What have we learned about lipids and cardiovascular risk from PCSK9 inhibitor outcome trials: ODYSSEY and FOURIER?

Abstract

The role of proprotein convertase subtilisin/kexin Type 9 (PCSK9) in the regulation of the low-density lipoprotein (LDL)-receptor and plasma cholesterol was identified in 2003. This seminal discovery led to the rapid exploitation of PCSK9 as a drug target. Fifteen years later, investigators have completed two large outcomes trials of monoclonal antibody inhibitors of PCSK9 (PCSK9Is). Evolocumab was evaluated in the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER), and alirocumab was tested in the Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY Outcomes) trials (Table 1). Treatment of patients with these agents has been remarkably successful in achieving lower plasma concentrations of LDL-cholesterol (LDL-C) than had ever previously been attainable with lipidlowering therapy. Therefore, in addition to the ‘headline’ event-rate reduction results of these trials, which will certainly inform clinical practice, scrutiny of the trial data can yield more general information about lipidlowering therapy. This commentary will briefly discuss what we have learned from outcome trials of evolocumab and alirocumab, and what the future holds for these agents.