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J Am Coll Cardiol, 2007; 50:409-418, doi:10.1016/j.jacc.2007.02.073 (Published online 31 July 2007).
© 2007 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: STATINS AND TOXICITY

Effect of the Magnitude of Lipid Lowering on Risk of Elevated Liver Enzymes, Rhabdomyolysis, and Cancer

Insights From Large Randomized Statin Trials

Alawi A. Alsheikh-Ali, MD, Prasad V. Maddukuri, MD, Hui Han, MD and Richard H. Karas, MD, PhD1,*

Molecular Cardiology Research Institute and Division of Cardiology, Department of Medicine, Tufts-New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts.

Manuscript received February 14, 2007; accepted February 21, 2007.

* Reprint requests and correspondence: Dr. Richard H. Karas, Molecular Cardiology Research Institute, Box #80, Tufts-New England Medical Center, 750 Washington Street, Boston, Massachusetts 02111. (Email: rkaras{at}tufts-nemc.org).

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.

Abbreviations and Acronyms
  HMG-CoA = hydroxyl methyl glutaryl coenzyme A
  LDL-C = low-density lipoprotein cholesterol


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