Simvastatin but not ezetimibe upregulates circulating PCSK9 levels: Evidence from a randomised trial

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 723-739-Lipids: Therapeutics & Case Reports
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-723
Ioanna Gouni-Berthold*1, Heiner Berthold2, Suzanne Benjannet3 and Nabil G Seidah4
1Univ of Cologne, Cologne, Germany, 2Charite University Medicine Berlin, 3Clin Res Instit of Montreal, Montral, QC, Canada, 4Clin Res Inst of Montreal, Montreal, QC, Canada
Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted inhibitor of the low-density lipoprotein (LDL) receptor and an important regulator of LDL metabolism. Elevated PCSK9 levels have been associated with cardiovascular risk. The purpose of this study was to investigate how ezetimibe and simvastatin, alone and in combination, affect PCSK9 circulating concentrations. Methods: A single center, randomized, parallel 3-group study in healthy men (mean age 32±9 years, body mass index 25.7±3.2 kg/m2) was performed. Each group of 24 subjects was treated for 14 days with either simvastatin 40 mg/d, ezetimibe 10 mg/d, or with both drugs. Multivariate analysis was used to investigate parameters influencing the change in PCSK9 concentrations under treatment. Results: The baseline plasma PCSK9 concentrations in the total cohort were 52±20 ng/mL with no differences between the groups. They were increased by 68±85% by simvastatin (P=0.0014), by 10±38% by ezetimibe (P=0.51) and by 67±91% by simvastatin+ezetimibe (P=0.0013). The increase in PCSK9 was inversely associated with baseline PCSK9 concentrations (Spearman’s R=–0.47, P<0.0001) and with the percent change in LDL cholesterol concentrations (Spearman’s R=–0.30, P<0.01). In multivariate analyses, only baseline PCSK9 concentrations (β=–1.68, t=–4.04, P<0.0001), percent change in LDL cholesterol from baseline (β=1.94, t=2.52, P=0.014), and treatment with simvastatin (P=0.016), but not ezetimibe (P=0.42), significantly influenced changes in PCSK9 levels. Parameters without effect on PCSK9 concentration changes were age, BMI, body composition, thyroid function, kidney function, glucose metabolism, adipokines, markers of cholesterol synthesis and absorption, and molecular markers of cholesterol metabolism.

Conclusions: Ezetimibe does not increase circulating PCSK9 concentrations while simvastatin does. When added to simvastatin, ezetimibe does not cause an incremental increase in PCSK9 concentrations. Changes in PCSK9 concentrations are tightly regulated and mainly influenced by baseline PCSK9 levels and changes in LDL cholesterol.

Nothing to Disclose: IG, HB, SB, NGS

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