Lipoprotein apheresis and proprotein convertase subtilisin/kexin type 9 inhibitors: Do we have a vanquishing new strategy?

Abstract

Data from randomised and observational trials have demonstrated a strong association between increasing levels of low-density lipoprotein cholesterol (LDL-C) and the risk of atherosclerotic cardiovascular disease. Familial hypercholesterolaemia (FH) is a hereditary autosomal dominant disorder with impaired function of LDL-C receptors, resulting in insufficient cellular binding and clearance of plasma LDL-C, and a lifelong elevated LDL-C levels. If left untreated, patients with FH have a 13-fold higher risk for coronary artery disease, and if treated with standard lipid-lowering medications (i.e. statins, ezetimibe) then a 10-fold higher risk. This emphasises the limitations of conventional lipid-lowering treatment in those patients. In addition to having increased levels of LDL-C, patients with FH also have an increased level of lipoprotein (a) (Lp(a)), comprising of LDL core and apolipoprotein (a). Increased levels of Lp(a) have strong proatherogenic and prothrombotic properties. Lp(a) is a risk factor for major coronary events. In patients with FH, increased levels of Lp(a) confer a five-fold higher risk of myocardial infarction. Standard lipid-lowering therapy has failed to significantly reduce Lp(a), but proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and nicotinic acid can decrease this lipid fraction by 25.5–36%. Lipoprotein apheresis enables extracorporeal removal of both LDL-C and Lp(a). In patients with increased Lp(a), this procedure significantly reduced the incidence of adverse cardiovascular events by 74%. Likewise, lipoprotein apheresis can have an impact on the reduction of LDL-C plasma levels of up to 80%. However, the beneficial effects of lipoprotein apheresis last only temporarily, and a rapid rebound is seen in the next few days, reaching a plateau during the second week. Consequently, a steady state of improved lipoprotein profile can be obtained only by repetitive apheresis at regular intervals, with concomitant diet and pharmacological treatment. Recent European Society of Cardiology (ESC) guidelines on the management of dyslipidaemias support lipoprotein apheresis for patients with homozygous FH, in whom pharmacological treatment demonstrated limited effectiveness. In some European countries, lipoprotein apheresis is approved for heterozygous FH and severe nonhereditary hypercholesterolaemia in the case of intolerance or refractoriness to standard lipid-lowering drugs. In spite of a clear beneficial effect, certain limitations of apheresis should be stressed: invasive venous approach, hypotensive reactions, potential interaction with angiotensin-converting-enzyme (ACE) inhibitors, need for repetitive procedures and cost. Considering these drawbacks, lipoprotein apheresis is not a convenient long-term strategy for the management of patients with FH. There has been a growing interest in establishing an adjuvant treatment capable of maintaining or even improving the lipid profile achieved by apheresis. The combined effect of apheresis and the adjuvant treatment would have a sustained impact on the reduction of cardiometabolic risk in patients with FH. PCSK9 is a protease synthetised in liver; it binds to LDL receptors and enables their degradation by lysosomes, resulting in an increase of LDL-C concentration. In FH, there are also high levels of PCSK9 due to the lack of LDL receptors, and PCSK9 positively correlates with LDL-C levels. Monoclonal antibodies targeting PCSK9 (i.e. PCSK9 inhibitors) have a proven benefit for the management of FH. A meta-analysis by Navarese et al. has shown a