Abstract
Very few studies have investigated the interrelations between proprotein convertase subtilisin/kexin type 9 (PCSK9) metabolism, cholesterol synthesis, and cholesterol absorption. We aimed to address this issue in a large clinical trial of 245 patients with hypercholesterolemia. Serum lipids, PCSK9, lathosterol (cholesterol synthesis marker), campesterol, and sitosterol (cholesterol absorption markers) were measured before and 4-8 weeks after the start of treatment with PCSK9-antibodies (alirocumab or evolocumab). The patients had mean (standard error) LDL-cholesterol and PCSK9 concentrations of 3.87 (0.10) mmol/l and 356 (17) ng/ml, respectively. Eighty-four patients received no lipid-lowering pretreatment, 26 ezetimibe, 38 statins, and 97 ezetimibe + statins. Circulating PCSK9 increased in parallel with the potency of lipid-lowering pretreatment with circulating PCSK9 being highest in the ezetimibe + statin group (P < 0.001). Treatment with PCSK9-antibodies strongly decreased LDL-cholesterol, lathosterol, campesterol, and sitosterol (all P < 0.001) but hardly affected noncholesterol sterol to cholesterol ratios. Lipid-lowering pretreatment was not associated with the effects of PCSK9-antibodies on noncholesterol sterols (all P > 0.05). Summing up, circulating PCSK9 is increased by cholesterol synthesis and absorption inhibitors. Increased PCSK9 expression may partly explain the strong reductions of LDL-cholesterol achieved with PCSK9-antibodies after such pretreatment. On the other hand, treatment with PCSK9-antibodies does not significantly change the balance between cholesterol synthesis and absorption.
Highlights
Mannheim, Germany; Synlab Academy,*** Synlab Holding Germany GmbH, 68161 Mannheim, Germany; and Klinik und Poliklinik für Kardiologie,††† Universitätsklinikum Leipzig, 04103 Leipzig, Germany
Proprotein convertase subtilisin/kexin type 9 (PCSK9)antibodies are increasingly used in patients with hypercholesterolemia who do not reach LDL-cholesterol treatment targets with the maximally tolerated doses of statins and ezetimibe [1, 2]
An interesting finding of the present study is that circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) increased in a stepwise manner with increasing potency of lipid-lowering pretreatment with statins and/or ezetimibe
Summary
Germany; Synlab Academy,*** Synlab Holding Germany GmbH, 68161 Mannheim, Germany; and Klinik und Poliklinik für Kardiologie,††† Universitätsklinikum Leipzig, 04103 Leipzig, Germany. PCSK9, lathosterol (cholesterol synthesis marker), campesterol, and sitosterol (cholesterol absorption markers) were measured before and 4–8 weeks after the start of treatment with PCSK9-antibodies (alirocumab or evolocumab). Treatment with PCSK9-antibodies strongly decreased LDL-cholesterol, lathosterol, campesterol, and sitosterol (all P < 0 .001) but hardly affected noncholesterol sterol to cholesterol ratios. G.S. reports grants and personal fees from Sanofi, grants and nonfinancial support from Amgen, nonfinancial support from Bayer, and grants from Numares outside the submitted work. U.K. reports personal fees from Fresenius Medical Care, Sanofi, Alexion, Berlin Chemie, Amgen, and Synlab Holding GmBH outside of the submitted work. Proprotein convertase subtilisin/kexin type 9 (PCSK9)antibodies are increasingly used in patients with hypercholesterolemia who do not reach LDL-cholesterol treatment targets with the maximally tolerated doses of statins and ezetimibe [1, 2]. Recent outcome trials have provided evidence that the two approved PCSK9-antibodies, alirocumab and evolocumab, reduce LDL-cholesterol and the risk of cardiovascular events [3, 4]
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