Statin-induced Myalgia Research Articles

Plasma statin concentrations do not correlate with statin-induced myalgia

Abstract Aims Statins are essential in cardiovascular prevention. Although well-tolerated, patient adherence is often suboptimal due to experienced musculoskeletal symptoms ranging from mild myalgia to rare life-threatening rhabdomyolysis. This study aimed to investigate the relationship between plasma concentrations of statin metabolites in patients experiencing myalgia without rhabdomyolysis. Methods and results Plasma concentrations of statin metabolites were quantitatively assessed using mass spectrometry across three case-control cohorts evaluating statin-induced myalgia. The analysis included a total of 373 patients from the MILANO study (N=85 with self -reported myalgia), the MONTREAL study (N=248 with clinically verified myalgia) and the STOMP study (N=40 with rechallenge-verified statin-induced myalgia). STOMP found no significant difference in the plasma concentrations of statin metabolites between statin naïve patients with myalgia (N=12) taking atorvastatin 80 mg daily and asymptomatic controls (N=28), including upon subsequent statin rechallenge. Both the MILANO and MONTREAL studies showed lower plasma concentrations of statin metabolites in patients with myalgias compared to controls. MILANO showed a significant difference in rosuvastatin lactone concentration in patients with myalgias compared to asymptomatic controls (P = 0.025). Similarly, MONTREAL showed significantly lower mean atorvastatin metabolite concentrations in affected patients versus controls (P values ranging from 0.0073 to 0.037). Atorvastatin dosages in MONTREAL ranged from 5 to 80 mg daily, the most frequent regimens being 20 mg (27% in cases; 24% in controls) and 40 mg (33% in cases; 37% in controls). Creatine kinase levels were measured in all cohorts and were not different between cases and controls. Conclusion Development of myalgias in patients with normal creatine kinase levels is not associated with higher statin metabolite plasma concentrations. Myalgias during statin therapy are not caused by pharmacokinetic abnormalities.

FRI097 A Case Of Evolocumab-induced Transaminitis Revealing A Gastrointestinal Melanoma

Abstract Disclosure: C. Nava Suarez: None. J.V. Mayrin: None. J. Prater: None. W. Jiang: None. Introduction: Proprotein convertase subtilisin/Kexin type 9 (PCSK-9) inhibitors, like evolocumab, are anti-lipid drugs with potent lipid-lowering effect, potential cardiovascular benefits, and good tolerability. They are monoclonal antibodies directed against the PCSK-9 hepatic receptor decreasing serum LDL-cholesterol. Although PCSK-9 inhibitors are usually safe, transaminitis has been reported in the literature a few times. Little is known about the mechanism of action of this injury and many clinicians are not familiar with this complication. Currently, there are no guidelines for dose adjustment in patients with advanced liver disease, and conflicting data on their effect on patients with established liver disease is emerging. We report a case of acute and intermittent transaminitis with the use of evolocumab that lead to the discovery of malignant melanoma in the patient’s gallbladder and jejunum. Case: A 74-year-old male with a past medical history of dyslipidemia, type 2 Diabetes Mellitus, and cutaneous melanoma 9 years priorly presented for a routine follow-up. He had been on evolocumab for a year after developing statin-induced myalgias. His physical exam was unremarkable. Routine blood work revealed new onset transaminitis almost 5 times above the upper limit of normal with AST 174 IU/L and ALT 230 IU/L (40 IU/L and 44 IU/L respectively). The rest of his liver panel was unremarkable. A liver ultrasound showed a 5 cm hyperechoic polypoid lesion within the gallbladder. No signs of choledocholithiasis were seen, potentially explaining the lack of bilirubin elevation; hepatic steatosis without cirrhosis was also seen. Given its higher sensitivity, MRCP confirmed the gallbladder mass. Liver enzymes were trended for more than 80 days, and intermittent elevation of serum transaminases coincided with the administration of evolocumab with normalization of the transaminases in between episodes. An open cholecystectomy confirmed the diagnosis of malignant melanoma of the gallbladder with an incidental jejunal metastasis. Oncologic treatment was initiated. Serum transaminases normalized following discontinuation of evolocumab and remain normal. Conclusion: As this case illustrates, serial monitoring of transaminases can reveal the presence of liver injury after initiation of PCSK-9 inhibitors, and further investigation with specialized liver imaging should be considered to exclude other differential diagnoses. Currently, there is little known about the hepatotoxic effect of these drugs and researchers are currently looking for possible causes. Theoretical mechanisms of injury include autoimmune cross-reactivity like with other monoclonal antibodies or progression of chronic liver disease. Clinicians should be aware of this potential side effect even though it is not a common one, given that many patients who start treatment may have underlying liver disease. Presentation: Friday, June 16, 2023

The cholesterol-lowering effect of statins is modified by LILRB5 intolerance genotype: Results from a recruit-by-genotype clinical trial.

Background/Aims: Statin intolerance leads to poor adherence to statin therapy, resulting in a failure to achieve desired cholesterol reduction and adverse outcomes. The LILRB5 Asp247Gly genotype has been identified as being associated with statin intolerance and statin-induced myalgia. We conducted a randomized clinical trial to examine its role in immune response through T regulatory cell aggregation and in achieving cholesterol reduction targets. Methods: A double-blind, cross-over, recruit-by-genotype trial was undertaken. A total of 18 participants who had either the Asp247Asp (T/T) genotype or the Gly247Gly (C/C) genotype were recruited to the study. Participants were randomised to receive placebo or atorvastatin 80mg daily for 28days. Following a washout period of 3weeks, they were then switched to the opposite treatment. Biochemical and immunological measurements as well as interviews were performed prior to and after both treatment periods. Within genotype group comparisons were performed using repeated measures Wilcoxon tests. Two-way repeated measures ANOVA with genotype and treatment as factors were used to compare changes in biochemical parameters between groups during placebo and atorvastatin periods. Results: Individuals with the Asp247Asp genotype had a greater increase in creatine kinase (CK) compared to those with Gly247Gly genotype in response to atorvastatin (p = 0.03). Those with Gly247Gly genotype had a mean non-HDL cholesterol reduction of 2.44 (95% CI:1.59 - 3.29) mmol/L while in Asp247Asp genotype group the mean reduction was 1.28 (95%CI: 0.48 - 2.07) mmol/L. The interaction between the genotype and atorvastatin treatment for total cholesterol (p = 0.007) and non-HDL cholesterol response was significant (p = 0.025). Immunological assessment showed no significant changes in aggregation of T regulatory cells by genotype. Conclusion: The Asp247Gly variant in LILRB5, previously associated with statin intolerance, was associated with differential increases in creatine kinase and total cholesterol and non-HDL cholesterol-lowering response to atorvastatin. Taken together, these results suggest that this variant could have utility in precision cardiovascular therapy.

Interactions Between Statins, Exercise, and Health: A Clinical Update

Interactions Between Statins, Exercise, and Health: A Clinical Update

A Prospective Single-Center Study of Incidence of Atorvastatin-Induced Myalgia in Korean Patients: Application of the Statin Myalgia Clinical Index

Background: Statin-induced myalgia is a common cause of discontinuation and a barrier that interferes with long-term treatment. The incidence of myalgia reported by previous atorvastatin trials in Korea ranged from 0.8% to 3.4%. This study assessed the incidence of myalgia after atorvastatin was administered to Korean patients with dyslipidemia. In addition, the Statin Myalgia Clinical Index (SMCI) was used to assess the likelihood that a patient’s myalgia was caused by atorvastatin.Methods: Dyslipidemic patients were eligible to participate if they were statin-naïve or treated with statins other than atorvastatin. Muscle complaints were assessed at the baseline, the 10-weeks visit and the final follow-up visit (16 weeks or later). The SMCI score was calculated if a patient developed myalgia, which was rated as probable, possible or unlikely related to the statin.Results: A total of 89 patients were analyzed. The atorvastatin doses ranged from 10 to 80 mg. Six (7%) patients reported new and unexplained muscle pain. Information on the timing of myalgia relative to stopping was unavailable in two patients. After excluding these two patients, three (3.4%) out of 87 patients were classified by the SMCI as having possible or probable atorvastatin-associated myalgia.Conclusions: In this study, the incidence of myalgia was higher than the incidences reported by the previous trials in Korea. However, the incidence of statin-associated myalgia assessed using SMCI was comparable to those of the trials. The SMCI may help diagnosis of statin-associated myalgia in clinical practice and optimize treatment for patients with myalgia.

Statin Intolerance and Noncompliance: An Empiric Approach

Statin Intolerance and Noncompliance: An Empiric Approach

Muscular Adverse Events Associated with Statins

Statins are an important group of lipid lowering medications that have helped to control cardiovascular mortality globally. Muscular side effects, mostly myalgia, is a known adverse event of statins. Intense physical activity, kidney or liver failure, hypothyroidism, inherited or metabolic myopathies, and some medications, are risk factors for statin-induced myalgia. Muscular adverse events are more often observed with higher doses or with the use of lipophilic statins. Much is not known about the precise mechanisms responsible for the statin related muscular adverse effects, a few hypothesis have been suggested. It is important to measure plasma creatine phosphokinase in subjects who encounter myalgia while being treated with statins. In this review we present some general safety information on muscular adverse events caused due to statins.

PREVALENCE AND PREDICTORS OF ADVERSE DRUG REACTIONS IN OLDER HYPERTENSIVE ADULTS

Objective: Polipharmacy is common in older people, thus increasing the risk of adverse drufg reactrions. This study aimed to analyse prevalence and predictors of the most relevant adverse drug reactions in older hypertensive adults. Design and method: We retrospectively analysed data on antihypertensive- and statin-related adverse drug reactions in adults aged 65 or older evaluated at the Hypertension Clinic of Careggi Hospital, Florance, Italy, between January 2018 and December 2019. Predictors were investigated using multivariate logistic regression. Results: Of 262 participants (mean age 75.9 years, 55.3% female), the 19% of the patients taking ACE-inhibitors reported cough while 33.6% of the patients taking calcium channel blockers (CCB) reported peripheral edema, occuring more frequently of amlodipine. The prevalence of statin-related myalgia was 23.5%. At multivariate analysis SNRI antidepressants and gastroesophageal reflux disease (GERD) were predictive of ACE-inibitors induced cough (OR 16.220, 95% CI 1.243 – 211.621; OR 4.207, 95% CI 1.249 – 4.171, respectively) and angiotensin-receptor antagonists were associated with an increased risk of peripheral edema on CCB (OR 2.500, 95% CI 1.095 - 5.710). GERD was predictive for statin-induced myalgia (OR 6.737, 95% CI 1.530 - 29.662). Conclusions: ACE inhibitor-induced cough, CCB-related peripheral edema and statin-induced myalgia are common in older hypertensive adults. SNRI antidepressants and GERD are independently associated with ACE inhibitor-induced cough, while angiotensin-receptor antagonists are predictive of CCB-related peripheral edema. GERD is also associated with statin myalgia.

Atorvastatin-Induced Myalgia in Iranian Patients: A Hospital-Based Study to Determine the Prevalence and Associated Risk Factors

Background: Statins are associated with several muscle complaints, such as: myositis, myalgia, muscle weakness, muscle spasms and rhabdomyolysis. Age, race, gender, dose of statin, concomitant medications, concomitant disorders and genetics have been reported as the most important risk factor for statin-induced myalgia. The aim of this study was to determine the prevalence and associated risk factors of atorvastatin-induced myalgia in hospitalized patients in Tehran, Iran. Methods: In this cross sectional study, a questionnaire was developed by expert panel opinions. The questionnaire was included various items regarding demographic data and myalgia evaluation factors. Seven hundred patients were included in the study and necessary data were gathered. Finally, the data were analyzed and a statistical model was designed to predict the myalgia risk factors. Results: The rate of myalgia was 44.3% among studied patients. By developing a multivariate logistic model, female gender (OR= 0.47, P-value<0.001) was one of the most important factors in myalgia occurrence. Conclusion: The results of this study suggest that gender, age, atorvastatin dose, duration of atorvastatin usage and presence of myotoxic disease are the main predictors of myalgia in Iranian population. Hence, the findings of this study can be considered to predict the myalgia incidence risk in Iranian population.

Mitochondrial G12630A variation is associated with statin-induced myalgia in Chinese patients with coronary artery disease

To identify mitochondrial gene variants associated with statin-induced myalgia in Chinese patients with coronary artery disease (CHD). This study was conducted in a cohort of 403 patients with CHD receiving rosuvastatin therapy, among whom 341 patients had complete follow-up data concerning myalgia and 389 patients had documented measurements of plasma creatine kinase (CK) level. All these patients underwent genetic analysis using GSA chip for detecting mitochondria gene variants associated with myalgia. A logistic regression model was used to assess the association between 69 mitochondrial single-nucleotide polymorphisms (SNPs) and myopathy in 341 patients. The impact of these mutation sites on CK levels in 389 patients was evaluated by linear regression analysis. G12630A variant was identified to correlate with an increased risk of myalgia in CHD patients (OR: 8.689, 95% CI: 1.586-47.6; P=0.01273), but CK levels did not differ significantly between patients with different genotypes of G12630A (P > 0.05). SNPs at T12285C and A13105G were found to significantly correlate with CK levels in these patients (P < 0.05). Mitochondrial G12630A variation is associated with statin-induced myalgia in patients with CHD, indicating the necessity of different treatment strategies for patients who carry this risk allele.

Effect of fixed dose combination of vitamin d with atorvastatin on serum lipid levels in hyperlipidemic patients

Background: Hyperlipidemia is a well documented risk factor for atherosclerosis, responsible for significant amount of ischemic strokes and heart disease globally. Studies have shown that vitamin D supplementation with atorvastatin has synergistic effects in lowering serum cholesterol concentrations and ameliorating statin-induced myalgia and myopathy. Aim and objective: To estimate the effect of fixed dose combination of 1000 I.U of Vitamin D3 and Atorvastatin 10mg per day for 3 months on serum HDL, VLDL and Triglyceride values in hyperlipidemic patients compared to those on Atorvastatin 10 mg per day alone. Methodology: The study was a Prospective multiple arm analytical observational study. History and medical details and Data of serum lipid profile investigation, routinely checked at 6 weeks intervals in patients of cardiology department, were collected from the 97 recruited patients for 3 months after obtaining written informed consent from each patient. Results: The results of our study showed a significant reduction in VLDL and Triglyceride Cholesterol values in two study groups at 12 weeks compared to baseline. No significant difference was observed between the two groups. 83% of patients in the study showed a significant elevation of HDL Cholesterol from baseline after 3 weeks of treatment. The mean percentage increase in HDL values from baseline to 3 weeks in Atorvastatin –Vitamin D group showed a significant difference compared with the other group.

Comparison of statin-induced myalgia between atorvastatin and rosuvastatin and among different duration of treatment groups: An observational study in a tertiary care hospital of West Bengal

Comparison of statin-induced myalgia between atorvastatin and rosuvastatin and among different duration of treatment groups: An observational study in a tertiary care hospital of West Bengal

Statin administration activates system xC- in skeletal muscle: a potential mechanism explaining statin-induced muscle pain.

Statins are a cholesterol-lowering drug class that significantly reduce cardiovascular disease risk. Despite their safety and effectiveness, musculoskeletal side-effects, particularly myalgia, are prominent and the most common reason for discontinuance. The cause of statin-induced myalgia is unknown, so defining the underlying mechanism(s) and potential therapeutic strategies is of clinical importance. Here we tested the hypothesis that statin administration activates skeletal muscle system xC-, a cystine/glutamate antiporter, to increase intracellular cysteine and therefore glutathione synthesis to attenuate statin-induced oxidative stress. Increased system xC- activity would increase interstitial glutamate; an amino acid associated with peripheral nociception. Consistent with our hypothesis, atorvastatin treatment significantly increased mitochondrial reactive oxygen species (ROS; 41%) and glutamate efflux (up to 122%) in C2C12 mouse skeletal muscle myotubes. Statin-induced glutamate efflux was confirmed to be the result of system xC- activation, as cotreatment with sulfasalazine (system xC- inhibitor) negated this rise in extracellular glutamate. These findings were reproduced in primary human myotubes but, consistent with being muscle-specific, were not observed in primary human dermal fibroblasts. To further demonstrate that statin-induced increases in ROS triggered glutamate efflux, C2C12 myotubes were cotreated with atorvastatin and various antioxidants. α-Tocopherol and cysteamine bitartrate reversed the increase in statin-induced glutamate efflux, bringing glutamate levels between 50 and 92% of control-treated levels. N-acetylcysteine (a system xC- substrate) increased glutamate efflux above statin treatment alone: up to 732% greater than control treatment. Taken together, we provide a mechanistic foundation for statin-induced myalgia and offer therapeutic insights to alleviate this particular statin-associated side-effect.

Administration of Geranylgeraniol in a Rodent Model of Statin-Induced Myalgia Prevents Skeletal Muscle Damage Without Adversely Affecting Cardiovascular Performance

Administration of Geranylgeraniol in a Rodent Model of Statin-Induced Myalgia Prevents Skeletal Muscle Damage Without Adversely Affecting Cardiovascular Performance

Validation of a clinically-relevant rodent model of statin-associated muscle symptoms for use in pharmacological studies

Various rodent models of statin-associated muscle symptoms (SAMS) have been used to investigate the aetiology of statin myotoxicity. Variability between these models, however, may be contributing to the ambiguity currently surrounding the pathogenesis of SAMS. Furthermore, few studies have assessed the reproducibility of these models. The aim of this study was to compare two established rodent models of statin myotoxicity, differing in treatment duration and dose, to determine which reproducibly caused changes characteristic of SAMS. Isolated skeletal muscle organ bath experiments, biochemical analyses, real-time quantitative-PCR and biometric assessments were used to compare changes in skeletal muscle and renal integrity in statin-treated animals and time-matched control groups. The SIM80 model (80 mg kg−1 day−1 simvastatin for 14 days) produced fibre-selective skeletal muscle damage characteristic of SAMS. Indeed, fast-twitch gastrocnemius muscles showed increased Atrogin-1 expression, reduced peak force of contraction and decreased Myh2 expression while slow-twitch soleus muscles were unaffected. Contrastingly, the SIM50 model (50 mg kg−1 day−1 simvastatin for 30 days) produced little evidence of significant skeletal muscle damage. Neither statin treatment protocol caused significant pathological changes to the kidney. The results of this study indicate that the SIM80 model induces a type of SAMS in rodents that resembles the presentation of statin-induced myalgia in humans. The findings support that the SIM80 model is reproducible and can thus be reliably used as a platform to assess the aetiology and treatment of this condition.

Clinical Approach to Statin-Induced Adverse Muscle Events: Challenges and Solutions

Statin-associated adverse muscle events play an important role in statin non adherence and discontinuation. Aspects of this clinical challenge including a lack of a uniform definition of statin-induced myalgia, the “nocebo” effect and its’ role in statin-induced adverse muscle events, pre-existing medical and lifestyle factors that can affect statin therapy, and restarting statin use in patients after prior discontinuation of statin therapy due to adverse muscle effects. This paper applies the recommendations of the National Lipid Association’s Statin Muscle Safety Task Force along with other studies to propose solutions for these challenges that statin-induced adverse muscle events present. Future large randomized controlled trials will be necessary for validation of these clinical interventions.

A common missense variant of LILRB5 is associated with statin intolerance and myalgia.

AimsA genetic variant in LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B) (rs12975366: T > C: Asp247Gly) has been reported to be associated with lower creatine phosphokinase (CK) and lactate dehydrogenase (LDH) levels. Both biomarkers are released from injured muscle tissue, making this variant a potential candidate for susceptibility to muscle-related symptoms. We examined the association of this variant with statin intolerance ascertained from electronic medical records in the GoDARTS study.Methods and resultsIn the GoDARTS cohort, the LILRB5 Asp247 variant was associated with statin intolerance (SI) phenotypes; one defined as having raised CK and being non-adherent to therapy [odds ratio (OR) 1.81; 95% confidence interval (CI): 1.34–2.45] and the other as being intolerant to the lowest approved dose of a statin before being switched to two or more other statins (OR 1.36; 95% CI: 1.07–1.73). Those homozygous for Asp247 had increased odds of developing both definitions of intolerance. Importantly the second definition did not rely on CK elevations. These results were replicated in adjudicated cases of statin-induced myopathy in the PREDICTION-ADR consortium (OR1.48; 95% CI: 1.05–2.10) and for the development of myalgia in the JUPITER randomized clinical trial of rosuvastatin (OR1.35, 95% CI: 1.10–1.68). A meta-analysis across the studies showed a consistent association between Asp247Gly and outcomes associated with SI (OR1.34; 95% CI: 1.16–1.54).ConclusionThis study presents a novel immunogenetic factor associated with statin intolerance, an important risk factor for cardiovascular outcomes. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a potential role for the immune system in their development. We identify a genetic group that is more likely to be intolerant to their statins.

Patients experiencing statin-induced myalgia exhibit a unique program of skeletal muscle gene expression following statin re-challenge.

Statins, the 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors, are widely prescribed for treatment of hypercholesterolemia. Although statins are generally well tolerated, up to ten percent of statin-treated patients experience myalgia symptoms, defined as muscle pain without elevated creatinine phosphokinase (CPK) levels. Myalgia is the most frequent reason for discontinuation of statin therapy. The mechanisms underlying statin myalgia are not clearly understood. To elucidate changes in gene expression associated with statin myalgia, we compared profiles of gene expression in skeletal muscle biopsies from patients with statin myalgia who were undergoing statin re-challenge (cases) versus those of statin-tolerant controls. A robust separation of case and control cohorts was revealed by Principal Component Analysis of differentially expressed genes (DEGs). To identify putative gene expression and metabolic pathways that may be perturbed in skeletal muscles of patients with statin myalgia, we subjected DEGs to Ingenuity Pathways (IPA) and DAVID (Database for Annotation, Visualization and Integrated Discovery) analyses. The most prominent pathways altered by statins included cellular stress, apoptosis, cell senescence and DNA repair (TP53, BARD1, Mre11 and RAD51); activation of pro-inflammatory immune response (CXCL12, CST5, POU2F1); protein catabolism, cholesterol biosynthesis, protein prenylation and RAS-GTPase activation (FDFT1, LSS, TP53, UBD, ATF2, H-ras). Based on these data we tentatively conclude that persistent myalgia in response to statins may emanate from cellular stress underpinned by mechanisms of post-inflammatory repair and regeneration. We also posit that this subset of individuals is genetically predisposed to eliciting altered statin metabolism and/or increased end-organ susceptibility that lead to a range of statin-induced myopathies. This mechanistic scenario is further bolstered by the discovery that a number of single nucleotide polymorphisms (e.g., SLCO1B1, SLCO2B1 and RYR2) associated with statin myalgia and myositis were observed with increased frequency among patients with statin myalgia.

Significant association between statin-associated myalgia and vitamin D deficiency among treated HIV-infected patients.

Several studies have shown a significant association between vitamin D deficiency and an increased risk of statin-related symptomatic myalgia in the general population, but there are no data among HIV-infected persons. A retrospective, cohort study was conducted to assess the incidence of symptomatic myalgia and elevation in serum creatine kinase level among HIV-positive adults on combination antiretroviral therapy and treated with atorvastatin or rosuvastatin for at least 12 months between 2011 and 2015 in our outpatient unit. A total of 545 patients (mean age 53.4 years) were enrolled into the study. Atorvastatin was prescribed in 55.8% of patients and rosuvastatin in 44.2%. After a mean duration of statin therapy of 29 months, an isolated symptomatic myalgia was diagnosed in 42 patients (7.7%) and a myalgia associated with elevated creatine kinase level in 25 (4.6%). The mean concentration of 25-hydroxyvitamin D was significantly lower in patients with myalgia (19.4 ng/ml) and with creatine kinase elevation and myalgia (22.8 ng/ml) than in those without muscle toxicity (32.1 ng/ml; P = 0.017 and 0.024, respectively). In stratified multivariable-adjusted logistic regression models, there was a statistically significant association between vitamin D deficiency and occurrence of symptomatic myalgia (P = 0.009) or creatine kinase elevation and myalgia (P = 0.046). Other factors significantly associated with development of myalgia were duration of statin therapy more than 24 months, history of myalgia, and age older than 60 years. In our observational study, vitamin D deficiency was significantly associated with a statin-induced myalgia among HIV-infected patients on combination antiretroviral therapy, in conformity with data of the general population.

N-of-1 Trials for Myalgia in People Taking a Statin

About 1 in 5 patients taking statins report some degree of muscular pain or other musculoskeletal symptom, but there is great controversy over what proportion is due to statin therapy. This uncertainty has considerable clinical significance, given the importance of adherence to statins and the increasing number of therapies available for statin intolerance. N-of-1 trials provide the most reliable assessment of causality for an individual person. However, only 8 N-of-1 trials have been reported for patients with possible statin-related myalgia, and for all 8 there was no evidence that the statin was causal 1DOI:10.7326/M13-19211DOI:10.7326/M13-1921. This study aims to evaluate the feasibility and sustainability of an information technology-enhanced N-of-1 trial service to improve the diagnosis of statin-induced myalgia in Australian general practice setting. N-of-1 (single-patient multiple crossover) trials (n = 15) of patients with prior history of intolerance of both atorvastatin 10 mg and rosuvastatin 5 mg monotherapy, who had myalgia occurring within three weeks of starting statin therapy and consequently discontinued statin use. Each person will go through 3 double-blind, crossover comparisons of statin versus matching placebo for a total of 27 weeks. Myalgia scores and Brief Pain Inventory Questionnaire will be recorded on a weekly basis during the study period. Blood sample collection will be done at baseline and at the end of each active treatment and control period to measure serum CK, ALT, AST, FGF21 and creatinine levels. To avoid unblinding of treatment allocation during the trial period, additional blood samples will be stored to measure lipid levels upon study completion. Genotype analysis will also be done at the end of the study to determine if genotype is associated with statin-induced myalgia. Patient and prescriber intentions to continue statin therapy at the end of the trial will also be assessed.