Abstract
PCSK9 inhibitors, monoclonal antibodies, are novel antihypercholesterolemic drugs. FDA first approved them in July 2015. PCSK9 protein (692-amino acids) was discovered in 2003. It plays a major role in LDL receptor degradation and is a prominent modulator in low-density lipoprotein cholesterol (LDL-C) metabolism. PCSK9 inhibitors are monoclonal antibodies that target PCSK9 protein in liver and inhibiting this protein leads to drastically lowering harmful LDL-C level in the bloodstream. Despite widespread use of the statin, not all the high-risk patients were able to achieve targeted level of LDL-C. Using PCSK9 inhibitors could lead to a substantial decrement in LDL-C plasma level ranging from 50% to 70%, either as a monotherapy or on top of statins. A large number of trials have shown robust reduction of LDL-C plasma level with the use of PCSK9 inhibitors as a monotherapy or in combination with statins in familial and nonfamilial forms of hypercholesterolemia. Moreover, PCSK9 inhibitors do not appear to increase the risk of hepatic and muscle-related side effects. PCSK9 inhibitors proved to be a highly potent and promising antihypercholesterolemic drug by decreasing LDL-R lysosomal degradation by PCSK9 protein. Statin drugs are known to have some pleiotropic effects. In this article, we are also focusing on the effects of PCSK9 inhibitor beyond LDL-C reduction like endothelial inflammation, atherosclerosis, its safety in patients with diabetes, obesity, and chronic kidney disease, and its influence on neurocognition and stroke.
Highlights
Heart disease is the leading cause of death in the US (23.7% of total deaths in 2011) [1]
The discovery of Proprotein convertase subtilisin/kexin type-9 (PCSK9) proteins has changed the dynamics of lipid control in hypercholesterolemic patients
PCSK9 inhibitors pave the path of achieving an extremely low plasma level of low-density lipoprotein cholesterol (LDL-C) and have shown to reduce lifetime risk for cardiovascular disease (CVD) events. They are involved in decreasing endothelial inflammation which is the key factor for atherosclerosis
Summary
Heart disease is the leading cause of death in the US (23.7% of total deaths in 2011) [1]. People with high cholesterol level are twice more likely to be suffering from heart disease than normal adults. 73.7 million or 31.7% of US adults are found to have high LDL-C. In the case of homozygous FH, the cholesterol level can be elevated even up to 1000 mg/dl (with LDL-C > 600 mg/dL) and in heterozygous FH this level may reach up to 350–550 mg/dl (with LDL-C = 200–400 mg/dL). Most of the untreated homozygous FH patients usually develop heart attack in their late teens and about half of the heterozygous FH suffer from heart disease at around 45 years for men and 55 to 60 years for females [4, 5]. According to 2013 AHA/ACC guidelines individuals with LDL-C level more than 190 mg/dl require high-intensity statin therapy to achieve 50% reduction. In a study only 21% of patients achieved the target LDL-C level with the use of statin as a single agent [7] and a data from the UK showed among patients using combination therapy (statin and ezetimibe) only 44% patients achieved the target LDL-C level [8]
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