Abstract
Barely a decade after the discovery of the gene encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) and its recognition as a key player in cholesterol metabolism, PCSK9 inhibition is now considered an exciting approach in the reduction of residual risk of cardiovascular disease. The progress from PCSK9 discovery to the development of targeted treatment has been unprecedented in terms of scale and speed. The first suggestion of a link between PCSK9 and hypercholesterolemia was published in 2003; a decade later, two meta-analyses of clinical trials comparing anti-PCSK9 treatment to placebo or ezetimibe, including >10,000 hypercholesterolemic individuals, were published. Currently, three PCSK9 inhibitors are being evaluated in clinical outcome trials and the results will determine the future of these lipid-lowering therapies by establishing their clinical efficacy in terms of cardiovascular event reduction, safety, and the consequences of prolonged exposure to very low levels of LDL-cholesterol. Irrespective of their outcomes, the exceptionally rapid development of these drugs exemplifies how novel technologies, genetic validation, and rapid clinical progression provide the tools to expedite the development of new drugs.
Highlights
Two decades after the results of the Scandinavian Simvastatin Survival Study first showed that statins effectively improve survival in patients with cardiovascular disease (CVD), initiating a revolution in the treatment of dyslipidemia [1], ezetimibe has been the only drug shown to further improve outcomes for dyslipidemic patients [2]
The present review focuses primarily on proprotein convertase subtilisin/kexin type 9 (PCSK9)-inhibiting antibodies due to their presently more advanced clinical development
Stein et al [17] demonstrated the ability of the PCSK9inhibiting antibody alirocumab to reduce low-density lipoprotein cholesterol (LDL-C) by more than 60 % in both healthy volunteers and patients with familial hypercholesterolemia (FH)
Summary
Two decades after the results of the Scandinavian Simvastatin Survival Study first showed that statins effectively improve survival in patients with cardiovascular disease (CVD), initiating a revolution in the treatment of dyslipidemia [1], ezetimibe has been the only drug shown to further improve outcomes for dyslipidemic patients [2]. The clinical potential of PCSK9 inhibition with monoclonal antibodies has been studied in more than 20 short-term clinical trials against various background lipid-lowering therapies and with both placebo and ezetimibe as a comparator treatment. Published trials of PCSK9 inhibitors have already demonstrated the potential to reach unprecedented low LDL-C levels in heterozygous FH and currently ongoing clinical outcome studies will establish whether addition of PCSK9 inhibition to current treatment confers sustained clinical benefit in this patient population (NCT Trial Identifier: NCT01968980) [40,41,42]. All of the four ongoing clinical outcome trials on PCSK9-inhibition antibodies include high-risk patients (either clinically manifest CVD or dyslipidemia) and will determine the efficacy of PCSK9 inhibitors added to lipid-lowering therapy in reducing major CVD event rates compared to placebo over approximately 5 years of follow-up (Table 1). Despite the fact that ongoing phase III trials will determine the safety of PCSK9 inhibition after 5 years of follow-up, post-marketing registration and extended follow-up studies are required to confirm their safety in the longer term
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
