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.
Highlights
Atherosclerotic cardiovascular disease (CVD) is the leading cause of mortality worldwide [1]
In the Reduction of low-density lipoprotein cholesterol (LDL-C) with proprotein convertase subtilisin/kexin type 9 (PCSK9) Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) trial, 167 patients with heterozygous familial hypercholesterolemia (FH) (HeFH) and poorly-controlled LDL-C (C2.6 mmol L-1 or 100 mg dL-1) despite maximally-tolerated statin therapy, were randomised 1:1:1 to receive evolocumab 350 mg, 420 mg or matched placebo, every four weeks
TESLA demonstrated that in the Evolocumab-treated HoFH patients, LDL-C was reduced by 31 % from baseline at week 12 compared with placebo (p \ 0.0001); no serious adverse side effects were noted
Summary
Atherosclerotic cardiovascular disease (CVD) is the leading cause of mortality worldwide [1]. In the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) trial, 167 patients with heterozygous FH (HeFH) and poorly-controlled LDL-C (C2.6 mmol L-1 or 100 mg dL-1) despite maximally-tolerated statin therapy, were randomised 1:1:1 to receive evolocumab 350 mg, 420 mg or matched placebo, every four weeks. The phase III, double-blind, double-dummy ODYSSEY-MONO trial evaluated the safety and efficacy of alirocumab as monotherapy in comparison with ezetimibe, over 24 weeks in patients with primary hypercholesterolemia and moderate cardiovascular risk, not otherwise receiving statins or other lipid-lowering therapy [65]. A total of 103 patients with LDL-C 2.6–4.9 mmol L-1 (100–190 mg dL-1), and 1–5 % 10-year risk of fatal cardiovascular events (estimated via the Systematic COronary Risk Evaluation [SCORE] tool) were randomised to receive either ezetimibe 10 mg or alirocumab, with the aim to achieve target HDL-C using the minimum effective dose of anti-PCSK9 antibody. To convert stated LDL-C values from mg dL-1 to mmol L-1 divide presented value by 38.67
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