Elevated levels of low-density lipoprotein cholesterol (LDL-C) have long been established as one of the most important risk factors for developing coronary artery disease (CAD) and other forms of atherosclerotic cardiovascular disease (CVD).1,2 Targeting LDL-C reduction has been effective in lowering cardiovascular risk.3,4 The use of HMGCoA reductase inhibitors (statins) for both primary and secondary cardiovascular disease prevention has become first-line therapy and has resulted in reduction of cardiovascular (CV) events and overall mortality.3 More recent guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA) have recommended intensification of statin therapy based on calculated atherosclerotic CVD risk and not based on LDL-C levels alone.5 However, despite reduction in LDL-C by 18–41 % (moderate doses) and 40–60 % (higher doses or more potent statins), there remains significant residual cardiovascular risk. In addition, there are many otherindividuals that have been unable to achieve sufficient LDL-C lowering or have been intolerant to the drug completely.6 Other cholesterol lowering agents (bile acid sequestrants, ezetimibe, niacin, fibrates) have been used in conjunction with statins to achieve historic LDL and/or non-HDL-C goals, however at this time their addition has not been proven to have added value in clinical cardiovascular outcomes.7–10 Due to continued inability to achieve adequate clinical benefit and ongoing incidence of statin intolerance, research for alternative therapies is of utmost priority. The discovery of proprotein convertase subtilisin/kexin Type 9 (PCSK9) has opened the possibility for effective and adjunctive therapy for those who are not optimised with statins while providing therapy in lowering cardiovascular risk in subjects who are intolerant and have little alternatives.
LDL Cholesterol Cellular Metabolism
Most LDL is cleared from the plasma by LDL receptors on hepatocytes. At neutral pH, the LDL-receptor (LDL-R) binds to apolipoprotein B-100 (apoB100) on LDL and LDL endocytosis ensues.11 In the acidic environment of the endosome, the LDL-R folds into a closed formation state, thereby releasing LDL.12 LDL-R is then recycled to the cell surface while LDL is transferred to a proteasome targeting it for further processing.13 The inability of LDLR-LDLP complex to dissociate routes the complex for degradation, thereby reducing LDL-R surface concentration. Regulation of the LDL-R is also driven by the intracellular concentration of cholesterol. In the setting of high intracellular cholesterol levels, LDL-R levels decrease and activity of HMG CoA synthase and reductase decrease by more than 90 %. Thus, in the setting of drugs that lower intracellular cholesterol, such as statins, LDL-R levels are increased and serum LDL-C levels are decreased.
B Cellular mechanism regulating cholesterol homeostasis is complex and involves balance between intracellular biosynthesis and exogenous uptake of cholesterol. Cholesterol uptake and intracellular biosynthesis is regulated by sterol regulatory element-binding protein (SREBP), a transcription factor located in the endoplasmic reticulum. When cholesterol levels on the endoplasmic reticulum membrane are low, a sterol sensor binds to SREBP and signals its movement from the endoplasmic reticulum to the Golgi apparatus where SREBP is further activated and transported to the nucleus.14 In the nucleus, SREBP acts as a transcription factor, increasing HMG coA reductase and LDLR gene expression.13