A new therapeutic avenue for slowing down atherosclerosis

This review analyzed the role of PCSK9 (protein convertase subtilisin/kexin type 9) in lipid (fat) metabolism and atherosclerosis, and therapeutic strategies targeting PCSK9.

PCSK9 is a protein which controls normal cholesterol uptake in the body, leading to high levels of low-density lipoprotein cholesterol (LDL-cholesterol). High levels of this cholesterol (hypercholesterolemia) are known to accelerate the process of atherosclerosis. Atherosclerosis occurs when fatty material is deposited within the artery wall, and is a major risk factor for strokes and heart attacks. Statins are a class of drugs commonly used to lower cholesterol levels.  However, as statins decrease cholesterol levels, PCSK9 production increases in response, and LDL-cholesterol levels rise again. Due to this, approximately 50% of patients treated with statins fail to reach recommended LDL-cholesterol levels. Genetic mutations which inhibit the function of PCSK9 have been previously shown to be associated with reduced LDL-cholesterol levels and cardiovascular risk. Therefore, targeting PCSK9 may be a therapeutic option for the treatment of hypercholesterolemia. The current review evaluated recent evidence regarding the PCSK9 inhibition and reducing cardiovascular risk. 

In pre-clinical lab trials, PCSK9 was found to significantly increase LDL-cholesterol levels in both human and mouse cells. In mice fed a high-cholesterol diet, high levels of PCSK9 were associated with accelerated development of atherosclerotic plaques. The use of monoclonal antibodies (proteins that specifically bind and neutralize other proteins) against PCSK9 resulted in an 80% reduction in LDL-cholesterol levels in animal studies.

In a phase I human trial of the same monoclonal antibody, now termed AMG145 or Evolocumab, LDL-cholesterol was significantly reduced with AMG145 injections compared to a placebo. On average, LDL-cholesterol was reduce by 64% among patients receiving AMG145. A separate trial showed that when patients were administered a combination of AMG145 and statins, LDL-cholesterol levels were reduced by an average of 75%, with no adverse events. A recent phase II trial, including over a 1000 patients and a follow-up period of 1 year, confirmed the efficiency of AMG145 in reducing LDL-cholesterol levels without significant adverse events. 

This review concluded that PCSK9 inhibition, with or without statin therapy, shows great potential in the management of hypercholesterolemia and the reduction of cardiovascular risk.

While recent evidence has shown AMG145 to be effective at reducing LDL-cholesterol levels, the direct effect of AMG145 on cardiovascular mortality has not yet been investigated.

Consult with your physician regarding the importance of managing blood cholesterol levels in reducing the risk of cardiovascular events.