Statin-associated Muscle Symptoms Research Articles

Incidence of statin-associated muscle symptoms in patients taking statins with RYR1 or CACNA1S variants.

Background: Statins are commonly used medications. Variants in SLCO1B1, CYP2C9, and ABCG2 are known predictors of muscle effects when taking statins. More exploratory genes include RYR1 and CACNA1S, which can also be associated with disease conditions. Methods: Patients with pathogenic/likely pathogenic variants in RYR1 or CACNA1S were identified through an elective genomic testing program. Through chart review, patients with a history of statin use were assessed for statin-associated muscle symptoms (SAMS) along with collection of demographics and other known risk factors for SAMS. Results: Of the 23 patients who had a pathogenic or likely pathogenic RYR1 or CACNA1S variant found, 12 had previous statin use; of these, SAMS were identified in four patients. Conclusion: These data contribute to previous literature suggesting patients with RYR1 variants may have an increased SAMS risk. Additional research will be helpful in further investigating this relationship and providing recommendations.

Decoding the Intricacies of Statin-Associated Muscle Symptoms.

Hyperlipidemia is the major cardiovascular morbidity and mortality risk factor. Statins are the first-line treatment for hyperlipidemia. Statin-associated muscle symptoms (SAMS) are the main reason for the discontinuation of statins among patients. The purpose of this review is to guide clinicians to recognize the difference between self-limited and autoimmune statin myopathy in addition to the factors that potentiate them. Finally, treatment strategies will be discussed. This review mostly focuses on new data in the past 3 years. Recent findings suggest that SAMS is a complex and multifactorial condition that involves mitochondrial dysfunction, oxidative stress, and immune-mediated mechanisms. Effective management of SAMS requires a thorough evaluation of the patient's symptoms, risk factors, and medication history, as well as consideration of alternative treatment options. While statins are effective in reducing the risk of cardiovascular events, their use is associated with a range of adverse effects, including SAMS.

Development and Validation of the Pharmacological Statin-Associated Muscle Symptoms Risk Stratification Score Using Electronic Health Record Data.

Statin-associated muscle symptoms (SAMS) can lead to statin nonadherence. This paper aims to develop a pharmacological SAMS risk stratification (PSAMS-RS) score using a previously developed PSAMS phenotyping algorithm that distinguishes objective vs. nocebo SAMS using electronic health record (EHR) data. Using our PSAMS phenotyping algorithm, SAMS cases and controls were identified from Minnesota Fairview EHR, with the statin user cohort divided into derivation (January 1, 2010, to December 31, 2018) and validation (January 1, 2019, to December 31, 2020) cohorts. A Least Absolute Shrinkage and Selection Operator regression model was applied to identify significant features for PSAMS. PSAMS-RS scores were calculated and the clinical utility of stratifying PSAMS risk was assessed by comparing hazard ratios (HRs) between fourth vs. first score quartiles. PSAMS cases were identified in 1.9% (310/16,128) of the derivation and 1.5% (64/4,182) of the validation cohorts. Sixteen out of 38 clinical features were determined to be significant predictors for PSAMS risk. Patients within the fourth quartile of the PSAMS scores had an over sevenfold (HR: 7.1, 95% confidence interval (CI): 4.03-12.45, derivation cohort) or sixfold (HR: 6.1, 95% CI: 2.15-17.45, validation cohort) higher hazard of developing PSAMS vs. those in their respective first quartile. The PSAMS-RS score is a simple tool to stratify patients' risk of developing PSAMS after statin initiation which could inform clinician-guided pre-emptive measures to prevent PSAMS-related statin nonadherence.

Skeletal muscle mitochondrial capacity in patients with statin-associated muscle symptoms (SAMS)

ObjectiveThe objective of this article is to evaluate near-infrared spectroscopy (NIRS), a non-invasive technique to assess tissue oxygenation and mitochondrial function, as a diagnostic tool for statin-associated muscle symptoms (SAMS).MethodsWe...

Effect of statin treatment on metabolites, lipids and prostanoids in patients with Statin Associated Muscle Symptoms (SAMS).

Between 5-10% of patients discontinue statin therapy due to statin-associated adverse reactions, primarily statin associated muscle symptoms (SAMS). The absence of a clear clinical phenotype or of biomarkers poses a challenge for diagnosis and management of SAMS. Similarly, our incomplete understanding of the pathogenesis of SAMS hinders the identification of treatments for SAMS. Metabolomics, the profiling of metabolites in biofluids, cells and tissues is an important tool for biomarker discovery and provides important insight into the origins of symptomatology. In order to better understand the pathophysiology of this common disorder and to identify biomarkers, we undertook comprehensive metabolomic and lipidomic profiling of plasma samples from patients with SAMS who were undergoing statin rechallenge as part of their clinical care. We report our findings in 67 patients, 28 with SAMS (cases) and 39 statin-tolerant controls. SAMS patients were studied during statin rechallenge and statin tolerant controls were studied while on statin. Plasma samples were analyzed using untargeted LC-MS metabolomics and lipidomics to detect differences between cases and controls. Differences in lipid species in plasma were observed between cases and controls. These included higher levels of linoleic acid containing phospholipids and lower ether lipids and sphingolipids. Reduced levels of acylcarnitines and altered amino acid profile (tryptophan, tyrosine, proline, arginine, and taurine) were observed in cases relative to controls. Pathway analysis identified significant increase of urea cycle metabolites and arginine and proline metabolites among cases along with downregulation of pathways mediating oxidation of branched chain fatty acids, carnitine synthesis, and transfer of acetyl groups into mitochondria. The plasma metabolome of patients with SAMS exhibited reduced content of long chain fatty acids and increased levels of linoleic acid (18:2) in phospholipids, altered energy production pathways (β-oxidation, citric acid cycle and urea cycles) as well as reduced levels of carnitine, an essential mediator of mitochondrial energy production. Our findings support the hypothesis that alterations in pro-inflammatory lipids (arachidonic acid pathway) and impaired mitochondrial energy metabolism underlie the muscle symptoms of patients with statin associated muscle symptoms (SAMS).

No benefit of vitamin D supplementation on muscle function and health-related quality of life in primary cardiovascular prevention patients with statin-associated muscle symptoms: A randomized controlled trial

Statins are the leading lipid-lowering drugs, reducing blood cholesterol by controlling its synthesis. Side effects are linked to the use of statins, in particular statin-associated muscle symptoms (SAMS). Some data suggest that vitamin D supplementation could reduce SAMS. The purpose of this study was to evaluate the potential benefits of the vitamin D supplement in a randomized controlled trial. Men (n=23) and women (n=15) (50.5 ± 7.7 years [mean ± SD]) in primary cardiovascular prevention, self-reporting or not SAMS, were recruited. Following 2 months of statin withdrawal, patients were randomized to supplementation (vitamin D or placebo). After 1 month of supplementation, statins were reintroduced. Before and 2 months after drug reintroduction, muscle damage (creatine kinase and myoglobin) was measured. Force (F), endurance (E) and power (P) of the leg extensors (ext) and flexors (fle) and handgrip strength (FHG) were also measured with isokinetic and handheld dynamometers, respectively. The Short Form 36 Health Survey (SF-36) questionnaire and a visual analog scale (VAS) were administrated to assess participants' self-reported health-related quality of life and SAMS intensity, respectively. Repeated-measures analysis was used to investigate the effects of time, supplementation, and their interaction, according to the presence of SAMS. Despite no change for objective measures, subjective measures worsened after reintroduction of statins, independent of supplementation (VAS, SF-36 mental component score, all p < 0.05). However, no interaction between time and supplementation according to the presence of SAMS was observed for any variables. Vitamin D supplementation does not appear to mitigate SAMS.

Potential role of geranylgeraniol in managing statin-associated muscle symptoms: a COVID-19 related perspective.

Myopathy is the most common side effect of statins, but it has not been addressed effectively. In anticipation of its wider use as a small molecule to complement the current COVID-19 management, a pharmacological solution to statin-associated muscle symptoms (SAMS) is warranted. Statins act by suppressing the mevalonate pathway, which in turn affects the downstream synthesis of isoprenoids required for normal physiological functions. CoQ10 and geranylgeraniol (GG) syntheses are reduced by statin use. However, CoQ10 supplementation has not been shown to reverse SAMS. GG is an obligatory substrate for CoQ10 synthesis, an endogenous nutrient critical for skeletal muscle protein synthesis. Multiple studies showed GG supplementation is effective in reversing SAMS. This opinion paper proposes employing GG to prevent SAMS in pleiotropic statin use, including usage in the post-COVID-19 pandemic era.

Prescribing statin therapy in physically (in)active individuals vs prescribing physical activity in statin-treated patients: A four-scenario practical approach

Statins are among the most commonly prescribed medications worldwide. Statin-associated muscle symptoms (SAMS) represent a frequent statin-related adverse effect associated with statin discontinuation and increased cardiovascular disease (CVD) events. Emerging evidence indicate that the majority of SAMS might not be actually caused by statins, and the nocebo/drucebo effect (i.e. adverse effects caused by negative expectations) might also explain SAMS. Physical activity (PA) is a cornerstone in the management of CVD risk. However, evidence of increased creatine-kinase levels in statin-treated athletes exposed to a marathon has been generalized, at least to some extent, to the general population and other types of PA. This generalization is likely inappropriate and might induce fear around PA in statin users. In addition, the guidelines for lipid management focus on aerobic PA while the potential of reducing sedentary behavior and undertaking resistance training have been overlooked. The aim of this report is to provide a novel proposal for the concurrent prescription of statin therapy and PA addressing the most common and clinically relevant scenarios by simultaneously considering the different stages of statin therapy and the history of PA. These scenarios include i) statin therapy initiation in physically inactive patients, ii) PA/exercise initiation in statin-treated patients, iii) statin therapy initiation in physically active patients, and iv) statin therapy in athletes and very active individuals performing SAMS-risky activities.

Genetic polymorphisms in ABCB1 are correlated with the increased risk of atorvastatin-induced muscle side effects: a cross-sectional study

Genetic factors are recognized as risk factors for statin-associated muscle symptoms (SAMS), which are the most common cause of statin intolerance. The aim of this study was to determine whether there is an association between polymorphisms 1236C > T, 2677G > T/A, and 3435C > T in the ABCB1 gene, encoding the efflux transporter of statins, and SAMS, as results on this topic are still controversial. A cross-sectional study was conducted on patients with or without SAMS using atorvastatin. The influence of non-genetic variables on SAMS was also evaluated. Our results show that patients with TT genotype in 1236C > T, 2677G > T/A, and 3435C > T polymorphisms had higher risk of developing SAMS, compared to wild type and heterozygous carriers together (OR 4.292 p = 0.0093, OR 5.897 p = 0.0023 and OR 3.547 p = 0.0122, respectively). Furthermore, TTT/TTT diplotype was also associated with a higher risk of SAMS, OR 9.234 (p = 0.0028). Only family history of cardiovascular disease was found to be a risk factor for SAMS, in addition to the known non-genetic variables. We believe that ABCB1 genotyping has great potential to be incorporated into clinical practice to identify high-risk patients in a timely manner.

Development and application of pharmacological statin-associated muscle symptoms phenotyping algorithms using structured and unstructured electronic health records data.

Statins are widely prescribed cholesterol-lowering medications in the United States, but their clinical benefits can be diminished by statin-associated muscle symptoms (SAMS), leading to discontinuation. In this study, we aimed to develop and validate a pharmacological SAMS clinical phenotyping algorithm using electronic health records (EHRs) data from Minnesota Fairview. We retrieved structured and unstructured EHR data of statin users and manually ascertained a gold standard set of SAMS cases and controls using the published SAMS-Clinical Index tool from clinical notes in 200 patients. We developed machine learning algorithms and rule-based algorithms that incorporated various criteria, including ICD codes, statin allergy, creatine kinase elevation, and keyword mentions in clinical notes. We applied the best-performing algorithm to the statin cohort to identify SAMS. We identified 16 889 patients who started statins in the Fairview EHR system from 2010 to 2020. The combined rule-based (CRB) algorithm, which utilized both clinical notes and structured data criteria, achieved similar performance compared to machine learning algorithms with a precision of 0.85, recall of 0.71, and F1 score of 0.77 against the gold standard set. Applying the CRB algorithm to the statin cohort, we identified the pharmacological SAMS prevalence to be 1.9% and selective risk factors which included female gender, coronary artery disease, hypothyroidism, and use of immunosuppressants or fibrates. Our study developed and validated a simple pharmacological SAMS phenotyping algorithm that can be used to create SAMS case/control cohort to enable further analysis which can lead to the development of a SAMS risk prediction model.

PCSK9 Inhibitor Therapy as an Alternative for Statin Intolerance

Scientific relevance. The main cause of cardiovascular pathologies is atherosclerosis, which is secondary to lipid metabolism disorders, in particular, the accumulation of low-density lipoprotein (LDL) cholesterol. Dyslipidaemia treatment with the largest evidence base predominantly includes statins in combination therapy, but their use is limited by into lerance in some patients. Alternatively, the treatment may include proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.Aim. The study aimed to analyse the applicability of PCSK9 inhibitors in patients with statin intolerance.Discussion. According to the literature analysis, the most common presentation of statin intolerance is statin-associated muscle symptoms. The pathogenesis of statin-associated adverse events is mainly mediated by HMGCoA reductase inhibition, treatment effects on cellular and subcellular processes and skeletal muscles, and patients’ genetic makeup. The mechanism of action of PCSK9 inhibitors is entirely different and involves binding and inactivation of the PCSK9 protein, which lowers blood LDL cholesterol levels. PCSK9 inhibitors have been associated with some adverse drug reactions, most notably immunogenicity; however, PCSK9 inhibitors effectively reduce LDL levels even if patients develop antibodies.Conclusions. Therefore, PCSK9 inhibitors are a safe, well-tolerated, and effec tive therapeutic strategy for hyperlipidaemia in patients with statin intolerance.

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.

Rapidly Occurring Statin-Associated Muscle Symptoms With Rosuvastatin.

Rapidly Occurring Statin-Associated Muscle Symptoms With Rosuvastatin.

Positivity of statin-associated muscle symptoms – Clinical index in a hypertensive population candidated to lipid-lowering therapy but not taking statins

Positivity of statin-associated muscle symptoms – Clinical index in a hypertensive population candidated to lipid-lowering therapy but not taking statins

Development and validation of an eco-friendly HPLC–UV method for determination of atorvastatin and vitamin D3 in pure form and pharmaceutical formulation

Statin-associated muscle symptoms are considered as obvious adverse effects of prolonged statin therapy such as myopathy, myalgia, and rhabdomyolysis. These side effects are associated with vitamin D3 deficiency and can be adjusted by amendment of serum vitamin D3 level. Green chemistry aims to decrease the harmful effects of analytical procedures. Here we have developed a green and eco-friendly HPLC method for the determination of atorvastatin calcium and vitamin D3. The two drugs were separated in less than 10 min on Symmetry column C18 (100 × 4.6 mm, 3.5 µm) using a mixture consisting of 0.1% ortho-phosphoric acid (OPA) (pH = 2.16) and ethanol as the mobile phase in gradient manner. We have used Green Analytical Procedure Index (GAPI) tools and the Analytical GREEnness Metric Approach (AGREE) for assessment of the greenness of our proposed method. The method proved linearity over concentration ranges of (5–40) and (1–8) µg/ml with low limit of detection of 0.475 and 0.041 µg/ml for atorvastatin calcium and vitamin D3 respectively. The method was successfully validated in accordance with ICH instructions and utilized for determination of the drugs of interest either in pure form or in their pharmaceuticals.

Histological Study for the Effect of Squalene Supplements on Muscles Rats Treated with Simvastatin

The present study aimed to reveal the biological vitality of squalene supplements and in combination with statins. Statins are a class of drugs that are regularly administered to decrease cholesterol. The main cause of statin discontinuation is the development of statin-associated muscle symptoms. Because of the statin-related myotoxicity phenotypes that are getting worse have been proposed, the study was conducted to examine the effects of squalene supplements in combination with statin. In the experiment, thirty male rats were divided into two group, (experimental one) five rats dosage with normal saline only and other rats administrated with cholesterol 1%/BW for 28 days. Then the second group was randomly divided into four groups (experimental two). The experiment lasted about during two months, the rats were administration as the following groups, first group: six rats used as a negative control group dosage with normal saline only; second group: six rats used as a positive control group dosage with normal cholesterol 1% only; third group: six rats administrated with cholesterol 1%/BW for 28 days then treated with simvastatin 40 mg/kg dosage orally every day for 4 weeks; forth group: six rats administrated with cholesterol 1%/BW for 28 days then treated with squalene 0.2 mg orally every day for 28 day, and fifth group: six rats will have administrated with cholesterol 1%/BW for 28 days then treated with simvastatin 40 mg/kg dosage orally with squalene every day for 28 day. In conclusion: we found from the study effect of squalene supplements on rats treated with statin to avoid side effect and protecting the muscles from damage caused by statin.

Impact of statin withdrawal on perceived and objective muscle function.

Statin-associated muscle symptoms (SAMS) are frequently reported. Nevertheless, few data on objective measures of muscle function are available. Recent data suggesting an important nocebo effect with statin use could confound such effects. The objective was to assess if subjective and objective measures of muscle function improve after drug withdrawal in SAMS reporters. Patients (59 men, 33 women, 50.3±9.6 yrs.) in primary cardiovascular prevention composed three cohorts: statin users with (SAMS, n = 61) or without symptoms (No SAMS, n = 15), and controls (n = 16) (registered at clinicaltrials.gov, NCT01493648). Force (F), endurance (E) and power (P) of the leg extensors (ext) and flexors (fle) and handgrip strength (Fhg) were measured using isokinetic and handheld dynamometers, respectively. A 10-point visual analogue scale (VAS) was used to self-assess SAMS intensity. Measures were taken before and after two months of withdrawal. Following withdrawal, repeated-measures analyses show improvements for the entire cohort in Eext, Efle, Ffle, Pext and Pfle (range +7.2 to +13.3%, all p≤0.02). Post-hoc analyses show these changes to occur notably in SAMS (+8.8 to +16.6%), concurrent with a decrease in subjective perception of effects in SAMS (VAS, from 5.09 to 1.85). Fhg was also improved in SAMS (+4.0 to +6.2%) when compared to No SAMS (-1.7 to -4.2%) (all p = 0.02). Whether suffering from "true" SAMS or nocebo, those who reported SAMS had modest but relevant improvements in muscle function concurrent with a decrease in subjective symptoms intensity after drug withdrawal. Greater attention by clinicians to muscle function in frail statin users appears warranted. This study is registered in clinicaltrials.gov (NCT01493648).

Restarting statins in a specialist lipid clinic setting

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Health Research Board. Background Statin therapy remains a gold standard in the primary and secondary prevention of cardiovascular disease (CVD).[1] Poor statin compliance and discontinuation due to statin intolerance (SI) remains a pervasive clinical issue.[1] Research has demonstrated that the prevalence of SI is overestimated with most SI symptoms being nocebo.[2-3] Our practice involves a patient centred intervention to restart statins with four components: 1) careful exclusion of differential diagnoses 2) an in-person discussion regarding SI based on contemporary evidence 3) an incremental introduction of statins starting at the lowest dose 4) virtual follow up to ensure implementation of the therapeutic plan. The aim of this study was to assess the effectiveness of this intervention in terms of statin reintroduction and subsequent cholesterol levels. Methods An ethically approved retrospective chart review was performed of consecutive adult patients attending a specialist lipid clinic over a six-month period in 2021. Patient data recorded included demographics, clinical characteristics, treatment received and biochemical profiles. Statistical analysis was performed using the Student T-test. Results This study included 370 patients. SI prevalence was 25% with 10% referred explicitly for SI. Patients with SI were predominantly female (71%). Statin-associated muscle symptoms were the most common SI (62%). Statin therapy was restarted in 48% of patients [Rosuvastatin: (62%), Simvastatin: (16%), Atorvastatin: (13%), Pravastatin: (9%)]. Restarting a statin demonstrated significantly improved mean reductions in both total cholesterol (TC) (P = 0.007) and low-density lipoprotein C (LDL-C) (P&amp;lt; 0.001) levels versus management with or without alternative lipid-lowering agents [primarily ezetimibe (30%)]. Statin restart: (TC mean reduction: 3.17 ± 2.27 mmol/L, LDL-C mean reduction: 2.93 ± 1.77 mmol/L). Management with or without alternative lipid-lowering agents: [TC mean reduction: 1.61 ± 1.46 mmol/L, LDL-C: 1.35 ± 0.93 mmol/L]. Conclusion This study highlights the prevalence of SI among patients attending a lipid clinic. Statins were successfully restarted in half of presenting cases and conferred significant improvement in both TC and LDL-C levels compared to management with or without alternative lipid-lowering agents. Interventions for SI are warranted given the high prevalence of nocebo effect and the undoubted benefits of statin treatment. Ideally such interventions should be replicated in a primary care setting.

Physical activity levels and statin therapy: differences between symptomatic and asymptomatic statin users

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Combining statin treatment and physical activity is highly effective to reduce cardiovascular diseases. Statin use may exacerbate statin-associated muscle symptoms (SAMS), making an active lifestyle more difficult for statin users. It is, however, unknown whether daily activity patterns differ between symptomatic and asymptomatic statin users. Purpose To objectively assess physical activity levels and sedentary time and compare these between long-term statin users with or without muscle complaints. Methods Ninety-seven symptomatic (66±9 years, 74% male) and 97 asymptomatic statin users, matched for age and gender in a 1:1 ratio, were recruited from general practitioners offices. Physical activity patterns were measured using the activPAL3 micro monitor, which was attached to the upper right thigh. Participants wore the activity monitor 24 hours per day during 7 consecutive days and were asked to maintain normal daily activities. Results Symptomatic statin users performed less physical activity of moderate to vigorous intensity per day (61.1 min, IQR: 43.1-77.0 min) compared to asymptomatic statin users (69.1 min, IQR: 50.7-94.6 min; P=0.02). There were no differences in physical activity levels of light intensity or sedentary time between the statin groups. Symptomatic statin users took less steps per day (7560 steps, IQR: 5649-9692 steps) compared to asymptomatic statins users (8721 steps, IQR 6306-11791 steps; P=0.02). Conclusion Symptomatic statin users have reduced levels of physical activity compared to asymptomatic statin users. These findings highlight the clinical relevance to explore possibilities for symptomatic statin users to increase physical activity levels and the associated health benefits.

Atorvastatin lactone/acid ratios are promising biomarkers for statin dependent muscular side effects in patients with coronary heart disease

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Vestre Viken Hospital Trust. Background In clinical practice, it is challenging and time-consuming to assess whether self-perceived statin associated muscle symptoms (SAMS) are caused by the statin or not, and diagnostic biomarkers are therefore requested [1]. Atorvastatin (ATV) metabolites, especially the lactones, have been associated with statin dependent muscular side effects [2, 3]. Purpose To assess ATV metabolites as potential diagnostic biomarkers for statin dependent muscular side effects in skeletal muscle tissue and correspondingly in blood plasma among patients with coronary heart disease (CHD). Methods In 2020, an open biomarker follow-up study included 26 of 71 CHD patients with self-perceived SAMS who had participated in a randomised double-blinded crossover trial (ATV 40 mg/day and matched placebo) in 2019. Twelve participants reported significantly more symptoms during blinded treatment with ATV than during placebo, whereas the remaining 14 patients reported no differences in muscle symptoms between the treatment periods. In the biomarker study, all participants received open treatment with ATV 40 mg/day for seven weeks followed by no statins for eight weeks. Muscle biopsies were collected from the vastus lateralis of the quadriceps muscle after the ATV treatment period (n=26) and after the no-statin period (n=23). Blood was collected both pre-dose, at the time of biopsy (T0) and one hour after statin intake (T1). ATV and its five major metabolites were measured in muscle homogenate and blood plasma with liquid chromatography tandem mass spectrometry. A subgroup of four patients had histological signs of statin dependent muscle cell damage and three paitent did not tolerate any statins (n=2) or only pravastatin 20mg/day (n=1). These seven patients were categorised as having statin dependent muscular side effects. Mann-Whitney test and ROC-analyses were performed with SPSS. Results The lactone/acid ratios (ATV lactone/acid, 2OH-ATV lactone/acid, 4OH-ATV lactone/acid, sum lactones/sum acids) in muscle were all numerically higher in the seven patients than the rest. A similar pattern was found for plasma ratios at T0 and T1. The 2OH-ATV ratio and the sum ATV ratio in muscle were significantly different (p= 0.008 and p=0.022) between those with and without statin dependent side effects. The areas under the ROC curve (AUC) were 0.84 and 0.82, with sensitivity of 71% and 67%, and specificity of 90% and 94% (Table 1 and Figure 1). In plasma, the sum ATV ratio at T0 and T1 and the ATV lactone/acid ratio at T1 appeared as the best discriminators: with AUCs ranging from 0.74 to 0.83 and sensitivity and specificity estimates at 86% and 74%, respectively. Conclusions ATV lactone/acid ratios, measured in blood plasma one hour after atorvastatin intake, appear as promising biomarkers for statin dependent muscular side effects. Our study provides candidate cut-off values that should be pursued further for the determination of diagnostic sensitivity and specificity.