HMG-CoA reductase inhibitors (statins) are a widely used class of drug, and like all medications, have potential for adverse effects (AEs). Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many nonmuscle statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity.

/pdf/statin-adverse-effects-a-review-of-the-literature-and-5byfkzyay5.pdf

Statin Adverse Effects: A Review of the Literature and Evidence for a Mitochondrial Mechanism

Rhabdomyolysis: an evaluation of 475 hospitalized patients.

We report patients from two neuromuscular centers who were evaluated between the years 2000 and 2008 and met the following criteria: (1) proximal muscle weakness occurring during or after treatment with statins; (2) elevated serum creatine kinase (CK); (3) persistence of weakness and elevated CK despite discontinuation of the statin; (4) improvement with immunosuppressive agents; and (5) muscle biopsy showing necrotizing myopathy without significant inflammation. Twenty-five patients fulfilled our inclusion criteria. Twenty-four patients required multiple immunosuppressive agents. Fifteen patients relapsed after being tapered off immunosuppressive therapy. Exposure to statins prior to onset was significantly higher in patients with necrotizing myopathy (82%) as compared to those with dermatomyositis (18%), polymyositis (24%), and inclusion-body myositis (38%) seen in the same time period. The lack of improvement following discontinuation of statins, the need for immunosuppressive therapy, and frequent relapse when treatment was tapered suggest an immune-mediated etiology for this rare, statin-associated necrotizing myopathy.

Immune-mediated necrotizing myopathy associated with statins.

The different autoimmune myopathies-for example, dermatomyositis, polymyositis, and immune-mediated necrotizing myopathies (IMNM)-have unique muscle biopsy findings, but they also share specific clinical features, such as proximal muscle weakness and elevated serum levels of muscle enzymes. Furthermore, around 60% of patients with autoimmune myopathy have been shown to have a myositis-specific autoantibody, each of which is associated with a distinct clinical phenotype. The typical clinical presentations of the autoimmune myopathies are reviewed here, and the different myositis-specific autoantibodies, including the anti-synthetase antibodies, dermatomyositis-associated antibodies, and IMNM-associated antibodies, are discussed in detail. This Review also focuses on a newly recognized form of IMNM that is associated with statin use and the production of autoantibodies that recognize 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the pharmacological target of statins. The contribution of interferon signaling to the development of dermatomyositis and the potential link between malignancies and the initiation of autoimmune myopathies are also assessed.

Autoimmune myopathies: Autoantibodies, phenotypes and pathogenesis

Anti-HMGCR myopathy was first recognized and characterized in patients with a history of statin exposure and immune-mediated necrotizing myopathy. After the discovery of anti-HMGCR autoantibodies, several international groups identified and characterized more patients, expanding the phenotypic spectrum of this disease to include pediatric patients and young adults without statin exposure and those with a chronic myopathy resembling limb-girdle muscular dystrophy. We provide a summary of clinical findings, pathologic features, muscle imaging, and immunogenetic risk factors of the disease. We also discuss the current treatment strategies and approaches to monitoring the therapeutic response. Lastly, we briefly summarize the current understanding of the pathophysiology of the disease and postulate a model for autoimmunity initiation and propagation in this disease.

Anti-HMGCR Myopathy.

Purpose Rhabdomyolysis and myositis are rare, dose-related complications of statins and fenofibrates. The outcome is favorable as a rule with rapid regression after stopping the responsible drug. Recently, various auto-immune disease with evidence of hypersensitivity to HMG-CoA reductase inhibitors or fibrates drugs have been reported. Less than ten cases of dermatomyositis and polymyositis due to cholesterol-lowering drugs (CLD) have been previously reported. Five more cases polymyositis associated with CLD are reported. Methods Symptoms were compatible with diagnosis of polymyositis according to Bohan and Peter and with previous reported criteria for drug-induced myopathy in all cases. None of these patients had previous other connective tissue disorders. Results Five patients (median age 68 [54-78], female N =4) with CLD treatment (statin N =4, fenofibrates N =1) have developed iatrogenic polymyositis. All of them presented both proximal muscular weakness and increased muscle enzyme levels. One patient had iatrogenic antisynthetase syndrome characterized by mechanic's hand, Raynaud's phenomenon and anti JO1 antibodies. One other had sclerodermic hand oedema. Antinuclear antibodies were positive in 4 cases and muscle biopsy revealed polymyositis infiltrate in 4 cases. CLD treatment was discontinued with partial clinical improvement in 3 cases. Clinical remission was obtained with corticosteroid (N =5) in association with immunosuppresive agents in 3 cases. Conclusion Muscular symptoms in patient with CLD treatment could be the first symptom of a polymyositis revealed or increased by this treatment and must encourage physician with antinuclear antibodies screening especially in case of proximal muscular weakness and increased muscle enzyme levels.

[Polymyositis induced or associated with lipid-lowering drugs: five cases].

Polymyosites induites ou associées aux traitements hypolipémiants

Resume Introduction. – Myalgies et rhabdomyolyse sont des effets secondaires rares, dose-dependants des traitements par statines et fibrates dont l’evolution est generalement favorable apres l’arret du traitement en cause. Recemment, la survenue de maladies auto-immunes sous statines et fibrates a ete rapportee. Au sein de ce groupe heterogene, moins de dix cas de dermatomyosites ou polymyosites ont ete decrits. Nous en rapportons cinq autres. Methodes. – La symptomatologie etait compatible a la fois avec le diagnostic de polymyosite selon Bohan et Peter et avec le diagnostic de myopathie medicamenteuse dans tous les cas. Aucun des cinq patients ne presentait d’antecedents de maladies auto-immunes. Resultats. – Cinq patients (âge median 68 ans [extremes 54–78], sexe feminin n = 4) sous traitement hypolipemiant (TH) (statine n = 4, fenofibrate n = 1) ont developpe une polymyosite iatrogene. A un tableau clinique de deficit musculaire rhizomelique s’associait dans tous les cas une myolyse biologique. Dans un cas, la presentation (mains de travailleurs, phenomene de Raynaud, anti-JO1) etait compatible avec un syndrome des antisynthetases. Il existait dans un autre cas un œdeme sclerodermiforme des mains. Les antinucleaires etaient retrouves dans 4 cas sur 5 et la biopsie musculaire confirmait le diagnostic de polymyosite dans 4 cas. L’arret du TH entrainait une amelioration partielle dans 3 cas. La remission complete a ete obtenue sous corticotherapie (n = 5) en association avec un traitement immunosuppresseur dans 3 cas. Conclusion. – L'apparition d’une symptomatologie musculaire chez un patient sous TH peut etre inaugurale d’une authentique polymyosite induite ou precipitee par le medicament et doit inciter a la realisation d’un dosage des anticorps antinucleaires en cas d’apparition d’une symptomatologie deficitaire ou d’une rhabdomyolyse.

Polymyosites induites ou associées aux traitements hypolipémiants ? A propos de cinq cas

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[Polymyositis induced or associated with lipid-lowering drugs: five cases].

Polymyosites induites ou associées aux traitements hypolipémiants

Polymyosites induites ou associées aux traitements hypolipémiants ? A propos de cinq cas