Benoit J Arsenault1, Francine Petrides2, Fatiha Tabet2, Weihang Bao3, G Kees Hovingh4, S Matthijs Boekholdt5, Stéphane Ramin-Mangata6, Olivier Meilhac6, David DeMicco3, Kerry-Anne Rye2, David D Waters7, John J P Kastelein4, Philip Barter2, Gilles Lambert8. 1. Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada; Department of Medicine, Faculty of Medicine, Université Laval, Québec, Québec, Canada. 2. School of Medical Sciences, The University of New South Wales, Sydney, New South Wales, Australia. 3. Pfizer Inc, New York, NY, USA. 4. Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. 5. Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands. 6. Inserm, UMR 1188 DéTROI, Université de La Réunion, Sainte-Clotilde, France. 7. Division of Cardiology, University of California, San Francisco, CA, USA. 8. Inserm, UMR 1188 DéTROI, Université de La Réunion, Sainte-Clotilde, France. Electronic address: gilles.lambert@univ-reunion.fr.
Abstract
BACKGROUND:Proprotein subtilisin kexin type 9 (PCSK9) and lipoprotein (a) [Lp(a)] levels are causative risk factors for coronary heart disease. OBJECTIVES: The objective of the study was to determine the impact of lipid-lowering treatments on circulating PCSK9 and Lp(a). METHODS: We measured PCSK9 and Lp(a) levels in plasma samples from Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events trial patients with coronary heart diseaseand/or type II diabetes (T2D) mellitus. Patients received atorvastatin, which was titrated (10, 20, 40, or 80 mg/d) to achieve low-density lipoprotein cholesterol levels <100 mg/dL (baseline) and were subsequently randomized either to atorvastatin + torcetrapib, a cholesterol ester transfer protein inhibitor, or to atorvastatin + placebo. RESULTS: At baseline, both plasma PCSK9 and Lp(a) were dose-dependently increased with increasing atorvastatin doses. Compared with patients without T2D, those with T2D had higher PCSK9 (357 ± 123 vs 338 ± 115 ng/mL, P = .0012) and lower Lp(a) levels (28 ± 32 vs 32 ± 33 mg/dL, P = .0005). Plasma PCSK9 levels significantly increased in patients treated with torcetrapib (+13.1 ±125.3 ng/mL [+3.7%], P = .005), but not in patients treated with placebo (+2.6 ± 127.9 ng/mL [+0.7%], P = .39). Plasma Lp(a) levels significantly decreased in patients treated with torcetrapib (-3.4 ± 10.7 mg/dL [-11.1%], P < .0001), but not in patients treated with placebo (+0.3 ± 9.4 mg/dL [+0.1%], P = .92). CONCLUSION: In patients at high cardiovascular disease risk, PCSK9 and Lp(a) are positively and dose-dependently correlated with atorvastatin dosage, whereas the presence of T2D is associated with higher PCSK9 but lower Lp(a) levels. Cholesterol ester transfer protein inhibition with torcetrapib slightly increases PCSK9 levels and decreases Lp(a) levels.
RCT Entities:
BACKGROUND: Proprotein subtilisin kexin type 9 (PCSK9) and lipoprotein (a) [Lp(a)] levels are causative risk factors for coronary heart disease. OBJECTIVES: The objective of the study was to determine the impact of lipid-lowering treatments on circulating PCSK9 and Lp(a). METHODS: We measured PCSK9 and Lp(a) levels in plasma samples from Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events trialpatients with coronary heart disease and/or type II diabetes (T2D) mellitus. Patients received atorvastatin, which was titrated (10, 20, 40, or 80 mg/d) to achieve low-density lipoprotein cholesterol levels <100 mg/dL (baseline) and were subsequently randomized either to atorvastatin + torcetrapib, a cholesterol ester transfer protein inhibitor, or to atorvastatin + placebo. RESULTS: At baseline, both plasma PCSK9 and Lp(a) were dose-dependently increased with increasing atorvastatin doses. Compared with patients without T2D, those with T2D had higher PCSK9 (357 ± 123 vs 338 ± 115 ng/mL, P = .0012) and lower Lp(a) levels (28 ± 32 vs 32 ± 33 mg/dL, P = .0005). Plasma PCSK9 levels significantly increased in patients treated with torcetrapib (+13.1 ± 125.3 ng/mL [+3.7%], P = .005), but not in patients treated with placebo (+2.6 ± 127.9 ng/mL [+0.7%], P = .39). Plasma Lp(a) levels significantly decreased in patients treated with torcetrapib (-3.4 ± 10.7 mg/dL [-11.1%], P < .0001), but not in patients treated with placebo (+0.3 ± 9.4 mg/dL [+0.1%], P = .92). CONCLUSION: In patients at high cardiovascular disease risk, PCSK9 and Lp(a) are positively and dose-dependently correlated with atorvastatin dosage, whereas the presence of T2D is associated with higher PCSK9 but lower Lp(a) levels. Cholesterol ester transfer protein inhibition with torcetrapib slightly increases PCSK9 levels and decreases Lp(a) levels.