Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials

J Am Coll Cardiol. 2007 Jul 31;50(5):409-18. doi: 10.1016/j.jacc.2007.02.073. Epub 2007 Jul 16.


Objectives: 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.

Background: Although it is often assumed that statin-associated adverse events are proportional to LDL-C reduction, that assumption has not been validated.

Methods: 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.

Results: 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).

Conclusions: 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.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Chemical and Drug Induced Liver Injury*
  • Cholesterol, LDL / drug effects*
  • Cholesterol, LDL / metabolism
  • Dose-Response Relationship, Drug
  • Fatty Acids, Monounsaturated / adverse effects
  • Fluvastatin
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects*
  • Hypercholesterolemia / drug therapy*
  • Hypercholesterolemia / metabolism
  • Indoles / adverse effects
  • Liver Diseases / enzymology
  • Lovastatin / adverse effects
  • Neoplasms / chemically induced
  • Neoplasms / epidemiology*
  • Pravastatin / adverse effects
  • Rhabdomyolysis / chemically induced*
  • Simvastatin / adverse effects


  • Cholesterol, LDL
  • Fatty Acids, Monounsaturated
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Indoles
  • Fluvastatin
  • Lovastatin
  • Simvastatin
  • Pravastatin