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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 CoQ 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.
Cardiovascular disease CVD is the leading cause of death in the United States, affecting 1 in 3 or High rates of statin discontinuation or nonadherence because of muscle complaints emphasize the need to Coq10 half life the mechanisms producing SAMS, as suboptimal statin use increases healthcare costs by increasing the risk of cardiac events 5—7 and increasing the use of more expensive medications, such as proprotein convertase subtilisin kexin type 9 PCSK9 inhibitors.
This review will discuss why CoQ10 depletion has been suggested as a cause of SAMS and the of clinical trials testing this hypothesis. Statin-associated side effects. Reprinted from reference 11 with permission. CoQ10 is a naturally occurring, fat-soluble coenzyme that resides in the hydrophobic portions of mammalian cellular membranes Approximately half of the body's supply of CoQ10 is obtained by endogenous synthesis and half by fat consumption CoQ10 plays a key role in energy production via mitochondrial electron transport during oxidative phosphorylation.
CoQ10 can carry 1 or 2 electrons through the transport chain 13so can be fully oxidized, partially oxidized, or fully reduced as ubiquinone, ubisemiquinone, or ubiquinol, respectively. CoQ10 also acts as an antioxidant by scavenging free radicals. CoQ10 is concentrated in the cells of organs with the highest energy requirements, such as the kidney, liver, and heart CoQ10 depletion is a logical candidate as a cause of statin myopathy for the following reasons: Statins alter lipid metabolism by inhibiting HMG-CoA reductase, the rate-limiting enzyme responsible for the synthesis of cholesterol in the mevalonate pathway.
This pathway also produces isoprenylated proteins and CoQ10 Figure 2. CoQ10 is a critical enzyme in mitochondrial energy production, and some evidence suggests that mitochondrial dysfunction contributes to SAMS. Muscle biopsies in 3 patients with SAMS and normal creatine kinase CK concentrations demonstrated histopathology findings consistent with mitochondrial dysfunction, including ragged red fibers, Coq10 half life intramuscular lipid, and reduced cytochrome oxidase staining.
The latter indicates lower mitochondrial function, as cytochrome oxidase is an important metabolic enzyme in mitochondria Statins may also lessen the increase in mitochondrial function produced by exercise training Mitochondrial complexes I, II, III, and IV increased with exercise training in the exercise-only group but not in the exercise training and statin group.
Similar reductions in the mitochondrial response to exercise training have been demonstrated in mice 17 treated with simvastatin. The blood CoQ10 concentration decreases during statin therapy.
The biological ificance of these decreases in CoQ10 concentrations Coq10 half life not clear. Muscle biopsy studies have shown reductions in intramuscular CoQ10 during statin therapy in some 19but not all, studies 20— CoQ10 is a mitochondrial protein, so other factors, such as myalgia from statin use, could decrease physical activity, which would reduce the muscle mitochondrial content and lower the CoQ10 concentrations. This makes it impossible to determine whether statin therapy produces CoQ10 depletion, leading to mitochondrial dysfunction and SAMS, or whether SAMS lead to reduced physical activity, reduced muscle mitochondria, and reduced CoQ10 concentrations.
The latter could explain why only a small of patients treated with statin therapy experience SAMS, despite the much more-universal decreases in circulating CoQ10 that occur with statin therapy. The CoQ2 gene encodes for para-hydroxybenzoate-polyprenyl transferase, the second enzyme in the CoQ10 synthetic pathway A genetic comparison of statin-intolerant and statin-tolerant subjects found that the ORs were 2.
We compared the frequency of 31 candidate genes for statin myopathy in patients with SAMS and asymptomatic statin-treated patients CoQ2 was also identified as possibly contributing to SAMS in a hypothesis-free, genome-wide association study in the same subjects This study examinedsingle nucleotide polymorphisms; because of the large of comparisons performed, none were ificantly different between the groups, including CoQ2.
Five of these trials, involving a total of patients, were evaluated by meta-analysis There are no diagnostic tests for SAMS, so it is unclear in these studies which subjects actually had muscle complaints owing to statins. We recruited subjects with a history of SAMS from our cholesterol management clinic.
Definite SAMS was diagnosed using a prestudy, run-in protocol. Subjects then entered a 4-wk no-treatment washout phase before being ased to the alternative treatment; subjects who were randomly ased to receive simvastatin first were crossed over to placebo, and vice versa. We recruited subjects; however, 43 Only However, This protocol was deed to select only individuals with confirmed myalgia for the CoQ10 treatment arm of the study. We sought to ensure adequate tissue concentrations throughout the trial, as this was a criticism of the prior studies.
We measured muscle pain according to the Brief Pain Inventory, time to pain onset, arm and leg muscle strength, and maximal oxygen uptake before and after each treatment.
Serum CoQ10 increased from 1. The goal in managing patients with SAMS is to get the patient on the highest tolerated statin dose, as statins are life-saving medications, and to combine statin treatment with other agents that lower LDL cholesterol and reduce atherosclerotic CVD risk Patients should be reassured that SAMS resolve with statin cessation.
Statin-induced necrotizing myositis is rare, with a prevalence of 1 in Many patients Coq10 half life able to tolerate the drugs once they know that their symptoms will resolve with cessation. We measure CK concentrations in all patients to document muscle injury if present and to ensure that patients who are willing to tolerate their symptoms do not have ificant muscle injury.
We also measure vitamin D concentrations, as low vitamin D concentrations have been associated with statin myopathy 27 ; to our knowledge, however, there are no randomized, placebo-controlled studies documenting that treating low vitamin D reduces SAMS. We then stop the statin until the patient is asymptomatic. Failure of the symptoms to resolve after 2—3 mo in a patient with a normal CK concentration argues against the statin as the cause of the symptoms.
Once the patient is asymptomatic, we try the same statin at a lower dose or try another statin. We often combine the lower dose statin with ezetimibe or use ezetimibe alone in patients unable to tolerate any statin. Red rice yeast is less effective than pharmacologic-grade statins and has a variable effect because of variability in its statin content.
Statins with longer half-lives, such as atorvastatin, rosuvastatin, and pitavastatin, can be used every other day or even twice weekly, and are often well tolerated in patients with prior SAMS. We also use other agents, such as the new PCSK9 inhibitors, in patients who qualify for these drugs. CoQ10 administration remains a popular therapy for treatment of SAMS among both physicians and the lay public, with 1. Despite the lack of effect in our and other studies, we also occasionally recommend CoQ10 supplementation to patients who inquire about it or in whom we question if statins are the cause of their symptoms.
This approach works well in some patients, but may simply be a placebo effect It should be mentioned that CoQ10 is influenced by dietary factors, such as dietary fat consumption, vitamin E supplementation, and alcohol intake, and may influence the Coq10 half life of CoQ10 Coq10 half life in patients with SAMS; however, this possibility has not been comprehensively explored in research studies.
Food sources with the highest concentrations of CoQ10 include organ meats, beef, pork, fatty fishes, chicken, and nuts Further, an additional uncertainty associated with supplementation of CoQ10 for the treatment of SAMS is whether oral administration of ubiquinone or its reduced form, ubiquinol, augments skeletal muscle CoQ10 to the same extent.
Despite this, data from human studies indicate that the effectiveness of CoQ10 for the treatment of SAMS is not affected by the redox status of CoQ10 This experience with CoQ10 provides 3 potentially useful lessons for research and clinical practice. First, a hypothesis deemed possible by several lines of deductive reasoning may still be wrong when tested in carefully conducted clinical trials. Second, it is critically important to determine that subjects enrolled in a clinical trial of a certain condition, in this case SAMS, actually have the phenotype to be examined.
Third, even when scientific studies demonstrate that any intervention is ineffective, the intervention, in this case CoQ10, may still be useful in some patients, perhaps through the placebo effect. Mechanistic studies and deductive reasoning suggest that CoQ10 dysregulation could be the cause, or could at least contribute, to SAMS. Clinical studies, however, have not documented its effectiveness in treating SAMS. Published in a supplement to Advances in Nutrition. The conference was organized by Columbia University's Institute of Human Nutrition its contents are solely the responsibility of the authors and do not necessarily represent the official views of Columbia Universityand with the aid of an unrestricted grant from Pharmavite, LLC.
The Supplement Coordinator for this supplement was Densie Webb. Supplement Coordinator disclosure: Densie Webb was compensated for overseeing the development and publication of the supplement. Airfare and hotel to attend the conference in New York were Coq10 half life, in addition to payment for work completed. Publication costs for this supplement were defrayed in part by the payment of charges. This publication must therefore be hereby marked "advertisement" in accordance with 18 USC section solely to indicate this fact. The opinions expressed in this publication are those of the author s and are not attributable to the sponsors or the publisher, Editor, or Editorial Board of Advances in Nutrition.
Author disclosures: ALZ, no conflicts of interest. Abbreviations used: CVD cardiovascular disease. Circulation ; 10 : e — Google Scholar. Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges. Curr Atheroscler Rep ; 14 1 : 1 — Circulation ; 25 Suppl 2 : S1 — Application of new cholesterol guidelines to a population-based sample. N Engl J Med ; 15 : — J Clin Lipidol ; 6 3 : — Discontinuation of statin therapy due to muscular side effects: a survey in real life. Nutr Metab Cardiovasc Dis ; 23 9 : — 5.
Adherence to cardiovascular therapy: a meta-analysis of prevalence and clinical consequences. Eur Heart J ; 34 38 : — 8.Coq10 half life
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