August 2010

[JLR] A Disruption Is Statin’

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The most widely prescribed cholesterol-reducing statin, atorvastatin, causes a rapid and sustained increase in PCSK9 serum levels in humans.

Maintaining normal cholesterol levels is critical for warding off heart disease. Proprotein convertase subtilisin kexin type 9 (PCSK9) is a major player in cholesterol regulation – mutations in this gene can lead to familial hypercholesterolemia, a genetic disorder characterized by abnormally high cholesterol levels and cardiovascular disease. Increased PCSK9 activity increases cholesterol levels by binding to low-density lipoprotein receptors (LDLR), which induces receptor degradation and the accumulation of low-density lipoproteins (LDL) in the bloodstream. Thus, high PCSK9 levels normally are associated with high cholesterol levels. However, a 16-week joint study by the University of Florida and Eli Lilly and Company used human volunteers to show that atorvastatin, a widely prescribed cholesterol-reducing drug, increases serum PCSK9 levels while lowering total cholesterol, triglycerides and LDL levels. This indicates that the relationship between PCSK9 and LDL serum levels are disrupted during atorvastatin treatment. Interestingly, the baseline or change in PCSK9 levels over the course of treatment did not strongly predict the change or endpoint LDL levels. Combined with previous results, this study suggests that doubling the normal atorvastatin dosage does not further reduce LDL levels in a dose-dependent manner. The authors suggest that the atorvastatin-induced increase in PCSK9 levels may be inhibiting a dose-dependent decrease in serum LDL levels, giving insight into why increasing dosage fails to achieve a proportional decrease in LDL serum levels.

High Dose Atorvastatin Causes a Rapid, Sustained Increase in Human Serum PCSK9 and Disrupts Its Correlation with LDL Cholesterol

Greg Welder, et al.

J. Lipid Res., published online June 5, 2010 

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