Statin Myopathy Research Articles

A novel investigation of statins myotoxic mechanism: effect of atorvastatin on respiratory muscles in hypoxic environment

Myopathy is a well-known adverse effect of statins, affecting a large sector of statins users. The reported experimental data emphasized on mechanistic study of statin myopathy on large muscles. Clinically, both large muscles and respiratory muscles are reported to be involved in the myotoxic profile of statins. However, the experimental data investigating the myopathic mechanism on respiratory muscles are still lacking. The present work aimed to study the effect of atorvastatin treatment on respiratory muscles using rat isolated hemidiaphragm in normoxic & hypoxic conditions. The contractile activity of isolated hemidiaphragm in rats treated with atorvastatin for 21 days was investigated using nerve stimulated technique. Muscle twitches, train of four and tetanic stimulation was measured in normoxic, hypoxic and reoxygenation conditions. Atorvastatin significantly increased the tetanic fade, a measure of muscle fatigability, in hypoxic conditions. Upon reoxygenation, rat hemidiaphragm regains its normal contractile profile. Co-treatment with coenzyme Q10 showed significant improvement in defective diaphragmatic contractility in hypoxic conditions. This work showed that atorvastatin treatment rapidly deteriorates diaphragmatic activity in low oxygen environment. The mitochondrial respiratory dysfunction is probably the mechanism behind such finding. This was supported by the improvement of muscle contractile activity following CoQ10 co-treatment.

Statin-associated immune-mediated necrotizing myopathy: a retrospective analysis of individual case safety reports from VigiBase.

Statins represent an effective treatment for hyperlipidaemia. Immune-mediated necrotising myopathy (IMNM), a form of statin myopathy, has recently been described, and is characterized by elevated creatine kinase, presence of antibodies against HMG-CoA and no improvement after drug discontinuation, even with immunosuppressive treatment. Information on IMNM is mainly from case reports and small case series. Therefore, all reported cases of IMNM in VigiBase, the WHO global database of individual case safety reports (ICSRs) including the underlying reporting patterns, were analysed to characterize more detailed this adverse drug reaction. ICSRs of IMNM up to October 1, 2016 were extracted from VigiBase. Corresponding case narratives were requested from responsible national authorities to maximize the available data. The reports were analysed in terms of reporting criteria, co-reported terms, patient demographics, clinical data, administered medication, latency time, seriousness of the reaction and outcome. One hundred one deduplicated ICSRs of IMNM were reported from 17 countriesuntil October 2016. Approximately two thirds of the cases were from the year 2016. Slightly more males than females were affected (52 [57%] males vs 39 [42%] females). Median reported patient age was 68years (range 16 - 87years). Ninety-one cases (99%) were classified as serious. Median latency time was 26months (range 1 - 288months). Median creatine kinase value was 6860U/L (range 576 - 35,000U/L). In total, eight patients (9%) had recovered from IMNM. Atorvastatin was the most frequently reported statin in 80% of cases. The number of IMNM reports has increased in recent years. IMNM associated with statin treatment seems to occur worldwide. Most IMNM cases were reported with atorvastatin. No dose dependency of statin-associated IMNM pathogenesis was identified.

Newer evidences and recommendations in lipidology

The correlation between cholesterol and risk reduction is unique: no J curve is seen even at extreme low levels. According to PRECISE-IVUS, the effect of intensive cholesterol lowering on plaque regression is more pronounced post-myocardial infarction syndrome than in chronic coronary disease. The importance of LDL-C lowering with ezetimibe in IMPROVE-IT (1.4 mmol/L compared to 1.8 mmol/L in the statin monotherapy arm) is expressed in several international guidelines and the indication spectrum of combination cholesterol lowering has broadened and strengthened. There is a strong evidence that myalgia during statin treatment is generally not caused by statins and it is not related to type or dose of the drug. With patience, the majority of patients can be made to become statin takers even with good quality of life; for those who cannot, ezetimibe monotherapy can be an alternative. Even though intensive cholesterol lowering is safe, avoiding statin myopathy should be emphasized. Despite the outstanding efficacy and safety of cholesterol lowering, Hungarian statin sales have decreased recently, in which driven dilettante public climate around the products may be of utmost importance. Everyone of us should counteract this according to the possibilities. Orv Hetil. 2018; 159(32): 1303-1309.

Dietary Supplements and Cardiovascular Diseases.

The market of nutritional supplements is expected to expand over 6%/year through 2018 due to growing interest in personal health, aging population, and promising personalized care products. The most used dietary supplements are fish oil, multivitamins, Vitamin D, and coenzyme Q10 (CoQ10) in this order, while probiotics is the fastest growing supplement. In the U.S., over 68% of the population use dietary supplements regularly. On the other hand, in the developed countries, cardiovascular diseases (CVDs) are the main cause of death and morbidity from the 1900s. The effects of most dietary supplements on cardiovascular risk and CVD have been studied for a long time. However, despite several studies explored the association of the various supplements to the cardiovascular risk, there is still a lack of consensus. Multivitamin supplementation has been advocated to reduce cardiovascular events; Vitamin D levels have been associated with the occurrence of coronary artery disease, heart failure, and atrial fibrillation; CoQ10 deficiency has been associated with myocardial dysfunction and with statin myopathy; probiotoics has been suggested to lower both blood pressure and circulating lipids. However, the study of the effects of dietary supplementations is not straightforward, since people assuming dietary supplements generally have a healthier diet and lifestyle, and randomized studies are rarely performed. In this review, we will summarize the findings linking dietary supplements to CVD with a special focus on novel insights.

Study protocol for statin web-based investigation of side effects (StatinWISE): a series of randomised controlled N-of-1 trials comparing atorvastatin and placebo in UK primary care

IntroductionStatins are effective at preventing cardiovascular disease, widely prescribed and their use is growing. Uncertainty persists about whether they cause symptomatic muscle adverse effects, such as pain and weakness, in...

Which nonautoimmune myopathies are most frequently misdiagnosed as myositis?

To discuss the spectrum of nonautoimmune myopathies that may be misdiagnosed as autoimmune myopathy. Inherited myopathies, such as dysferlinopathy, calpainopathy, and facioscapulohumeral dystrophy may be misdiagnosed as autoimmune myopathy, especially when they have inflammatory muscle biopsies. Inclusion body myositis is frequently misdiagnosed as polymyositis when rimmed vacuoles are absent on muscle biopsy, and a careful neuromuscular evaluation is not performed. Hypothyroid myopathy can be misdiagnosed as immune-mediated necrotizing myopathy if thyroid function tests, including a T4 level, are not obtained. Self-limited statin myopathy can be distinguished from statin-associated autoimmune myopathy because patients with the former do not have autoantibodies recognizing 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Autoimmune myopathies can usually be distinguished from nonautoimmune myopathies based on a combination of the patient history, neuromuscular exam, laboratory findings, and/or muscle biopsy features.

Statins Affect Skeletal Muscle Performance: Evidence for Disturbances in Energy Metabolism.

Statin myopathy is linked to disturbances in mitochondrial function and exercise intolerance. To determine whether differences exist in exercise performance, muscle function, and muscle mitochondrial oxidative capacity and content between symptomatic and asymptomatic statin users, and control subjects. Cross-sectional study. Department of Physiology, Radboud University Medical Center. Long-term symptomatic and asymptomatic statin users, and control subjects (n = 10 per group). Maximal incremental cycling tests, involuntary electrically stimulated isometric quadriceps-muscle contractions, and biopsy of vastus lateralis muscle. Maximal exercise capacity, substrate use during exercise, muscle function, and mitochondrial energy metabolism. Peak oxygen uptake, maximal work load, and ventilatory efficiency were comparable between groups, but both statin groups had a depressed anaerobic threshold compared with the control group (P = 0.01). Muscle relaxation time was prolonged in both statin groups compared with the control group and rate of maximal force rise was decreased (Ptime×group < 0.001 for both measures). Mitochondrial activity of complexes II and IV was lower in symptomatic statin users than control subjects and tended to be lower for complex (C) III (CII: P = 0.03; CIII: P = 0.05; CIV: P = 0.04). Mitochondrial content tended to be lower in both statin groups than in control subjects. Statin use attenuated substrate use during maximal exercise performance, induced muscle fatigue during repeated muscle contractions, and decreased muscle mitochondrial oxidative capacity. This suggests disturbances in mitochondrial oxidative capacity occur with statin use even in patients without statin-induced muscle complaints.

PCSK9 in context: A contemporary review of an important biological target for the prevention and treatment of atherosclerotic cardiovascular disease.

The identification of the critical role of proprotein convertase subtilisin/kexin type 9 (PCSK9) has rapidly led to the development of PCSK9 inhibition with monoclonal antibodies (mAbs). PCSK9 mAbs are already in limited clinical use and are the subject of major cardiovascular outcomes trials, which, if universally positive, could see much wider clinical application of these agents. Patients with familial hypercholesterolaemia are the most obvious candidates for these drugs, but other patients with elevated cardiovascular risk, statin intolerance or hyperlipoproteinaemia(a) may also benefit. PCSK9 mAbs, administered once or twice monthly, reduce LDL cholesterol levels by 50% to 70%, and appear to be safe and acceptable to patients over at least 2 years of treatment; however, treatment-emergent adverse effects are not always identified in clinical trials, as well-evidenced by statin myopathy. Inclisiran is a promising RNA-based therapy that promotes the degradation of PCSK9 mRNA transcripts and has similar efficacy to mAbs, but with a much longer duration of action. The cost-effectiveness and long-term safety of therapies targeted at inhibiting PCSK9 remain to be demonstrated if they are to be used widely in coronary prevention.

Management of statin myopathy

Management of statin myopathy

Statin-associated immune-mediated myopathy: biology and clinical implications.

In the last 6 years, our understanding of statin-associated myopathy expanded to include not only a toxic myopathy with limited and reversible side-effects but also an autoimmune variety in which statins likely induce an autoimmune myopathy that is both associated with a specific autoantibody and responsive to immunosuppression and immune modulation. This review widens the reader's understanding of statin myopathy to include an autoimmune process. Statin-associated immune-mediated myopathy provides an example of an environmental trigger (statins) directly implicated in an autoimmune disease associated with a genetic predisposition as well as potential risk factors including concomitant diseases and specific statins. Given a median exposure to statins of 38 months, providers should be aware that anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) myopathy may occur even after several years of statin exposure. It is important for the reader to understand the clinical presentation of statin-associated immune-mediated myopathy and the difference in its clinical presentation to that of statins as direct myotoxins. Prompt recognition of such an entity allows the clinician to immediately stop the offending agent if it has not already been discontinued as well as to recognize that statin rechallenge is not a likely option, and that prompt treatment with immunosuppression and/or immunomodulation is usually of enormous benefit to the patient in restoring muscle strength and physical function. VIDEO ABSTRACT.

Statin-induced Myopathy

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide. HMGCoA reductase inhibitors or “statins” reduce low density lipoprotein cholesterol and reduce the risks of myocardial infarction, stroke and death in the presence of dyslipidaemia. In consequence, statins are prescribed to a large number of patients requiring primary or secondary prevention. A variety of side-effects may arise during the course of statin treatment which interfere with the quality of patients’ lives and reduce their compliance with therapy. Muscle symptoms constitute the most common of these side-effects and are the most frequent reason for discontinuing treatment. This review defi nes the muscle, tendon and joint disorders encountered by patients on statin treatment, their possible relationship to statin use, and the factors that facilitate the emergence of symptoms. The subtypes of statin myopathy are discussed and a general defi nition of statin myopathy is offered. Expert advice on managing statin myopathy is summarised.

Development and validation of algorithms for the detection of statin myopathy signals from electronic medical records.

The purpose of this study was to develop and validate sensitive algorithms to detect hospitalized statin-induced myopathy (SIM) cases from electronic medical records (EMRs). We developed four algorithms on a training set of 31,211 patient records from a large tertiary hospital. We determined the performance of these algorithms against manually curated records. The best algorithm used a combination of elevated creatine kinase (>4× the upper limit of normal (ULN)), discharge summary, diagnosis, and absence of statin in discharge medications. This algorithm achieved a positive predictive value of 52-71% and a sensitivity of 72-78% on two validation sets of >30,000 records each. Using this algorithm, the incidence of SIM was estimated at 0.18%. This algorithm captured three times more rhabdomyolysis cases than spontaneous reports (95% vs. 30% of manually curated gold standard cases). Our results show the potential power of utilizing data and text mining of EMRs to enhance pharmacovigilance activities.

Use of pharmacogenetic testing to prevent adverse drug reactions during statin therapy

The number of patients receiving statins increases every year and due to the fact that they should take statins during their lives, the problem of their safety use comes to the forefront. The paper analyzes the safety of using the medications of this group and discusses the diagnosis of myopathies induced by statins and the occurrence of immune-mediated statin myopathies. It considers a personalized approach to prescribing statins, analyzes Russian and foreign experience in using pharmacogenetics to reduce the risk of myopathies, publishes the results of the authors' experience in clinically introducing pharmacogenetic testing at hospitals, and analyzes the long-term results of determining the polymorphism of the SLCO1B1 gene for the prediction of the risk of adverse events when using statins and estimating patient compliance to prescribed treatment.

Statin associated myopathy in clinical practice. Results of DAMA study

Background and objectiveMuscle symptoms, with or without elevation of creatine kinase are one of the main adverse effects of statin therapy, a fact that sometimes limits their use. The aim of this study was to evaluate the clinical characteristics of patients treated with statins who have complained muscle symptoms and to identify possible predictive factors. Patients and methodsA cross-sectional one-visit, non-interventional, national multicenter study including patients of both sexes over 18 years of age referred for past or present muscle symptoms associated with statin therapy was conducted. 3845 patients were recruited from a one-day record from 2001 physicians. ResultsMyalgia was present in 78.2% of patients included in the study, myositis in 19.3%, and rhabdomyolysis in 2.5%. Patients reported muscle pain in 77.5% of statin-treated individuals, general weakness 42.7%, and cramps 28.1%. Kidney failure, intense physical exercise, alcohol consumption (>30g/d in men and 20g/d in women) and abdominal obesity were the clinical situations associated with statin myopathy. ConclusionsMyalgia followed by myositis are the most frequent statin-related side effects. It should be recommended control environmental factors such as intense exercise and alcohol intake as well as abdominal obesity and renal function of the patient treated with statins.

Statin Therapy as Primary Prevention in Exercising Adults: Best Evidence for Avoiding Myalgia.

This review aims to determine whether active adults who begin statins and develop myalgia reduce or stop activity to become less symptomatic. If this occurs, strategies to mitigate symptoms are explored. Should these strategies fail, the question of whether exercise is an adequate alternative to statin therapy is addressed. PubMed, Google Scholar, and the Cochrane Database were searched with keywords designed to retrieve information on statin myopathy in exercising adults. Statins are well tolerated by most people who exercise; however, caution is warranted in those who exercise at high levels, in the elderly, and in those receiving high-dose therapy. Several strategies improve statin tolerance while maintaining exercise levels, based on low-quality evidence. If statins are not tolerated, a continuing physical activity program can provide equivalent or superior cardiometabolic protection. Statins may occasionally present a barrier to physical activity. A number of strategies exist that can reduce the risk of myopathy. If a choice between exercise and statins becomes necessary, exercise provides equal benefit in terms of cardiovascular protection and superior mortality reduction, with improved quality of life.

Economic Evaluation of a Pharmacogenomics Test for Statin-Induced Myopathy in Cardiovascular High-Risk Patients Initiating a Statin.

BackgroundStatins are the mainstay hypercholesterolemia treatment and reduce the risk of cardiovascular events in patients. However, statin therapy is often interrupted in patients experiencing musculoskeletal pain or myopathy, which are common in this patient group. Currently, the standard tests for diagnosing statin myopathies are difficult to interpret. A pharmacogenomics (PGx) test to diagnose statin-induced myopathy would be highly desirable.MethodsWe developed a Markov state model to assess the cost-effectiveness of a hypothetical PGx test, which aims to identify statin-induced myopathy in high-risk, secondary prevention cardiovascular patients. The alternative strategy hypothesized is that physicians or patients interrupt the statin therapy in the presence of musculoskeletal pain. Our model includes health states specific to the PGx test outcome which assesses the impact of test errors.ResultsAssuming a perfect test, the results indicate that the PGx test strategy dominates when the test costs less than CAN$356, when the strategy is cost neutral. These results are robust to deterministic and probabilistic sensitivity analyses.ConclusionOur base-case results show that a PGx test for statin-induced myopathy in a high-risk, secondary prevention of a cardiovascular event population would be a dominant solution for a test cost of CAN$356 or less. Furthermore, the modelling of the complete range of diagnostic test outcomes provide a broader understanding of the economic value of the pharmacogenomics test.

Data Mining of the US FDA’s Adverse Events Reporting System Database to Evaluate Drug–Drug Interactions Associated with Statin-Induced Rhabdomyolysis

With the rise in polypharmacy, it is increasingly important to identify drug–drug interactions (DDIs) that cause serious adverse events in a timely manner. The purpose of the study was to investigate the utility of systematic data mining of the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for interactions between statins (HMG-CoA reductase inhibitors) and other drugs that underlie a higher risk for rhabdomyolysis. The strength of association for the reporting of rhabdomyolysis with each statin–drug combination was measured using Bayesian data mining scores, the Interaction Signal Score (INTSS), and simple proportions that were calculated as the reporting odds ratio (ROR). Scores >1.0 indicate disproportionately higher than expected reporting. A manual case review highlighted strengths and limitations of these measures. As expected, clarithromycin and cyclosporine produced high measures of disproportionate reporting of rhabdomyolysis with lovastatin and simvastatin. Drugs with no known predilection to contribute to statin myopathy produced scores <1.0 when paired with each statin. In contrast, in some instances INTSS values were <1.0 when measures of DDI with statin–drug pairs known to interact. This might be due to masking by high numbers of reports linked to the non-statin drug alone. The manual review identified dose as an important risk factor; however, this risk factor could not have been systematically identified without informatics enhancements. While disproportionality methods represent a promising tool for identifying a potential serious DDI, opportunities remain for improvements in both data mining algorithms and the acquisition of adequately informative data.

Miopatía asociada al uso de estatinas en la práctica clínica. Resultados del estudio DAMA

Background and objectiveMuscle symptoms, with or without elevation of creatin kinase are one of the main adverse effects of statin therapy, a fact that sometimes limits their use. The aim of this study was to evaluate the clinical characteristics of patients treated with statins who have complained muscle symptoms and to identify possible predictive factors. Patients and methodsA cross-sectional one-visit, non-interventional, national multicenter study including patients of both sexes over 18 years of age referred for past or present muscle symptoms associated with statin therapy was conducted. 3,845 patients were recruited from a one-day record from 2,001 physicians. ResultsMyalgia was present in 78.2% of patients included in the study, myositis in 19.3%, and rhabdomyolysis in 2.5%. Patients reported muscle pain in 77.5% of statin-treated individuals, general weakness 42.7%, and cramps 28.1%. Kidney failure, intense physical exercise, alcohol consumption (>30g/d in men and 20g/d in women) and abdominal obesity were the clinical situations associated with statin myopathy. ConclusionsMyalgia followed by myositis are the most frequent statin-related side effects. It should be recommended control environmental factors such as intense exercise and alcohol intake as well as abdominal obesity and renal function of the patient treated with statins.

A Peculiar Formula of Essential Amino Acids Prevents Rosuvastatin Myopathy in Mice.

Myopathy, characterized by mitochondrial oxidative stress, occurs in ∼10% of statin-treated patients, and a major risk exists with potent statins such as rosuvastatin (Rvs). We sought to determine whether a peculiar branched-chain amino acid-enriched mixture (BCAAem), found to improve mitochondrial function and reduce oxidative stress in muscle of middle-aged mice, was able to prevent Rvs myopathy. Dietary supplementation of BCAAem was able to prevent the structural and functional alterations of muscle induced by Rvs in young mice. Rvs-increased plasma 3-methylhistidine (a marker of muscular protein degradation) was prevented by BCAAem. This was obtained without changes of Rvs ability to reduce cholesterol and triglyceride levels in blood. Rather, BCAAem promotes de novo protein synthesis and reduces proteolysis in cultured myotubes. Morphological alterations of C2C12 cells induced by statin were counteracted by amino acids, as were the Rvs-increased atrogin-1 mRNA and protein levels. Moreover, BCAAem maintained mitochondrial mass and density and citrate synthase activity in skeletal muscle of Rvs-treated mice beside oxygen consumption and ATP levels in C2C12 cells exposed to statin. Notably, BCAAem assisted Rvs to reduce oxidative stress and to increase the anti-reactive oxygen species (ROS) defense system in skeletal muscle. Innovation and Conclusions: The complex interplay between proteostasis and antioxidant properties may underlie the mechanism by which a specific amino acid formula preserves mitochondrial efficiency and muscle health in Rvs-treated mice. Strategies aimed at promoting protein balance and controlling mitochondrial ROS level may be used as therapeutics for the treatment of muscular diseases involving mitochondrial dysfunction, such as statin myopathy. Antioxid. Redox Signal. 25, 595-608.

Coenzyme Q-10 in Human Health: Supporting Evidence?

Coenzyme Q-10 (CoQ10) is a widely used alternative medication or dietary supplement and one of its roles is as an antioxidant. It naturally functions as a coenzyme and component of oxidative phosphorylation in mitochondria. Decreased levels have been demonstrated in diseased myocardium and in Parkinson disease. Farnesyl pyrophosphate is a critical intermediate for CoQ10 synthesis and blockage of this step may be important in statin myopathy. Deficiency of CoQ10 also has been associated with encephalomyopathy, severe infantile multisystemic disease, cerebellar ataxia, nephrotic syndrome, and isolated myopathy. Although supplementation with CoQ10 has been reported to be beneficial in treating hypertension, congestive heart failure, statin myopathy, and problems associated with chemotherapy for cancer treatement, this use of CoQ10 as a supplement has not been confirmed in randomized controlled clinical trials. Nevertheless, it appears to be a safe supplementary medication where usage in selected clinical situations may not be inappropriate. This review is an attempt to actualize the available information on CoQ10 and define its potential benefit and appropriate usage.