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Author + information
- Roeland Huijgen, MD⁎,
- S. Matthijs Boekholdt, MD, PhD⁎,†,
- Benoit J. Arsenault, PhD⁎,
- Weihang Bao, PhD‡,
- Jean-Michel Davaine, MD§,
- Fatiha Tabet, PhD∥,
- Francine Petrides, BSc∥,
- Kerry-Anne Rye, PhD∥,¶,
- David A. DeMicco, PharmD‡,
- Philip J. Barter, MD, PhD∥,¶,
- John J.P. Kastelein, MD, PhD⁎ and
- Gilles Lambert, PhD§∥,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Gilles Lambert, Inserm U957, Faculté de Médecine, 1 Rue Gaston Veil, 44035 Nantes Cedex 1, France
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Objectives The purpose of this study was to investigate whether high levels of circulating proprotein convertase subtilisin kexin type 9 (PCSK9) would increase cardiovascular risk in statin-treated patients.
Background Statins activate low-density lipoprotein (LDL) receptor gene expression, thus lowering plasma LDL levels. But statins also activate the expression of PCSK9, a secreted inhibitor of the LDL receptor, thereby limiting their beneficial effects.
Methods We have measured the plasma PCSK9 levels of 1,613 patients with stable coronary heart disease enrolled in the Treating to New Targets study, a randomized trial that compared the efficacy of high- versus low-dose atorvastatin. 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 cardiovascular events (MCVEs).
Results Circulating PCSK9 levels measured at randomization 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.
Conclusions PCSK9 levels predict cardiovascular events in patients treated with low-dose atorvastatin. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691)
The TNT study and the analyses described in this paper were funded by Pfizer Inc. Dr. Arsenault is supported by a post-doctoral fellowship from the Fonds de la recherche en santé du Québec. Dr. Kastelein is a recipient of the lifetime achievement award of the Dutch Heart Foundation, 2010T082. Dr. Lambert is a recipient of the project grant 1010867 from the National Health and Medical Research Council of Australia. Dr. DeMicco is an employee of Pfizer. Dr. Barter has received honraria for lectures from and is on the advisory board for Pfizer. Dr. Kastelein has received consultancy fees from Pfizer. All other authors have reported that they have no relationships relevant to the contents to this paper to disclose.