Statin-related drug-induced liver injury / 中华肝脏病杂志

Statins are a kind of prescription drug that is widely used to treat hyperlipidemia, coronary artery disease, and other atherosclerotic diseases. A common side effect of statin use is a mild rise in liver aminotransferases, which occurs in less than 3% of patients. Statin-related liver injury is most commonly caused by atorvastatin and simvastatin, but severe liver injury is uncommon. Therefore, understanding and evaluating hepatotoxicity and weighing the benefits and risks is of great significance to better realize the protective effect of statins.

Glycemic effects of simvastatin: Where do we stand?

ABSTRACT In clinical practice, simvastatin is usually used in the treatment of dyslipidemia patients and those at risk of or with established cardiovascular disease. However, previous studies have shown that simvastatin has the potential to affect glycemic parameters as it reportedly reduced insulin secretion and sensitivity. The exact mechanism by which simvastatin affects glycemia is still unknown, but previous studies have postulated the involvement of the glucose-insulin secretion mechanism. This review focuses on the effects of simvastatin, either alone or in combination with other lipid lowering agents, antidiabetics and antihypertensives, on glucose homeostasis. Some studies have reported that simvastatin might impair the levels of glucose metabolism markers in the blood while others have reported no effect or improvement in glycemia.

Sintomas musculares relacionados ao uso de estatinas / Statin-associated muscle symptoms

Nas últimas duas décadas, comprovou-se que a terapia com estatinas é o instrumento isolado mais potente para atenuar o risco cardiovascular, e seu uso frequente foi enfatizado como um dos elementos mais importantes para reduzir a mortalidade cardiovascular nos países desenvolvidos. Uma incidência igualmente frequente de sintomas musculares em usuários de estatinas levanta a possibilidade de um nexo de causalidade, que leva a uma entidade patológica conhecida como sintomas musculares associados a estatinas (SMAS). Estudos e ensaios clínicos mecanicistas destinados a estudar os SMAS levaram a uma definição clara da sua história natural e incidência exata. Essa informação é essencial para evitar riscos desnecessários de formas graves de SMAS. Ao mesmo tempo, essa compreensão concreta dos SMAS evita o diagnóstico exagerado e a suspensão desnecessária de uma das mais poderosas estratégias de prevenção atuais. Nesse contexto, este artigo de revisão reuniu todas as informações disponíveis sobre o assunto, que são apresentadas em detalhe neste documento como a base da identificação e tratamento dos SMAS

In the last 2 decades, statin therapy has proved to be the most potent isolated instrument for attenuating cardiovascular risk, and its frequent use has been highlighted as one of the most important elements for reducing cardiovascular mortality in developed countries. An equally frequent incidence of muscle symptoms in statin users raises the possibility of a causal link, leading to a disease entity known as statin-associated muscle symptoms (SAMS). Mechanistic studies and clinical trials designed to the study of SAMS have led to a clear definition of its natural history and accurate incidence. This information is vital for avoiding unnecessary risk of severe forms of SAMS. At the same time, this concrete understanding of SAMS prevents over-diagnosis and unnecessary suspension of one of the most powerful prevention strategies available today. In this context, this review has gathered all the available information on the issue, which is presented in detail, in this document, as the basis for the identification and management of SAMS

Evaluation of Sexual Dimorphism in the Efficacy and Safety of Simvastatin/Atorvastatin Therapy in a Southern Brazilian Cohort / Papel do Dimorfismo Sexual na Eficácia e Segurança da Terapia com Sinvastatina ou Atorvastatina em uma Coorte no Sul do Brasil

Background: Dyslipidemia is the primary risk factor for cardiovascular disease, and statins have been effective in controlling lipid levels. Sex differences in the pharmacokinetics and pharmacodynamics of statins contribute to interindividual variations in drug efficacy and toxicity. Objective: To evaluate the presence of sexual dimorphism in the efficacy and safety of simvastatin/atorvastatin treatment. Methods: Lipid levels of 495 patients (331 women and 164 men) were measured at baseline and after 6 ± 3 months of simvastatin/atorvastatin treatment to assess the efficacy and safety profiles of both drugs. Results: Women had higher baseline levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) compared with men (p < 0.0001). After treatment, women exhibited a greater decrease in plasma TC and LDL-C levels compared with men. After adjustment for covariates, baseline levels of TC and LDL-C influenced more than 30% of the efficacy of lipid-lowering therapy (p < 0.001), regardless of sex. Myalgia [with or without changes in creatine phosphokinase (CPK) levels] occurred more frequently in women (25.9%; p = 0.002), whereas an increase in CPK and/or abnormal liver function was more frequent in in men (17.9%; p = 0.017). Conclusions: Our results show that baseline TC and LDL-C levels are the main predictors of simvastatin/atorvastatin therapy efficacy, regardless of sex. In addition, they suggest the presence of sexual dimorphism in the safety of simvastatin/atorvastatin. The effect of sex differences on receptors, transporter proteins, and gene expression pathways needs to be better evaluated and characterized to confirm these observations. .

Fundamento: A dislipidemia é o principal fator de risco para doenças cardiovasculares e as estatinas são efetivas no controle do perfil lipídico. Diferenças sexuais na farmacocinética e farmacodinâmica contribuem para a variação interindividual na eficácia e toxicidade de fármacos. Objetivo: Avaliar a existência de dimorfismo sexual na eficácia e segurança do tratamento com sinvastatina/atorvastatina. Métodos: 495 sujeitos (331 mulheres e 164 homens) tiveram seus níveis lipídicos mensurados antes e após 6±3 meses de tratamento com sinvastatina/atorvastatina para avaliação dos perfis de eficácia e segurança. Resultados: As mulheres apresentaram maiores níveis basais de colesterol total, LDL-C e HDL-C quando comparadas aos homens (p < 0,0001). Após o tratamento, mulheres tiveram uma maior redução dos níveis de colesterol total e de LDL-C que homens. Após ajuste para covariáveis, foi observado que os níveis basais de colesterol total e de LDL-C são responsáveis por cerca de 30% da eficácia (p < 0,001), independentemente do sexo. Mialgia (com ou sem alteração de creatina fosfoquinase - CPK) ocorreu mais frequentemente em mulheres (25,9%) (p = 0,002), enquanto o aumento isolado de CPK e alterações de função hepática foram mais frequentemente observados em homens (17,9%) (p = 0,017). Conclusões: Nossos resultados demonstram que os níveis basais de colesterol total e LDL-C são os maiores preditores da eficácia do tratamento, independente do sexo. Adicionalmente, sugerimos que existe dimorfismo sexual na segurança do tratamento com sinvastatina/atorvastatina. O efeito das diferenças sexuais em receptores, proteínas transportadoras e rotas de expressão gênica devem ser avaliados ...

Adjuvant effects of classical music on simvastatin induced reduction of anxiety but not object recognition memory in rats

Simvastatin is one of many hydroxymethylglutaryl-coenzyme-A reductase inhibitors that are prescribed to lower cholesterol. Some emerging evidence indicates that classical music can serve as an effective adjuvant in rats treated with simvastatin. Moreover, simvastatin and classical music have been shown to influence some cognitive functions. To further understand the mechanisms of action, we exposed rats to classical music for 1 month, and then treated them orally with simvastatin. The behavioral experiments suggested that exposure to subchronic simvastatin (1 or 10 mg/kg/day) reduced anxiety levels in the elevated plus-maze and open-field test in rats exposed to Mozart music. The recognition object test results indicated that simvastatin altered non-spatial working memory only at the 1 mg/kg/day dose and improved both short- and long-term object recognition. No significant differences were found between Mozart music and silence in the object recognition test, suggesting that music did not significant affect learning and memory in adult rats. We hypothesize that the anxiolytic, but not object-recognition memory, effects of simvastatin and classical music occur through similar mechanisms, providing an important foundation for future preclinical and clinical research...

Influence of PPARA, RXRA, NR1I2 and NR1I3 gene polymorphisms on the lipid-lowering efficacy and safety of statin therapy / Influência de polimorfismos nos genes PPARA, RXRA, NR1I2 e NR1I3 na eficácia hipolipemiante e na segurança da terapia com estatinas

OBJECTIVE: The aim of the present study was investigate the association between six genetic variants in the nuclear receptor genes PPARA, RXRA, NR1I2 and NR1I3 and the lipid-lowering efficacy and safety of statin therapy. SUBJECTS AND METHODS: The study was carried out on 240 Brazilian hypercholesterolemic patients on simvastatin and atorvastatin therapy. The polymorphisms were analyzed by PCR-based methods. RESULTS: The NR1I3 rs2307424 genotype distribution was different between subjects with and without adverse drug reactions. Among subjects in the ADR group, no T/T homozygotes were observed for this polymorphism, while in the non-ADR group the frequency of this genotype was 19.4% (P = 0.007, after multiple testing corrections P = 0.042). CONCLUSION: The polymorphisms investigated in PPARA (rs1800206), RXRA (rs11381416), and NR1I2 (rs1523130) did not influence the lipid-lowering efficacy and safety of statin. Our results show the possible influence of NR1I3 genetic variant on the safety of statin.

OBJETIVO: O objetivo deste estudo foi investigar a associação de seis variantes genéticas nos genes de receptores nucleares PPARA, RXRA, NR1I2 e NR1I3 na eficácia hipolipemiante e na segurança da terapia com estatinas. SUJEITOS E MÉTODOS: O estudo foi realizado com 240 pacientes hipercolesterolêmicos em terapia com sinvastina e atorvastatina. Os polimorfismos foram analisados por meio de métodos baseados em PCR. RESULTADOS: A distribuição da frequência genotípica do polimorfismo NR1I3 rs2307424 foi diferente entre os pacientes com e sem efeito adverso à medicação; entre os sujeitos do grupo com efeitos adversos, nenhum homozigoto T/T foi observado, enquanto no grupo de indivíduos sem efeitos adversos a frequência desse genótipo foi 19,4% (P = 0,007, após correção para múltiplos testes P = 0,042). CONCLUSÃO: Os polimorfismos investigados nos genes PPARA (rs1800206), RXRA (rs11381416) e NR1I2 (rs1523130) não foram associados com eficácia hipolipemiante e segurança da terapia com estatinas. Nossos resultados mostram uma possível influência de variantes do gene NR1I3 (rs2307424) no desenvolvimento de efeitos adversos à terapia com estatinas.

Uso de simvastatina en la prevención de la isquemia cerebral en la hemorragia subaracnoídea aneurismática / Use of simvastatin in brain ischemia prevention in aneurysmal subarachnoid hemorrhage

Introducción: El vasoespasmo cerebral es una complicación temida y aun no resuelta en los pacientes que cursan con hemorragia subaracnoídea neurismática (HSA), y que significa una importante morbi-mortalidad en dichos pacientes. Material y métodos: Se revisaron los registros de 161 pacientes ingresados en el Hospital Carlos Van Buren de Valparaíso por HSA entre entre Mayo de 2007 y Agosto de 2009, comparando la aparición de complicaciones isquémicas y resultados funcionales, según fuesen o no tratados con Simvastatina (40 mg/día). Resultados: El grupo de pacientes tratados con Simvastatina presentó significativamente menos infartos cerebrales (9,30 por ciento vs. 24,58 por ciento, p=0,02) y menos mortalidad intrahospitalaria (1,24 por ciento vs. 11,80 por ciento, p=0,04). Conclusiones: Si bien el diseño del estudio impide atribuir las diferencias encontradas al uso de Simvastatina, dado el contexto del mismo, es muy probable que así sea. El uso de estatinas en la hemorragia subaracnoídea aneurismática, como profilaxis del vasoespasmo es aún un tema controversial y promisorio, que se encuentra en plena etapa de estudio y desarrollo.

Background: Vasospasm is a feared complication in patients who present with aneurysmal subarachnoid hemorrhage (SAH) and that means significant morbidity and mortality in these patients. Material and methods: We reviewed the records of 161 patients admitted to the Hospital Carlos Van Buren with SAH between May 2007 and August 2009, comparing the occurrence of ischemic complications and functional results as they were or not treated with simvastatin (40mg/day). Results: The patient group treated with simvastatin had significantly fewer strokes (p = 0.02) and fewer hospital mortality (p = 0.04). Conclusions: Although the study design precludes attributing the differences found when using simvastatin, given the context, it is likely to be so. The use of statins in aneurismal subarachnoid hemorrhage for vasospasm prophylaxis is still a controversial and promising topic, wich is under full development and study.

Eficacia y seguridad de Ezetimiba/Simvastatina en pacientes con hipercolesterolemia primaria / Efficacy and Safety of Ezetimibe/Simvastatin in patients with primary hypercholesterolemia

Evaluar la eficacia y seguridad de ezetimiba/simvastatina en la reducción del colesterol LDL en pacientes con hipercolesterolemia. MATERIALES Y MÉTODOS Estudio fase IV, abierto, multicéntrico realizado entre Abril y Diciembre del 2005, en 163 Pacientes con hipercolesterolemia primaria tratados con ezetimiba/simvastatina (10/20mg/día) durante 6 semanas, manteniendo una dieta. El perfil lipídico fué evaluado antes y después del tratamiento. RESULTADOS Se incluyeron 163 pacientes con hipercolesterolemia. La terapia con ezetimiba/simvastatina (10/20mg) produjo un cambio porcentual significativo en los niveles de LDL-c de - 45.5 por ciento (p menor que 0.001). Además, se observaron cambios en los otros parámetros lipídicos: Colesterol Total -33.5 por ciento (p menor que 0.001), HDL-C +1.29 por ciento (p: 0.54) y Triglicéridos -33.8 por ciento (p menor que 0.001). La reducción del LDL-C fue observada en el 95 por ciento de la población total y en relación al LDL-C meta (menor que 130 mg/dl) se logró en el 75 por ciento; en el grupo de mayor de 65 años se logró el LDL-C meta en el 85,3 por ciento. Estos beneficios se asociaron a una baja incidencia de efectos adversos: 24 eventos (14.72 por ciento) fundamentalmente cefalea (4,29 por ciento), trastornos gastrointestinales (4,29 por ciento) y músculo esqueléticos (3,07 por ciento). CONCLUSIONES La administración de ezetimiba/simvastatina (10/20mg) resultó ser eficaz al disminuir los niveles de LDL-c así como de otras lipoproteínas, con un adecuado perfil de seguridad y tolerabilidad observado durante el tratamiento. La administración de ezetimiba/simvastatina (10/20mg) mostró un perfil de seguridad y tolerancia muy favorable, a corto plazo, en el tratamiento de pacientes con dislipidemia.

Combinação de fármacos na abordagem das dislipidemias: associação entre estatinas e niacina / Combination of drugs: statins and niacin

A combinação de estatinas com niacina se apresenta como uma atraente associação, na presença de dislipidemia mista com níveis de HDL baixo, quando monoterapia é insuficiente para o alcance das metas lipídicas. Benefícios clínicos foram observados com a combinação de estatinas com niacina nos estudos FATS, HATS e ARBITER 2, mostrando atenuação no desenvolvimento da aterosclerose e/ou redução de eventos coronários, acompanhados de alterações lipídicas favoráveis. Em geral, esta combinação é bem tolerada. Recomenda-se monitoração adequada das enzimas hepáticas e muscular e, ainda, titulação cuidadosa de cada uma das drogas combinadas.

Protective effect of coenzyme Q10 in simvastatin and gemfibrozil induced rhabdomyolysis in rats.

Administration of simvastatin (80 mg/kg, po. evening dose) and gemfibrozil (600 mg/kg, po twice) for 30 days produced significant decrease in the level of reduced glutathione, superoxide dismutase, catalase and increase in the level of lipid peroxidation and various serum parameters (creatine phosphokinase, lactate dehydrogenase, serum glutamate oxaloacetate transaminase, creatinine, urea and blood urea nitrogen). This suggested involvement of oxidative stress in rhabdomyolysis. Increase in the level of reduced glutathione, superoxide dismutase, catalase and decrease in the level of lipid peroxidation and serum parameters after administration of antioxidant CoQ10 (10 mg/kg.ip) proved the protective effect of CoQ10 in rhabdomyolysis.

Rabdomiólise devido ao uso de estatina em altas doses: relato de caso / High doses statins administration causing rhabdomyolysis: case report

A rabdomiólise tem sido motivo de publicação na literatura médica há mais de 50 anos. Nas últimas décadas, com o advento das estatinas, usadas na prevenção primária e secundária da doença cardiovascular, este assunto volta como importante complicação, muitas vezes fatal, do uso desta classe de drogas. A rabdomiólise associada ao uso das estatinas ocorre principalmente devido a associações medicamentosas. A seguir, descreveremos um caso de uma paciente em uso de altas doses de Sinvastatina, devido à doença aterosclerótica difusa, que desenvolveu quadro compatível com rabdomiólise resultando em óbito.

Erupción linfomatoide secundaria a atorvastatina: reporte de dos casos / Secondary lymphomatoid reaction to atorvastatin: report of two cases

Reacción linfomatoide secundaria a drogas es un tipo de seudolinfoma cutáneo, frecuentemente reportado con el uso de anticonvulsivantes. La relación patogénica es poco clara, si bien hay algunas teorías sobre depresión del sistema inmune y proliferación linfocitaria inducida por la droga involucrada. Presentamos dos casos de erupción linfomatoide secundaria a atorvastatina diagnosticados en nuestro Servicio.

Peripheral nerve affection in patients with hyperlipidemia: a clinical and electrophysiological study

Familial hypercholesterolemia is a common genetic disorder, in its heterozygous form occur in 1:500 of the general population. Peripheral neuropathy has been reported with this disorder, some related it to the use of lipid-lowering agents [statins], others related it to the disease itself. This study was conducted on 3 groups of patients: 1[st] group; 15 patients with familial hypercholesterolemia receiving statins for variable durations, 2[nd] group: 15 newly diagnosed patients with familial hypercholesterolemia not receiving statins, and a 3[rd] group: 15 healthy matching controls. None of the subjects in the 3 groups had any disease causing peripheral neuropathy e.g. diabetes mellitus, renal failure, alcohol abuse... etc. All patients and controls were subjected to nerve conduction studies in both lower limbs; sensory and motor. None of the patients or controls had symptoms or signs of peripheral neuropathy. Electrophysiohgical studies didn't show any abnormalities in 2[nd] group and controls. In patients taking statins, 3 patients had neurophysiological evidence of sensory axonal neuropathy. The results of the present study support the previous reports that statins could be a cause of sensory polyneuropathy. Further investigations are recommended to determine which patient should discontinue statin treatment and identify other treatment options

Simvastatin-induced mononeuropathy multiplex: case report

Polineuropatia induzida por estatina é assunto vigente na literatura médica. Relatamos um possível caso de mononeuropatia múltipla induzida pelo uso de sinvastatina em um homem de 63 anos, em uso de sinvastatina. Após o diagnóstico de dislipidemia, iniciou fraqueza e parestesia assimétrica em membros. O estudo eletromiográfico mostrou alterações compatíveis com mononeuropatia múltipla. As causas mais comuns de mononeuropatia múltipla foram descartadas com a realização de exames complementares pertinentes. O paciente melhorou com a descontinuação da sinvastatina.

Flutamide-induced hepatotoxicity with possible potentiation by simvastatin.

We report a 65 years old male who presented with jaundice in February 2000. He was operated for prostate carcinoma and started on flutamide in May 1999. He developed anorexia in mid January and frank jaundice by end February. LFT showed cholestatic picture. Liver biopsy showed cholestasis. Flutamide was stopped and patient made slow recovery. Possible additional hepatotoxicity of simvastatin is discussed.

Myopathy secondary to simvastatin in a type 2 diabetic patient.

The most important but rare adverse effect of simvastatin is myopathy. In megatrials with simvastatin, the overall incidence of myopathy is 0.025%. We present a case of myopathy presenting as proximal muscle weakness in both upper limbs secondary to simvastatin which reversed spontaneously after cessation of the drug.