Invited commentary Lipoprotein apheresis and proprotein convertase subtilisin/kexin type 9 inhibitors: Do we have a vanquishing new strategy? Ivana Veljic ´ 1 , Marija Polovina 1,2 , Ivan Milinkovic ´ 1 and Petar M Seferovic ´ 2 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. 1 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. 2 If left untreated, patients with FH have a 13-fold higher risk for coronary artery dis- ease, and if treated with standard lipid-lowering medi- cations (i.e. statins, ezetimibe) then a 10-fold higher risk. 3 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). 4 Increased levels of Lp(a) have strong proatherogenic and prothrombotic properties. 5 Lp(a) is a risk factor for major coronary events. 6 In patients with FH, increased levels of Lp(a) confer a five-fold higher risk of myocardial infarction. 4 Standard lipid-lowering therapy has failed to signifi- cantly reduce Lp(a), but proprotein convertase subtili- sin/kexin type 9 (PCSK9) inhibitors and nicotinic acid can decrease this lipid fraction by 25.5–36%. 7–9 Lipoprotein apheresis enables extracorporeal removal of both LDL-C and Lp(a). 10 In patients with increased Lp(a), this procedure significantly reduced the incidence of adverse cardiovascular events by 74%. 11 Likewise, lipoprotein apheresis can have an impact on the reduction of LDL-C plasma levels of up to 80%. 12 However, the beneficial effects of lipopro- tein apheresis last only temporarily, and a rapid rebound is seen in the next few days, reaching a plateau during the second week. 13 Consequently, a steady state of improved lipoprotein profile can be obtained only by repetitive apheresis at regular intervals, with concomi- tant diet and pharmacological treatment. 12,13 Recent European Society of Cardiology (ESC) guide- lines on the management of dyslipidaemias support lipo- protein apheresis for patients with homozygous FH, in whom pharmacological treatment demonstrated limited effectiveness. 14 In some European countries, lipo- protein apheresis is approved for heterozygous FH and severe nonhereditary hypercholesterolaemia in the case of intolerance or refractoriness to standard lipid-lowering drugs. 12 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. 12 Considering these drawbacks, lipoprotein apheresis is not a conveni- ent long-term strategy for the management of patients with FH. There has been a growing interest in estab- lishing 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 reduc- tion of cardiometabolic risk in patients with FH. PCSK9 is a protease synthetised in liver; it binds to LDL receptors and enables their degradation by lyso- somes, resulting in an increase of LDL-C concentra- tion. 15,16 In FH, there are also high levels of PCSK9 due to the lack of LDL receptors, and PCSK9 positively correlates with LDL-C levels. 17 Monoclonal antibodies targeting PCSK9 (i.e. PCSK9 inhibitors) have a proven benefit for the management of FH. 18 A meta-analysis by Navarese et al. has shown a 1 Department of Cardiology, Clinical Center of Serbia, Serbia 2 Faculty of Medicine, University of Belgrade, Serbia Corresponding author: Petar M Seferovic ´, Faculty of Medicine, Belgrade University, 8 Dr Subotic ´a, 11000 Belgrade, Serbia. Email: seferovic.petar@gmail.com European Journal of Preventive Cardiology 2019, Vol. 26(7) 739–742 ! The European Society of Cardiology 2018 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/2047487318817671 journals.sagepub.com/home/ejpc