PCSK9 inhibitors in the current management of atherosclerosis

Abstract

The history of proprotein convertase subtilisin/kexin type 9 (PCSK9) in medical science is fascinating and the evolution of knowledge of its function has resulted in new medications of major importance for the cardiovascular (CV) patient. PCSK9 functions as a negative control or feedback for the cell surface receptors for low-density lipoprotein including its component of cholesterol (LDL-C). The initial and key findings were that different abnormalities of PCSK9 can result in an increase or a decrease of LDL-C because of more or less suppression of cell surface receptors. These observations gave hints and awoke interest that it might be possible to prepare monoclonal antibodies to PCSK9 and decrease its activity, after which there should be more active LDL-C cell receptors. The rest is a fascinating story that currently has resulted in two PCSK9 inhibitors, alirocumab and evolocumab, which, on average, decrease LDL-C approximately 50%. Nevertheless, if there are no contraindications, statins remain the standard of prevention for the high-risk CV patient and this includes both secondary and primary prevention. The new inhibitors are for the patient that does not attain the desired target for LDL-C reduction while taking a maximum statin dose or who does not tolerate any statin dose whatsoever. Atherosclerosis can be considered a metabolic disease and the clinician needs to realize this and think more and more of CV prevention. These inhibitors can contribute to both the stabilization and regression of atherosclerotic plaques and thereby avoid or delay major adverse cardiac events. (United States).

PCSK9: A novel inflammation modulator in atherosclerosis?

“…PCSK9, independent of its enzymatic activity, induces the low‐density lipoprotein receptor (LDLR) degradation in the liver, resulting in increasing in the circulating LDL‐C (cholesterol) levels (Della Badia, Elshourbagy, & Mousa, ; Seidah, Abifadel, Prost, Boileau, & Prat, ; Soutar, ). Therefore, PCSK9 has been increasingly appreciated to play a key role in atherosclerosis (Huynh, ; Li & Li, ; Seidah, Awan, Chretien, & Mbikay, ; Whayne, ). Although an increase in blood LDL‐C by PCSK9 is important in atherogenesis, many studies suggest that PCSK9 accelerates atherosclerosis through mechanisms that are beyond its effects on LDL‐C levels (Cariou, Ding, & Mehta, ; Denis et al, ; Shapiro & Fazio, ; Tavori et al, ).…”

Trends and hotspots in familial hypercholesterolemia: A bibliometric systematic review from 2002 to 2022

“…More LDL-C receptors are expressed as a result of PCSK9 medicines’ blocking of PCSK9 proteins, which decreases the LDC-C level. [ 45 , 46 ] IgG1 and IgG2 monoclonal antibodies called alirocumab and evolocumab, respectively, block the PCSK9 enzyme and stop the loss of LDL receptors. [ 47 , 48 ] Lower levels of LDL-C are caused by an increase in LDL receptors on the surface of hepatocytes.…”

Antibody-Based Therapeutics for Atherosclerosis and Cardiovascular Diseases

“…From 1315 sites, the ODYSSEY trial enrolled 18,924 patients diagnosed with acute coronary syndrome (ACS) within 12 months prior to study inclusion [ 55 ]. After 2.8 years, the LDL-c level in the alirocumab group was 54.7% lower than that in the placebo group, and the incidence of the primary outcome of non-fatal MI, fatal or non-fatal ischemic stroke, and unstable angina requiring hospitalization was lower in the alirocumab group (9.5%) than in the placebo group (11.1%) [ 52 , 56 ].…”