and neutrophil gelatinase-associated lipocalin (NGAL) in both plasma and tissue in patients with aneurysmal disease.
Methods:
We performed a prospective, single-blind, multicenter, control group clinical drug trial on 184 patients of both sexes >18 years old with a diagnosis of arterial aneurysmal disease. Enrolled patients were divided into two groups: Group I under statin treatment and Group II not taking statins. In addition, 122 patients without aneurysmal disease and under statin treatment were enrolled as a control group (Group III). The expression of MMPs and NGAL in plasma was evaluated using ELISA, while their expression in endothelial tissues was evaluated using Western blot.
Results:
The ELISA test revealed greater plasma levels (p < 0.01) of MMPs and NGAL in Groups I and II vs. Group III. Western blot analysis showed higher expression (p < 0.01) of MMPs and NGAL in Group II vs. Group I, and this increase was significantly higher (p < 0.01) in patients treated with low potency statins compared to high potency ones.
Conclusions:
MMPs and NGAL seem to play a major role in the development of aneurysms, and their modulation by statins suggests that these drugs could be used to prevent arterial aneurysmal disease.
... Accordingly, the potential protective effect of CoQ10 on statin myotoxicity was reported. Studies had shown that CoQ10 improves the myopathic manifestations induced by statins in animals (El-Ganainy et al., 2016) as well as in humans (Fedacko et al., 2012;Zlatohlavek et al., 2012). ...
Myopathy is a well-known adverse effect of statins, affecting a large sector of statins users. The reported experimental data emphasized on mechanistic study of statin myopathy on large muscles. Clinically, both large muscles and respiratory muscles are reported to be involved in the myotoxic profile of statins. However, the experimental data investigating the myopathic mechanism on respiratory muscles are still lacking. The present work aimed to study the effect of atorvastatin treatment on respiratory muscles using rat isolated hemidiaphragm in normoxic & hypoxic conditions. The contractile activity of isolated hemidiaphragm in rats treated with atorvastatin for 21 days was investigated using nerve stimulated technique. Muscle twitches, train of four and tetanic stimulation was measured in normoxic, hypoxic and reoxygenation conditions. Atorvastatin significantly increased the tetanic fade, a measure of muscle fatigability, in hypoxic conditions. Upon reoxygenation, rat hemidiaphragm regains its normal contractile profile. Co-treatment with coenzyme Q10 showed significant improvement in defective diaphragmatic contractility in hypoxic conditions. This work showed that atorvastatin treatment rapidly deteriorates diaphragmatic activity in low oxygen environment. The mitochondrial respiratory dysfunction is probably the mechanism behind such finding. This was supported by the improvement of muscle contractile activity following CoQ10 co-treatment.
... Several clinical studies confirmed the beneficial effect of CoQ10 to reduce pain and weakness of skeletal muscle induced by statins. Different types and different daily doses of CoQ10 (30 to 200 mg per day when taking statins) are used to reduce muscle pain [20][21][22][23][24]. Patients with coronary artery disease and hyperlipoproteinemia who were taking statins and used 300 mg CoQ10/day, had increased antioxidant enzymes and decreased inflammatory markers (tumor necrosis alpha, IL-6) [23]. ...
... In a recent study of 28 patients, decreased muscle pain and sensitivity was observed after a 6-month administration of coenzyme Q10 at a dose of 30 mg twice daily. 147 Fedacko et al. 148 evaluated the possible benefits of coenzyme Q10 and selenium supplementation administered to 60 patients with statin-associated myopathy in a small double-blinded study. Selenium (200 mg/d) and coenzyme Q10 (200 mg/d) supplementation of statin-treated patients resulted in symptomatic attenuation of statin-associated myopathy in absolute numbers and intensity. ...
The Canadian Consensus Working Group has updated its evaluation of the literature pertaining to statin intolerance and adverse effects. This overview introduces a pragmatic definition of statin intolerance (goal-inhibiting statin intolerance) that emphasizes the effects of symptoms on achieving nationally vetted goals in patients fulfilling indications for lipid-lowering therapy and cardiovascular risk reduction. The Canadian Consensus Working Group provides a structured framework for avoiding, evaluating and managing goal-inhibiting statin intolerance. Particularly difficult practice situations are reviewed, including management in young and elderly individuals, and in athletes and labourers. Finally, targeted at specialty practitioners, more detailed analyses of specific but more unusual adverse effects ascribed to statins are updated including evidence regarding new-onset diabetes, cognitive dysfunction, cataracts, and the rare but important immune-mediated necrotizing myopathy.
... The current evidence does not support CoQ10 supplementation in statins' myopathy (Schaars and Stalenhoef, 2008). However, Zlatohlavek et al. (2012) found that administration of CoQ10 for six months significantly decreased statin-induced muscle pain. Moreover, CoQ10 inhibited RANKL-induced osteoclast activation and stimulated osteoblasts, suggesting its potential use in treatment of osteoporosis (Moon et al., 2013). ...
Objective
Statins’ therapy in osteoporosis can aggravate muscle damage. This study was designed to assess which agent, l-carnitine or coenzyme Q10, could enhance the anti-osteoporotic effect of atorvastatin while antagonizing myopathy in ovariectomized rats.
Methods
Forty-eight female Sprague Dawley rats were used; forty rats were ovariectomized while eight were sham-operated. Eight weeks post-ovariectomy, rats were divided into ovariectomized-untreated group and four ovariectomized-treated groups (n=8) which received by gavage (mg/(kg·d), for 8 weeks) 17β-estradiol (0.1), atorvastatin (50), atorvastatin (50)+l-carnitine (100), or atorvastatin (50)+coenzyme Q10 (20). At the end of therapy, bone mineral density (BMD), bone mineral content (BMC), and serum levels of bone metabolic markers (BMMs) and creatine kinase (CK) were measured. Femurs were used for studying the breaking strength and histopathological changes.
Results
Treatment with atorvastatin+l-carnitine restored BMD, BMC, and bone strength to near normal levels. Estrogen therapy restored BMD and BMC to near normal levels, but failed to increase bone strength. Although atorvastatin and atorvastatin+coenzyme Q10 improved BMD, BMC, and bone strength, they failed to restore levels to normal. All treatments decreased BMMs and improved histopathological changes maximally with atorvastatin+l-carnitine which restored levels to near normal. Atorvastatin aggravated the ovariectomy-induced increase in CK level while estrogen, atorvastatin+l-carnitine, and atorvastatin+coenzyme Q10 decreased its level mainly with atorvastatin+l-carnitine which restored the level to near normal.
Conclusions
Coadministration of l-carnitine, but not coenzyme Q10, enhances the anti-osteoporotic effect of atorvastatin while antagonizing myopathy in ovariectomized rats. This could be valuable in treatment of osteoporotic patients. However, further confirmatory studies are needed.
... Humans or animals fed non-vegetarian diet will have higher CoQ10 intake and its absorption varies with the amount and uptake increases with increase in fat content. The absorption of reduced form is more than the oxidized CoQ10 and with its large molecular weight about 60% of intake excreted through the faeces (Zlatohlavek et al., 2012). The yeast fermentation technique which involves with inclusion of B-vitamins in their culture is the major form of industrial CoQ10 synthesis. ...
The essentiality of nutrients keeps on changing with the advancement in nutritional research and genetic gain. The genetic gain especially in poultry sector is very high which results in increase in nutrient requirement of both the essential and non-essential nutrients. For the rapid growth the requirement of essential nutrients reaches many folds which are in direct relation with the performance, but the requirement for non-essential nutrients is an indirect one. Most of the dispensable amino acids, vitamin C, carnitine, etc. which are being synthesized endogenously are now a days unable to meet the birds requirements that warrants the dietary supply. Another important nutrient is coenzyme Q10 (CoQ10) which endogenously synthesized is now gaining much attention as a supplement for fast growing broilers. The CoQ10 can be termed as multi-functionary as each and every cell in the body needs this but quantity is being high for very active organs like heart, lungs, liver, kidney, etc. They are essential for cellular oxidative phosphorylation and regenerative antioxidant. The supplementation of CoQ10 improved the feed efficiency with reducing the electron leaks from mitochondria and increases total antioxidant capacity. For this property, CoQ10 is widely used in human medicine especially persons suffering from cardiac, neurological disorder, hypercholesterolemic condition and also even in cancer. The CoQ10 in poultry draws first attention when it is found to reducing the ascites mortality in marketable broilers. Thereafter, the advantages of CoQ10 is started to exploit with much attention to ascites, feed efficiency, cholesterol lowering effect nutraceutical and nutrigenomic property both in poultry and swine industry.
... Cholesterol-lowering drugs (statins) which inhibit this enzyme could induce a fall in CoQ10 (Langsjoen & Langsjoen, 2003). Based on several studies, patients taking statins are recommended to receive CoQ10 supplementation (Suzuki et al., 2008;Hamilton et al., 2009;Eussen et al., 2010;Wynn, 2010;Avis et al., 2011;Zlatohlavek et al., 2012;Littlefield et al., 2013). Exogenous CoQ10 can be produced either extraction from animal tissues, chemical synthesis or microorganism fermentation (Cheng et al., 2010). ...
Abstract Coenzyme Q10 (CoQ10), also known as ubiquinone or ubidecarenone, is a powerful, endogenously produced, intracellularly existing lipophilic antioxidant. It combats reactive oxygen species (ROS) known to be responsible for a variety of human pathological conditions. Its target site is the inner mitochondrial membrane (IMM) of each cell. In case of deficiency and/or aging, CoQ10 oral supplementation is warranted. However, CoQ10 has low oral bioavailability due to its lipophilic nature, large molecular weight, regional differences in its gastrointestinal permeability and involvement of multitransporters. Intracellular delivery and mitochondrial target ability issues pose additional hurdles. To maximize CoQ10 delivery to its biopharmaceutical target, numerous approaches have been undertaken. The review summaries the current research on CoQ10 bioavailability and highlights the headways to obtain a satisfactory intracellular and targeted mitochondrial delivery. Unresolved questions and research gaps were identified to bring this promising natural product to the forefront of therapeutic agents for treatment of different pathologies.
... The role of coenzyme Q10 administration has attracted much attention; however, results from (typically uncontrolled) published studies have, so far, yielded variable results. Therefore, the routine administration of such agents in SAM patients is not yet recommended (McKenney et al. 2006, Young et al. 2007, Zlatohlavek et al. 2012. ...
Statin-associated myopathy (SAM) represents a broad spectrum of disorders from insignificant myalgia to fatal rhabdomyolysis. Its frequency ranges from 1-5 % in clinical trials to 15-20 % in everyday clinical practice. To a large extent, these variations can be explained by the definition used. Thus, we propose a scoring system to classify statin-induced myopathy according to clinical and biochemical criteria as 1) possible, 2) probable or 3) definite. The etiology of this disorder remains poorly understood. Most probably, an underlying genetic cause is necessary for overt SAM to develop. Variants in a few gene groups that encode proteins involved in: i) statin metabolism and distribution (e.g. membrane transporters and enzymes; OATP1B1, ABCA1, MRP, CYP3A4), ii) coenzyme Q10 production (e.g. COQ10A and B), iii) energy metabolism of muscle tissue (e.g. PYGM, GAA, CPT2) and several others have been proposed as candidates which can predispose to SAM. Pharmacological properties of individual statin molecules (e.g. lipophilicity, excretion pathways) and patients´ characteristics influence the likelihood of SAM development. This review summarizes current data as well as our own results.
Background
The gene
Methods
Adult patients with SAMS (on low doses of atorvastatin and simvastatin)-induced myalgia/myopathy (n=278), patients on statins but without SAMS (n=293) and population (part of the post-MONICA [Multinational MONItoring of trends and determinants in CArdiovascular disease] study) controls (n=561) were genotyped (polymerase chain reaction-restriction fragment length polymorphism [PCR-RFLP] assay) for rs6535454 and rs4693075 polymorphisms within the
Results
Distribution of rs6535454 in patients with SAMS (GG=51.1%, GA=40.0%, AA=8.9%) did not significantly differ (p=0.33; respectively 0.32 for codominant models of the analysis) from that in the population controls (GG=48.1%, GA=45.0%, AA=6.9%) or the SAMS-unaffected patients (GG=49.8%, GA=40.3%, AA=9.7%). Similarly, neither rs4693075 was associated with SAMS (CC=36.8%, CG=48.2%, GG=15.0% in patients suffering SAMS vs. CC=36.6%, CG=47.5%, GG=15.9 in controls and CC=35.8%, CG=48.2%, GG=15.9% in symptom-free patients, p=0.94 and 0.95 for codominant models of the analysis). Also, the haplotype distributions were not significantly different between the groups analyzed.
Conclusions
The polymorphisms of the
Coenzyme Q10 (CoQ10) has a potential role in the prevention and treatment of heart failure through improved cellular bioenergetics. In addition, it has antioxidant, free radical scavenging, and vasodilatory effects that may be beneficial. Although critical illness in intensive care unit is associated with decreased circulating CoQ10 levels, the clinical significance of CoQ10 levels during acute phase in the patients of cardiovascular disease remains unclear. We enrolled 257 consecutive cardiovascular patients admitted to the coronary care unit (CCU). Serum CoQ10 levels were measured after an overnight fast within 24 h of admission. We examined the comparison of serum CoQ10 levels between survivors and in-hospital mortalities in patients with cardiovascular disease. Serum CoQ10 levels during the acute phase in patients admitted to the CCU had similar independent of the diagnosis. CoQ10 levels were significantly lower in patients with in-hospital mortalities than in survivors (0.43 ± 0.19 vs. 0.55 ± 0.35 mg/L, P = 0.04). In patients admitted to the CCU, CoQ10 levels were negatively associated with age and C-reactive protein levels, and positively associated with body mass index, total cholesterol, and high-density lipoprotein cholesterol levels. Low CoQ10 levels correlated with low diastolic blood pressure. Multivariate logistic regression analysis demonstrated that low CoQ10 levels were an independent predictor of in-hospital mortality. Low serum CoQ10 levels during acute phase are significantly associated with cardiovascular risk and in-hospital mortality in patients admitted to the CCU.
The Science of Fitness: Power, Performance, and Endurance clearly explains the vital connection between diet and exercise in the human body. With this knowledge, you can use the right exercise and nutrition to obtain a higher quality life, prevent disease, and slow the aging process. Authored in a straightforward style and with color images throughout, this book explores the cellular science behind fitness, protein synthesis, and healthy living. With it you will learn the most recent and important discoveries in the relationships between physical fitness, nutrition, weight loss, and weight management. It provides key information on the body's mitochondrial processes and their role in aging, along with well-informed discussions on general nutrition, sports nutrition, exercise physiology, how to enhance athletic performance, and how exercise strengthens the mind. Whether you are interested in how to eat healthy, train for your first (or next) marathon, take your fitness to the next level, find the best super foods, or simply want to improve your vitality through healthy, doable practices, this book will help you on your journey regardless of age or fitness level. Presents the connection between exercise, nutrition, and physiology in a way that is ideal for both experienced athletes and newcomers Provides the scientific basis for mitochondrial functions and their relationship to fitness, protein synthesis, quality of life, and the aging process Synthesizes the latest research on nutrition, sports nutrition, super foods, and the brain/body connection Co-Authored by legendary cyclist Greg LeMond, who illustrates key points using his own athletic journey.
Background:
About 4.6 million persons in Germany are now taking statins, i.e., drugs that inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase. Statins lower the concentration of low-density lipoproteins (LDL) and thereby lessen the rate of cardiovascular events; the size of this effect depends on the extent of lowering of the LDL cholesterol concentration. Muscle symptoms are a clinically relevant side effect of statin treatment.
Methods:
This review is based on pertinent publications retrieved by a selective literature search, and on the current recommendations of the European Atherosclerosis Society.
Results:
At least 5% of patients taking statins have statin-associated muscle symptoms (SAMS). The etiology of SAMS is heterogeneous. SAMS may seriously impair quality of life and cause complications of variable severity, up to and including rhabdomyolysis (in about 1 in 100 000 cases). SAMS often lead to a reduction in the prescribed dose of the statin, while also negatively affecting drug adherence. More than 90% of patients with SAMS can keep on taking statins over the long term and gain the full clinical benefit of statin treatment after a switch to another type of statin or a readjustment of the dose or frequency of administration. If the LDL cholesterol concentration is not adequately lowered while the patient is taking a statin in the highest tolerable dose, combination therapy is indicated.
Conclusion:
SAMS are important adverse effects of statin treatment because they lessen drug adherence. Patients with SAMS should undergo a thorough diagnostic evaluation followed by appropriate counseling. In most cases, statins can be continued, with appropriate adjustments, even in the aftermath of SAMS.
HMG-CoA reductase inhibitors, a class of drugs commonly referred to as statins, decrease the cellular production of mevalonate which is necessary in the biosynthesis of cholesterol, statins’ intended target. An often overlooked consequence of the mechanism of statin action is that they unavoidably diminish all downstream biosynthetic products in the mevalonate pathway, which includes coenzyme Q10 (CoQ10), dolichol, and a family of isoprenoids including selenoproteins and heme A. This collateral damage affects numerous aspects of cell physiology – not only disrupting all cholesterol-related functions, but severely impairing CoQ10 related mitochondrial ATP production, mitochondrial DNA protection by CoQ10, and the viable process of cell division. While the biochemical implications of this pathway suppression were well understood in the 1980s, in the 1990s the clinical characteristics of statin adverse effects became more narrowly viewed in terms of only cholesterol reduction and CoQ10 depletion. By and large, the potential adverse consequences of decreasing cholesterol were ignored or viewed as inconsequential in comparison to the perceived benefit of cholesterol lowering on human health. Over the following 20 years, a number of studies have focused on CoQ10 depletion and on the ability of supplemental CoQ10 to either prevent or diminish these statin adverse effects. Unfortunately, it has become increasingly evident that such an amelioration of CoQ10 depletion in the setting of statin use has only a palliative effect on skeletal and cardiac myopathy.
The mechanism(s) underlying the occurrence of statin-induced myopathy are ill defined, but the results of observational studies and clinical trials provide compelling evidence that skeletal muscle toxicity is a frequent, dose-dependent, adverse event associated with all statins. It has been suggested that reduced availability of metabolites produced by the mevalonate pathway rather than intracellular cholesterol lowering per se might be the primary trigger of toxicity, however other alternative explanations have gained credibility in recent years. Aim of this review is: i) to describe the molecular mechanisms associated to statin induced myopathy including defects in isoprenoids synthesis followed by altered prenylation of small GTPase, such as Ras and Rab proteins; ii) to present the emerging aspects on pharmacogenetics, including CYP3A4, OATP1B1 and glycine amidinotransferase (GATM) polymorphisms impacting either statin bioavailability or creatine synthesis; iii) to summarize the available epidemiological evidences; and iii) to discuss the concepts that would be of interest to the clinicians for the daily management of patients with statin induced myopathy. The interplay between drug-environment and drug-drug interaction in the context of different genetic settings contribute to statins and skeletal muscles toxicity. Until specific assays/algorithms able to combine genetic scores with drug-drug-environment interaction to identify patients at risk of myopathies will become available, clinicians should continue to monitor carefully patients on polytherapy which include statins and be ready to reconsider dose, statin or switching to alternative treatments. The beneficial effects of adding agents to provide the muscle with the metabolites, such as CoQ10, affected by statin treatment will also be addressed.
Lowering serum lipid levels is part of the foundation of treating and preventing clinically significant cardiovascular disease. Recently, the American Heart Association/American College of Cardiology released cholesterol guidelines which advocate for high efficacy statins rather than LDL-c goals for five patient subgroups at high risk for cardiovascular disease. Therefore, it is critical that clinicians have an approach for managing side-effects of statin therapy. Statins are associated with myopathy, transaminase elevations, and an increased risk of incident diabetes mellitus among some patients; connections between statins and other processes, such as renal and neurologic function, have also been studied with mixed results. Statin-related adverse effects might be minimized by careful assessment of patient risk factors. Strategies to continue statin therapy despite adverse effects include switching to another statin at a lower dose and titrating up, giving intermittent doses of statins, and adding non-statin agents. Non-statin lipid-lowering drugs have their own unique limitations. Management strategies and algorithms for statin-associated toxicities are available to help guide clinicians. Clinical practice should emphasize tailoring therapy to address each individual's cholesterol goals and risk of developing adverse effects on lipid-lowering drugs.
The Proceedings of a Canadian Working Group Consensus Conference, first published in 2011, provided a summary of statin-associated adverse effects and intolerance and management suggestions. In this update, new clinical studies identified since then that provide further insight into effects on muscle, cognition, cataracts, diabetes, kidney disease, and cancer are discussed. Of these, the arenas of greatest controversy pertain to purported effects on cognition and the emergence of diabetes during long-term therapy. Regarding cognition, the available evidence is not strongly supportive of a major adverse effect of statins. In contrast, the linkage between statin therapy and incident diabetes is more firm. However, this risk is more strongly associated with traditional risk factors for new-onset diabetes than with statin itself and any possible negative effect of new-onset diabetes during statin treatment is far outweighed by the cardiovascular risk reduction benefits. Additional studies are also discussed, which support the principle that systematic statin rechallenge, and lower or intermittent statin dosing strategies are the main methods for dealing with suspected statin intolerance at this time.
To characterize the risk factors, rate of occurrence, onset, nature and impact of mild to moderate muscular symptoms with high-dosage HMG-CoA reductase inhibitor (statin) therapy in general practice.
The Prédiction du Risque Musculaire en Observationnel (Prediction of Muscular Risk in Observational conditions, PRIMO) survey was an observational study of muscular symptoms in an unselected population of 7924 hyperlipidemic patients receiving high-dosage statin therapy in a usual care, outpatient setting in France. Information on patient demographics, treatment history and muscular symptoms was obtained by questionnaires.
Multivariate analysis revealed the strongest predictors for muscular symptoms to be a personal history of muscle pain during lipid-lowering therapy (odds ratio, OR, 10.12, 95% CI 8.23-12.45; P < 0.0001), unexplained cramps (OR 4.14; 95% CI 3.46-4.95; P < 0.0001) and a history of creatine kinase (CK) elevation (OR 2.04; 95% CI 1.55-2.68; P < 0.0001). Overall, muscular symptoms were reported by 832 patients (10.5%), with a median time of onset of 1 month following initiation of statin therapy. Muscular pain prevented even moderate exertion during everyday activities in 315 patients (38%), while 31 (4%) were confined to bed or unable to work. Fluvastatin XL was associated with the lowest rate of muscular symptoms (5.1%) among individual statins.
PRIMO demonstrated that mild to moderate muscular symptoms with high-dosage statin therapy may be more common and exert a greater impact on everyday lives than previously thought. Knowledge of the risk factors for muscular symptoms will allow identification and improved management of high-risk patients. The risk of muscular symptoms with fluvastatin XL treatment may be lower than with high dosages of other statins.
The present guidelines are based on the recommendations published in 2005 entitled "Prevention of Cardiovascular Diseases in Adulthood" summarizing the conclusions of nine Czech medical societies and agree with them in the assessment of individual risk of mortality from cardiovascular disease (CVD) according to SCORE tables. They reflect new research data in pathophysiology of dyslipidemias (DLP) and particularly the results of recent clinical trials of lipid-lowering therapy and their meta-analyses. They establish priorities for the screening and management of DLP, present suitable diagnostic methods, additional investigations of potential use in risk assessment, including some emerging risk factors and detection of sub-clinical atherosclerosis in persons in a moderate-risk category. Major changes include a lower LDL-cholesterol treatment target (< 2.0 mmol/L for all CVD individuals) and a possible use of apolipoprotein B as a secondary target in selected persons (< 0.9 g/L in high risk without CVD, < 0.8 g/L for CVD patients) and nonHDL-cholesterol (< 3.3 mmol/L in high risk without CVD, < 2.8 mmol/L for CVD patients). Therapy of individual DLP phenotypes (monotherapy and combination therapy) as well as basic principles for control examination at lipid-lowering medication are described. Recommended therapeutic lifestyle changes are shown. Enclosed are five annexes: DLP diagnosis; causes of secondary DLP; additional investiga- tions of potential use in risk stratification; familial hypercholesterolemia; list of recommended foods; two variants of SCORE tables for risk assessment for the Czech Republic; the scheme of recommended procedures and treatment algorithm in DLP asymptomatic individuals.
Coenzyme Q₁₀ (CoQ₁₀) is essential for all cells, and deficiency has been implicated in cardiovascular disease. Plant phytosterols inhibit cholesterol absorption, and may thereby also reduce cardiovascular risk. This study compared the relative bioavailability of CoQ₁₀ solubilized in low-dose soybean phytosterols (SterolQ₁₀) with a generic CoQ₁₀ solubilizate. In a randomized, cross-over design, 36 healthy males received a single 100 mg dose of CoQ₁₀, as SterolQ₁₀ or generic CoQ₁₀, with a two-week washout between treatments. Plasma CoQ₁₀ was analysed at baseline, and at 2, 4, 6, 8 and 10 h after supplement ingestion. Subjects were then administered either 100 mg/day of generic CoQ₁₀ or SterolQ₁₀ for 4 weeks. Fasting plasma CoQ₁₀ levels were measured at baseline and following supplementation. The two preparations were bioequivalent in regard to the area under the curve (AUC(0-10h) ) and maximum increase in concentration (C(max) ), with geometric mean ratios of 0.89 (CI 0.81-0.98) and 0.88 (CI 0.80-0.96), respectively. Four-weeks of CoQ₁₀ resulted in a comparable twofold increase in CoQ₁₀ levels for both formulations (p < 0.001), which was similar between preparations (p = 0.74). The combined CoQ₁₀ and phytosterol formulation, SterolQ₁₀, showed bioequivalence to the generic CoQ₁₀ following a single CoQ₁₀ dose, and demonstrated comparable bioavailability following multiple dose administration.
Statin-associated muscle symptoms are a relatively common condition that may affect 10% to 15% of statin users. Statin myopathy includes a wide spectrum of clinical conditions, ranging from mild myalgia to rhabdomyolysis. The etiology of myopathy is multifactorial. Recent studies suggest that statins may cause myopathy by depleting isoprenoids and interfering with intracellular calcium signaling. Certain patient and drug characteristics increase risk for statin myopathy, including higher statin doses, statin cytochrome metabolism, and polypharmacy. Genetic risk factors have been identified, including a single nucleotide polymorphism of SLCO1B1. Coenzyme Q10 and vitamin D have been used to prevent and treat statin myopathy; however, clinical trial evidence demonstrating their efficacy is limited. Statin-intolerant patients may be successfully treated with either low-dose statins, alternate-day dosing, or using twice-weekly dosing with longer half-life statins. An algorithm is presented to assist the clinician in managing myopathy in patients with dyslipidemia.
Statins are associated with muscle complaints, including myositis. The mechanism through which statin use causes muscle toxicity is unknown. One of the theories is that statin therapy reduces coenzyme Q10 levels in muscle mitochondria, which leads to muscle injury and myopathy. The aim of the present article is to review published data on the association between coenzyme Q10 and statin-associated myopathy.
Studies have consistently shown that statins reduce coenzyme Q10 levels in serum and that supplementation of coenzyme Q10 increases these levels. However, the effect of statin therapy on coenzyme Q10 levels in muscle has been conflicting. Recently, two pilot studies on coenzyme Q10 supplementation in statin-induced myopathy and one study on the effect of coenzyme Q10 supplementation on serum muscle enzyme levels were published. These three studies were the first randomized trials with coenzyme Q10 supplementation in hypercholesterolemic patients treated with statins. The results of these trials have been contradictory; whereas one seems to support supplementation with coenzyme Q10, the other two do not.
This review summarizes the current evidence on coenzyme Q10 supplementation in statin-induced myopathy. We conclude that the present evidence does not support coenzyme Q10 supplementation in statin-induced myopathy.
Statins, which are commonly used drugs for hypercholesterolemia, inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. Important nonsterol compounds, such as ubiquinone, are also derived from the same synthetic pathway. Therefore it has been hypothesized that statin treatment causes ubiquinone deficiency in muscle cells, which could interfere with cellular respiration causing severe adverse effects. In this study we observed decreased serum levels but an enhancement in muscle tissue ubiquinone levels in patients with hypercholesterolemia after 4 weeks of simvastatin treatment. These results indicate that ubiquinone supply is not reduced during short-term statin treatment in the muscle tissue of subjects in whom myopathy did not develop.
It has been hypothesized that treating hypercholesterolemic patients with statins will lead not only to a reduction in cholesterol, but also to inhibited synthesis of other compounds which derive from the synthetic pathway of cholesterol. In theory, this could further lead to ubiquinone deficiency in muscle cell mitochondria, disturbing normal cellular respiration and causing adverse effects such as rhabdomyolysis. Furthermore, ubiquinone is one of the lipophilic antioxidants in low-density lipoprotein (LDL), and therefore it has also been hypothesized that statin treatment will reduce the antioxidant capacity of LDL. We investigated the effect of 6 months of simvastatin treatment (20 mg/day) on skeletal muscle concentrations of high-energy phosphates and ubiquinone by performing biopsies in 19 hypercholesterolemic patients. Parallel assays were performed in untreated control subjects. The muscle high-energy phosphate and ubiquinone concentrations assayed after simvastatin treatment were similar to those observed at baseline and did not differ from the values obtained in control subjects at the beginning and end of follow-up. These results do not support the hypothesis of diminished isoprenoid synthesis or energy generation in muscle cells during simvastatin treatment. Furthermore, the results of analysis of antioxidant concentrations in LDL before and after simvastatin treatment indicate that the antioxidant capacity of LDL is maintained in simvastatin-treated patients.
1Statins inhibit synthesis of mevalonate, a precursor of ubiquinone that is a central compound of the mitochondrial respiratory chain. The main adverse effect of statins is a toxic myopathy possibly related to mitochondrial dysfunction.
2This study was designed to evaluate the effect of lipid-lowering drugs on ubiquinone (coenzyme Q10) serum level and on mitochondrial function assessed by blood lactate/pyruvate ratio.
3Eighty hypercholesterolaemic patients (40 treated by statins, 20 treated by fibrates, and 20 untreated patients, all 80 having total cholesterol levels >6.0 mmol l−1) and 20 healthy controls were included. Ubiquinone serum level and blood lactate/pyruvate ratio used as a test for mitochondrial dysfunction were evaluated in all subjects.
4Lactate/pyruvate ratios were significantly higher in patients treated by statins than in untreated hypercholesterolaemic patients or in healthy controls (P<0.05 and P<0.001). The difference was not significant between fibrate-treated patients and untreated patients.
5Ubiquinone serum levels were lower in statin-treated patients (0.75 mg l−1±0.04) than in untreated hypercholesterolaemic patients (0.95 mg l−1±0.09; P<0.05).
6We conclude that statin therapy can be associated with high blood lactate/pyruvate ratio suggestive of mitochondrial dysfunction. It is uncertain to what extent low serum levels of ubiquinone could explain the mitochondrial dysfunction.
Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are associated with skeletal muscle complaints, including clinically important myositis and rhabdomyolysis, mild serum creatine kinase (CK) elevations, myalgia with and without elevated CK levels, muscle weakness, muscle cramps, and persistent myalgia and CK elevations after statin withdrawal. We performed a literature review to provide a clinical summary of statin-associated myopathy and discuss possible mediating mechanisms. We also update the US Food and Drug Administration (FDA) reports on statin-associated rhabdomyolysis. Articles on statin myopathy were identified via a PubMed search through November 2002 and articles on statin clinical trials, case series, and review articles were identified via a PubMed search through January 2003. Adverse event reports of statin-associated rhabdomyolysis were also collected from the FDA MEDWATCH database. The literature review found that reports of muscle problems during statin clinical trials are extremely rare. The FDA MEDWATCH Reporting System lists 3339 cases of statin-associated rhabdomyolysis reported between January 1, 1990, and March 31, 2002. Cerivastatin was the most commonly implicated statin. Few data are available regarding the frequency of less-serious events such as muscle pain and weakness, which may affect 1% to 5% of patients. The risk of rhabdomyolysis and other adverse effects with statin use can be exacerbated by several factors, including compromised hepatic and renal function, hypothyroidism, diabetes, and concomitant medications. Medications such as the fibrate gemfibrozil alter statin metabolism and increase statin plasma concentration. How statins injure skeletal muscle is not clear, although recent evidence suggests that statins reduce the production of small regulatory proteins that are important for myocyte maintenance.
Myopathy, probably caused by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition in skeletal muscle, rarely occurs in patients taking statins. This study was designed to assess the effect of high-dose statin treatment on cholesterol and ubiquinone metabolism and mitochondrial function in human skeletal muscle.
Forty-eight patients with hypercholesterolemia (33 men and 15 women) were randomly assigned to receive 80 mg/d of simvastatin (n = 16), 40 mg/d of atorvastatin (n = 16), or placebo (n = 16) for 8 weeks. Plasma samples and muscle biopsy specimens were obtained at baseline and at the end of the follow-up.
The ratio of plasma lathosterol to cholesterol, a marker of endogenous cholesterol synthesis, decreased significantly by 66% in both statin groups. Muscle campesterol concentrations increased from 21.1 +/- 7.1 nmol/g to 41.2 +/- 27.0 nmol/g in the simvastatin group and from 22.6 +/- 8.6 nmol/g to 40.0 +/- 18.7 nmol/g in the atorvastatin group (P = .005, repeated-measurements ANOVA). The muscle ubiquinone concentration was reduced significantly from 39.7 +/- 13.6 nmol/g to 26.4 +/- 7.9 nmol/g (P = .031, repeated-measurements ANOVA) in the simvastatin group, but no reduction was observed in the atorvastatin or placebo group. Respiratory chain enzyme activities were assessed in 6 patients taking simvastatin with markedly reduced muscle ubiquinone and in matched subjects selected from the atorvastatin (n = 6) and placebo (n = 6) groups. Respiratory chain enzyme and citrate synthase activities were reduced in the patients taking simvastatin.
High-dose statin treatment leads to changes in the skeletal muscle sterol metabolism. Furthermore, aggressive statin treatment may affect mitochondrial volume.
Treatment of hypercholesterolemia with statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) is effective in the primary and secondary prevention of cardiovascular disease. However, statin use is often associated with a variety of muscle-related symptoms or myopathies. Myopathy may be related in part to statin inhibition of the endogenous synthesis of coenzyme Q10, an essential cofactor for mitochondrial energy production. The aim of this study is to determine whether coenzyme Q10 supplementation would reduce the degree of muscle pain associated with statin treatment. Patients with myopathic symptoms were randomly assigned in a double-blinded protocol to treatment with coenzyme Q10 (100 mg/day, n = 18) or vitamin E (400 IU/day, n = 14) for 30 days. Muscle pain and pain interference with daily activities were assessed before and after treatment. After a 30-day intervention, pain severity decreased by 40% (p <0.001) and pain interference with daily activities decreased by 38% (p <0.02) in the group treated with coenzyme Q10. In contrast, no changes in pain severity (+9%, p = NS) or pain interference with daily activities (-11%, p = NS) was observed in the group treated with vitamin E. In conclusion, results suggest that coenzyme Q10 supplementation may decrease muscle pain associated with statin treatment. Thus, coenzyme Q10 supplementation may offer an alternative to stopping treatment with these vital drugs.
The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are the cornerstone of therapy for dyslipidemia. A significant portion of patients are not adherent to statin therapy, due to either intolerance from muscle symptoms or fears of myopathy reported in the media. The diagnosis and management of patients with statin-induced myopathy will be reviewed.
Based on a review of healthy clinical-trial participants, the placebo-corrected incidences of minor muscle pain, myopathy (with significant elevations in creatinine kinase), and rhabdomyolysis are 190, 5, and 1.6 per 100,000 patient years, respectively. More recent prospective observational data yield better, real-world estimates of muscle complaints (>10%) in patients started on high-dose statins. Current data suggest that important patient characteristics, statin-drug pharmacokinetics, and statin-drug interactions play a role in myopathy. Myopathy is more related to statin dose and blood levels than to LDL reductions. Evidence for managing myopathic patients with coenzyme Q10 is not conclusive.
It is important to maintain perspective by looking at the impact of statin myopathy relative to the impact of preventing atherosclerotic complications. The potential benefits of therapy must outweigh the risks. In the case of statin therapy the benefit/risk ratio is overwhelmingly positive.
The long-term efficacy and safety of HMG-CoA reductase inhibitors (statins) have been established in large multicenter trials. Inhibition of this enzyme, however, results in decreased synthesis of cholesterol and other products downstream of mevalonate, such as CoQ10 or dolichol. This was a randomized double-blind, placebo-controlled study that examined the effects of CoQ10 and placebo in hypercholesterolemic patients treated by atorvastatin. Eligible patients were given 10mg/day of atorvastatin for 16 weeks. Half of the patients (n=24) were supplemented with 100mg/day of CoQ10, while the other half (n=25) were given the placebo. Serum LDL-C levels in the CoQ10 group decreased by 43%, while in the placebo group by 49%. The HDL-C increment was more striking in the CoQ10 group than in the placebo group. All patients showed definite reductions of plasma CoQ10 levels in the placebo group, by 42%. All patients supplemented with CoQ10 showed striking increases in plasma CoQ10 by 127%. In conclusion atorvastatin definitely decreased plasma CoQ10 levels and supplementation with CoQ10 increased their levels. These changes in plasma CoQ10 levels showed no relation to the changes in serum AST, ALT and CK levels. Further studies are needed, however, for the evaluation of CoQ10 supplementation in statin therapy.
Myalgia is the most frequently reported adverse side effect associated with statin therapy and often necessitates reduction in dose, or the cessation of therapy, compromising cardiovascular risk management. One postulated mechanism for statin-related myalgia is mitochondrial dysfunction through the depletion of coenzyme Q(10), a key component of the mitochondrial electron transport chain. This pilot study evaluated the effect of coenzyme Q(10) supplementation on statin tolerance and myalgia in patients with previous statin-related myalgia. Forty-four patients were randomized to coenzyme Q(10) (200 mg/day) or placebo for 12 weeks in combination with upward dose titration of simvastatin from 10 mg/day, doubling every 4 weeks if tolerated to a maximum of 40 mg/day. Patients experiencing significant myalgia reduced their statin dose or discontinued treatment. Myalgia was assessed using a visual analogue scale. There was no difference between combined therapy and statin alone in the myalgia score change (median 6.0 [interquartile range 2.1 to 8.8] vs 2.3 [0 to 12.8], p = 0.63), in the number of patients tolerating simvastatin 40 mg/day (16 of 22 [73%] with coenzyme Q(10) vs 13 of 22 [59%] with placebo, p = 0.34), or in the number of patients remaining on therapy (16 of 22 [73%] with coenzyme Q(10) vs 18 of 22 [82%] with placebo, p = 0.47). In conclusion, coenzyme Q(10) supplementation did not improve statin tolerance or myalgia, although further studies are warranted.
Reducing high levels of plasmatic lipoids (LDL-cholesterol and triglycerides) is one of the most important steps in the prevention and treatment of cardiovascular diseases. In the majority of cases, treatment based on lifestyle changes (changes in dietary habits, more physical activity) is not sufficient and pharmacotherapy becomes necessary. Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are a well tolerated first-choice drug in patients with dyslipidemia. However, great variability of statin effects has been observed in different patients on the same therapy, and the cause clearly resides in different genetic characteristics of each individual, influencing the effect of therapy. The influence of different genetic variants has been described, but the control of response to hypolipidemic therapy is most likely subject to polygenic control. The analysis of multiple gene combinations may help detect the "hyper-" and "hypo-" responders, i.e. individuals with a good response to treatment (allowing for starting with a lower dose of the drug), and those with an insufficient response to treatment (in whom statin shall not be the drug of first choice), or it may help detect the patients who are more likely to develop severe adverse events. Studies with different designs describe that for instance genes (and their variants) for cytochromes, apolipoprotein E and A1 and cholesterol 7alpha-hydroxylase may be important genetic determinants of the effect of pharmacological treatment of dyslipidemia and play a role in the individualisation of treatment.