Plasma PCSK9 Levels and Clinical Outcomes in the TNT (Treating to New Targets) Trial: A Nested Case-Control Study

Study Questions:

Do proprotein convertase subtilisin kexin type 9 (PCSK9) levels predict cardiovascular (CV) risk in patients on statin therapy?


Plasma levels of PCSK9 were measured in 1,613 patients with stable coronary heart disease enrolled in the TNT study. After a run-in period with atorvastatin 10 mg daily, patients were randomized to either continue with 10 mg or be up-titrated to 80 mg of atorvastatin, and followed during 5 years for major CV events.


Circulating PCSK9 levels were predictive of clinical outcomes in the group randomized to remain on atorvastatin 10 mg (p = 0.039), but not in the group that intensified atorvastatin treatment to 80 mg (p = 0.24). Further, PCSK9 levels measured 1-year post-randomization did not change upon increase of the statin dose.


The authors concluded that PCSK9 levels predict CV events in patients treated with low-dose atorvastatin.


PCSK9 is a protease that targets low-density lipoprotein (LDL) receptors for destruction, leading to reduced LDL clearance capacity and elevated LDL levels. Recent clinical trials have demonstrated that antibody-mediated inhibition of PCSK9 leads to marked reduction in LDL levels, even in statin-treated patients. Because loss and gain of function mutations of PCSK9 have been associated with reduced and increased CVD respectively, PCSK9 inhibition is a promising approach for lowering LDL and reducing CV events. Interestingly, statin therapy leads to both up-regulation of LDL receptors and also PCSK9 expression, which could limit the therapeutic effect of statins. Although this study demonstrated that PCSK9 levels were not associated with lipid levels in patients on statins, and not predictive of risk in patients on high-dose atorvastatin, this does not mean that inhibition of PCSK9 will not have beneficial effects when added to statins. The impact of PCSK9 inhibitors on clinical events in patients on statins will require additional trials. PCSK9 inhibition could be particularly useful in statin-intolerant patients and in patients who do not reach LDL goals on high-dose statins.

Clinical Topics: Dyslipidemia, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Mutation, Pyrroles, Proprotein Convertases, Risk, Coronary Artery Disease, Trinitrotoluene, Case-Control Studies, Biological Markers, Cardiology, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Heptanoic Acids

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