(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Liver-Diseases

The "statins," or hydroxymethylglutaryl coenzyme A (HMG-CoA)-reductase inhibitors, are a generally safe class of drugs that are widely used throughout the world and are rarely associated with severe hepatotoxicity. In this article, two cases of severe hepatotoxicity attributed to statin use are presented. In addition, a detailed summary of previously published cases of statin hepatotoxicity and the risks and benefits of statins in patients with chronic liver disease are presented. Drug-induced liver injury (DILI) from statins typically presents with an acute hepatocellular liver injury pattern, although mixed or cholestatic injury patterns have also been reported. Nonspecific autoantibodies as well as clinical, laboratory, and histological features of an autoimmune-like hepatitis may be present in some patients with statin hepatotoxicity. Despite their widespread use, acute liver failure and death have rarely been reported in patients with statin hepatotoxicity. Multiple retrospective studies as well as a large prospective randomized controlled trial demonstrate that statins can safely be given to hyperlipidemic patients with compensated chronic liver disease.

Topics: Adult; Aged; Aged, 80 and over; Atorvastatin; Autoimmunity; Biomarkers; Biopsy; Chemical and Drug Induced Liver Injury; Chronic Disease; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Indoles; Liver; Liver Diseases; Male; Middle Aged; Practice Guidelines as Topic; Pyrroles; Risk Assessment; Treatment Outcome; Young Adult

We sought to assess the relationship between the magnitude of low-density lipoprotein cholesterol (LDL-C) lowering and rates of elevated liver enzymes, rhabdomyolysis, and cancer.. Although it is often assumed that statin-associated adverse events are proportional to LDL-C reduction, that assumption has not been validated.. Adverse events reported in large prospective randomized statin trials were evaluated. The relationship between LDL-C reduction and rates of elevated liver enzymes, rhabdomyolysis, and cancer per 100,000 person-years was assessed using weighted univariate regression.. In 23 statin treatment arms with 309,506 person-years of follow-up, there was no significant relationship between percent LDL-C lowering and rates of elevated liver enzymes (R2 <0.001, p = 0.91) or rhabdomyolysis (R2 = 0.05, p = 0.16). Similar results were obtained when absolute LDL-C reduction or achieved LDL-C levels were considered. In contrast, for any 10% LDL-C reduction, rates of elevated liver enzymes increased significantly with higher statin doses. Additional analyses demonstrated a significant inverse association between cancer incidence and achieved LDL-C levels (R2 = 0.43, p = 0.009), whereas no such association was demonstrated with percent LDL-C reduction (R2 = 0.09, p = 0.92) or absolute LDL-C reduction (R2 = 0.05, p = 0.23).. Risk of statin-associated elevated liver enzymes or rhabdomyolysis is not related to the magnitude of LDL-C lowering. However, the risk of cancer is significantly associated with lower achieved LDL-C levels. These findings suggest that drug- and dose-specific effects are more important determinants of liver and muscle toxicity than magnitude of LDL-C lowering. Furthermore, the cardiovascular benefits of low achieved levels of LDL-C may in part be offset by an increased risk of cancer.

Topics: Chemical and Drug Induced Liver Injury; Cholesterol, LDL; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Liver Diseases; Lovastatin; Neoplasms; Pravastatin; Rhabdomyolysis; Simvastatin