Abstract 14235: Plasma PCSK9 Levels and Clinical Outcomes in the Treating to New Targets Trial: A Nested Case-Control Study
Background - Statins activate low-density lipoprotein (LDL) receptor gene expression, thus lowering plasma LDL levels. But statins also activate the expression of proprotein convertase subtilisin kexin type 9 (PCSK9), a secreted inhibitor of the LDL receptor, thereby limiting their beneficial effects. Clinical studies have shown that statin therapy may increase plasma PCSK9 levels. Here, we have hypothesized that increasing statin dose would increase circulating PCSK9 levels and that high levels of PCSK9 would in fact increase cardiovascular risk in statin treated patients.
Methods and Results - We have measured plasma PCSK9 in a subgroup of patients with stable coronary heart disease (CHD) enrolled in the Treating to New Targets (TNT) clinical trial. After a run in period with atorvastatin 10 mg daily, patients were randomized to either continue with 10 mg (n=849) or to 80 mg of atorvastatin (n=764), and followed 5 years for major cardiovascular events (MCVE). MCVE was defined as CHD death, nonfatal, non-procedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke. PCSK9 levels one year after randomization did not differ significantly between the 10 and 80 mg atorvastatin treatment groups (318 ng/mL; IQR 231-417 ng/mL vs. 311 ng/mL; IQR 231-407 ng/mL, P=0.82). There were no significant differences between the two treatment groups in terms of change in PCSK9 between the randomization and 1-year post-randomization levels. Circulating PCSK9 levels measured at randomization were predictive of clinical outcomes in the group randomized to remain on atorvastatin 10 mg (adjusted hazard ratio per 100 ng/ml of PCSK9 level = 1.08 [95% CI, 1.04-1.16], p=0.026), but not in the group that intensified atorvastatin treatment to 80 mg (adjusted hazard ratio per 100 ng/ml of PCSK9 level = 0.95 [95% CI, 0.86-1.04], p=0.22).
Conclusion - Increasing statin dose from 10 to 80 mg did not increase plasma PCSK9 levels. PCSK9 levels predict cardiovascular events in patients treated with low dose atorvastatin.
- © 2011 by American Heart Association, Inc.