Article

High-dose statins and skeletal muscle metabolism in humans: A randomized, controlled trial

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Abstract

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.

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... 68,69 In addition, secondary CoQ10 deficiency may occur. In this regard, the inhibitory effect of statins on the mevalonate pathway ( Figure 1) may reduce CoQ10 levels by 16-54% 64 and cause mitochondrial dysfunction, revealed by inhibition of mitochondrial ETC complexes, 70,71 disruption of mitochondrial membrane potential, decrease in mitochondrial DNA (mtDNA) copy number, interference with oxidative phosphorylation, mitochondrial swelling, and release of cytochrome c. 71,72 However, decrease in plasma CoQ10 level is mostly due to the reduction of circulating lipoproteins, because around 74% of CoQ10 is carried in the blood by apo B-containing lipoproteins. 64 Accordingly, no significant difference in CoQ10 to total cholesterol ratio was found before and after statin treatment. ...
... 73 In a randomized controlled trial, 8 weeks of treatment with simvastatin 80 mg/day but not the treatment with atorvastatin 40 mg/day or placebo was associated with a significant decrease in muscle ubiquinone concentration. 72 Analyses from a subgroup of patients showed that those with markedly reduced muscle CoQ10 had concurrent reduction in respiratory chain enzyme and citrate synthase activities. 72 However, conflicting data showing either increase or no change in muscle ubiquinone concentrations after both short-term and long-term statin treatments have been provided. ...
... 72 Analyses from a subgroup of patients showed that those with markedly reduced muscle CoQ10 had concurrent reduction in respiratory chain enzyme and citrate synthase activities. 72 However, conflicting data showing either increase or no change in muscle ubiquinone concentrations after both short-term and long-term statin treatments have been provided. [74][75][76] Recent meta-analyses on the topic have led to controversial results about the effectiveness of CoQ10 supplementation in statin-treated patients in improving SIM and SAMS. ...
Article
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Statins are a family of drugs that are used for treating hyperlipidaemia with a recognized capacity to prevent cardiovascular disease events. They inhibit β‐hydroxy β‐methylglutaryl‐coenzyme A reductase, i.e. the rate‐limiting enzyme in mevalonate pathway, reduce endogenous cholesterol synthesis, and increase low‐density lipoprotein clearance by promoting low‐density lipoprotein receptor expression mainly in the hepatocytes. Statins have pleiotropic effects including stabilization of atherosclerotic plaques, immunomodulation, anti‐inflammatory properties, improvement of endothelial function, antioxidant, and anti‐thrombotic action. Despite all beneficial effects, statins may elicit adverse reactions such as myopathy. Studies have shown that mitochondria play an important role in statin‐induced myopathies. In this review, we aim to report the mechanisms of action of statins on mitochondrial function. Results have shown that statins have several effects on mitochondria including reduction of coenzyme Q10 level, inhibition of respiratory chain complexes, induction of mitochondrial apoptosis, dysregulation of Ca²⁺ metabolism, and carnitine palmitoyltransferase‐2 expression. The use of statins has been associated with the onset of additional pathological conditions like diabetes and dementia as a result of interference with mitochondrial pathways by various mechanisms, such as reduction in mitochondrial oxidative phosphorylation, increase in oxidative stress, decrease in uncoupling protein 3 concentration, and interference in amyloid‐β metabolism. Overall, data reported in this review suggest that statins may have major effects on mitochondrial function, and some of their adverse effects might be mediated through mitochondrial pathways.
... The etiology of statin-induced myalgia is not fully understood, but several studies have suggested a key role for depleted muscle coenzyme Q10 (CoQ10, also known as ubiquinone) levels [9][10][11] and impaired mitochondrial function [12][13][14]. CoQ10 is a vitamin-like molecule partly supplied from the diet but, like cholesterol, the majority is synthesized endogenously by the mevalonate pathway [15], which is inhibited by statins [16]. ...
... The hypothesis that links statins to reduced CoQ10 synthesis, mitochondrial dysfunction, and myalgia is biologically plausible, but since it arose from case reports in the early 1990s [63,64], it has not been confirmed in any large randomized controlled trials. While some studies have associated statin therapy and statin-induced myalgia with altered mitochondrial function [65][66][67] and others have found reduced muscle CoQ10 in statin users [9,65], an association between impaired mitochondrial function reduced muscle CoQ10 levels, and statin-induced myalgia has still not been confirmed in the literature. This study adds doubt to the proposed benefits of CoQ10 supplementation on statin-induced myalgia, and to whether the mechanism underlying statin-induced myalgia involves reduced muscle CoQ10 levels and impaired mitochondrial function as a consequence. ...
Article
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Myalgia and new-onset of type 2 diabetes have been associated with statin treatment, which both could be linked to reduces coenzyme Q10 (CoQ10) in skeletal muscle and impaired mitochondrial function. Supplementation with CoQ10 focusing on levels of CoQ10 in skeletal muscle and mitochondrial function has not been investigated in patients treated with statins. To investigate whether concomitant administration of CoQ10 with statins increases the muscle CoQ10 levels and improves the mitochondrial function, and if changes in muscle CoQ10 levels correlate with changes in the intensity of myalgia. 37 men and women in simvastatin therapy with and without myalgia were randomized to receive 400 mg CoQ10 daily or matched placebo tablets for eight weeks. Muscle CoQ10 levels, mitochondrial respiratory capacity, mitochondrial content (using citrate synthase activity as a biomarker), and production of reactive oxygen species were measured before and after CoQ10 supplementation, and intensity of myalgia was determined using the 10 cm visual analogue scale. Muscle CoQ10 content and mitochondrial function were unaltered by CoQ10 supplementation. Individual changes in muscle CoQ10 levels were not correlated with changes in intensity of myalgia. CoQ10 supplementation had no effect on muscle CoQ10 levels or mitochondrial function and did not affect symptoms of myalgia.
... Disturbances in mitochondrial respiratory chain complexes have also been observed. Spectrophotometric assays showed a reduction in complex II, III, and IV activity in six patients with a substantial reduction in muscle ubiquinone levels treated with simvastatin 80 mg/day for 8 weeks [13]. This reduction was not seen after treatment with atorvastatin 40 mg/day or placebo. ...
... In fact, CoQ10 concentrations in muscle were almost identical to those measured in 15 untreated, normolipidemic men (pre, 78 μmol/kg, and post, 85 μmol/kg, in the treated hypercholesterolemic and pre, 88 μmol/kg, and post, 95 μmol/ kg, in the untreated normolipidemic men). Another trial randomized hypercholesterolemic men and women to either simvastatin 80 mg/day, atorvastatin 40 mg/day, or placebo for 8 weeks and noted a decrease in muscle concentration of CoQ10 of 34% only in the simvastatin-treated group [13]. It can therefore be argued that the effects of statins on muscle CoQ10 concentrations may be drug and dose dependent. ...
Chapter
In this chapter we summarize the evidence for a central role of mitochondrial dysfunction in statin-associated muscle symptoms. Statin-related mitochondrial dysfunction can manifest itself in skeletal muscle by inducing a plethora of architectural and biochemical adaptations. Structural changes seen in biopsy specimens, including red ragged fibers, cytochrome oxidase-negative myofibers, and lipid-loaded vacuoles, are signs of mitochondrial respiratory chain dysfunction. Disturbances in mitochondrial energy metabolism are shown through increased lactate/pyruvate ratios, disruption of beta-oxidation, a decrease in mitochondrial DNA, and disturbances in electron transport chain complex activities. Apoptosis of myofibers may occur as a result of mitochondrial-mediated apoptosis and the formation of reactive oxygen species. Furthermore the role of coenzyme Q10 deficiency and disturbances in calcium homeostasis in relation to statin-induced mitochondrial dysfunction will be discussed.
... Additionally, simvastatin (SIM) administration increases the muscle and serum levels of oxidative stress markers [Kwak et al., 2012;Ghalwash et al., 2018]. Moreover, muscle biopsies taken from patients receiving SIM showed reduced muscle coenzyme Q 10 (CoQ 10 ) levels [Päivä et al., 2005]. ...
... Moreover, several clinical studies show that statins decrease serum CoQ 10 levels [Bargossi et al., 1994;Davidson et al., 1997;Mortensen et al., 1997], an effect which is probably due to a reduction in circulating LDL [Marcoff and Thompson, 2007]. Furthermore, muscle CoQ 10 concentrations are reduced in patients treated with high doses of SIM [Päivä et al., 2005]. On the other hand, Fukami et al. [1993] reported no change in muscle CoQ 10 levels in SIMtreated animals despite severe muscle lesions. ...
Article
Statins are the most widely prescribed cholesterol-lowering drugs to reduce the risk of cardiovascular diseases. Statin-induced myopathy is the major side effect of this class of drugs. Here, we studied whether standardized leaf extracts of ginkgo biloba (EGb761) would improve simvastatin (SIM)-induced muscle changes. Sixty Wistar rats were allotted into six groups: control group, vehicle group receiving 0.5% carboxymethyl cellulose (CMC) for 30 days, SIM group receiving 80 mg/kg/day SIM in 0.5% CMC orally for 30 days, SIM withdrawal group treated with SIM for 16 days and sacrificed 14 days later, and EGb761-100 and EGb761-200 groups posttreated with either 100 or 200 mg/kg/day EGb761 orally. Muscle performance on the rotarod, serum creatine kinase (CK), coenzyme Q10 (CoQ10), serum and muscle nitrite, muscle malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) activities were estimated. Additionally, muscle samples were processed for histopathological evaluation. We found that SIM decreased muscle performance on the rotarod, serum CoQ10, as well as muscle SOD and CAT activities while it increased serum CK, serum and muscle nitrite, as well as muscle MDA levels. SIM also induced sarcoplasmic vacuolation, splitting of myofibers, disorganization of sarcomeres, and disintegration of myofilaments. In contrast, posttreatment with EGb761 increased muscle performance, serum CoQ10, as well as muscle SOD and CAT activities while it reduced serum CK as well as serum and muscle nitrite levels in a dose-dependent manner. Additionally, EGb761 reversed SIM-induced histopathological changes with better results obtained by its higher dose. Interestingly, SIM withdrawal increased muscle performance on the rotarod, reduce serum CK and CoQ10, and reduced serum and muscle nitrite while it reversed SIM-induced histopathological changes. However, SIM withdrawal was not effective enough to restore their normal values. Additionally, SIM withdrawal did not improve SIM-induce muscle MDA, SOD, or CAT activities during the period studied. Our results suggest that EGb761 posttreatment reversed SIM-induces muscle changes possibly through its antioxidant effects, elevation of CoQ10 levels, and antagonizing mitochondrial damage.
... While important for generally reducing major cardiovascular risk factors and events, there are potential deleterious impacts of statins on skeletal muscle function [3]. Statins have been reported to reduce skeletal muscle oxidative capacity [4,5], oxidative enzyme content [6] and mitochondrial respiration [7][8][9]. Statin use in middle-aged adults has also been shown to completely block cardiorespiratory and mitochondrial adaptations expected with aerobic exercise training [10]. ...
... As muscle pain and cramping were used as endpoints for the vigorous calf exercise (up to 7 min in duration) [5], their findings may be associated with significant muscle acidity and contribute to exercise intolerance reported by some patients on statin therapy [19]. Prior studies have also shown a reduction in mitochondrial volume and enzyme content with simvastatin use [6] and reduced mitochondrial respiration in patients on statin therapy [4,9]. Baseline VO 2 peak was not reduced with statin therapy, consistent with prior findings in older adults [20]. ...
Article
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Background Statin use is widely recognized for improving cardiovascular health, but questions remain on how statin use influences skeletal muscle, particularly mitochondrial function. Study objective, design and participants The influence of statin therapy and exercise (EX) on aerobic capacity was determined. In Study1, skeletal muscle aerobic capacity was measured before and after 80 mg atorvastatin therapy. In Study2, aerobic capacity (skeletal muscle and whole body) was measured before and after a 12-week exercise randomized control trial in older adults (age = 67 ± 5 yrs.), a subset of which were on chronic low-moderate intensity statin therapy. Main outcome measures Muscle oxidative capacity was determined from the phosphocreatine recovery rate constant (kPCr) using ³¹P Magnetic Resonance Spectroscopy. Whole body peak oxygen uptake (VO2 peak) was measured during a graded exercise test with indirect calorimetry. Results High dose statin therapy resulted in a 12% reduction in muscle oxidative capacity (pre = 1.34 ± 0.34 min⁻¹, post = 1.17 ± 0.25 min⁻¹, p = 0.004). Similarly, chronic low-moderate dose statin therapy was associated with lower muscle oxidative capacity at baseline (1.50 ± 0.35 min⁻¹) compared to non-statin users (1.88 ± 0.047 min⁻¹, p = 0.019). Following EX, muscle oxidative capacity increased by 35–40% (statin: Pre: 1.39 ± 0.44 vs. Post: 1.88 ± 0.47 min⁻¹, no statin Pre: 1.86 ± 0.58 vs. Post: 2.58 ± 0.85 min⁻¹) compared to control groups (Pre: 1.74 ± 0.27 vs Post: 1.75 ± 0.49 min⁻¹, p = 0.001). VO2 peak increased by 11% for EX groups (Pre: 18.8 ± 2.8 vs. Post: 20.8 ± 3.0 ml·kg⁻¹·min⁻¹) following training compared to a small decline in controls (Pre: 21.8 ± 3.7 vs. Post: 20.8 ± 3.04 ml·kg⁻¹·min⁻¹, p = 0.001). Conclusions Statin therapy resulted in reduced muscle oxidative capacity. Aerobic exercise improved skeletal muscle oxidative capacity and whole-body aerobic capacity during statin therapy.
... Statininduced myopathy is associated with mitochondrial dysfunction [42] and mtDNA depletion [43]. The effect statins exert on mitochondrial OXPHOS capacities could be established by a randomized controlled trial, that showed a reduction of respiratory chain enzyme and citrate synthase activities [44]. It appears that the crucial role played by mitochondria in the energy-demanding skeletal muscle tissue makes them highly vulnerable to dysfunction. ...
... Statin-induced myopathy is associated with mitochondrial dysfunction [42] and mtDNA depletion [43]. The effect statins exert on mitochondrial OXPHOS capacities could be established by a randomized controlled trial, that showed a reduction of respiratory chain enzyme and citrate synthase activities [44]. It appears that the crucial role played by mitochondria in the energy-demanding skeletal muscle tissue makes them highly vulnerable to dysfunction. ...
Article
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The sporadic form of inclusion body myositis (IBM) is the most common late-onset myopathy. Its complex pathogenesis includes degenerative, inflammatory and mitochondrial aspects. However, which of those mechanisms are cause and which effect, as well as their interrelations, remain partly obscured to this day. In this review the nature of the mitochondrial dysregulation in IBM muscle is explored and comparison is made with other muscle disorders. Mitochondrial alterations in IBM are evidenced by histological and serum biomarkers. Muscular mitochondrial dynamics is disturbed, with deregulated organelle fusion leading to subsequent morphological alterations and muscle displays abnormal mitophagy. The tissue increases mitochondrial content in an attempt to compensate dysfunction, yet mitochondrial DNA (mtDNA) alterations and mild mtDNA depletion are also present. Oxidative phosphorylation defects have repeatedly been shown, most notably a reduction in complex IV activities and levels of mitokines and regulatory RNAs are perturbed. Based on the cumulating evidence of mitochondrial abnormality as a disease contributor, it is therefore warranted to regard IBM as a mitochondrial disease, offering a feasible therapeutic target to be developed for this yet untreatable condition.
... 113 Muscle coenzyme Q10 levels and respiratory chain activities were significantly reduced by simvastatin, but not by atorvastatin. 114 Simvastatin, but not atorvastatin, reduced muscle mtDNA levels. 115 Patients with MD may be prone to develop statin myopathy. ...
Article
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Mitochondrial disorders are a group of metabolic conditions caused by impairment of the oxidative phosphorylation system. There is currently no clear evidence supporting any pharmacological interventions for most mitochondrial disorders, except for coenzyme Q10 deficiencies, Leber hereditary optic neuropathy, and mitochondrial neurogastrointestinal encephalomyopathy. Furthermore, some drugs may potentially have detrimental effects on mitochondrial dysfunction. Drugs known to be toxic for mitochondrial functions should be avoided whenever possible. Mitochondrial patients needing one of these treatments should be carefully monitored, clinically and by laboratory exams, including creatine kinase and lactate. In the era of molecular and 'personalized' medicine, many different physicians (not only neurologists) should be aware of the basic principles of mitochondrial medicine and its therapeutic implications. Multicenter collaboration is essential for the advancement of therapy for mitochondrial disorders. Whenever possible, randomized clinical trials are necessary to establish efficacy and safety of drugs. In this review we discuss in an accessible way the therapeutic approaches and perspectives in mitochondrial disorders. We will also provide an overview of the drugs that should be used with caution in these patients.
... Malate dehydrogenase reversibly catalyzes the oxidation of malate to oxaloacetate that can be utilized in the TCA cycle and amino acid production [38]. Down-regulation of this enzyme indicated that a high level of lovastatin supplementation (6 mg/kg BW) results in the impairment of mitochondrial function, which is in agreement with the study by Päivä et al. [39] which reported a reduction of mitochondria volume in skeletal muscle following aggressive statin treatment. ...
Article
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This study was conducted to examine the effects of different levels of lovastatin on the histological and sarcoplasmic proteome profile of goat skeletal muscle. A total of 20 intact male Saanen goats were randomly assigned in equal numbers to four groups and fed a total mixed ration containing 50% rice straw, 22.8% concentrates and 27.2% of various proportions of untreated or treated palm kernel cake (PKC) to achieve the target daily intake levels of 0 (Control), 2 (Low), 4 (Medium) or 6 (High) mg lovastatin/kg BW. A histological examination discovered that the longissimus thoracis et lumborum muscle of animals from the Medium and High treatment groups showed abnormalities in terms of necrosis, degeneration, interstitial space and vacuolization. Our preliminary label-free proteomics analysis demonstrates that lovastatin supplementation induced complex modifications to the protein expression patterns of the skeletal muscle of the goat which were associated with the metabolism of carbohydrate and creatine, cell growth and development processes and other metabolic processes. The changes in these biochemical processes indicate perturbations in energy metabolism, which could play a major role in the development of myopathy. In conclusion, the present study suggests that supplementation of naturally produced lovastatin above 4 mg/kg BW could adversely affecting the health and wellbeing of treated animals.
... Mitochondrial dysfunction is frequently cited as a mechanism for statin-induced myopathy (51). Statin may impair skeletal muscle mitochondria function by decreasing citrate synthase (52), and/or ubiquinone (coenzyme Q10 (39)) activity. Measures of mitochondrial respiratory capacity using high-resolution respirometry in permeabilized muscle fibers is an integrative measure of mitochondrial enzymes function. ...
Article
Background Statins reduce atherogenic dyslipidemia and cardiovascular disease (CVD) risk in metabolic syndrome individuals (MetS). Exercise-training could also contribute to reduce CVD by improving cardiorespiratory fitness and fat oxidation. However, statin use could interfere with training adaptations. Methods One hundred and six MetS were divided into statin users (STATIN group, n=46) and statin-naïve (CONTROL group, n=60). Groups were matched by age, weight, and MetS components. Subjects completed 16 weeks of high intensity interval training (HIIT). Before and after HIIT, muscle biopsies were collected to assess mitochondrial content (citrate synthase (CS) activity) and the activity of the rate limiting β-oxidation enzyme (3-hydroxyacyl-CoA-dehydrogenase (HAD)). Fasting plasma glucose, insulin, TG, HDL-c and LDL-c concentrations were measured. Exercise maximal fat oxidation (FOMAX) and oxygen uptake (VO2PEAK) were determined. Results Training improved MetS similarly in both groups (MetS Z-score -0.26±0.38 vs -0.22±0.31; P<0.001 for time and P=0.60 for time x group). Before training, STATIN had reduced muscle HAD activity and whole body FOMAX compared to CONTROL. However, 16-weeks of HIIT increased HAD and FOMAX in both groups (P<0.03, time-effect). STATIN did not prevent the increases in CS with HIIT observed in CONTROL (38% vs 64%, respectively; P<0.001, time-effect). Conversely, with training VO2PEAK improved less in STATIN than in CONTROL (12% vs 19%, respectively; P=0.013, time x group effect). Conclusion Chronic statin use in MetS does not interfere with exercise training improvements in MetS components, FOMAX or mitochondrial muscle enzymes (i.e., CS and HAD). However, STATIN attenuated the improvements in VO2PEAK with training.
... The best studied mechanism is the statin-induced alteration in cellular energy utilization and mitochondrial dysfunc- tion. An increase in the metabolism of carbohydrates at the expense of fatty acids has been observed in myopathic statin users (289). Biopsies of patients with SAMS often show unusual lipid accumulation, consistent with decreased mitochondrial oxidative metabolism (305). ...
Article
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Drugs are prescribed to manage or prevent symptoms and diseases, but may sometimes cause unexpected toxicity to muscles. The symptomatology and clinical manifestations of the myotoxic reaction can vary significantly between drugs and between patients on the same drug. This poses a challenge on how to recognize and prevent the occurrence of drug-induced muscle toxicity. The key to appropriate management of myotoxicity is prompt recognition that the symptoms of patients may be drug-related and to be aware that inter-individual differences in susceptibility to drug-induced toxicity exist. The most prevalent and well-documented drug class with unintended myotoxicity are the statins, but even today new classes of drugs with unintended myotoxicity are being discovered. This review will start off by explaining the principles of drug-induced myotoxicity and the different terminologies used to distinguish between grades of toxicity. The main part of the review will focus on the most important pathogenic mechanisms by which drugs can cause muscle toxicity, which will be exemplified by drugs with high-risk of muscle toxicity. This will be done by providing information on the clinical and laboratory features, muscle electromyography and biopsy findings, pathological mechanism and management for a specific drug from each pathogenic classification. In addition, rather new classes of drugs with unintended myotoxicity will be highlighted. Furthermore, we will explain why it is so difficult to diagnose a drug-induced muscle disease, and which tests can be used as a diagnostic aid. Lastly, a brief description will be given on how to manage and treat drug-induced myotoxicity.
... Coenzyme Q10 is also obtained from the diet, although dietary intake of CoQ10 only has a marginal effect on plasma CoQ10 concentrations. 1 Coenzyme Q10 supplements are available over-the-counter in most countries, and supplementation has been reported to have a beneficial effect for patients with breast cancer, 2 heart failure, 3 and mitochondrial encephalomyopathy, 4 among others. Plasma CoQ10 levels are reduced in patients undergoing statin (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) therapy 5,6 and in patients with heart failure. 7 Inhibiting HMG-CoA reductase reduces tissue levels of cholesterol in humans by limiting the intrinsic biosynthesis of cholesterol, and also inhibits the intrinsic biosynthesis of CoQ10. ...
Article
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Introduction: Statin-associated myalgia occurs in about 1-3% of patients in the medical literature. Plasma CoQ10 levels are reduced in patients undergoing statin. Objective: The primary outcome was the detection of clinical symptoms and the perception of pain evaluated throughout specific questionnaires. The secondary outcome was the variation in lipid profile and the variation in safety parameters. Methods: We enrolled 60 Caucasian patients, intolerant to statins. During the run-in period, patients underwent a 1-month wash-out period during which statins were stopped. At the end of the wash-out period, if CPK and/or transaminases returned within an acceptable range, statins were re-introduced at half of the previously taken dose. After one month, patients were randomized to take either a liquid CoQ10 supplement or a placebo for three months at 100 mg/day. Results: The Clinical Index Score for myalgia assessment was lower after 3 months with CoQ10, while it did not change with the placebo. The VAS score was lower after 3 months of CoQ10 supplementation, while no variation was recorded with the placebo. In the group treated with the dietary supplement, CoQ10 plasma concentrations were inversely correlated with CPK levels, Clinical Index Score absolute values, and VAS. Conclusion: The addition of CoQ10 with half dosage statin in patients with previous intolerance to statins improves the perception of clinical symptoms such as asthenia, myalgia or pain.
... The reason for the switch from mitochondrial ATP generation to glycolysis may be a decrease in mitochondrial function by simvastatin, as shown in the current but also in previous studies. 3,7,[27][28][29] In the current study, we found decreases in the activity of complex I and II-linked substrates, which is compatible with an impaired activity of complex I and II or also of complex III. A decrease in complex III activity by simvastatin has been described by Schirris et al. 3 An impaired activity of the electron transport chain, in particular of complex I or III, is a well-established reason for mitochondrial production of reactive oxygen species (ROS). ...
Article
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Aim: Statins decrease cardiovascular complications, but can induce myopathy. Here, we explored the implication of PGC-1α in statin-associated myotoxicity. Methods: We treated PGC-1α knockout (KO), PGC-1α over-expression (OE) and wild-type mice (WT) mice orally with 5 mg simvastatin kg-1 day-1 for 3 weeks and assessed muscle function and metabolism. Results: In WT and KO mice, but not in OE mice, simvastatin decreased grip strength, maximal running distance and vertical power assessed by ergometry. Post exercise plasma lactate concentrations were higher in WT and KO compared to OE mice. In glycolytic gastrocnemius, simvastatin decreased mitochondrial respiration, increased mitochondrial ROS production and free radical leak in WT and KO, but not in OE mice. Simvastatin increased mRNA expression of Sod1 and Sod2 in glycolytic and oxidative gastrocnemius of WT, but decreased it in KO mice. OE mice had a higher mitochondrial DNA content in both gastrocnemius than WT or KO mice and simvastatin exhibited a trend to decrease the citrate synthase activity in white and red gastrocnemius in all treatment groups. Simvastatin showed a trend to decrease the mitochondrial volume fraction in both muscle types of all treatment groups. Mitochondria were smaller in WT and KO compared to OE mice and simvastatin further reduced the mitochondrial size in WT and KO mice, but not in OE mice. Conclusions: Simvastatin impairs skeletal muscle function, muscle oxidative metabolism and mitochondrial morphology preferentially in WT and KO mice, whereas OE mice appear to be protected, suggesting a role of PGC-1α in preventing simvastatin-associated myotoxicity.
... Statins can affect skeletal muscle mitochondria in vitro by inhibiting respiratory chain complexes and oxidative capacity [12,13], decreasing mitochondrial membrane potential [13], uncoupling oxidative phosphorylation, inducing mitochondrial swelling and apoptosis [13] and decreasing mitochondrial density [14]. Statins also uncouple state 2 respiration and can inhibit the activity of the complexes of the respiratory chain in liver mitochondria, but the effect is drug-dependent (simvastatin has a strong deteriorating effect, while pravastatin does not seem to affect hepatic mitochondria) [15]. ...
Article
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Statins and fibrates are widely used for the management of hypertriglyceridemia but they also have limitations, mostly due to pharmacokinetic interactions or side effects. It is conceivable that some adverse events like liver dysfunction or gastrointestinal discomfort are caused by mitochondrial dysfunction. Data about the effects of statins and fibrates on mitochondrial function in different organs are inconsistent and partially contradictory. The aim of this study was to investigate the effect of pravastatin (statin) and gemfibrozil (fibrate) on hepatic and colonic mitochondrial respiration in tissue homogenates. Mitochondrial oxygen consumption was determined in colon and liver homogenates from 48 healthy rats after incubation with pravastatin or gemfibrozil (100, 300, 1000 μM). State 2 (substrate dependent respiration) and state 3 (adenosine diphosphate: ADP-dependent respiration) were assessed. RCI (respiratory control index)—an indicator for coupling between electron transport chain system (ETS) and oxidative phosphorylation (OXPHOS) and ADP/O ratio—a parameter for the efficacy of OXPHOS, was calculated. Data were presented as a percentage of control (Kruskal–Wallis + Dunn’s correction). In the liver both drugs reduced state 3 and RCI, gemfibrozil-reduced ADP/O (complex I). In the colon both drugs reduced state 3 but enhanced ADP/O. Pravastatin at high concentration (1000 µM) decreased RCI (complex II). Pravastatin and gemfibrozil decrease hepatic but increase colonic mitochondrial respiration in tissue homogenates from healthy rats.
... Çoğunlukla iyi tolere edilirken, SAMS (Statinle ilişkili kas hastalıkları), statin intoleransının ve tedavinin kesilmesinin en yaygın nedenidir. Genetik yatkınlıklar ve ilaç etkileşimleri gibi bir dizi faktör, SAMS riskinde artış ile ilişkilendirilmiştir. Literatürdeki kanıtlar, SAMS'un en olası nedeni olan statin kaynaklı mitokondriyal disfonksiyona [10,11] işaret ederken, mitokondriyal disfonksiyona yol açan kesin işlemler henüz tam olarak anlaşılamamıştır [12] . ...
... Very few studies have actually examined the level of CoQ10 in muscle, probably due to the invasive nature of human muscle biopsies. While these studies did demonstrate significant decreases (30%) in muscle CoQ10 levels, they failed to demonstrate a decrease in ATP synthesis and no myopathic side effects were reported [102,103]. Since muscle toxicity seems to be patient specific and somewhat rare (the same is true for liver toxicity caused by troglitazone and nefazodone), it is most likely that patients will have either underlying mitochondrial dysfunction (for example, a silent mitochondrial disease) or have different levels of transporter expression (MCT4 in the case of statin accumulation) due to polymorphism in enzymes involved in statin metabolism [104]. Beyond the effect on CoQ10, statins have been reported to have direct effects on the ETC, especially the lipophilic statins, simvastatin and fluvastatin. ...
Article
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Mitochondrial function declines with age, leading to a variety of age-related diseases (metabolic, central nervous system-related, cancer, etc.) and medication usage increases with age due to the increase in diseases. Drug-induced mitochondrial toxicity has been described for many different drug classes and can lead to liver, muscle, kidney and central nervous system injury and, in rare cases, to death. Many of the most prescribed medications in the geriatric population carry mitochondrial liabilities. We have demonstrated that, over the past decade, each class of drugs that demonstrated mitochondrial toxicity contained drugs with both more and less adverse effects on mitochondria. As patient treatment is often essential, we suggest using medication(s) with the best safety profile and the avoidance of concurrent usage of multiple medications that carry mitochondrial liabilities. In addition, we also recommend lifestyle changes to further improve one’s mitochondrial function, such as weight loss, exercise and nutrition.
... Only simvastatin led to changes in skeletal muscle sterol metabolism, reduced muscle ubiquinone, and impaired respiratory chain enzyme activity. 65 In line with this evidence, a more recent study has shown that SAMS is associated with the off target inhibition of mitochondrial complex III by statin lactones. 66 Consequently, polymorphisms of uridine 5 0 -diphospho-glucurosyltransferases (UGTs), the enzyme converting statins to the lactone form, 67 could predispose to statin-induced myopathies. ...
Article
Treatment with statins, inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, has proven beneficial preventive effects on cardiovascular events. However, discontinuation due to intolerance and nonadherence remain two of the major gaps in both primary and secondary prevention. This leads many patients with high-risk of atherosclerotic cardiovascular disease (ASCVD) to be inadequately treated or not to achieve the target lipid level goals, and as consequence they undergo an increased risk of cardiovascular events. The aim of this review is thus to give an overview of the reasons for discontinuation and on the possible mechanisms behind them. Although statins, as a class, are generally safe, they are associated with an increased risk of diabetes mellitus and hepatic transaminase elevations. Incidence of cataracts or cognitive dysfunction and others presented in the literature (e.g., proteinuria and haematuria) have been never confirmed to have a causal link. Conversely, debated remains the effect on myalgia. Muscle side effects are the most commonly reported, although myalgia is still believed by some to be the result of a nocebo/drucebo effect. Concerning mechanisms behind these side effects no clear conclusions have been reached. Thus, if on one side it is important to identify individuals either at higher risk to develop a side effect, or with confirmed risk factors and conditions of statin intolerance, on the other side alternative strategies should be identified to avoid an increased ASCVD risk.
... In comparison, it is less clear whether statin treatment also reduces the skeletal muscle CoQ10 content. Low dose statin treatment (20 mg simvastatin per day) did not reduce the skeletal muscle CoQ10 content [92], whereas higher doses (80 mg simvastatin per day) were associated with a small decrease in the CoQ10 content [93]. It is currently not clear, however, whether this possible decrease in skeletal muscle CoQ10 is associated with myopathy and whether exogenous CoQ10 is beneficial for patients with statin-associated myopathy. ...
Article
Statins lower the serum low-density lipoprotein cholesterol and prevent cardiovascular events by inhibiting 3-hydroxy-3-methyl-glutaryl-CoA reductase. Although the safety of statins is documented, many patients ingesting statins may suffer from skeletal muscle-associated symptoms (SAMS). Importantly, SAMS are a common reason for stopping the treatment with statins. Statin-associated muscular symptoms include fatigue, weakness and pain, possibly accompanied by elevated serum creatine kinase activity. The most severe muscular adverse reaction is the potentially fatal rhabdomyolysis. The frequency of SAMS is variable but in up to 30% of the patients ingesting statins, depending on the population treated and the statin used. The mechanisms leading to SAMS are currently not completely clarified. Over the last 15 years, several research articles focused on statin-induced mitochondrial dysfunction as a reason for SAMS. Statins can impair the function of the mitochondrial respiratory chain, thereby reducing ATP and increasing ROS production. This can induce mitochondrial membrane permeability transition, release of cytochrome c into the cytosol and induce apoptosis. In parallel, statins inhibit activation of Akt, mainly due to reduced function of mTORC2, which may be related to mitochondrial dysfunction. Mitochondrial dysfunction by statins is also responsible for activation of AMPK, which is associated with impaired activation of mTORC1. Reduced activation of mTORC1 leads to increased skeletal muscle protein degradation, impaired protein synthesis and stimulation of apoptosis. In this paper, we discuss some of the different hypotheses how statins affect skeletal muscle in more detail, focusing particularly on those related to mitochondrial dysfunction and the impairment of the Akt/mTOR pathway.
... La rosuvastatina, de más reciente introducción, tiene un perfil semejante de seguridad [74][75][76][77]. La elevación de enzimas musculares como CK puede no ser útil para la evaluación de la toxicidad muscular, debido a que existe poca correlación [78]. Determinaciones mayores a 10 veces el límite superior normal usualmente se acompaña de mioglobinuria, hiperkalemia y, potencialmente, insuficiencia renal aguda [79]. ...
... After the remaining 41 full-text articles were reviewed, 29 articles were excluded due to improper comparisons, irrelevant outcomes, and/or unavailable outcomes. Finally, 12 articles [17][18][19][20][21][22][23][24][25][26][27][28] with 1776 participants published in English from 1993 to 2018, with sample sizes ranging from 19 to 1103 participants and intervention durations ranging from 14 days to 26 weeks, were entered into our meta-analysis ( Fig. 1 ...
Article
Full-text available
Background The effect of statin treatment on circulating coenzyme Q10 (CoQ10) has been studied in numerous randomized controlled trails (RCTs). However, whether statin treatment decreases circulating CoQ10 is still controversial. Methods PubMed, EMBASE, and the Cochrane Library were searched to identify RCTs to investigate the effect of statin treatment on circulating CoQ10. We calculated the pooled standard mean difference (SMD) using a fixed effect model or random effect model to assess the effect of statin treatment on circulating CoQ10. The methodological quality of the studies was determined according to the Cochrane Handbook. Publication bias was evaluated by a funnel plot, the Egger regression test, and the Begg–Mazumdar correlation test. Results Twelve RCTs with a total of 1776 participants were evaluated. Compared with placebo, statin treatment resulted in a reduction of circulating CoQ10 (SMD, − 2.12; 95% CI, − 3.40 to − 0.84; p = 0.001), which was not associated with the duration of statin treatment (Exp, 1.00; 95% CI, 0.97 to 1.03; p = 0.994). Subgroup analysis demonstrated that both lipophilic statins (SMD, − 1.91; 95% CI, − 3.62 to 0.2; p = 0.017) and hydrophilic statins (SMD, − 2.36; 95% CI, − 4.30 to − 0.42; p = 0.028) decreased circulating CoQ10, and no obvious difference was observed between the two groups (SMD, − 0.20; 95% CI, − 0.208 to 0.618; p = 0.320). In addition, both low-middle intensity statins (SMD, − 2.403; 95% CI, − 3.992 to − 0.813; p < 0.001) and high intensity statins (SMD, − 1.727; 95% CI, − 2.746 to − 0.709; p < 0.001) decreased circulating CoQ10. Meta-regression showed that the effect of statin on decreasing circulating CoQ10 was not closely associated with the duration of statin treatment (Exp, 1.00; 95% CI, 0.97 to 1.03; p = 0.994). Conclusions Statin treatment decreased circulating CoQ10 but was not associated with the statin solution, intensity, or treatment time. The findings of this study provide a potential mechanism for statin-associated muscle symptoms (SAMS) and suggest that CoQ10 supplementation may be a promising complementary approach for SAMS. Electronic supplementary material The online version of this article (10.1186/s40001-018-0353-6) contains supplementary material, which is available to authorized users.
... The muscle CoQ10 levels were comparable among groups in the current study, indicating that CoQ10 is not associated with statin treatment and the development of myalgia. The few studies that have investigated the association between statins and muscle CoQ10 levels have yielded conflicting results (32)(33)(34). The comparable CoQ10 levels in the current study were unexpected because CoQ10 is synthesized downstream of 3-hydroxy-3methyl-glutaryl-coenzyme A, which is inhibited by statins. ...
Article
Background Myalgia is a common side effect to statin therapy, but the underlying mechanism is unknown. Statins may reduce Coenzyme Q10 (CoQ10) which is an essential electron carrier in the mitochondrial electron transport system, thereby impairing mitochondrial respiratory function potential leading to myalgia. Objectives To investigate whether statin induced myalgia is coupled to reduced intramuscular CoQ10 concentration and impaired mitochondrial respiratory function. Methods 64 men and women in simvastatin therapy were recruited. 25 who experienced myalgia were allocated to the myalgic group. The remaining 39 statin users had no symptoms of myalgia (non-sympt). 20 men and women with untreated high blood cholesterol levels were recruited as control group. Blood and muscle samples were obtained. Intramuscular CoQ10 concentration was measured, and mitochondrial respiratory function and reactive oxygen species (ROS) production were measured. Citrate Synthase (CS) activity was used as a biomarker for mitochondrial content in skeletal muscle. Results Intramuscular CoQ10 concentration was comparable between groups. Mitochondrial complex II-linked respiration was reduced in the statin myalgic and statin non-symptomatic groups compared to control. When mitochondrial respiration was normalized to CS activity respiration rate was higher in the myalgic group compared to non-symptomatic and control group. Maximal ROS production was similar between groups. Discussion Our results suggests that statin therapy impairs mitochondrial complex-II linked respiration, but the mitochondrial capacity for complex I+II linked respiration is intact. Myalgia is not coupled to reduced intramuscular CoQ10 levels. Intrinsic mitochondrial respiratory capacity is increased with statin induced myalgia, but not accompanied by increased ROS production.
... The mechanism of statin-induced myopathy is not yet clear, but one possible mechanism is mitochondrial dysfunction resulting from a reduction in circulating/intramuscular CoQ10. 3,4 The RCT results 15,17,[24][25][26][27][28] demonstrated that statins reduced circulating CoQ10 by 16% to 54%; a meta-analysis 6 of 6 RCTs also suggested a significant reduction in plasma CoQ10 after statin treatment, regardless of the statin solution, treatment diphosphate and the activity of mitochondrial complex I and IV, which contributes to mitochondrial dysfunction. [31][32][33][34] Recently, polymorphisms in the coenzyme Q2 gene, important in the synthesis of CoQ10, were reportedly strongly associated with statin-induced myopathy. ...
Article
Full-text available
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.
... Some studies have proposed that statin-induced mitotoxicity may be mediated by diminished CoQ10 content with consequent impairment of mitochondrial respiration [111,[226][227][228][229][230][231][232][233][234]. On the other hand, our group has provided evidence that under our experimental conditions, the reduction of mitochondrial respiration associated with CoQ10 depletion was mainly due to its free radical scavenging action rather than its electron carrier function. ...
... Besides anti-hyperglycemia drugs, lipid-lowering HMG-CoA reductase inhibitors (e.g., statins) are commonplace in the management of (pre)diabetes. In the 1990/2000s, it was shown that statin use may lead to mitochondrial dysfunction and muscle damage (Thompson et al., 1997;Päivä et al., 2005;Draeger et al., 2006;Schick et al., 2007), prompting a hypothesis that statin treatment may blunt the beneficial effect of exercise. Meex et al. (2010) found that statin treatment (between 5 and 40 mg/day of atorvastatin, simvastatin, rosuvastatin, or pravastatin) combined with regular aerobic plus resistance training more robustly increased insulin sensitivity than training alone. ...
Article
In the context of type 2 diabetes, inter-individual variability in the therapeutic response of blood glucose control to exercise exists to the extent that some individuals, occasionally referred to as "non-responders," may not experience therapeutic benefit to their blood glucose control. This narrative review examines the evidence and, more importantly, identifies the sources of such inter-individual variability. In doing so, this review highlights that no randomized controlled trial of exercise has yet prospectively measured inter-individual variability in blood glucose control in individuals with prediabetes or type 2 diabetes. Of the identified sources of inter-individual variability, neither has a prospective randomized controlled trial yet quantified the impact of exercise dose, exercise frequency, exercise type, behavioral/environmental barriers, exercise-meal timing, or anti-hyperglycemic drugs on changes in blood glucose control, in individuals with prediabetes or type 2 diabetes. In addition, there is also an urgent need for prospective trials to identify molecular or physiological predictors of inter-individual variability in the changes in blood glucose control following exercise. Therefore, the narrative identifies critical science gaps that must be filled if exercise scientists are to succeed in optimizing health care policy recommendations for type 2 diabetes, so that the therapeutic benefit of exercise may be maximized for all individuals with, or at risk of, diabetes.
... However, according to the meta-analyses conducted by Banach et al., Q10 supplementation does not prevent the occurrence of statin-induced myopathy [22]. There are also other available hypotheses, not related to vitamin D [23,24]; one of them is based on the assumption that among patients receiving high doses of statins there is a decrease in fat synthesis by inhibiting acetyl coenzyme A carboxylase leading to increased beta-oxidase resulting in muscle injury [25]. Of course, there are also genetic predispositions that may be of great importance in myalgia associated with statin therapy [24]. ...
Chapter
Statin intolerance, whereby adverse effects of statins result in the cessation of therapy or suboptimal dosing, is associated with an increased risk of cardiovascular events. Statin-associated muscle symptoms are overwhelmingly the most commonly reported adverse effects of statin therapy and contribute to statin intolerance. The prevalence of vitamin D deficiency is increasing in many populations. Some available, mainly observational, studies have found vitamin D deficiency to be independently associated with muscle weakness and myopathy and have found evidence of a greater prevalence of vitamin D deficiency in patients who experience SAMS than those with good adherence to statin therapy.
... The pathological mechanisms underlying the myotoxicity of statins are not well understood. However, it has been suggested that statins could cause muscle damage by decreasing the pro- duction of ubiquinone, a protein in charge of stabilizing the cell membrane that also plays an important role in the mitochondrial respiratory chain 31 ; increasing levels of sterols in the muscle fibers, which can increase the toxic effects of statins in the muscle 32 or related with the overexpression of artrogin-1, a key gen involved in skeletal muscle atrophy. 33 The prevalence of musculoskeletal pain has been reported in observational studies to be 3-33% higher in patients taking statins. ...
Article
Statins inhibit the critical step of cholesterol synthesis in which 3-hydroxy-3-methylglutaryl coenzyme A (HMGC) is transformed to mevalonate by the enzyme HMGC reductase. By doing so, they have a potent lipid-lowering effect that reduces cardiovascular risk and decreases mortality. Since the mevalonate pathway also influences endothelial function, the inflammatory response, and coagulation, the effects of statins reach well beyond their cholesterol lowering properties. As with all drugs, statins may have adverse effects; these include musculoskeletal symptoms, increased risk of diabetes, and higher rates of hemorrhagic stroke. However, the frequency of adverse effects is extremely low and, in selected patient populations, the benefits of statins considerably outweigh the potential risks.
... However, supplementation of CoQ10 in patients treated with statins offered conflicting results regarding the benefit in reduction of SAMS or CK levels [9] or superoxide production by blood cells (regardless the presence of SAMS) [13]. This is most probably due to the fact that serum and muscle ubiquinone levels are differently modulated and, since the serum levels of ubiquinone did not correlate with the activities of the ETS enzymes, CoQ should not be used as a marker when assessing the effects of statins on energy metabolism [55]. Instead, the level of mitochondrial superoxide in peripheral blood cells has recently emerged as putative biomarker for SAMS [13]. ...
Article
Full-text available
Statins are the cornerstone of lipid-lowering therapy. Although generally well tolerated, statin-associated muscle symptoms (SAMS) represent the main reason for treatment discontinuation. Mitochondrial dysfunction of complex I has been implicated in the pathophysiology of SAMS. The present study proposed to assess the concentration-dependent ex vivo effects of three statins on mitochondrial respiration in viable human platelets and to investigate whether a cell-permeable prodrug of succinate (complex II substrate) can compensate for statin-induced mitochondrial dysfunction. Mitochondrial respiration was assessed by high-resolution respirometry in human platelets, acutely exposed to statins in the presence/absence of the prodrug NV118. Statins concentration-dependently inhibited mitochondrial respiration in both intact and permeabilized cells. Further, statins caused an increase in non-ATP generating oxygen consumption (uncoupling), severely limiting the OXPHOS coupling efficiency, a measure of the ATP generating capacity. Cerivastatin (commercially withdrawn due to muscle toxicity) displayed a similar inhibitory capacity compared with the widely prescribed and tolerable atorvastatin, but did not elicit direct complex I inhibition. NV118 increased succinate-supported mitochondrial oxygen consumption in atorvastatin/cerivastatin-exposed platelets leading to normalization of coupled (ATP generating) respiration. The results acquired in isolated human platelets were validated in a limited set of experiments using atorvastatin in HepG2 cells, reinforcing the generalizability of the findings.
... [8] Rundek et al. demonstrated a 50% reduction in CoQ10 levels within 30 days of atorvastatin therapy at a dose of 80 mg daily, and another study concluded similar results with high-dose simvastatin. [9][10][11] The inhibition of mevalonate and isoprenoids including farnesyl pyrophosphate and geranylgeranyl pyrophosphate has also been implicated. The reduction of these isoprenoids are hypothesized to inactivate the action of GTPases, increasing cytosolic calcium and subsequently altering cellular function, increasing apoptosis, and ultimately leading to myotoxicity. ...
Article
Statins are one of the most widely used and reputable medications worldwide, with strong evidence of mitigating cardiovascular complications and with a generally favorable safety profile. Nevertheless, statins have commonly come under scrutiny, owing to their associations with muscle disorders. Statins are known to cause a range of effects on muscles, varying from mild self-limiting symptoms to detrimental muscular necrosis. In particular, there has been emerging evidence of statin-associated necrotizing autoimmune myositis related to the presence of anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) autoantibodies. Patients often demonstrate proximal muscle weakness and hyperCKemia, and treatment guidelines are not robust owing to the rarity of the disease. Nevertheless, literature provides evidence for use of corticosteroids, and there are emerging data supporting the incorporation of immunomodulatory agents such as methotrexate, intravenous immunoglobulin, and rituximab. In performing this review, we searched databases in PubMed and EMBASE written in English and limited to the last two decades. Keywords used included “statin,” “myositis,” “autoimmune myopathy,” “anti-HMGCR,” and “necrotising.” Articles were selected by relevance to the topic, and articles pertaining to antisignal recognition particle myopathy and other forms of myositis were excluded.
... 25 Another mechanism is that impaired cholesterol synthesis may lead to decreased coenzyme Q10 levels, which in turn may cause impaired mitochondrial enzyme activity and resultant myopathy. 26 Finally, another potential mechanism is that statins may deplete isoprenoids, which are implicated in preventing myofiber apoptosis. 27 Whereas evidence is limited on risk factors of statin-induced myopathy, some studies have proposed advanced age, female sex, impaired hepatic and renal metabolism, low BMI, alcohol use, surgery, trauma, and dietary effects. ...
Article
Full-text available
Objective To evaluate the association between statin use and symptom severity, tender point count, fatigue, cognition, mood, and sleep issues in patients with fibromyalgia (FM). Methods Between May 2012 and November 2013, 668 patients with FM were surveyed. Patients were stratified into statin users and statin nonusers. Primary outcome was FM symptom severity (FIQ-R questionnaire) and tender point count. Secondary outcomes included fatigue (MFI-20), cognitive dysfunction (MASQ), anxiety (GAD-7), depression (PHQ-9), and sleep issues (SPI-II). Regression analysis assessed for differences in these clinical outcomes between statin users and statin nonusers and adjusted for age, sex, body mass index, ethnicity, tobacco use, opioid use, and neuropathic medication use. Results Of the FM patients, 79 (11.8%) were statin users, whereas 589 (88.2%) reported no current statin use. Compared with the control cohort, statin users were older (55.0±11.3 years vs 46.2±12.9 years; P<.001) and had a higher body mass index (33.0±7.0 kg/m² vs 29.8±7.7 kg/m²; P=.001). Adjusted linear regression revealed no association between statin use and symptom severity (total FIQ-R scores, 57.7±18.3 vs 59.0±18.1; adjusted β coefficient, −0.4; 95% CI, −4.8 to 4.1; P=.871). There was also no association between statin use and tender point count (14.8±4.1 vs 14.5±4.2; adjusted β coefficient, 0.2; 95% CI, −0.8 to 1.2; P=.732). Secondary outcome analysis revealed no difference between statin users and statin nonusers in metrics measuring fatigue, cognition, anxiety, depression, and sleep problems. Conclusion Administration of statin therapy for at least 1 month is not a risk factor for worse symptom burden in patients with FM. Statin therapy should be offered to dyslipidemic FM patients with an appropriate medical indication to optimize their cardiovascular health.
... It has been found that copy number depletion caused by antiretroviral therapy [63] or AKT2 deficiency [64] is associated with enhanced sarcopenia. Likewise, statins are well known for increasing the risk of sarcopenia [65,66,67] and have consistently been associated with reduction in mitochondrial copy number [68,69,70]. Conversely, increase in mtDNA content through exercise [71,72] or overexpression of TFAM [73] and parkin [74] have been found to protect against sarcopenia and muscle atrophy. ...
Preprint
Full-text available
The expansion of deleted mitochondrial DNA (mtDNA) molecules has been linked to ageing, particularly in skeletal muscle fibres; its mechanism has remained unclear for three decades. Previous accounts assigned a replicative advantage to the deletions, but there is evidence that cells can, instead, selectively remove defective mtDNA. We present a spatial model that, without a replicative advantage, but instead through a combination of enhanced density for mutants and noise, produces a wave of expanding mutations with wave speed consistent with experimental data, unlike a standard model based on replicative advantage. We provide a formula that predicts that the wave speed drops with copy number, in agreement with experimental data. Crucially, our model yields travelling waves of mutants even if mutants are preferentially eliminated. Justified by this exemplar of how noise, density and spatial structure affect muscle ageing, we introduce the mechanism of stochastic survival of the densest, an alternative to replicative advantage, that may underpin other phenomena, like the evolution of altruism.
... In statin therapy, a deficiency in CoQ10 status has been suggested as a possible contributing factor to the myopathic side effects associated with this pharmacotherapy [58]. Although a number of studies have reported evidence of a deficit in plasma/serum CoQ10 following statin therapy, few studies have directly assessed muscle status, and of these, only one has reported evidence of CoQ10 deficiency [14,59]. The decrease in circulatory CoQ10 status following statin therapy may reflect the decrease in blood low density lipoprotein (LDL) status induced by this pharmacotherapy [14]. ...
Article
Full-text available
Coenzyme Q10 (CoQ10) has a number of vital functions in all cells, both mitochondrial and extramitochondrial. In addition to its key role in mitochondrial oxidative phosphorylation, CoQ10 serves as a lipid soluble antioxidant, plays an important role in fatty acid, pyrimidine and lysosomal metabolism, as well as directly mediating the expression of a number of genes, including those involved in inflammation. In view of the central role of CoQ10 in cellular metabolism, it is unsurprising that a CoQ10 deficiency is linked to the pathogenesis of a range of disorders. CoQ10 deficiency is broadly classified into primary or secondary deficiencies. Primary deficiencies result from genetic defects in the multi-step biochemical pathway of CoQ10 synthesis, whereas secondary deficiencies can occur as result of other diseases or certain pharmacotherapies. In this article we have reviewed the clinical consequences of primary and secondary CoQ10 deficiencies, as well as providing some examples of the successful use of CoQ10 supplementation in the treatment of disease.
... It also remains unknown to what extent statins concentrate in different tissue types after chronic therapy. However, in vivo studies, indicate that the use of statins is associated with impairment of mitochondrial function [mitochondrial respiratory capacity and reactive oxygen species (ROS) production] in skeletal muscle [17][18][19][20] . Statin treatment has also been shown to reduce skeletal muscle mitochondrial content and concentrations of the mitochondrial coenzyme ubiquinone (Q10) 17,18 . ...
Article
Full-text available
Statins lower the risk of cardiovascular events but have been associated with mitochondrial functional changes in a tissue-dependent manner. We investigated tissue-specific modifications of mitochondrial function in liver, heart and skeletal muscle mediated by chronic statin therapy in a Göttingen Minipig model. We hypothesized that statins enhance the mitochondrial function in heart but impair skeletal muscle and liver mitochondria. Mitochondrial respiratory capacities, citrate synthase activity, coenzyme Q10 concentrations and protein carbonyl content (PCC) were analyzed in samples of liver, heart and skeletal muscle from three groups of Göttingen Minipigs: a lean control group (CON, n = 6), an obese group (HFD, n = 7) and an obese group treated with atorvastatin for 28 weeks (HFD + ATO, n = 7). Atorvastatin concentrations were analyzed in each of the three tissues and in plasma from the Göttingen Minipigs. In treated minipigs, atorvastatin was detected in the liver and in plasma. A significant reduction in complex I + II-supported mitochondrial respiratory capacity was seen in liver of HFD + ATO compared to HFD ( P = 0.022). Opposite directed but insignificant modifications of mitochondrial respiratory capacity were seen in heart versus skeletal muscle in HFD + ATO compared to the HFD group. In heart muscle, the HFD + ATO had significantly higher PCC compared to the HFD group ( P = 0.0323). In the HFD group relative to CON, liver mitochondrial respiration decreased whereas in skeletal muscle, respiration increased but these changes were insignificant when normalizing for mitochondrial content. Oral atorvastatin treatment in Göttingen Minipigs is associated with a reduced mitochondrial respiratory capacity in the liver that may be linked to increased content of atorvastatin in this organ.
... Furthermore, many commonly used drugs affect mitochondria. For example, β-blockers inhibit mitochondrial respiratory chain complex 1 enzyme (84) and statins inhibit CoQ10 synthesis, reduce citrate synthase activity, important for the Krebs cycle and the electron transport chain enzyme (85). Other medication classes with mitochondrial effects include antidepressants, analgesics, antipsychotics, antihyperlipidemics, antidiabetics, and barbiturates, which either directly affect the mitochondrial DNA or mitochondrial enzymes for glycolysis and β-oxidation (86). ...
Article
The gut microbiome has pervasive bi-directional relationships with pharmacotherapy, chronic disease, and physical and cognitive function. We conducted a narrative review of the current literature to examine the relationships between the gut microbiome, medication use, sarcopenia and frailty, and cognitive impairment. Data from in vitro experiments, in vivo experiments in invertebrates and complex organisms, and humans indicate associations between the gut microbiome and geriatric syndromes. Better understanding of the direct and indirect roles of the microbiome may inform future prevention and management of geriatric syndromes.
... The best described drug-interaction with Q10 in muscle is with statins, which is a frequently prescribed class of drugs for the lowering of low density lipoprotein cholesterol in human patients. Statins have been shown to decrease Q10 concentrations in skeletal muscle of human patients [59][60][61] and in myocardial tissue in animal models [62]. For the present study, it is fortunate that dogs are rarely prescribed statins and none of the dogs in the study were on statins. ...
Article
Full-text available
Congestive heart failure (CHF) has been associated with depleted myocardial coenzyme Q10 (Q10) concentrations in human patients. The aim of this study was to investigate associations between myocardial Q10 concentrations and myxomatous mitral valve disease (MMVD) severity in dogs. Furthermore, citrate synthase (CS) activity was analysed to determine if a reduction in myocardial Q10 was associated with mitochondrial depletion in the myocardium. Thirty Cavalier King Charles spaniels (CKCS) in MMVD stages B1 (n = 11), B2 (n = 5) and C (n = 14) according to the American College of Veterinary Internal Medicine (ACVIM) guidelines and 10 control (CON) dogs of other breeds were included. Myocardial Q10 concentration was analysed in left ventricular tissue samples using HPLC-ECD. CKCS with congestive heart failure (CHF; group C) had significantly reduced Q10 concentrations (median, 1.54 µg/mg; IQR, 1.36–1.94), compared to B1 (2.76 µg/mg; 2.10–4.81, p < 0.0018), B2 (3.85 µg/mg; 3.13–4.46, p < 0.0054) and CON dogs (2.8 µg/mg; 1.64–4.88, p < 0.0089). CS activity was comparable between disease groups. In conclusion, dogs with CHF due to MMVD had reduced myocardial Q10 concentrations. Studies evaluating antioxidant defense mechanisms as a therapeutic target for treatment of CHF in dogs are warranted.
Article
Background The combination of statin therapy and physical activity reduces cardiovascular disease risk in patients with hyperlipidemia more than either treatment alone. However, mitochondrial dysfunction associated with statin treatment could attenuate training adaptations. Objectives This study determined whether moderate intensity exercise training improved muscle and exercise performance, muscle mitochondrial function, and fiber capillarization in symptomatic and asymptomatic statin users. Methods Symptomatic (n = 16; age 64 ± 4 years) and asymptomatic statin users (n = 16; age 64 ± 4 years) and nonstatin using control subjects (n = 20; age 63 ± 5 years) completed a 12-week endurance and resistance exercise training program. Maximal exercise performance (peak oxygen consumption), muscle performance and muscle symptoms were determined before and after training. Muscle biopsies were collected to assess citrate synthase activity, adenosine triphosphate (ATP) production capacity, muscle fiber type distribution, fiber size, and capillarization. Results Type I muscle fibers were less prevalent in symptomatic statin users than control subjects at baseline (P = 0.06). Exercise training improved muscle strength (P < 0.001), resistance to fatigue (P = 0.01), and muscle fiber capillarization (P < 0.01), with no differences between groups. Exercise training improved citrate synthase activity in the total group (P < 0.01), with asymptomatic statin users showing less improvement than control subjects (P = 0.02). Peak oxygen consumption, ATP production capacity, fiber size, and muscle symptoms remained unchanged in all groups following training. Quality-of-life scores improved only in symptomatic statin users following exercise training (P < 0.01). Conclusions A moderate intensity endurance and resistance exercise training program improves muscle performance, capillarization, and mitochondrial content in both asymptomatic and symptomatic statin users without exacerbating muscle complaints. Exercise training may even increase quality of life in symptomatic statin users. (The Effects of Cholesterol-Lowering Medication on Exercise Performance [STATEX]; NL5972/NTR6346)
Article
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3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are extremely well tolerated but are associated with a range of mild-to-moderate statin-associated muscle symptoms (SAMS). Estimates of SAMS incidence vary from <1% in industry-funded clinical trials to 10-25% in nonindustry-funded clinical trials and ∼60% in some observational studies. SAMS are important because they result in dose reduction or discontinuation of these life-saving medications, accompanied by higher healthcare costs and cardiac events. The mechanisms that produce SAMS are not clearly defined. Statins block the production of farnesyl pyrophosphate, an intermediate in the mevalonate pathway, which is responsible for the production of coenzyme Q10 (CoQ10). This knowledge has prompted the hypothesis that reductions in plasma CoQ10 concentrations contribute to SAMS. Consequently, CoQ10 is popular as a form of adjuvant therapy for the treatment of SAMS. However, the data evaluating the efficacy of CoQ10 supplementation has been equivocal, with some, but not all, studies suggesting that CoQ10 supplementation mitigates muscular complaints. This review discusses the rationale for using CoQ10 in SAMS, the results of CoQ10 clinical trials, the suggested management of SAMS, and the lessons learned about CoQ10 treatment of this problem.
Article
Over the long-term, at least half of patients started on statins will discontinue them. Statin noncompliance can be defined as discontinuing therapy for whatever reason. This results from four causes: dysfunction of the health care system; fear of side effects (nocebo effect); disorders of the musculoskeletal system or other organs misconstrued as statin related; and true statin myotoxicity. Statin intolerance here represents discontinuation due to perceived side effects. For statin intolerance in patients with clinical atherosclerotic cardiovascular disease, the goal is an LDL level < 70 mg/dL Treatment includes maximally tolerated statin dosage, adding non-statin drugs, and if necessary, a PCSK9 inhibitor. For primary prevention in patients at intermediate risk, as determined by risk factors, coronary artery calcium should be measured for deciding on statin therapy. For patients having zero calcium, a statin can be withheld for a decade before rescanning. If original calcium score is 1-99 Agatston units, a statin can be delayed for five years before rescanning. When the score is ≥ 100, statin therapy is indicated.
Article
Statins are among the most frequently prescribed drugs in Germany. Their benefits in lowering cardiovascular risk are beyond dispute. Nevertheless, many patients complain of side effects from statin therapy, including statin-associated muscle symptoms (SAMS) in particular. Despite their relative frequency, it is difficult to objectively diagnose them, as the time until appearance of first symptoms, the nature of the complaints and the severity of muscle problems vary widely. This narrative review summarizes the causes of SAMS as well as new possibilities regarding their diagnosis and therapy.
Article
Purpose of review The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are a class of lipid-lowering medications by inhibiting the enzyme HMG-CoA reductase. Statins are important drugs for the prevention of cardiovascular disease. The prominent value of statins is well established during the past three decades. The efficacy and safety of statins have been evaluated in many large randomized controlled trials. Recent findings Currently, emerging concerns with statin-induced liver toxicity (SILT) and muscle toxicity (SIMT) have been introduced. However, exact mechanisms of SILT and SIMT have not been well understood. Moreover, there is an increasing concern currently about their safety associated with genetic polymorphisms. Thus, this article reviews the mechanisms of statin-drug interactions and their adverse effects with a particular focus on SILT and SIMT. It is recommended that the specific pharmacology for the different statins should be understood to maximize their benefit and minimize statin-induced toxicity. Significant toxicity may be induced by statin-drug interactions, and understanding how certain drugs interact with statins will help physicians in safely prescribing these agents.
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Human ageing is determined by degenerative alterations and processes with different manifestations such as gradual organ dysfunction, tissue function loss, increased population of aged (senescent) cells, incapability of maintaining homeostasis and reduced repair capacity, which collectively lead to an increased risk of diseases and death. The inhibitors of HMG-CoA reductase (statins) are the most widely used lipid-lowering agents, which can reduce cardiovascular morbidity and mortality. Accumulating evidence has documented several pleiotropic effects of statins in addition to their lipid-lowering properties. Recently, several studies have highlighted that statins may have the potential to delay the ageing process and inhibit the onset of senescence. In this review, we focused on the anti-ageing mechanisms of statin drugs and their effects on cardiovascular and non-cardiovascular diseases.
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LR: 20061115; JID: 7501160; 0 (Antilipemic Agents); 0 (Cholesterol, HDL); 0 (Cholesterol, LDL); 57-88-5 (Cholesterol); CIN: JAMA. 2001 Nov 21;286(19):2401; author reply 2401-2. PMID: 11712930; CIN: JAMA. 2001 Nov 21;286(19):2400-1; author reply 2401-2. PMID: 11712929; CIN: JAMA. 2001 Nov 21;286(19):2400; author reply 2401-2. PMID: 11712928; CIN: JAMA. 2001 Nov 21;286(19):2400; author reply 2401-2. PMID: 11712927; CIN: JAMA. 2001 May 16;285(19):2508-9. PMID: 11368705; CIN: JAMA. 2003 Apr 16;289(15):1928; author reply 1929. PMID: 12697793; CIN: JAMA. 2001 Aug 1;286(5):533-5. PMID: 11476650; CIN: JAMA. 2001 Nov 21;286(19):2401-2. PMID: 11712931; ppublish
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We report our studies on the metabolic defects which caused a newborn infant to present with a severe lactic acidemia (25 mM) and to die on the 3rd d after birth despite intensive supportive measures. The mitochondrial fractions prepared from skeletal muscle and liver oxidised NAD+-linked substrates and succinate slowly. Spectrophotometric assays for complexes I, II, and III of the respiratory chain demonstrate a specific defect of complex III in the skeletal muscle and liver mitochondrial fractions. The concentrations of cytochrome b were 75% lower in the skeletal muscle and heart mitochondria than in control preparations. The amount of non-heme iron sulphur protein of complex III was low in skeletal muscle, liver, and heart. This case differs from previous reports of complex III deficiency in three respects: the patient presented in the neonatal period, the defect was expressed in several tissues, and it was fatal.
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We studied 6 mitochondrial enzymes in crude extracts and isolated mitochondria from 5 children with pathologically proven subacute necrotizing encephalomyelopathy (Leigh syndrome). Samples were taken from brain (5 patients), skeletal muscle (4 patients), liver (4 patients), kidney (4 patients), heart (1 patient), and cultured fibroblasts (3 patients). An isolated defect of cytochrome c oxidase (COX) activity was found in brain (decrease of activity to 15 to 39% of the normal mean), muscle (9 to 20%), kidney (1 to 67%), and in the 1 available heart (4%) from a patient with cardiopathy. COX activity was also decreased in liver of 3 patients (2 to 13% of normal) and in cultured fibroblasts of 2 patients (18 and 27%), but it was normal in both liver and fibroblasts from 1 patient. Immunotitration using polyclonal antibodies against human heart COX showed essentially normal amounts of cross-reacting enzyme protein in various tissues from different patients. Electrophoresis of COX immunoprecipitated from brain mitochondrial extracts showed normal patterns of COX subunits in 2 patients. This study confirms the theory that COX deficiency is an important cause of Leigh syndrome.
Article
A method for estimating the cholesterol content of the serum low-density lipoprotein fraction (Sf- 0.20)is presented. The method involves measure- ments of fasting plasma total cholesterol, tri- glyceride, and high-density lipoprotein cholesterol concentrations, none of which requires the use of the preparative ultracentrifuge. Cornparison of this suggested procedure with the more direct procedure, in which the ultracentrifuge is used, yielded correlation coefficients of .94 to .99, de- pending on the patient population compared. Additional Keyph rases hyperlipoproteinemia classifi- cation #{149} determination of plasma total cholesterol, tri- glyceride, high-density lipoprotein cholesterol #{149} beta lipo proteins
Article
Ubiquinone, or coenzyme Q, is a mitochondrial component with antioxidant properties. It has been suggested that ubiquinone therapy may have clinical benefits in some diseases with mitochondrial dysfunction and that the antioxidant effects could be useful, for example, in the prevention of atherosclerosis. Based on this clinical interest, guidelines for the interpretation of ubiquinone analyses are needed. Our results show that serum and muscle ubiquinone levels vary over a wide range in healthy subjects. The serum levels of ubiquinone depend mostly on the amount of ubiquinone-containing lipoproteins in circulation. Physical activity markedly affects muscle tissue levels of ubiquinone. We observed that serum and muscle tissue ubiquinone levels do not correlate with each other, suggesting that they are independently regulated.
Article
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.
Article
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.
Article
In patients with high cholesterol levels, lowering the cholesterol level reduces the risk of coronary events, but the effect of lowering cholesterol levels in the majority of patients with coronary disease, who have average levels, is less clear. In a double-blind trial lasting five years we administered either 40 mg of pravastatin per day or placebo to 4159 patients (3583 men and 576 women) with myocardial infarction who had plasma total cholesterol levels below 240 mg per deciliter (mean, 209) and low-density lipoprotein (LDL) cholesterol levels of 115 to 174 mg per deciliter (mean, 139). The primary end point was a fatal coronary event or a nonfatal myocardial infarction. The frequency of the primary end point was 10.2 percent in the pravastatin group and 13.2 percent in the placebo group, an absolute difference of 3 percentage points and a 24 percent reduction in risk (95 percent confidence interval, 9 to 36 percent; P = 0.003). Coronary bypass surgery was needed in 7.5 percent of the patients in the pravastatin group and 10 percent of those in the placebo group, a 26 percent reduction (P=0.005), and coronary angioplasty was needed in 8.3 percent of the pravastatin group and 10.5 percent of the placebo group, a 23 percent reduction (P=0.01). The frequency of stroke was reduced by 31 percent (P=0.03). There were no significant differences in overall mortality or mortality from noncardiovascular causes. Pravastatin lowered the rate of coronary events more among women than among men. The reduction in coronary events was also greater in patients with higher pretreatment levels of LDL cholesterol. These results demonstrate that the benefit of cholesterol-lowering therapy extends to the majority of patients with coronary disease who have average cholesterol levels.
Article
The long-term safety profile of simvastatin, established over 10 years of clinical use, is excellent. The principal adverse effect of all inhibitors of hydroxymethylglutarate co-enzyme A (HMG-CoA) reductase, myopathy, is infrequent. Simvastatin is a substrate for cytochrome P450 3A4 (CYP3A4). CYP3A4 inhibitors can elevate the plasma concentration of HMG-CoA reductase inhibitory activity derived from simvastatin. Clinical experience has shown that concomitant use of potent inhibitors of CYP3A4 increase the risk for myopathy. Evaluation of data from clinical trials and postmarketing surveillance allows assessment of whether concomitant use of weaker CYP3A4 inhibitors, as represented by calcium channel blockers, has any effect on the risk of myopathy. Cases of myopathy in long-term clinical megatrials and in analyses of postmarketing adverse event reports have been surveyed. In megatrials with simvastatin, the overall incidence of myopathy was 0.025%. The proportion of patients developing myopathy who were taking a calcium channel blocker with simvastatin (1 of 3) was similar to the proportion of patients taking a calcium channel blocker overall. Among marketed-use adverse event reports, concomitant medication with a potent CYP3A4 inhibitor was more frequent among reports of myopathy than among reports of nonmusculoskeletal adverse events. No excess use of calcium channel blockers among myopathy reports was observed. We conclude that the overall risk of myopathy during treatment with simvastatin is very low. Potent CYP3A4 inhibitors, especially cyclosporine, significantly increase the risk. There is no evidence that weaker CYP3A4 inhibitors such as calcium channel blockers increase the risk.
Article
Elevated levels of low-density lipoprotein (LDL) cholesterol promote the development of atherosclerosis and coronary heart disease. Simvastatin 80 mg/day will be more effective than simvastatin 40 mg/day at reducing LDL cholesterol and will be well tolerated. Two similar, randomized, multicenter, controlled, double-blind, parallel-group, 48-week studies were performed to evaluate the long-term lipid-altering efficacy and safety of simvastatin 80 mg/day in patients with hypercholesterolemia. One study conducted in the US enrolled patients meeting the National Cholesterol Education Program (NCEP) LDL cholesterol criteria for pharmacologic treatment. In the other multinational study, patients with LDL cholesterol levels > or = 4.2 mmol/l were enrolled. At 20 centers in the US and 19 countries world-wide, 1,105 hypercholesterolemic patients, while on a lipid-lowering diet, were randomly assigned at a ratio of 2:3 to receive simvastatin 40 mg (n = 436) or 80 mg (n = 669) once daily for 24 weeks. Those patients completing an initial 24-week base study were enrolled in a 24-week blinded extension. Patients who had started on the 80 mg dose in the base study continued on the same dose in the extension, while those who had started on the 40 mg dose were rerandomized at a 1:1 ratio to simvastatin 40 or 80 mg in the extension. There was a significant advantage in the LDL cholesterol-lowering effect of the 80 mg dose compared with that of the 40 mg dose, which was maintained over the 48 weeks of treatment. The mean percentage reductions (95% confidence intervals) from baseline in LDL cholesterol for the 40 and 80 mg groups were 41% (42, 39) and 47% (48, 46), respectively, for the 24-week base study, and 41% (43, 39) and 46% (47, 45), respectively, after 48 weeks of treatment (p < 0.001 between groups). Larger reductions in total cholesterol and triglycerides were also observed with the 80 mg dose compared with the 40 mg dose at Weeks 24 and 48. Both doses were well tolerated, with close to 95% of patients enrolled completing the entire 48 weeks of treatment. Myopathy (muscle symptoms plus creatine kinase increase > 10 fold upper limit of normal) and clinically significant hepatic transaminase increases (> 3 times the upper limit of normal) occurred infrequently with both doses. There was no significant difference between the groups in the number of patients with such increases, although there were more cases for both with the 80 mg dose. Compared with the 40 mg dose, simvastatin 80 mg produced greater reductions in LDL cholesterol, total cholesterol, and triglycerides. Both doses were well tolerated.
Article
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors specifically inhibit HMG-CoA reductase in the liver, thereby inhibiting the biosynthesis of cholesterol. These drugs significantly reduce plasma cholesterol level and long term treatment reduces morbidity and mortality associated with coronary heart disease. The tolerability of these drugs during long term administration is an important issue. Adverse reactions involving skeletal muscle are not uncommon, and sometimes serious adverse reactions involving skeletal muscle such as myopathy and rhabdomyolysis may occur, requiring discontinuation of the drug. Occasionally, arthralgia, alone or in association with myalgia, has been reported. In this article we review scientific data provided via Medline, adverse drug reaction case reports from the Swedish Drug Information System (SWEDIS) and the World Health Organization’s International Drug Information System (INTDIS) database, focusing on HMG-CoA reductase inhibitor-related musculoskeletal system events. Cytochrome P450 (CYP) 3A4 is the main isoenzyme involved in the metabolic transformation of HMG-CoA reductase inhibitors. Individuals with both low hepatic and low gastrointestinal tract levels of CYP3A4 expression may be at in increased risk of myotoxicity due to potentially higher HMG-CoA reductase inhibitor plasma concentrations. The reported incidence of myotoxic reactions in patients treated with this drug class varies from 1 to 7% and varies between different agents. The risk of these serious adverse reactions is dose-dependent and may increase when HMG-CoA reductase inhibitors are prescribed concomitantly with drugs that inhibit their metabolism, such as itraconazole, cyclosporin, erythromycin and nefazodone. Electrolyte disturbances, infections, major trauma, hypoxia as well as drugs of abuse may increase the risk of myotoxicity. It is important that the potentially serious adverse reactions are recognised and correctly diagnosed so that the HMG-CoA reductase inhibitor may at once be withdrawn to prevent further muscular damage.
Article
Rosuvastatin (formerly ZD4522) is a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) with distinct pharmacologic properties. Compared with most other statins, it is relatively hydrophilic, similar in this respect to pravastatin. Rosuvastatin has been shown to be a comparatively potent inhibitor of HMG-CoA reductase activity in a purified preparation of the catalytic domain of the human enzyme, as well as in rat and human hepatic microsomes. In rat hepatocytes, rosuvastatin was found to have significantly higher potency as an inhibitor of cholesterol synthesis than 5 other statins. Rosuvastatin was approximately 1,000-fold more potent in rat hepatocytes than in rat fibroblasts. Further studies in rat hepatocytes demonstrated that rosuvastatin is taken up into these cells by a high-affinity active uptake process. Rosuvastatin was also taken up selectively into the liver after intravenous administration in rats. Potent and prolonged HMG-CoA reductase inhibitory activity has been demonstrated after oral administration to rats and dogs. Pharmacokinetic studies in humans using oral doses of 5 to 80 mg showed that maximum plasma concentrations and areas under the concentration-time curve are approximately linear with dose. The terminal half-life is approximately 20 hours. Studies with human hepatic microsomes and human hepatocytes have suggested little or no metabolism via the cytochrome P-450 3A4 isoenzyme. On the basis of these observations, it is suggested that rosuvastatin has the potential to exert a profound effect on atherogenic lipoproteins.
Article
Cardiovascular disease (CVD) is the leading cause of death in the USA and other industrialized countries. A large number of epidemiological studies have established a direct correlation between diet and the development and progression of atherosclerosis. Several studies have shown the incidence of CVD to be lower in populations consuming a predominantly plant-based diet, as compared to meat-based diets. Besides being low in fat and cholesterol, vegetarian and Asian diets contain a large variety of phytochemicals, which may function in the body. For example, phytosterols (PS) are plant sterols that interfere with the absorption of cholesterol from the intestine when present in adequate amounts. Although PS may also function at a cellular level in the body, there are few studies examining the action of PS on cells involved in atherosclerosis. The purpose of this study was to examine the effect of dietary PS on vascular smooth muscle cell (VSMC) growth and function, since VSMC play a central role in the development of atherosclerosis. VSMC were treated with 16 microM cholesterol, 25-hydroxycholesterol, campesterol and beta-sitosterol (SIT) using an ethanol as a vehicle. Cell growth was determined by cell counting and cell proliferation by DNA synthesis, which was measured by [(3)H]-thymidine incorporation. Cholesterol supplementation had no effect on cell growth and proliferation. 25-Hydroxycholesterol decreased cell growth by 68% and DNA synthesis by 99%. SIT was found to inhibit VSMC growth more effectively than campesterol. Of the two PS, campesterol decreased cell growth by 16% and SIT decreased cell growth by 30%. DNA synthesis was decreased 25% by SIT supplementation but was not influenced by campesterol or cholesterol supplementation. Cholesterol, campesterol and SIT were not cytotoxic to VSMC and did not significantly alter cell viability. 25-Hydroxycholesterol, however, was cytotoxic and decreased cell viability by 45% as determined by lactate dehydrogenase release and a trypan blue dye exclusion test. De novo cholesterol synthesis was decreased 28% by campesterol, 49% by SIT and 23% by cholesterol. Beta-sitosterol exhibited a greater effect on cholesterol synthesis than campesterol or cholesterol supplementation. Measurement of cell sterol content demonstrated incorporation of PS into VSMC at the expense of cholesterol. Campesterol decreased VSMC cholesterol content by 36%, representing 40% of the total sterol content following treatment. Beta-sitosterol decreased VSMC cholesterol by 41% following supplementation and represented 49% of the total sterol amount. Cholesterol treatment did not alter the cholesterol content of the cells. Prostacyclin production was significantly altered by PS treatment. Basal prostacyclin release was increased 43% by campesterol and 81% by SIT. A23187 stimulated prostacyclin release was increased 25% by campesterol and 54% by SIT. SIT supplementation induced a greater effect on prostacyclin release from VSMC than cholesterol or campesterol supplementation. The in vitro results presented here suggest that dietary PS, especially SIT, may offer protection from the VSMC hyperproliferation found in atherosclerosis. Further in vivo research is needed to support these observations.
Article
Sitosterolemia is a rare, recessively inherited disease characterized clinically by accelerated atherosclerosis and xanthomas and biochemically by hyperabsorption and retention of sitosterol and other plant sterols in tissues. Decreased cholesterol biosynthesis and inhibition of 3-hydroxy-3-methylgluratyl coenzyme A (HMG-CoA) reductase and other enzymes in the biosynthetic pathway have been associated with enhanced low-density lipoprotein (LDL) receptor function. We examined the effects of cholesterol and sitosterol on sterol concentrations and composition and HMG-CoA reductase activity in monocyte-derived macrophages (MDM) from 12 control and 3 homozygous sitosterolemic subjects. The cells were cultured up to 7 days in media devoid of plant sterols, but containing increasing amounts of serum cholesterol. Before culture, MDM from the homozygous sitosterolemic subjects contained 22% more total sterols than cells from control subjects. Plant sterols and stanols represented 15.6% of MDM total sterols in sitosterolemic cells, but only 3.8% in control cells. After 7 days of culture in 10% delipidated serum (DLS) (20 microg/mL cholesterol, no sitosterol), all plant sterols were eliminated so that cells from both phenotypes contained only cholesterol. When DLS was replaced with fetal bovine serum (FBS) (300 micromL cholesterol), with and without addition of 200 microg/mL LDL, cholesterol levels in MDM from sitosterolemic subjects increased 108% (P <.05) compared with a 65% increase (P <.04) in control MDM cultured similarly. MDM HMG-CoA reductase activity from the 3 sitosterolemic subjects, which was significantly lower than controls at baseline (24 +/- 3 v 60 +/- 10 pmol/mg/min, P <.05), was not downregulated by increased cellular cholesterol levels, as observed in control cells. Control MDM were also cultured in medium that contained 10% DLS and was supplemented with 100 microg/mL cholesterol or sitosterol dissolved in ethanol or the ethanol vehicle alone. In contrast to cellular cholesterol accumulation, which significantly downregulated HMG-CoA reductase activity (-53%, P <.05), the increase in cellular sitosterol up to 25.1% of total sterols did not change MDM HMG-CoA reductase activity. Evidence of a normal HMG-CoA reductase protein in sitosterolemic cells, which was not derepressed upon removal of cellular sitosterol, and the failure of cellular sitosterol to inhibit normal HMG-CoA reductase activity argue against feedback inhibition by sitosterol as a mechanism for low reductase activity in this disease. The larger accumulation of sterols and inadequate downregulation of HMG-CoA reductase in MDM may be mechanisms for foam cell formation and explain, in part, the increased risk of atherosclerosis in sitosterolemia.
Article
Catalytic activity of oxidative phosphorylation complexes is maintained following separation by Blue Native polyacrylamide gel electrophoresis (BN-PAGE). In BN-PAGE gels, using histochemical staining methods, we have demonstrated enzymatic activity of the complexes I, II, IV, and V in heart and skeletal muscle, liver, and cultured skin fibroblasts. The combination of BN-PAGE and catalytic staining can be successfully applied for detection of complex deficiencies. Tissues from 18 patients with deficiency in the oxidative phosphorylation as detected by spectrophotometric assay were used (10 patients complex IV, three patients complex I, one patient complex II, one patient complex I+III, three patients complex I+IV). The gene defect was located in nuclear DNA in five patients and mitochondrial DNA in one patient. In samples from patients with a severe deficiency, almost complete absence of the corresponding enzyme band is observed after catalytic staining in the gel. In patients with known partial deficiency, a milder decrease of the corresponding enzyme band is demonstrated. The amount of protein in complexes I, V, and III can easily be evaluated in samples from heart and skeletal muscle after separation by BN-PAGE using silver or Coomassie staining. The protein amount in complex IV is difficult to visualize by silver staining but easier by the Coomassie technique. In samples from liver and cultured skin fibroblasts, evaluation of protein amount is more difficult due to high background staining. In these tissues, immunoblotting can be done after BN-PAGE and subsequent transfer to a nitrocellulose membrane.
Article
Previous studies have shown that patients with early onset of Alzheimer disease and vascular dementia have higher levels of circulating brain-derived 24S-hydroxycholesterol (cerebrosterol). Two recent epidemiological studies indicated that treatment with inhibitors of cholesterol synthesis (statins) reduces the incidence of Alzheimer disease. To test the hypothesis that treatment with high-dosage simvastatin reduces circulating levels of 24S-hydroxycholesterol. Prospective, 24-week treatment trial for lowering of cholesterol levels. We conducted assessments at baseline, week 6, and week 24. An academic outpatient clinical study. Eighteen patients who met the criteria for hypercholesterolemia. Treatment with 80 mg/d of simvastatin at night. Plasma lipoprotein levels were measured enzymatically; lathosterol, by means of gas chromatography; and 24S-hydroxycholesterol, by means of gas chromatography-mass spectrometry. Simvastatin reduced total plasma cholesterol levels by 36% and 35% after 6 and 24 weeks, respectively (P<.001). Lathosterol levels were reduced by 74% and 72%, respectively, and the ratio of lathosterol to cholesterol, an indicator of whole-body cholesterol synthesis, was reduced by 60% and 61%, respectively (P<.001). Plasma 24S-hydroxycholesterol levels were lowered by 45% and 53%, respectively (P<.001). The ratio of 24S-hydroxycholesterol to cholesterol also decreased significantly (-12% [P=.01] and -23% [P<.002], respectively). The further reduction of 24S-hydroxycholesterol levels and its ratio to cholesterol from weeks 6 to 24 was also significant (P=.02 for both). The greater reduction of plasma concentrations of 24S-hydroxycholesterol compared with cholesterol indicates that simvastatin in a dosage of 80 mg/d reduces cholesterol turnover in the brain. The present results might describe a possible mechanism of how long-term treatment with statins could reduce the incidence of Alzheimer disease.
Article
The 3-hydroxy-3-methyl coenzyme A (HMG-CoA) reductase inhibitors or statins, specifically inhibit the enzyme HMG-CoA in the liver, thereby inhibiting the rate limiting step in cholesterol biosynthesis and so reducing plasma cholesterol levels. Numerous studies have consistently demonstrated that cholesterol lowering with statin therapy reduces morbidity and mortality from coronary heart disease, whilst recent evidence has demonstrated that benefits of statin therapy may also extend into stroke prevention. Since hypercholesterolaemia is a chronic condition, the long-term safety and tolerability of these agents is an important issue. Numerous large-scale clinical trials have consistently demonstrated a positive safety and tolerability profile for statins. Hepatic, renal and muscular systems are rarely affected during statin therapy, with adverse reactions involving skeletal muscle being the most common, ranging from mild myopathy to myositis and occasionally to rhabdomyolysis and death. Postmarketing data supports the positive safety and tolerability profile of statins, with an overall adverse event frequency of less than 0.5% and a myotoxicity event rate of less than 0.1%. The recent withdrawal of cerivastatin from the world market due to deaths from rhabdomyolysis has, however, focused attention on the risk of adverse events and in particular myotoxicity associated with statins. Indeed, initial clinical trial data supports postmarketing data, demonstrating a higher incidence of myotoxicity associated with cerivastatin, particularly when used in combination with fibrates. The potential mechanisms underlying statin-induced myotoxicity are complex with no clear consensus of opinion. Candidate mechanisms include intracellular depletion of essential metabolites and destabilisation of cell membranes, resulting in increased cytotoxicity. Cytochrome P450 3A4 is the main isoenzyme involved in statin metabolism. Reduced activity of this enzyme due to either reduced expression or inhibition by other drugs prescribed concomitantly such as cyclosporin or itraconazole may increase drug bioavailability and the risk of myotoxicity. Such factors may partly account for the interindividual variability in susceptibility to statin-induced myotoxicity, although other as of yet unclarified, genetic factors may also be involved. The risk of rhabdomyolysis is increased with combination fibrate-statin therapy, with initial evidence suggesting that gemfibrozil-statin combination may particularly increase the risk of myotoxicity, with pharmacodynamic as well as pharmacokinetic mechanisms being involved.