Inhibitors of Protein Convertase Subtilisin/Kexin 9 (PCSK9) and Acute Coronary Syndrome (ACS): The State-of-the-Art

Abstract

Acute Coronary Syndrome (ACS) remains one of the most frequent causes of morbidity and mortality in the world. Although the age- and gender-adjusted incidence of ACS is decreasing, the mortality associated with this condition remains high, especially 1-year after the acute event. Several studies demonstrated that PCSK9 inhibitors therapy determine a significant reduction of major adverse cardiovascular events (MACE) in post-ACS patients, through a process of plaque modification, by intervening in lipid metabolism and platelet aggregation and finally determining an improvement in endothelial function. In the EVACS (Evolocumab in Acute Coronary Syndrome) study, evolocumab allows >90% of patients to achieve LDL-C < 55 mg/dL according to ESC/EAS guidelines compared to 11% of patients who only receive statins. In the EVOPACS (EVOlocumab for Early Reduction of low-density lipoprotein (LDL)-cholesterol Levels in Patients With Acute Coronary Syndromes) study, evolocumab determined LDL levels reduction of 40.7% (95% CI: 45.2 to 36.2; p < 0.001) and allowed 95.7% of patients to achieve LDL levels <55 mg/dL. In ODYSSEY Outcome trial, alirocumab reduced the overall risk of MACE by 15% (HR = 0.85; CI: 0.78–0.93; p = 0.0003), with a reduced risk of all-cause mortality (HR = 0.85; CI: 0.73–0.98: nominal p = 0026), and fewer deaths for coronary heart disease (CHD) compared to the control group (HR = 0.92; CI: 0.76–1.11; p = 0.38). The present review aimed at describing the beneficial effect of PCSK9 inhibitors therapy early after ACS in reducing LDL circulating levels (LDL-C) and the risk of major adverse cardiovascular events, which was very high in the first year and persists higher later after the acute event.

Association Between Circulating Proprotein Convertase Subtilisin/Kexin Type 9 Concentrations and Cardiovascular Events in Cardiovascular Disease: A Systemic Review and Meta-Analysis

“…Besides the lipid-lowering effect of PCSK9, it plays a major role in the inflammatory reaction, platelet aggregation, and endothelial apoptosis contributing to atherosclerosis (29)(30)(31). Among the top 10 genetic variants associated with elevated LDL-C concentrations, a PCSK9 variant had the weakest association with elevated LDL-C concentrations but had the third strongest effect on the risk of MI (32).…”

Dyslipidemia in Transplant Patients: Which Therapy?

“…The association between higher Lp(a) circulating concentrations and increased CVD risk has been assessed [ 22 , 23 ]; furthermore, a reduction in these levels in patients treated with proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors was shown to reduce CV risk [ 24 , 25 ].…”

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors Use for Atherogenic Dyslipidemia in Solid Organ Transplant Patients

“…The hepatocytes, where PCSK9 is primarily expressed, are the main drivers for LDL particle removal from blood, through endocytosis mediated by the LDL receptor (LDLR) expressed on these cells’ membrane [ 27 ]. PCSK9 target the epidermal growth factor-like repeat homology domain A (EGFA-like) located on the LDLR, so LDLR and LDL particles are enabled to separate, and the entire complex is directed to lysosomes for degradation, avoiding the receptor recycling on the cell surface, and reducing, in this way, the clearance of LDL particles from plasma [ 17 , 26 ].…”

“…In recent years, a therapy with Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors is available for patients suffering from familial hypercholesterolemia or who are defined as very-high risk for the occurrence of cardiovascular events by the European Society of Cardiology guidelines on dyslipidemia [ 15 , 16 ]. They are human monoclonal antibodies which have proven to be safe and effective in reducing the incidence of major cardiac adverse events (MACE) in the general population [ 17 , 18 , 19 ].…”