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Supplements PCSK9 Inhibitors: A Guide for Managed Care
Epidemiology and Management of Hyperlipidemia
Samantha Karr, PharmD, FCCP, BCPS, BCACP, BC-ADM
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PCSK9 Inhibitors and Managing Cost in the Managed Care Setting
Sheila L. Stadler, PharmD, BCPS-AQ Cardiology, CLS; and Thomas J. Cook, PhD, RPh

PCSK9 Inhibitors and Managing Cost in the Managed Care Setting

Sheila L. Stadler, PharmD, BCPS-AQ Cardiology, CLS; and Thomas J. Cook, PhD, RPh
In patients with hypercholesterolemia who have atherosclerotic cardiovascular disease and/or familial hypercholesterolemia, a new class of drugs may be helpful in reducing serum levels of low-density lipoprotein cholesterol (LDL-C) beyond maximally tolerated statin therapy. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower LDL-C through a different mechanism of action than standard cholesterol-lowering therapies. Currently approved PCSK9 inhibitors are the monoclonal antibodies alirocumab and evolocumab. Although the drugs produce substantial reductions in LDL-C, cost issues and efficacy in preventing cardiovascular events should be evaluated when considering the adoption of PCSK9 inhibitors in the managed care setting.
Am J Manag Care. 2017;23:-S0
Whether aiming for a percentage reduction  or for specific numerical targets, reducing low-density lipoprotein cholesterol (LDL-C) is a core component of lipid management in the prevention of cardiovascular disease (CVD) and related sequelae. 1-3 The steps of the cholesterol cycle provide numerous potential targets for pharmacologic intervention to reduce LDL-C. The primary mechanisms of action of current standard lipid-lowering therapies focus on specific steps of the cholesterol cycle: statins inhibit hydroxymethyl glutaryl coenzyme A reductase, which decreases cholesterol synthesis and upregulates LDL receptors (LDLRs); bile salt sequestrants bind bile acids in the distal gastrointestinal tract to reduce enterohepatic recycling; and ezetimibe inhibits intestinal cholesterol absorption. Research on other targets in the cholesterol cycle may yield promising pharmacologic agents to complement or supplant current lipid-lowering strategies.2,3

Many patients with hypercholesterolemia do not respond sufficiently to standard lipid-lowering therapies. They may not tolerate the adverse effects (AEs) of statins or they may have familial hypercholesterolemia (FH) that limits the effectiveness of lipid-lowering therapies. For these patients, alternative pharmacologic approaches may be necessary to lower LDL-C to help avoid cardiovascular (CV) events. Guidance on such alternative approaches is described in the 2016 report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. The report provides a detailed decision pathway for the use of nonstatin therapies in treating 4 patient groups.1

PCSK9 Inhibitors: Alirocumab and Evolocumab
Mechanism of Action
A novel target in the cholesterol cycle is the protein, proprotein convertase subtilisin/kexin type 9 (PCSK9), which plays a major role in the uptake of LDL-C into hepatocytes (Figure4).4 Individuals with loss-of-function mutations in PCSK9 have reduced levels of LDL-C and are protected from CVD.5,6

LDL-C, through its apolipoprotein B100 carrier protein, binds to LDLRs on the cell surface of hepatocytes, after which PCSK9 binds to LDLR on the hepatocyte surface. Cellular uptake of this complex occurs via endocytosis. Bound PCSK9 then directs the resulting endocytic vesicle to the lysosome for degradation. Lysosomal degradation of the LDLR decreases the concentration of receptors, which are responsible for clearing LDL-C from the bloodstream. When PCSK9 binding is inhibited, however, LDLRs avoid lysosomal degradation and are recycled to the cell surface to bind more LDL-C particles.7 This recycling of LDLRs, prompted by the lack of bound PCSK9, leads to an increased clearance of LDL-C from the plasma, thus reducing LDL-C levels.7,8

One efficient mechanism for inhibiting PCSK9 binding is to use monoclonal antibodies (mAbs) that target PCSK9 (Figure4). Recently approved PCSK9 inhibitors, alirocumab and evolocumab, bind to free PCSK9 in the plasma, thus preventing PCSK9 binding to LDLRs9,10

LDLRs and PCSK9 are also linked at the transcription level. Regulation of LDLR and PCSK9 expression occurs via the sterol regulatory element-binding protein-2 (SREBP-2) such that induction of SREBP-2 leads to increased production of LDLRs and PCSK9.11 Statins have been reported to increase PCSK9 levels12 while also reducing LDL-C levels.13,14 This apparently dichotomous scenario led researchers to postulate that the LDL-C–lowering effects of statins could be enhanced by inhibiting PCSK9,11 a hypothesis that came to fruition with the approvals of alirocumab and evolocumab, the current PCSK9 inhibitors on the market in the United States.

Alirocumab is a human mAb of the immunoglobulin G1 (IgG1) isotype that is manufactured in Chinese hamster ovary (CHO) cells.15 Evolocumab, also manufactured in CHO cells, is a human mAb of the IgG2 isotype.16 Both alirocumab and evolocumab bind PCSK9 with high affinity at subnanomolar and nanomolar ranges for alirocumab and evolocumab, respectively.17,18 The binding of the antibodies to free PCSK9 in the plasma prevents PCSK9 binding to the LDLR, leading to reductions in plasma LDL-C through the mechanism described above.

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