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Statins are widely used crucial drugs for the primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD). Although generally well tolerated, statin intolerance can unfortunately limit statin use, with statin-associated muscle symptoms (SAMS) being the most common side effect associated with its discontinuation. Statin intolerance is an inability to tolerate a dose of statin required to sufficiently reduce an individual's cardiovascular risk, limiting the effective treatment of patients at risk of or with cardiovascular disease (CVD). Statin myopathy is a broad entity encompassing self-limited/toxic and autoimmune aetiologies. As statins are a mainstay of therapy in those with or at risk for CVD and offer a mortality benefit, it is critical to determine whether one's symptoms are truly statin-associated before discontinuing the drug. This review article aims to provide an update on the epidemiology, pathophysiology, clinical features, diagnosis, evaluation and management of statin myopathy and to elucidate key differences between autoimmune and self-limited types., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose of Review: 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: 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., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Statin-associated autoimmune myopathy is a rare condition associated with the formation of autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Underlying environmental and genetic risk factors remain poorly understood. American Indians have high rates of cardiovascular disease and associated co-morbidities that require lipid-lowering therapies. We observed this autoimmune myopathy in a series of American Indian statin users in rural Arizona., Methods: We reviewed the charts of six American Indian patients with statin-associated autoimmune myopathy. We provide an illustrative case in addition to summaries of clinical presentations and treatment courses., Results: This is the first report of statin-associated autoimmune myopathy in American Indians. These cases were all identified at the same geographically isolated hospital that exclusively serves an American Indian population with only 1800 statin users. There is relatively low migration. Each case was consistent with the previously described classical presentations for the disease. All six of our cases had diabetes and developed myopathy on high-dose atorvastatin, often with a recent change in statin type or dose., Conclusion: Providers serving American Indians need to be aware of the possibility of statin-associated autoimmune myopathy and familiar with its presentation. Larger, inclusive, population-based investigations are needed to elucidate risk factors for this condition, in particular the potential interactions between predisposing HLA alleles, diabetes and specific statin exposures. This is necessary to identify effective and safe lipid-lowering medications., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To determine the safety of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in patients with statin-associated anti-3-hydroxy-3-methlyglutaryl coenzyme A reductase (anti-HMGCR)-positive immune-mediated necrotizing myopathy (IMNM)., Methods: Muscle strength was assessed in anti-HMGCR-positive patients at each visit before and after initiation of PCSK9 inhibitors. The trends in creatine kinase (CK) levels and serum anti-HMGCR antibody titers were monitored over time., Results: Among 122 anti-HMGCR-positive patients, we identified 8 patients who were receiving PCSK9 inhibitors for hyperlipidemia. Patients were followed up for an average of 1.5 years (range 3-37 months), and none exhibited reduction in muscle strength. The mean ± SD CK level prior to the initiation of PCSK9 inhibitors was 956 ± 1,137 IU/liter, which was reduced to 419 ± 393 IU/liter at their last visit. Anti-HMGCR antibody titers followed a similar trend. Notably, in 2 patients, the initiation of the lipid-lowering medication was followed by unanticipated spontaneous clinical improvement and reduction in immunosuppression., Conclusion: PCSK9 inhibitors are safe for long-term use as a cholesterol-lowering agent in patients with statin-associated IMNM., (© 2019, American College of Rheumatology.)

Introduction: Statins reduce cardiovascular disease risk and are generally well tolerated, yet up to 0.5% of statin-treated patients develop incapacitating muscle symptoms including rhabdomyolysis. Our objective was to identify clinical factors related to statin-associated muscle symptoms (SAMS)., Methods: Clinical and laboratory characteristics were evaluated in 748 statin-treated Caucasians (634 with SAMS and 114 statin-tolerant controls). Information was collected on statin type, concomitant drug therapies, muscle symptom history, comorbidities, and family history. Logistic regression was used to identify associations., Results: Individuals with SAMS were 3.6 times (odds ratio [OR] 3.60, 95% confidence interval [CI] 2.08-6.22) more likely than statin-tolerant controls to have a family history of heart disease. Additional associations included obesity (OR 3.08, 95% CI 1.18, 8.05), hypertension (OR 2.24, 95% CI 1.33, 3.77), smoking (OR 2.08, 95% CI 1.16, 3.74), and statin type., Discussion: Careful medical monitoring of statin-treated patients with the associated coexisting conditions may ultimately reduce muscle symptoms and lead to improved compliance. Muscle Nerve 59:537-537, 2019., (© 2018 Wiley Periodicals, Inc.)

The inflammatory myopathies, which include dermatomyositis, polymyositis, and the immune-mediated necrotizing myopathies, are a heterogeneous group of autoimmune diseases that manifest with muscle, skin, or lung damage. Collectively, these autoimmune diseases result from loss of tolerance to a select group of self-antigens, although the precise mechanism through which this occurs is not known. Infection, malignancy, and certain medications including statins and the immune checkpoint inhibitors used in cancer therapy have been identified as potential immunologic triggers of the inflammatory myopathies. Some of these triggers are classically associated with specific myositis-specific autoantibodies (MSAs). The strong association between certain triggers and MSAs provides insights into how an immunologic event can lead to loss of tolerance to specific self-antigens, resulting in autoimmune disease. In this review, we discuss the proposed triggers of the inflammatory myopathies and their associations with MSAs, and provide insights into how these triggers may result in the inflammatory myopathies.

Purpose of Review: The use of statins has increased exponentially over the last 2 decades. Consequently, side effects have also increased, with muscle-related side effects commonly reported., Recent Findings: Although once thought to be only associated with self-limited direct myotoxicity, statins have recently been described in association with an autoimmune myopathy in association with antibodies directed against 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate limiting enzyme in cholesterol synthesis and the pharmacologic target of statins. Since this discovery, various cohorts have been identified worldwide and highlight both similarities and differences among them., Summary: Recent studies from different fields have revealed diverse aspects of anti-HMGCR-associated immune-mediated necrotizing myopathy (IMNM). HMGCR IMNM is a unique autoimmune disease characterized by a well defined environmental trigger (statins) and a strong association with a genetic risk factor (Human leukocyte antigen D related B 111 : 01). New diagnostic modalities have been established to confirm the presence of anti-HMGCR antibody and confirm the diagnosis of HMGCR IMNM. Clinical studies have shown that disease severity, as measured by muscle strength, as well as the rate of response to treatment have been associated with age at disease onset. Furthermore, a case series supported that intravenous immunoglobulin administration, perhaps even as monotherapy, may be a beneficial therapeutic intervention for selected patients.

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

Statin-related myopathy (SRM) undermines drug adherence that is critical for achieving the benefits of lipid-lowering therapy. While the exact mechanism of SRM remains largely unknown, recent evidence supports specific genetic and immunologic influence on the development of intolerance. Genes of interest include those involved in the pharmacokinetics of statin response (i.e. drug metabolism, uptake transporters, and efflux transporters), pharmacodynamics (i.e. drug toxicity and immune-mediated myopathy), and gene expression. We examine the influence of genetic and immunologic variation on the pharmacokinetics, pharmacodynamics, and gene expression of SRM., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Statins up-regulate expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme in cholesterol synthesis and the major target of autoantibodies in statin-associated immune-mediated necrotizing myopathy. As muscle cells regenerate, they express high levels of HMGCR, which may sustain the immune response even after statin therapy is stopped. Awareness of this entity will help physicians who prescribe statins to take action to limit the associated morbidity., (Copyright© 2014 The Cleveland Clinic Foundation.)

Objective: To investigate the association of anti-hydroxymethylglutaryl-coenzyme A reductase (anti-HMGCR) myopathy with HLA class I and II antigens., Methods: HLA antigens were determined in 1) 20 white and 8 African American anti-HMGCR patients, 2) 487 white and 167 African American controls, and 3) 51 white subjects with mild self-limited statin intolerance., Results: White anti-HMGCR patients had a higher frequency of the combination HLA-DR11, DQA5, and DQB7 than controls or statin-intolerant subjects (70% versus 17%; odds ratio [OR] 11.7 [95% confidence interval (95% CI) 4.0-35.3], P = 4.1 × 10(-7) and 70% versus 21%; OR 8.3 [95% CI 2.2-33.9], P = 5.4 × 10(-4) , respectively). This combination was not increased in African American anti-HMGCR subjects compared to controls (13% versus 3%; OR 4.6 [95% CI 0.2-53.3], P = 0.2). However, DR11 was increased in African American anti-HMGCR patients compared to controls (88% versus 21%; OR 26.4 [95% CI 3.1-590.3], P = 0.0002). High-resolution mapping showed that 95% with DR11 had DRB1*11:01. DQA1 and DQB6 were less frequent in white anti-HMGCR-positive patients compared to controls (25% versus 65%; OR 0.2 [95% CI 0.1-0.5], P = 5.5 × 10(-4) and 0% versus 45%; OR 0.0 [95% CI 0.0-0.3], P = 2.1 × 10(-5) , respectively). DRB11 was not associated with particular disease features., Conclusion: DRB1*11:01 is associated with an increased risk of anti-HMGCR myopathy in whites and African Americans. These findings suggest a mechanistic link between statin exposure, increased HMGCR expression, and the possible presentation of HMGCR-derived peptide(s) by DRB1*11:01., (Copyright © 2012 by the American College of Rheumatology.)

Background: Cardiovascular disease is one of the major causes of death in systemic lupus erythematosus (SLE). A study was undertaken to investigate whether treatment with statins would reduce subclinical measures of atherosclerosis over a 2-year period., Methods: 200 patients with SLE without clinical cardiovascular disease were randomised to receive atorvastatin 40 mg daily or an identical placebo. At baseline and after 2 years of follow-up, helical CT scanning (for coronary artery calcium) and carotid duplex (for intima media thickness/plaque) were performed. Patients were seen for measures of disease activity at 1 month, 3 months and quarterly thereafter. The primary outcome variable was change in coronary artery calcium., Results: At baseline, 43% had coronary artery calcium. At 2 years there was no significant difference between the groups in progression of coronary artery calcium, carotid intima media thickness or carotid plaque. There was no significant difference between the groups in disease activity, measures of inflammation or endothelial cell activation., Conclusion: This study provides no evidence that atorvastatin reduces subclinical measures of atherosclerosis or disease activity over 2 years in patients with SLE. In fact, it does not appear to reduce biochemical measures of inflammation. The anti-inflammatory effects of statins observed in the general population were not replicated in this SLE clinical trial. Clinicaltrials.gov (NCT 00120887).

Objective: In addition to inducing a self-limited myopathy, statin use is associated with an immune-mediated necrotizing myopathy (IMNM), with autoantibodies that recognize ∼200-kd and ∼100-kd autoantigens. The purpose of this study was to identify these molecules to help clarify the disease mechanism and facilitate diagnosis., Methods: The effect of statin treatment on autoantigen expression was addressed by immunoprecipitation using sera from patients. The identity of the ∼100-kd autoantigen was confirmed by immunoprecipitation of in vitro-translated 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) protein. HMGCR expression in muscle was analyzed by immunofluorescence. A cohort of myopathy patients was screened for anti-HMGCR autoantibodies by enzyme-linked immunosorbent assay and genotyped for the rs4149056 C allele, a predictor of self-limited statin myopathy., Results: Statin exposure induced expression of the ∼200-kd/∼100-kd autoantigens in cultured cells. HMGCR was identified as the ∼100-kd autoantigen. Competition experiments demonstrated no distinct autoantibodies recognizing the ∼200-kd protein. In muscle biopsy tissues from anti-HMGCR-positive patients, HMGCR expression was up-regulated in cells expressing neural cell adhesion molecule, a marker of muscle regeneration. Anti-HMGCR autoantibodies were found in 45 of 750 patients presenting to the Johns Hopkins Myositis Center (6%). Among patients ages 50 years and older, 92.3% had taken statins. The prevalence of the rs4149056 C allele was not increased in patients with anti-HMGCR., Conclusion: Statins up-regulate the expression of HMGCR, the major target of autoantibodies in statin-associated IMNM. Regenerating muscle cells express high levels of HMGCR, which may sustain the immune response even after statins are discontinued. These studies demonstrate a mechanistic link between an environmental trigger and the development of sustained autoimmunity. Detection of anti-HMGCR autoantibodies may facilitate diagnosis and direct therapy., (Copyright © 2011 by the American College of Rheumatology.)

Purpose of Review: Statin therapy has become the mainstay of treatment for lipid lowering, demonstrating cardiovascular risk reduction. Associated with statin popularity are misconceptions and fears of untoward side effects on muscle. This review clarifies the terminology relating to statin-related muscle disease; explores potential pathogenic mechanisms; reviews current estimates of statin myopathy prevalence; and examines diagnosis and management., Recent Findings: The fundamental mechanism of statin myopathy remains elusive but is believed to be a class effect. The most common explanation for the cause of toxic muscle injury invokes the deficiency of one of three main synthetic products in the 3-hydroxy-3-methylglutaryl-coenzyme A reductase pathway. Recent studies have revealed several patients with statin-induced rhabdomyolysis who also have metabolic muscle defects, indicating that statin use may unmask presymptomatic metabolic myopathies. Although statin-related myotoxicity is believed to be a noninflammatory, toxic myopathy, experimental evidence suggests that it may be triggered by an autoimmune reaction or, conversely, initiate an autoimmune process. The precise mechanism is uncertain., Summary: As a class, statins appear to be usually safe, well tolerated agents with an excellent risk: benefit profile. The etiology and pathogenesis of statin myopathy are poorly understood owing to the relative rarity of its existence.