Statin-induced Myopathy Research Articles

Allelic frequencies of polymorphism c.521T>C (rs4149056) favor preemptive SLCO1B1 genotyping in Armenia.

Statins represent an important pharmacological factor for the prevention of cardiovascular diseases but may also cause severe cases of myotoxicity. Numerous studies have described the association of the SLCO1B1 gene variant c.521C with statin-induced myopathy across different populations. This study aimed at evaluating the usefulness of preemptive SLCO1B1 genotyping in Armenia. A total of 202 Armenian patients referred to the Center of Medical Genetics and Primary Health Care in Yerevan for upper respiratory tract infection between January and May 2022 were included in this study. Genotyping for SLCO1B1 c.521T>C (rs4149056) was performed using a commercially available real-time PCR assay (RealFast™). In total, 3/202 (1.5 %) samples were C/C homozygotes and 52/202 (25.7 %) were T/C heterozygotes, associated with a high and increased risk for statin-induced myopathy, respectively. The SLCO1B1 c.521C allelic frequency was 14.4 %. The observed allele frequency of 14.4 % for thec.521C variant is slightly lower than frequencies reportedfrom Europe, but relatively high compared to Asianpopulations, suggesting that preemptive SLCO1B1 genotyping could be a useful approach for the reduction of statin-induced adverse effects in Armenia.

Effectiveness of Coenzyme Q10 Supplementation in Statin-Induced Myopathy: A Systematic Review.

Statins are among the most widely prescribed drugs for treating dyslipidemia and reducing the incidence of heart disease and stroke. However, they come with a wide range of side effects, from myopathy to necrotizing rhabdomyolysis, as well as diabetes, hepatotoxicity, and sleep problems. The most common side effect of statins is statin-induced myopathy, often leading to discontinuation of statin therapy and noncompliance in many patients. This study aims to assess the effectiveness of coenzyme Q10 (CoQ10) supplementation as a treatment for patients with statin-induced myopathy. This systematic review was conducted by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. Relevant studies were identified through searches of Medline, PMC, PubMed, Science Direct, and Google Scholar. Only randomized control trials and meta-analyses of oral CoQ10 supplementation versus placebo in adults with statin-associated myalgia were included. The risk of bias was assessed using the Cochrane Risk of Bias tool (The Cochrane Collaboration, London, England, UK) and the measurement tool for the "assessment of multiple systematic reviews" (AMSTARtool). Out of 5,000 records identified, only five were selected for this review: one meta-analysis and four randomized controlled trials. All of these studies were conducted between 2010 and 2023, involving a total of 800 patients. All randomized controlled trials showed improvement in statin-associated myopathy with CoQ10 supplementation, along with or without a reduced dosage of statins, without any notable side effects of CoQ10. Therefore, it can be deduced that CoQ10 supplementation significantly ameliorates statin-induced musculoskeletal symptoms.

The impact of SLCO1B1 single nucleotide polymorphism and non-genetic factors on statin-induced myopathy

Abstract Funding Acknowledgements None. Background Statins, also known as HMG CoA Reductase Inhibitors, are a class of drugs considered the drug of choice for treating hypercholesterolemia. Statins are well tolerated; however, they may cause severe myopathy in 20% to 30% of patients, due to the individual variation regarding its efficacy and related adverse effects. Of these, comes the Single Nucleotide Polymorphism (SNP) T521C of the SLCO1B1 gene that encodes the protein involved in the trafficking of statins from the blood to hepatocytes which is called Organic Anion Transport Protein 1B1 (OATP1B1). The T521C single nucleotide polymorphism (SNP) results in a substitute of valine with alanine resulting in a decreased or lack of functional protein. Purpose The aim is to determine the frequency of the high-risk C allele and to define its impact on statin-induced myopathy in Syrian patients on statins. In addition to the non-genetic factors that may affect the ability to develop statin-induced myopathy. Methods This was an observational case-control study that had ethical approval from Damascus University (No.433/ 2020). The case group included 44 patients on statins who experienced myopathy, 18 patients who had increased creatinine kinase levels (CK), and 26 patients with normal CK levels, while the control group encompassed 56 patients who were taking statins and had no muscular adverse events. The DNA was extracted from each sample and then genotyped using standard sequencing of specific PCR products using a specific pair of primers. Results The age of patients in the case arm ranged between 27 and 84 years with an average ± SD of (58.2 ± 12.7 years), 70% of them were males. In comparison with (53.34 ± 12.4 years) in the control arm, 66% of them were males without a statistically significant differences (p=0.672, 0.057) respectively. The statin type and dose have a statistically non-significant effect, the average statin dose in the case arm and the control arm was 26.02 mg and 31.27 mg respectively (p=0.072). While the statin type treatment varied as 59% used atorvastatin and 39% used rosuvastatin in the case group compared with 71% used atorvastatin and 27% used rosuvastatin in the control group, without a statistically significant difference (p=0.252). The frequency of the C allele reaches 19.3% and is distributed in three genotypes: wild-type TT (68%), heterozygote TC (25%), and homozygote CC (7%) in the case arm, while it does not exceed 8% in the control arm with the absence of the CC genotype. Only a statistically significant difference was found in the frequency of the CC genotype between these two groups (p=0.047). Conclusion Our study is the first to identify the frequency of the 521T>C SNP of the SLCO1B1 gene in Syrian patients taking statins. Our data reveals a high prevalence of risk allele C in the patients who suffer from statin-induced myopathy with a statically significant difference from the control arm (p=0.026).

Role of Formoterol on Myogenic Regulatory Factor to Ameliorate Statin-induced Myopathy

Objective: To investigate the effects of β2-adrenergic agonist formoterol on expression of myogenic regulatory factor myogenin in statin-induced myopathies in rats
 Methods: Adult male Sprague-Dawley rats were randomized into control (A), statin-only (B), and statin + formoterol groups (C) (n=30 per group). The control group A received no treatment. B group received simvastatin at 60 mg/kg/day by oral gavage for 12 weeks to induce myotoxicity. C group received simvastatin at 60 mg/kg/day plus formoterol at 3 μg/kg/day by oral gavage for 12 weeks. After 12 weeks, extensor digitorum longus muscles were dissected and 5 μm transverse sections were immunostained for myogenin expression. One cross section was selected from each of the specimen for study. Myogenin-positive nuclei were quantified in 8 random 40x magnification fields per muscle section by a blinded investigator. Data was analyzed using IBM SPSS.
 Results: Myogenin-positive nuclei were minimal in the control (A) group and statin-only (B) groups. In contrast, the statin + formoterol (C) group exhibited a significant increase in myogenin-positive nuclei compared to both control and statin-only groups (p<0.001), indicating enhanced muscle regeneration.
 Conclusion: Formoterol treatment augmented skeletal muscle repair pathways in a rat model of statin-induced myopathy, potentially via activation of quiescent muscle satellite cells and upregulation of myogenic regulatory factor myogenin in group C.

Dantrolene and coenzyme Q10 as a suggested combination therapy to statin-induced myopathy in high fat diet rats: A possible interference with ROS/ TGF-β / Smad4 signaling pathway

One of the major hitches for statins' utilization is the development of myotoxicity. Versatile studies reported that the underlining molecular mechanisms including coenzyme Q10 (CoQ10)/ubiquinone depletion, as well as the disturbance in the cytoplasmic Ca2+ homeostasis. Therefore, we investigated the consequences of supplementing CoQ10 and dantrolene, a cytoplasmic Ca2+ reducing agent, in combination with simvastatin. This adjuvant therapy normalized the simvastatin-mediated elevation in serum ALT, AST, CK-MM, as well as tissue Ca2+ content, in addition to suppressing the simvastatin-mediated oxidative stress in simvastatin-treated rats, while having no effect upon statin-induced antihyperlipidemic effect. Additionally, the combination inhibited the simvastatin-induced TGF-β/ Smad4 pathway activation. Collectively, the current study emphasizes on the potential utilization of dantrolene and CoQ10 as an adjuvant therapy to statins treatment for improving their side effect profile.

The Role of Mitochondria in Statin-Induced Myopathy.

Statins represent the primary therapy for combatting hypercholesterolemia and reducing mortality from cardiovascular events. Despite their pleiotropic effects in lowering cholesterol synthesis, circulating cholesterol, as well as reducing the risk of other systemic diseases, statins have adverse events in a small, but significant, population of treated patients. The most prominent of these adverse effects is statin-induced myopathy, which lacks precise definition but is characterised by elevations in the muscle enzyme creatine kinase alongside musculoskeletal complaints, including pain, weakness and fatigue. The exact aetiology of statin-induced myopathy remains to be elucidated, although impaired mitochondrial function is thought to be an important underlying cause. This may result from or be the consequence of several factors including statin-induced inhibition of coenzyme Q10 (CoQ10) biosynthesis, impaired Ca2+ signalling and modified reactive oxygen species (ROS) generation. The purpose of this review article is to provide an update on the information available linking statin therapy with mitochondrial dysfunction and to outline any mechanistic insights, which may be beneficial in the future treatment of myopathic adverse events.

Recurrent statin-induced rhabdomyolysis: Commonly overlooked drug

Statin-induced muscle pain and myopathy are common. However, statin-induced rhabdomyolysis causing severe nephropathy is somehow uncommon. Here, we present the case of a 68-year-old patient on statin therapy after percutaneous coronary intervention. We want to highlight the fact that physicians should differentiate muscle pain without biochemical derangement and with severe rhabdomyolysis leading to acute kidney injury and hyperkalemia. Patients should be made aware of this commonly overlooked drug causing severe complications.

Fluvastatin-induced myofibrillar damage is associated with elevated ROS, and impaired fatty acid oxidation, and is preceded by mitochondrial morphological changes

Previously, we showed that fluvastatin treatment induces myofibrillar damage and mitochondrial phenotypes in the skeletal muscles of Drosophila. However, the sequential occurrence of mitochondrial phenotypes and myofibril damage remains elusive. To address this, we treated flies with fluvastatin for two and five days and examined their thorax flight muscles using confocal microscopy. In the two-day fluvastatin group, compared to the control, thorax flight muscles exhibited mitochondrial morphological changes, including fragmentation, rounding up and reduced content, while myofibrils remained organized in parallel. In the five-day fluvastatin treatment, not only did mitochondrial morphological changes become more pronounced, but myofibrils became severely disorganized with significantly increased thickness and spacing, along with myofilament abnormalities, suggesting myofibril damage. These findings suggest that fluvastatin-induced mitochondrial changes precede myofibril damage. Moreover, in the five-day fluvastatin group, the mitochondria demonstrated elevated H2O2 and impaired fatty acid oxidation compared to the control group, indicating potential mitochondrial dysfunction. Surprisingly, knocking down Hmgcr (Drosophila homolog of HMGCR) showed normal mitochondrial respiration in all parameters compared to controls or five-day fluvastatin treatment, which suggests that fluvastatin-induced mitochondrial dysfunction might be independent of Hmgcr inhibition. These results provide insights into the sequential occurrence of mitochondria and myofibril damage in statin-induced myopathy for future studies.

Statin Myopathy: A Case series

Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) immune-mediated necrotizing myopathy (anti-HMGCR IMNM) is a rare adverse effect associated with the use of statin medications [1]. While the investigation remains ongoing, statin exposure is thought to induce mitochondrial dysfunction due to inhibition of HMGCR, subsequently triggering an inflammatory cascade with oxidative stress and autoantibodies (aAbs) against HMGCR, ultimately leading to an immune-mediated necrotizing myopathy (IMNM) [2]. Clinical presentation may involve dermatomyositis-like features ranging from myalgias to severe and progressive proximal muscle weakness, often persisting after cessation of the offending statin [3]. Serum studies typically reveal significantly elevated Creatine Kinase (CK) levels, often ranging from 10 to 100 times the upper limit of normal [4]. Presumptive diagnosis is confirmed via muscle biopsy, which typically reveals necrotic fibers with minimal inflammatory cell infiltrates [5]. In addition to withdrawal of the offending agent, treatment may involve immunomodulatory medications (e.g. intravenous immunoglobulin (IVIG), steroids, and/or Rituximab). For most patients, resolution typically occurs over months, sometimes years. This paper highlights three cases of statin-induced myopathy and the clinical implications for providers in prompt recognition, diagnosis, and management of this rare condition. Further research is needed to better understand both the risk factors and underlying mechanisms in order to increase awareness, optimize care, and minimize the morbidity associated with this adverse drug reaction.

Investigation of the Association of GATM Gene Polymorphisms with Statin-Induced Myopathy

Investigation of the Association of GATM Gene Polymorphisms with Statin-Induced Myopathy

Editor's Summaries of the Articles Published in This Issue of Precision Medicine Communications

In this issue, Shah and colleagues reviewed and discussed the pharmacogenetics of tacrolimus in solid organ transplant patients, Ullah and colleagues performed a meta-analysis on the association of GABRG2 rs211037 gene polymorphism with epilepsies and pharmacoresistance to anti-epileptic drugs, Mansoor and colleagues carried out an integrative investigation for the prioritization of candidate genes and unveiled their interaction with celecoxib for targeted therapeutic applications, Nimra and Robab reviewed the pharmacogenomics of Leukemia for unlocking personalized treatment strategies, Hussain and colleagues investigated the association of GATM gene polymorphism with statin-induced myopathy.

Formoterol Induces Muscle Regeneration Through Myogenic Regulatory Factor MyoD in Rat Model of Statin-Induced Myopathy

<p><strong>ABSTRACT</strong></p>
 <p><strong>Background and Objective:</strong> Statins can induce myopathy; however, the impact on muscle regeneration remains unclear. β2-agonists may mitigate statin myotoxicity. This study investigated the effects of simvastatin and formoterol on skeletal muscle regeneration and injury using a rat model.<br /><strong>Methods:</strong> Adult Sprague-Dawley rats (n = 90) were divided into three groups: control (A), simvastatin treatment (B), and simvastatin plus formoterol treatment (C). The rats were kept at room temperature for 3 months where an animal house diet was available ad libitum. Simvastatin was administered orally once a day, by oral gavage for 12 weeks; formoterol was concurrently administered to one group. Extensor digitorum longus muscles were analyzed for the myogenic differentiation factor (MyoD) by immunohistochemistry. Serum lactate dehydrogenase (LDH) levels were quantified as a marker of muscle damage.<br /><strong>Results:</strong> MyoD-positive myonuclei were significantly increased in the C group (simvastatin plus formoterol group) compared to the A and B Groups (control and simvastatin-only groups) (p < 0.05). Serum LDH levels were significantly lower in group C than in groups A and B (p < 0.05).<br /><strong>Conclusion:</strong> Formoterol alleviates statin-associated muscle injury in a rat model as evidenced by increased MyoD expression and decreased LDH levels. The activation of dormant satellite cells and increased expression of MyoD indicate the potential of formoterol to promote muscle regeneration.</p>

Skeletal Muscle Type-Dependent Effect of Atorvastatin on FoxO3a and Akt in Hypercholesterolemic Rats

Statins are one of the most commonly used lipid-lowering drugs reducing the risk of mortality due to cardiovascular diseases. They are well tolerated and have relatively few side effects which mainly affect skeletal muscle. The impact of statins on skeletal muscle functions depends on the composition of the muscle fibers type. One of the mechanisms of statin-induced myopathy is imbalance between muscle protein synthesis and breakdown.Transcription factor FoxO3a is a key factor regulating muscle protein breakdown. The activity of FoxO3a is regulated namely by phosphorylation via PI3K/Akt pathway. Active, phosphorylated Akt catalyzes the phosphorylation and thus inactivation of FoxO3a. The purpose of our study was to evaluate the effect of atorvastatin on FoxO3a and Akt in different skeletal muscles in rats with diet-induced hypercholesterolemia. Atorvastatin (20 mg/kg b.w./day) or the vehicle was administered orally 21 days. FoxO3a, Akt and their phosphorylated protein levels were assayed by Western blot in gastrocnemius and soleus muscle. Additionally, muscle total protein level and serum CK activity were measured. In the gastrocnemius muscle atorvastatin decreased total FoxO3a and P-FoxO3a levels with no changes in Akt and P-Akt level. In contrast, in soleus muscle atorvastatin did not change the level of P-FoxO3a. However, total FoxO3a and the P-Akt level decreased. Serum CK activity did not change in both muscle under atorvastatin treatment. In conclusion, the results of our study indicate that atorvastatin affects FoxO3a and Akt in a muscle type-dependent manner.

Abstract 16715: Rare or Disregarded; A Case of Autoimmune Myopathy

Introduction: Statin-induced myopathy can present with symptoms ranging from mild myalgia to significant muscle weakness. This case report highlights how statin-induced autoimmune myopathy often goes undiagnosed. Case Presentation: We present a 69 year old male with a past medical history of coronary artery disease who presented with myalgia and progressive proximal muscle weakness for 2 months. On admission, creatinine kinase (CK) level was noted to be elevated at 8323 u/L. Atorvastatin was held on admission and the patient received intravenous (IV) fluid as treatment for presumed rhabdomyolysis. Although CK was trending down, the patient did not show any significant improvement in muscle weakness or myalgia. At this point, myositis was suspected, so a myositis panel including anti-HMG Co-A Reductase antibody was ordered and the patient was started on IV steroids. Anti-HMG Co-A Reductase antibody was positive and the rest of myopathy workup was negative; meanwhile, the patient's muscle weakness significantly improved. The patient was discharged on a methylprednisolone with close outpatient rheumatology follow-up. Discussion: Drug-induced rhabdomyolysis is one of many causes of myalgia. It is crucial to review a patient’s medication list and discontinue any possible medications that are possible offenders. Statin-induced myopathy should also be suspected when typical treatment for rhabdomyolysis is failing. Statin induced autoimmune myopathy is associated with muscle weakness, elevated CK and a positive anti-HMG Co-A Reductase antibody, which requires discontinuation of Statin and initiation of immunosuppressive therapy. Conclusions: This case report highlights the importance of early identification and management of statin-induced autoimmune myopathy as a possible differential diagnosis in patients with muscle weakness, elevated CK levels while on statin therapy who do not respond to IV fluid alone.

Statin-Induced Myopathy

Scientific relevance. Being the main class of medicinal products for dyslipidaemia treatment, statins are widely used in clinical practice in various patient populations. However, statins can cause statin-associated muscle symptoms (SAMS), which are the most frequent and, in some cases, even life-threatening adverse reactions associated with these medicinal products.Aim. The study aimed to perform a systematic review of the epidemiology, classification, and physiological pathogenesis of SAMS, risk factors for this complication, and clinical guidelines for primary care physicians regarding the identification and treatment of patients with SAMS.Discussion. SAMS is an umbrella term that covers various forms of myopathies associated with satin therapy. According to the published literature, the prevalence of SAMS varies considerably and may depend on the study design, inclusion criteria, and the medicinal product used. SAMS has multiple putative pathogenic pathways that include genetically determined processes, abnormalities in mitochondrial function, defects in intracellular signalling and metabolic pathways, and immune-mediated reactions. The main known risk factors for developing SAMS include high-dose statins, drug–drug interactions, genetic polymorphisms, female sex, older age, Asian race, history of kidney, liver, and muscle disease, and strenuous physical activity. Given the lack of universally recognised algorithms for diagnosing SAMS, clinicians should consider the clinical presentation and the temporal relationship between statin therapy and symptoms. Other factors to consider include changes in muscle-specific enzyme levels and, in some cases, the results of blood tests for antibodies to 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase.Conclusions. To ensure the safety of statin therapy, it is essential to raise clinicians’ awareness of the risk factors for SAMS, indicative clinical and laboratory findings, and the need for dynamic patient monitoring, including the involvement of clinical pharmacologists.

Rosuvastatin-induced myopathy in a case of undiagnosed Vitamin D deficiency

For patients who qualify, statins are among the most frequently prescribed drugs for the primary and secondary prevention of cardiovascular disease. A wide range of clinical manifestations, from generalized muscle aches to severe necrotizing myositis, are present in statin-induced myopathy. Here, we present a case of a 49-year-old woman with Vitamin D deficiency who developed statin-induced myopathy 45 days after starting rosuvastatin. A 49-year-old female was admitted to the hospital with a history of lower back pain and bilateral lower limb pain for 7 days. Her ongoing medications include ticagrelor 90 mg BD, metoprolol 25 mg OD, nicorandil 5 mg BD, telmisartan 20 mg OD, dapagliflozin 10 mg OD, metformin 1000 mg OD, vildagliptin 100 mg OD, pantoprazole 40 mg OD, and rosuvastatin 40 mg OD, which were started 45 days back when she was diagnosed with ischemic heart disease. On neurological evaluation, muscle weakness was present in the lower extremities with proximal muscle involvement more than the distal muscle, power at the hip was 2/5, knee and ankle joint were 4/5, knee and ankle reflex were 2/5, and the plantar reflex was normal, with no upper limb involvement. Laboratory investigation on the day of admission revealed elevated creatine phosphokinase (9873.00 U/L) and serum creatinine (2.45 mg/dl). Arterial blood gas analysis revealed a high anion gap with increased lactate levels. Vitamin D levels were found to be insufficient, and serum calcium was in the low normal range. Magnetic resonance imaging of the bilateral lower limb revealed bilaterally symmetrical abnormal edematous signal in muscles of the gluteal region, extensor, adductor, and flexor compartment indicative of myopathy. Volitional testing revealed the presence of spontaneous activity, and an electromyography study revealed that the interference pattern was complete with early recruitment, similar to what is seen in inflammatory myopathy. The motor unit action potential was polyphasic with short duration and amplitude. She was diagnosed with statin-induced myopathy with acute kidney injury. In this case, initiation of rosuvastatin and Vitamin D deficiency were the only positive associated factors that were responsible for myopathy and acute kidney injury and liver injury. Despite the reported incidence of myopathy and renal toxicity by rosuvastatin in the present era, rosuvastatin holds a major market across the globe. Although the case was successfully treated by withholding rosuvastatin, it added to significant morbidity and health-care costs. Therefore, this case report not only calls for increased pharmacovigilance when prescribing rosuvastatin but also adds to the already existing safety controversies surrounding this drug.

Dysfunctional endocannabinoid CB1 receptor expression and signaling contribute to skeletal muscle cell toxicity induced by simvastatin

Statins are the most prescribed lipid-lowering agents worldwide. Their use is generally safe, although muscular toxicity occurs in about 1 in 10.000 patients. In this study, we explored the role of the endocannabinoid system (ECS) during muscle toxicity induced by simvastatin. In murine C2C12 myoblasts exposed to simvastatin, levels of the endocannabinoids AEA and 2-AG as well the expression of specific miRNAs (in particular miR-152) targeting the endocannabinoid CB1 gene were increased in a time-dependent manner. Rimonabant, a selective CB1 antagonist, exacerbated simvastatin-induced toxicity in myoblasts, while only a weak opposite effect was observed with ACEA and GAT211, selective orthosteric and allosteric agonists of CB1 receptor, respectively. In antagomiR152-transfected myoblasts, simvastatin toxicity was in part prevented together with the functional rescue of CB1. Further analyses revealed that simvastatin in C2C12 cells also suppresses PKC and ERK signaling pathways, which are instead activated downstream of CB1 receptor stimulation, thus adding more insight into the mechanism causing CB1 functional inactivation. Importantly, simvastatin induced similar alterations in skeletal muscles of C57BL/6 J mice and primary human myoblasts. In sum, we identified the dysregulated expression of the endocannabinoid CB1 receptor as well as the impairment of its downstream signaling pathways as a novel pathological mechanism involved in statin-induced myopathy.

Molecular pharmacology of coenzyme Q10 in the context of treatment of hyperlipidemic conditions

Background. Therapy of hyperlipidemia with synthetic statin drugs is characterized by a number of side effects. In particular, statin-dependent myopathy occurs as a result of statin inhibition of biosynthesis of cofactor coenzyme Q10 (CoQ10), which plays a central role in the electron transport chains during adenosine triphosphate (ATP) synthesis in mitochondria.Objective: systematic analysis of scientific publications on CoQ10 pharmacology with an emphasis on its effect on the lipid profile.Material and methods. The analysis included 16,788 articles found by “coenzyme Q10 OR ubiquinone" query in the PubMed/MEDLINE biomedical publications database. Topological and metric big data analysis methods were used developed in the scientific school of Academician of the Russian Academy of Sciences Yu.I. Zhuravlev.Results. A much wider range of CoQ10 pharmacological effects was established than simply supporting ATP biosynthesis. Coenzyme Q10 exhibits pronounced lipid-lowering, anti-asthenic, and anti-inflammatory effects and can be successfully used in the treatment of asthenic conditions, cardiovascular pathology (including hyperlipidemia and statin-induced myopathy), carbohydrate metabolism disorders (insulin resistance), and diverse neurological diseases. CoQ10 supplements reduce mortality by 50% in patients with cardiovascular diseases, improve glycemic control in insulin resistance, kidney function, and are useful in the treatment of migraine and neurodegenerative pathologies (Parkinson's disease, etc.).Conclusion. Experimental data and evidence base indicate the potential of using CoQ10 in patients with hyperlipidemia and other cardiovascular system diseases.

A gene risk score using missense variants in SLCO1B1 is associated with earlier onset statin intolerance.

The efficacy of statin therapy is hindered by intolerance to the therapy, leading to discontinuation. Variants in SLCO1B1, which encodes the hepatic transporter OATB1B1, influence statin pharmacokinetics, resulting in altered plasma concentrations of the drug and its metabolites. Current pharmacogenetic guidelines require sequencing of the SLCO1B1 gene, which is more expensive and less accessible than genotyping. In this study, we aimed to develop an easy, clinically implementable functional gene risk score (GRS) of common variants in SLCO1B1 to identify patients at risk of statin intolerance. A GRS was developed from four common variants in SLCO1B1. In statin users from Tayside, Scotland, UK, those with a high-risk GRS had increased odds across three phenotypes of statin intolerance [general statin intolerance (GSI): ORGSI 2.42; 95% confidence interval (CI): 1.29-4.31, P=0.003; statin-related myopathy: ORSRM 2.51; 95% CI: 1.28-4.53, P=0.004; statin-related suspected rhabdomyolysis: ORSRSR 2.85; 95% CI: 1.03-6.65, P=0.02]. In contrast, using the Val174Ala genotype alone or the recommended OATP1B1 functional phenotypes produced weaker and less reliable results. A meta-analysis with results from adjudicated cases of statin-induced myopathy in the PREDICTION-ADR Consortium confirmed these findings (ORVal174Ala 1.99; 95% CI: 1.01-3.95, P=0.048; ORGRS 1.76; 95% CI: 1.16-2.69, P=0.008). For those requiring high-dose statin therapy, the high-risk GRS was more consistently associated with the time to onset of statin intolerance amongst the three phenotypes compared with Val174Ala (GSI: HRVal174Ala 2.49; 95% CI: 1.09-5.68, P=0.03; HRGRS 2.44; 95% CI: 1.46-4.08, P<0.001). Finally, sequence kernel association testing confirmed that rare variants in SLCO1B1 are associated with the risk of intolerance (P=0.02). We provide evidence that a GRS based on four common SLCO1B1 variants provides an easily implemented genetic tool that is more reliable than the current recommended practice in estimating the risk and predicting early-onset statin intolerance.

Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy

Statins are a mainstay intervention for cardiovascular disease prevention, yet their use can cause rare severe myopathy. HMG-CoA reductase, an essential enzyme in the mevalonate pathway, is the target of statins. We identified nine individuals from five unrelated families with unexplained limb-girdle like muscular dystrophy and bi-allelic variants in HMGCR via clinical and research exome sequencing. The clinical features resembled other genetic causes of muscular dystrophy with incidental high CPK levels (>1,000U/L), proximal muscle weakness, variable age of onset, and progression leading to impaired ambulation. Muscle biopsies in most affected individuals showed non-specific dystrophic changes with non-diagnostic immunohistochemistry. Molecular modeling analyses revealed variants to be destabilizing and affecting protein oligomerization. Protein activity studies using three variants (p.Asp623Asn, p.Tyr792Cys, and p.Arg443Gln) identified in affected individuals confirmed decreased enzymatic activity and reduced protein stability. In summary, we showed that individuals with bi-allelic amorphic (i.e., null and/or hypomorphic) variants in HMGCR display phenotypes that resemble non-genetic causes of myopathy involving this reductase. This study expands our knowledge regarding the mechanisms leading to muscular dystrophy through dysregulation of the mevalonate pathway, autoimmune myopathy, and statin-induced myopathy.