The PCSK9 revolution and the potential of PCSK9-based therapies to reduce LDL-cholesterol


  • Nabil G Seidah Laboratory of Biochemical Neuroendocrinology, IRCM; Affiliated to the University of Montreal, 110 Pine Av- enue West, Montreal, QC, H2W 1R7 Canada



[first paragraph of article]

A large number of clinical trials over the last 30 years have firmly consolidated the importance of lowering low density lipoprotein cholesterol (LDLc) in the prevention of cardiovascular diseases (CVD) and its associated devastating sequelae. While healthy diets and exercise are highly recommended to lower LDLc levels, in many individuals with high baseline levels of LDLc, this is not sufficient to bring levels down to recommended target values in order to prevent recurrent coronary heart disease and cardiovascular complications. This is especially true for patients at high risk of premature cardiovascular death and disability, including those with familial hypercholesterolaemia (FH). FH is a very common inherited disease – affecting at least 30 million people worldwide, with an overall incidence of 1:200 globally – of whom ≤ 1% have been diagnosed. The advent of HMG-CoA reductase inhibitors, also known as ‘‘statins’’, and their first application to hypercholesterolemic patients over 30 years ago, has revolutionized the treatment of FH patients and resulted in substantial lowering of LDLc. In addition, cholesterol– lowering drugs, such as ‘‘ezetimibe’’ that blocks cholesterol absorption from the gut by inhibiting the Niemann-Pick C1-like 1 (NPC1L1) transporter, have also been successful and a 7-year IMPROVE-IT trial revealed that a ‘‘simvastatin-ezetimibe’’ combination resulted in an incremental lowering of LDLc levels and a modest 2% improved cardiovascular outcomes.3 Therefore, it became clear that additional treatments are needed to substantially decrease LDLc and efficiently protect against CVD. 






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