PCSK9 inhibitors in the prevention of cardiovascular disease

Abstract

Reducing plasma levels of low-density lipoprotein cholesterol (LDL-C) remains the cornerstone in the primary and secondary prevention of cardiovascular disease. However, lack of efficacy and adverse effects mean that a substantial proportion of patients fail to achieve acceptable LDL-C levels with currently available lipid-lowering drugs. Over the last decade, inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic strategy to reduce residual cardiovascular disease risk. Binding of PCSK9 to the LDL receptor targets the receptor for lysosomal degradation. The recognition that inhibition of PCSK9 increases LDL receptor activity has led to the development of a number of approaches to directly target PCSK9. Numerous monoclonal antibodies against PCSK9 are currently being evaluated in phase 3 trials, involving various patient categories on different background lipid-lowering therapies. Current evidence shows reductions in LDL-C levels of up to 70 % may be achieved with PCSK9 inhibition, independent of background statin therapy. This review examines the most recent evidence and future prospects for the use of PCSK9 inhibitors in the prevention of cardiovascular disease.Keywords Low-density lipoprotein Á Proprotein convertase subtilisin kexin type 9 (PCSK9) Á Prevention Á Monoclonal antibody Á Evolocumab Á Alirocumab

PCSK9 inhibitors: when statins aren't enough

“…Gene mutations that increase PCSK9 function occur in some individuals with familial hypercholesterolaemia; conversely, mutations that decrease PCSK9 function are associated with low levels of LDL cholesterol. 25 PCSK9 inhibitors prevent the formation of the enzyme-receptor complex, preserving LDL receptors and thereby increasing hepatic LDL uptake from the circulation. They also increase levels of favourable HDL cholesterol in the circulation.…”

Farmakoterapia skojarzona w heterozygotycznej rodzinnej hipercholesterolemii

“…W ostatniej dekadzie prowadzone są badania kliniczne z nową grupa leków hipolipemizujących -inhibitorami PCSK9 [2,[43][44][45]. Enzym PCSK9, wiążąc się z receptorami LDL w lizozomie hepatocytów, powoduje degradację receptorów.…”

“…W toku są badania z ewolokumabem (FOURIER), alirokumabem (ODYSSEY OUTCOMES) i bokocizumabem (SPIRE1 i SPIRE2) [45].…”

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Therapy

“…4 Given the proven benefit of LDL-C reduction in lowering rates of major cardiovascular events, 5 PCSK9 inhibitors (PCSK9i) have been developed as a novel class of medications for use in high-risk populations. 6, 7 Two monoclonal antibodies that inactivate PCSK9, alirocumab and evolocumab, have been approved by the Food and Drug Administration (FDA) for use along with diet and maximally tolerated statin therapy in patients with familial hypercholesterolemia (FH) or clinical atherosclerotic cardiovascular disease (ASCVD) who require additional LDL-C lowering. 8, 9 Alirocumab and evolocumab reduce LDL-C levels by up to 60% and may decrease major adverse cardiovascular events.…”