Abstract
For more than half a century, low-density lipoprotein cholesterol (LDL-C) has been recognized as a major risk factor for incident atherosclerotic cardiovascular disease. The discovery of proprotein convertase subtilisin-kexin type 9 (PCSK9) in 2003, which prevents LDL-C receptor recycling, identified a new target for drug intervention. Recently, two large-scale randomized clinical outcomes trials involving fully human anti-PCSK9 monoclonal antibodies tested the hypothesis that targeting this pathway would reduce cardiovascular events. Both the FOURIER (Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk) and ODYSSEY OUTCOMES trials met their primary efficacy endpoints, confirming findings reported earlier that major adverse cardiovascular events can be reduced by a further lowering of LDL-C beyond that achieved with statin therapy. In both trials, there were incremental reductions in LDL-C of > 50% from baseline, with no major safety concerns, over the trials' median follow-up time (2.2 and 2.8 years, respectively). While there were differences in design, lipid management and overall results, key messages from both studies were similar. However, post-publication, additional questions have arisen, especially regarding drug effects over the long-term, including a potential mortality benefit.