In 2005, a loss-of-function mutation was found, supporting the concept that inhibitors of the enzyme could help lower LDL cholesterol and consequently reduce atherosclerotic cardio-vascular events.

Monoclonal antibodies to PCSK9 are now available to treat patients at high atherosclerotic risk — either due to familial hypercholesterolemia with intact LDL receptors who would have otherwise needed plasmapheresis, or because of having LDL levels far above guideline limits despite maximal therapy with moderate- or high-intensity statins. However, data supporting clinical outcomes with PCSK9-inhibitor use is lacking. 

Prior studies have shown that patients with angiographically established CAD who were already on chronic statin therapy and were randomized to receive treatment with PCSK9 inhibitors had significant plaque regression compared to the placebo group.However, translating those findings into clinical benefits on hard endpoints — such as cardiovascular death — has been difficult.

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Results of the FOURIER trial were recently published in The New England Journal of Medicine, and the findings were presented at the American College of Cardiology 66th Annual Session & Expo (ACC.17) with mixed reviews.2

The goal of the trial was to provide some of the much-needed evidence regarding the risk reduction of cardiovascular events attributable to the addition of PCSK9 inhibitors to guideline-directed antilipid therapies, and to evaluate for potential side effects of very low LDL levels.

The study was funded by Amgen. A total of 27,564 individuals from 49 countries who had established atherosclerotic cardiovascular disease and LDL levels greater than or equal to 70 mg/dl, and who were already on statin therapy, were randomized to receive either evolocumab or a placebo. 

Participants were monitored for a median follow-up period of only 2.2 years, despite original plans for 4 years of follow-up due to higher than expected​ event rates in the primary and secondary end-points.