The role of PCSK9 in Familial Hypercholesterolemic subjects and in subjects at high cardiovascular risk treated with statins and a CETP inhibitor

Abstract

Cardiovascular disease (CVD) is one of the leading causes of death in the developing world, killing one Australian every twelve minutes (www.heartfoundation.com.au). Hypercholesterolemia and long term elevated LDL-cholesterol (LDL-C) levels are linked to the formation of atherosclerotic plaques, which can eventually lead to myocardial infarction or stroke. It is therefore essential to lower LDL-C levels in order to reduce cardiovascular (CV) risk. The low density lipoprotein receptor (LDLR) removes and degrades LDL particles from circulation. Proprotein convertase subtilisin kexin type 9 (PCSK9) regulates cholesterol metabolism by degrading the LDLR. A number of pharmaceutical companies have created therapeutic agents known as PCSK9 inhibitors, which bind to and block PCSK9. PCSK9 inhibitors in combination with existing lipid lowering treatments have been shown to significantly decrease circulating LDL-C levels in a wide variety of subjects. The aim of thesis was to examine the biology of PCSK9 in subjects with familial hypercholesterolemia (FH), in subjects at high CV risk and in subjects treated with a CETP inhibitor. The ex vivo and in vitro studies in this thesis demonstrated that statins increased, recombinant PCSK9 decreased, and the PCSK9 inhibitor restored LDLR cell surface expression in all heFH and receptor defective hoFH subjects. However, LDLR cell surface expression was not affected in receptor negative hoFH subjects. In subjects at high CV risk the administration of ascending atorvastatin doses increased plasma PCSK9 levels at each individual dose. Subjects with diabetes who were treated with atorvastatin also had significantly higher plasma PCSK9 levels compared to subjects without diabetes. However, the administration of the CETP inhibitor, torcetrapib had no effect on circulating PCSK9 levels in subjects with or without diabetes. These results from this thesis provided a novel insight into PCSK9 biology and have important clinical implications for subjects diagnosed with FH and in subjects at high CV risk. The results from these studies support current clinical trial results and provide strong in vitro and ex vivo evidence for the use of PCSK9 inhibitors in all heFH, receptor defective hoFH and statin treated subjects at high CV risk with or without type 2 diabetes.