Hypercholesterolemia, a condition marked by high levels of cholesterol in the blood affects over 30 million adults in the USA and is responsible for 2.6 million deaths and 29.7 million disability life adjusted years worldwide. It is caused by genetic mutations but environmental factors such as diet, smoking, age and sex may aggravate the condition. The significant mutations are seen in APOB, LDLR, LDLRAP1, and PCSK9 genes. The high plasma cholesterol tends to deposit in organs leading to atherosclerosis, tendon xanthomas and athropathies. Diagnosis is by measuring LDL levels with fasting LDL levels >190 mg/dL in adults in the absence of any other causes leading to a suspicion of the disease. Genetic tests are used to confirm familial hypercholesterolemia. First line treatment is lifestyle adjustments including diet, smoking cessation and regular physical exercise. Pharmacological therapy includes statins alone or with adjuvants such as Ezetimibe, Niacin, Fibrates, Bile acid sequestrants or the newer Lomitapide and Mipomersen. A new class of drugs called PCSK9 inhibitors have been developed to treat hypercholesterolemia. They block the PCSK9 enzyme that binds to LDL receptors leading to their degradation. The effect of these drugs is less LDLR degradation, therefore more available receptors to bind and process cholesterol. Currently in the market are the monoclonal antibodies against PCSK9 namely Evolocumab and Alirocumab. Bococizumab has passed Phase II clinical trials and is proceeding to Phase III before approval for market distribution. Despite their excellent efficacy in lowering LDL, these drugs are relatively expensive and available only as subcutaneous injections.

This challenge is being address by research into other inhibitors of this enzyme. They will be in the form of adnectins, small molecules, RNA interference and vaccines. This these will discuss further the currently available PCSK9 inhibitors, those under development as well as giving an overview of hypercholesterolemia, especially the familial type.