Atorvastatin-induced Myopathy Research Articles

A case report on atorvastatin-induced myopathy

Statins are the most commonly used lipid-lowering drugs in cardiovascular patients. Atorvastatin is a majorly used statin. Atorvastatin will induce myopathy; it is a rare side effect. In my case report, the patient experiencing muscle cramps for 3 years on and off. He consulted a cardiologist. The doctor advised rosuvastatin. He has been on rosuvastatin for 6 months. From the last 6 months, he had not experienced any myopathy symptoms.

Atorvastatin Induces Mitochondria-Dependent Ferroptosis via the Modulation of Nrf2-xCT/GPx4 Axis.

As one of the cornerstones of clinical cardiovascular disease treatment, statins have an extensive range of applications. However, statins commonly used have side reactions, especially muscle-related symptoms (SAMS), such as muscle weakness, pain, cramps, and severe condition of rhabdomyolysis. This undesirable muscular effect is one of the chief reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. Moreover, the underlying mechanism of muscle cell damage is still unclear. Here, we discovered that ferroptosis, a programmed iron-dependent cell death, serves as a mechanism in statin-induced myopathy. Among four candidates including atorvastatin, lovastatin, rosuvastatin, and pravastatin, only atorvastatin could lead to ferroptosis in human cardiomyocytes (HCM) and murine skeletal muscle cells (C2C12), instead of human umbilical vein endothelial cell (HUVEC). Atorvastatin inhibits HCM and C2C12 cell viability in a dose-dependent manner, accompanying with significant augmentation in intracellular iron ions, reactive oxygen species (ROS), and lipid peroxidation. A noteworthy investigation found that those alterations particularly occurred in mitochondria and resulted in mitochondrial dysfunction. Biomarkers of myocardial injury increase significantly during atorvastatin intervention. However, all of the aforementioned enhancement could be restrained by ferroptosis inhibitors. Mechanistically, GSH depletion and the decrease in nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPx4), and xCT cystine–glutamate antiporter (the main component is SLC7A11) are involved in atorvastatin-induced muscular cell ferroptosis and damage. The downregulation of GPx4 in mitochondria-mediated ferroptosis signaling may be the core of it. In conclusion, our findings explore an innovative underlying pathophysiological mechanism of atorvastatin-induced myopathy and highlight that targeting ferroptosis serves as a protective strategy for clinical application.

Association of SLCO1B1 and ABCB1 Genetic Variants with Atorvastatin-induced Myopathy in Patients with Acute Ischemic Stroke.

Certain patients experience muscle-related adverse effects after taking atorvastatin. Genetic factors play an important role in the occurrence of statin-induced myopathy. We aimed to identify genetic variants associated with statin-induced myotoxicity. We prospectively enrolled 1,102 acute ischemic stroke patients who underwent atorvastatin treatment for the first time after admission. Patients were separated into case and control groups after a follow-up of 3 months. We used a biochemical definition of myopathy consisting of serum creatine kinase values more than ten times the upper limit of normal for the reference laboratory (150 U/L). Fifty single nucleotide polymorphisms (SNPs) from seven genes of ABCB1, CoQ2, HTR3B, RYR2, CYP3A5, HTR7 and SLCO1B1 were selected and genotyped. The effects of genetic polymorphisms on myopathy were observed. 61 cases and 110 controls were recruited in the study. Compared with the controls, the cases had a significant higher mutant frequency of the allele A (ABCB1, rs2373588) (OR = 2.01, 95%CI = 1.10-3.67, P = 0.001) and a significant lower mutant frequency of the allele A (SLCO1B1, rs976754) (OR = 1.85, 95%CI = 1.12-3.03, P = 0.042). Genotypes or alleles of the other SNPs had no significant difference between the two groups (P > 0.05). Our findings reveal that SLCO1B1 and ABCB1 genetic variants are associated with statin-induced myopathy. These are valuable biomarkers for the evaluation of atorvastatin safety.

The possible protective effects of vitamin D and L-carnitine against used atorvastatin-induced myopathy and hepatotoxicity

Statins are widely used antihyperlipidemic drugs. The occurrence of side effects mainly myopathy and hepatotoxicity leads to discontinuation of treatments with these drugs. It is suggested that these side effects are due to mitochondrial dysfunction, decreased antioxidant activity, and induction of inflammatory and apoptotic mediators. It was noticed that vitamin D and L-carnitine possess antioxidant activities and inhibit apoptotic protein expression. Statin-induced hepatotoxicity and myopathy was done by oral administration of atorvastatin (50 mg/kg/day) to rats. Other rats were treated with atorvastatin and vitamin D3 (500 IU/kg/day) or atorvastatin and L-carnitine (300 mg/kg/day). The administration of vitamin D3 and L-carnitine led to inhibition of oxidative stress in the liver and skeletal muscles providing a protective effect. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine kinase (CK) increased by atorvastatin were significantly reduced by administration of vitamin D3 and L-carnitine. Histopathologically, vitamin D3 and L-carnitine administration provided a good protection for hepatic injury and muscle tissue against atorvastatin toxic effects. The use of vitamin D3 and L-carnitine produced a protective effect against atorvastatin-induced myotoxicity and hepatotoxicity. This protective effect was indicated by reduced oxidative stress and reduction of serum levels of ALT, AST, and CK.

Can Alfacalcidol ameliorate Atorvastatin-induced myopathy in adult male rats? A histological study

ABSTRACTIntroduction: Atorvastatin (Ator), is the treatment of choice for reducing blood cholesterol. Most adverse effects associatedwith Statins therapy are muscle-related. Alfacalcidol (ALF), a vitamin D analog commonly used in osteoporosis; showedbeneficial effects beyond the skeleton including muscle.Aim of the work: Investigating the possible protective effect of ALF in Atorvastatin induced myopathy in rats.Materials and Methods: Twenty-one adult male albino rats were divided equally into 3 groups: Group I (control). GroupΙΙ (Ator): received Atorvastatin (10 mg/kg/day). Group ΙΙΙ (Ator-ALF): received Ator concomitantly with Alfacalcidol(0.5 μg/kg/day). After 4 weeks of daily oral medications administration, blood samples from all rats were analyzed for creatinephosphokinase (CPK). The middle parts of biceps femoris muscles were processed for paraffin blocks for Hematoxylin andEosin stain and cytochrome C immunohistochemical stain that subjected to morphometric and statistical studies. Moreover,resin blocks were processed for semithin and ultrathin sections examination.Results: In group II, light microscopic examination revealed fragmented and tapered muscle fibers, in addition to loss ofregular pattern of transverse striation. Many fibers in transverse section acquired an irregular outline. Statistically, elevatedCPK level, decreased mean muscle fiber diameter and increased mean area % of cytochrome C immunoreactivity comparedto the control were recorded. Electron microscopic examination showed dissolution of many myofibrils and mitochondriaeither disfigured giant or with destructed cristae. However, group III showed muscle fibers that are almost comparable to thecontrol group with clear transverse striations. That is confirmed statistically by decreased CPK level, increased mean musclefiber diameter and decreased mean area % of cytochrome C immunoreactivity versus group II. While ultrastructurally, fewareas of myofibrillar dissolution were noted.Conclusion: Alfacalcidiol has a protective effect on Ator induced myopathy confirmed by the biochemical analysis, light andelectron microscopic examination as well as via morphometric studies.

Elucidation of the mechanism of atorvastatin-induced myopathy in a rat model.

Myopathy is among the well documented and the most disturbing adverse effects of statins. The underlying mechanism is still unknown. Mitochondrial dysfunction related to coenzyme Q10 decline is one of the proposed theories. The present study aimed to investigate the mechanism of atorvastatin-induced myopathy in rats. In addition, the mechanism of the coenzyme Q10 protection was investigated with special focus of mitochondrial alterations. Sprague-Dawely rats were treated orally either with atorvastatin (100mg/kg) or atorvastatin and coenzyme Q10 (100mg/kg). Myopathy was assessed by measuring serum creatine kinase (CK) and myoglobin levels together with examination of necrosis in type IIB fiber muscles. Mitochondrial dysfunction was evaluated by measuring muscle lactate/pyruvate ratio, ATP level, pAkt as well as mitochondrial ultrastructure examination. Atorvastatin treatment resulted in a rise in both CK (2X) and myoglobin (6X) level with graded degrees of muscle necrosis. Biochemical determinations showed prominent increase in lactate/pyruvate ratio and a decline in both ATP (>80%) and pAkt (>50%) levels. Ultrastructure examination showed mitochondrial swelling with disrupted organelle membrane. Co-treatment with coenzyme Q10 induced reduction in muscle necrosis as well as in CK and myoglobin levels. In addition, coenzyme Q10 improved all mitochondrial dysfunction parameters including mitochondrial swelling and disruption. These results presented a model for atorvastatin-induced myopathy in rats and proved that mitochondrial dysfunction is the main contributor in statin-myopathy pathophysiology.

Red yeast rice and coenzyme Q10 as safe alternatives to surmount atorvastatin-induced myopathy in hyperlipidemic rats.

Statins are the first line treatment for the management of hyperlipidemia. However, the primary adverse effect limiting their use is myopathy. This study examines the efficacy and safety of red yeast rice (RYR), a source of natural statins, as compared with atorvastatin, which is the most widely used synthetic statin. Statin interference with the endogenous synthesis of coenzyme Q10 (CoQ10) prompted the hypothesis that its deficiency may be implicated in the pathogenesis of statin-associated myopathy. Hence, the effects of combination of CoQ10 with either statin have been evaluated. Rats were rendered hyperlipidemic through feeding them a high-fat diet for 90 days, during the last 30 days of the diet they were treated daily with either atorvastatin, RYR, CoQ10, or combined regimens. Lipid profile, liver function tests, and creatine kinase were monitored after 15 and 30 days of drug treatments. Heart contents of CoQ9 and CoQ10 were assessed and histopathological examination of the liver and aortic wall was performed. RYR and CoQ10 had the advantage over atorvastatin in that they lower cholesterol without elevating creatine kinase, a hallmark of myopathy. RYR maintained normal levels of heart ubiquinones, which are essential components for energy production in muscles. In conclusion, RYR and CoQ10 may offer alternatives to overcome atorvastatin-associated myopathy.

Pharmacogenetics of Statin-Induced Myopathy: A Focused Review of the Clinical Translation of Pharmacokinetic Genetic Variants.

Statins are the most commonly prescribed drugs in the United States and are extremely effective in reducing major cardiovascular events in the millions of Americans with hyperlipidemia. However, many patients (up to 25%) cannot tolerate or discontinue statin therapy due to statin-induced myopathy (SIM). Patients will continue to experience SIM at unacceptably high rates or experience unnecessary cardiovascular events (as a result of discontinuing or decreasing their statin therapy) until strategies for predicting or mitigating SIM are identified. A promising strategy for predicting or mitigating SIM is pharmacogenetic testing, particularly of pharmacokinetic genetic variants as SIM is related to statin exposure. Data is emerging on the association between pharmacokinetic genetic variants and SIM. A current, critical evaluation of the literature on pharmacokinetic genetic variants and SIM for potential translation to clinical practice is lacking. This review focuses specifically on pharmacokinetic genetic variants and their association with SIM clinical outcomes. We also discuss future directions, specific to the research on pharmacokinetic genetic variants, which could speed the translation into clinical practice. For simvastatin, we did not find sufficient evidence to support the clinical translation of pharmacokinetic genetic variants other than SLCO1B1. However, SLCO1B1 may also be clinically relevant for pravastatin- and pitavastatin-induced myopathy, but additional studies assessing SIM clinical outcome are needed. CYP2D6*4 may be clinically relevant for atorvastatin-induced myopathy, but mechanistic studies are needed. Future research efforts need to incorporate statin-specific analyses, multi-variant analyses, and a standard definition of SIM. As the use of statins is extremely common and SIM continues to occur in a significant number of patients, future research investments in pharmacokinetic genetic variants have the potential to make a profound impact on public health.

No effect of combined coenzyme Q10 and selenium supplementation on atorvastatin-induced myopathy

Objective. The aim of the present study was to evaluate the possible effects of Q10 and selenium supplementation on statin-induced myopathy (SIM), both for subjective symptoms and muscle function. Design. Patients (N = 43) who had experienced previous or ongoing SIM on atorvastatin therapy were recruited. Following a 6-week washout period during which no statins were administered, the patients were re-challenged with 10 mg of atorvastatin. Patients (N = 41) who experienced SIM continued the atorvastatin treatment and were in addition randomized to receive 12 weeks supplement of 400 mg Q10 and 200 μg selenium per day or a matching double placebo. SIM was assessed using 3 validated symptom questionnaires, and a muscle function test was performed at the beginning and at the end of the study. Results. The patients receiving the active supplement experienced significant increases in their serum Q10 and selenium concentrations compared with the group receiving placebo. No statistically significant differences in symptom questionnaire scores or muscle function tests were revealed between the groups. Conclusions. Despite substantial increases in the serum Q10 and selenium levels following the oral supplementation, this study revealed no significant effects on SIM compared with the placebo.Trial registration: ClinicalTrials.gov identifier: NCT00113477.

Genetic predisposition to atorvastatin-induced myopathy: a case report

The major clinical complication of statins is a variety of muscle complaints ranging from myalgia to rhabdomyolysis. There is growing evidence that carriers of genetic polymorphisms in the enzymes and transporters implicated in statin disposition, particularly the SLCO1B1 gene, are at increased risk of myotoxicity. Our objective is to report on two cases of statin-induced myopathy occurring in a family with two patients who are carriers of the loss of function SLCO1B1 genetic variant and to briefly review the related literature. Patient 1, a 48-year-old man with history of coronary artery disease, experienced rapidly evolving muscle pain and weakness of the extremities during treatment with atorvastatin 40 mg. Patient 2, a 65-year-old man, father of patient 1, had symptoms similar to those of his son after 2 weeks' treatment with the same statin. Atorvastatin was stopped in both cases, and symptoms resolved. On the basis of family relationship between the two patients, it was possible to hypothesize a genetic basis for the myopathy. Genotyping showed the patients to be carriers of the rs4363657 polymorphism of SLCO1B1 gene. The two cases reported here and the brief literature review emphasize the impact of genetic factors on the risk of myopathy with statins. Although genotyping all patients before initiating therapy is not recommended at present, pharmacogenetic testing may be useful for new patients who have a family history of statin-induced myopathy.

Development of a Population Pharmacokinetic Model for Atorvastatin Acid and Its Lactone Metabolite

Atorvastatin lactone, a metabolite of the HMG-CoA reductase inhibitor (statin) atorvastatin acid, is believed to be myotoxic. Our objectives were to develop a population pharmacokinetic model for atorvastatin acid and its lactone metabolite and to identify patient characteristics that are predictive of variability in the pharmacokinetic parameters of the parent drug and its lactone metabolite. Twenty-six subjects, 13 of whom had experienced atorvastatin-induced myopathy, received atorvastatin 10 mg once daily for 7 days. Plasma samples taken on day 7 at 0 hours (predose) and 0.5, 1, 1.5, 2, 3, 5, 7, 9, 12, 22 and 24 hours post-dose were analysed for both atorvastatin acid and atorvastatin lactone, using a validated liquid chromatography assay with tandem mass spectrometry, and the data were modelled using nonlinear mixed-effects modelling software (NONMEM). The influence of the patients' demographic characteristics, biochemical indices and pharmacogenomics was evaluated. Final model validation was carried out using a visual predictive check. The pharmacokinetics of atorvastatin acid and atorvastatin lactone were best described by two- and one-compartment models, respectively. The main pharmacokinetic parameters of atorvastatin acid (mean [relative standard error {RSE}]) for a subject with mean covariate values were the first-order absorption rate constant (3.5 h-1 fixed); oral clearance (504 L/h [29%]); apparent volume of the central compartment (3250 L [16.5%]); and apparent volume of the peripheral compartment (2170 L [9.3%]). The main pharmacokinetic parameters of atorvastatin lactone (mean [RSE]) were the apparent clearance to atorvastatin acid (24 L/h [154%]); apparent total body clearance (116 L/h [9.5%]); and apparent volume of distribution (137 L [33.7%]). The value of aspartate transaminase was identified as a significant covariate for the apparent volume of the central compartment for atorvastatin acid and for the apparent total body clearance of atorvastatin lactone, signifying the importance of liver function in atorvastatin pharmacokinetics. The visual predictive plots demonstrated that the model adequately described the pharmacokinetics of both species. A population pharmacokinetics model was developed and validated to describe atorvastatin acid and its lactone metabolite concentration-time data. This model may be useful for atorvastatin dose individualization or analysis of sparse data.

Exposure of atorvastatin is unchanged but lactone and acid metabolites are increased several-fold in patients with atorvastatin-induced myopathy

The most serious side effect from statin treatment is myopathy, which may proceed to rhabdomyolysis. This is the first study to investigate whether the pharmacokinetics of either atorvastatin or its metabolites, or both, is altered in patients with atorvastatin-related myopathy compared with healthy controls. A 24-hour pharmacokinetic investigation was performed in 14 patients with atorvastatin-related myopathy. Relevant polymorphisms in SLCO1B1 (encoding organic anion transporting polypeptide 1B1), MDR1/ABCB1 (encoding P-glycoprotein), and CYP3A5 (encoding cytochrome P450 3A5) were determined. Data from 15 healthy volunteers were used as controls. No statistically significant difference in systemic exposure of atorvastatin was observed between the 2 groups. However, patients with atorvastatin-related myopathy had 2.4-fold and 3.1-fold higher systemic exposures of the metabolites atorvastatin lactone (P<.01) and p-hydroxyatorvastatin (P<.01), respectively, compared with controls. There were no differences in frequencies of SLCO1B1, MDR1, and CYP3A5 polymorphisms between the 2 groups. This study disclosed a distinct difference in the pharmacokinetics of atorvastatin metabolites between patients with atorvastatin-related myopathy and healthy control subjects. These results are of importance in the further search for the mechanism of statin-induced myopathy.

OATP-C(OATP01B1)*15 is associated with statin-induced myopathy in hypercholesterolemic patients

Background Statins are associated with muscle complaints ranging from myalgia to rhabdomyolysis. We studied the genetic contribution to the risk of the statin-induced myopathy by comparing frequencies of mutant alleles of candidate genes in case and control groups. Methods We studied ten Japanese patients with abnormal increase in plasma creatinine kinase or severe muscle complaints, in comparison with control patients (n=26) who received statins but had no myopathy. DNA samples were genotyped for 152 SNPs/mutations in eight candidate genes selected from genes responsible for inherited rhabdomyolysis and those involved in the metabolism or transport of stains. Results No mutations or SNPs were detected in the genes of inherited rhabdomyolysis except for 128G>A in VLCAD, of which frequency was almost the same as that of the controls. For CYP3A4 and MRP2, one and two SNPs were detected respectively, but there was no significant difference between the groups. However, we found a significant association between OATP-C*15 and pravastatin- or atorvastatin-induced myopathy (P A in MDR1 and simvastatin- or atorvastatin-incuced myopathy was also observed (P<0.05). Conclusions The results suggest that OATP-C*15 is one of the susceptible factors for development of myopathy in patients taking pravastatin or atorvastatin. Clinical Pharmacology & Therapeutics (2005) 77, P21–P21; doi: 10.1016/j.clpt.2004.11.081