PCSK9 Mutations in Familial Hypercholesterolemia: from a Groundbreaking Discovery to Anti-PCSK9 Therapies

AbstractPurpose of ReviewIn 2003, Abifadel et al. (Nat. Genet. 34:154 –156, 2003) identifiedPCSK9, encoding proprotein convertase subtilisin/kexin type 9, as the third causal gene for autosomal dominant hypercholesterolemia. This review focuses on the main steps from this major breakthrough in familial hypercholesterolemia (FH) to the latest clinical trials with the anti-PCSK9 antibodies.Recent FindingsThe year 2015 was remarkable in cardiovascular disease through the field of cholesterol. Nearly 30  years after the discovery of statins, a new class of effective lipid-lowering drugs has emerged: the anti-PCSK9 antibodies. The discovery of the first gain-of-function mutations ofPCSK9 in FH rapidly became the center of interest of researchers worldwide. Preclinical and clinical studies launched by pharmaceutical companies led to the first three anti-PCSK9 antibodies, two of which (evolocumab and alirocumab) reduce LDL cholesterol levels by 50 –60% and received FDA and European Medicines Agency approvals in 2015 on top of statin therapy. Recently, results of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, the outcome trial of evolocumab over 2.2 years, showed a reductio n of 15–20% in the risk of major cardiovascular outcomes in high-risk patients receiving statin therapy. Results of ODYSSEY OUTCOMES trial, evaluating the effect of alirocumab in 18,000 patients with established CVD are also eagerly awaite...
Source: Current Atherosclerosis Reports - Category: Cardiology Source Type: research