Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels.

P lasma LDL cholesterol level is a major determinant of cardiovascular disease (CVD) risk. The striking results of the early large-scale statin trials showed that LDL levels can be reduced by 30–40% with comparable percentage reductions in CVD risk. More recent trials show that there is progressively greater relative risk reduction as the on-treatment level of LDL drops. In the JUPITER trial (1), rosuvastatin treatment of healthy subjects who had elevated CRP levels lowered LDL cholesterol levels 50% [from a baseline median of 108 mg/dL to 55 mg/dL (25% had values 44 mg/ dL)] and resulted in a 50% reduction in all CVD events. We recently suggested that an ‘‘ideal’’ LDL cholesterol level of 50 mg/dL should be the target goal of therapy in all high-risk subjects (2), but the Jupiter trial extends this concept to an even larger population and supports the concept that ‘‘the lower the LDL the better’’ is a reasonable position. However, achieving LDL levels of 50 mg/dL or even lower in patients with high initial values is often not possible with statins alone, even with maximum dosages. Such patients often require 2 or even 3 different drugs to reach a LDL level 100 mg/dL, much less 50 mg/dL, and such combinations increase the risk of side effects. Consequently, the search for new cholesterol-lowering interventions continues apace. In this issue of PNAS, Chan et al. (3) describe dramatic cholesterol lowering in nonhuman primates with the use of a mAb against proprotein convertase subtilisin/ kexin type 9 (PCSK9), a recently described key regulator of hepatocyte LDL receptor (LDL-R) expression.