The Evolving Future of PCSK9 Inhibitors

Variants in proprotein convertase subtilisin/kexin type 9 (PCSK9) provide insights into mechanisms regulating low-density lipoprotein (LDL) levels. Human monoclonal antibodies that target PCSK9 lower LDL cholesterol (LDL-C) levels by 55% to 72% in different high-risk patient groups. Clinical trials with PCSK9 inhibitors have demonstrated reductions in atherosclerotic cardiovascular disease events, particularly in patients with recent acute coronary syndrome, multivessel coronary artery disease, or peripheral arterial disease. Commonly observed profound reductions in LDL-C to levels <25 mg/dl have been accompanied by even lower rates of atherosclerotic cardiovascular disease events, thus supporting the concept that there may be no lower limit for LDL-C. Aggressive LDL-C lowering with fully human PCSK9 monoclonal antibodies has been accompanied by a safety profile that has been very favorable. On the basis of clinical trial evidence, LDL lowering with PCSK9 inhibitors is recommended for high-risk patients with LDL-C levels ≥70 mg/dl on maximally tolerated oral therapies including statins and/or ezetimibe.