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PCSK9 Inhibitors Provided By: National Lipid Association’S Therapeutics Committee

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PCSK9 Inhibitors Provided By: National Lipid Association’S Therapeutics Committee EBM Tools for Practice: A National Lipid Association Best Practices Guide: PCSK9 Inhibitors Provided by: National Lipid Association’s Therapeutics Committee DEAN A. BRAMLET, MD, FNLA DAVID R. NEFF, DO 2017-18 Co-Chair, NLA Therapeutics Committee 2017-18 Co-Chair, NLA Therapeutics Committee Assistant Consulting Professor of Medicine President, Midwest Lipid Association Duke University Michigan State University Medical Director, Cardiovascular Diagnostic Center College of Osteopathic Medicine The Heart & Lipid Institute of Florida Associate Clinical Professor St. Petersburg, FL Department of Family & Community Medicine Diplomate, American Board of Clinical Lipidology Ingham Regional Medical Center Lansing, MI DEAN G. KARALIS, MD, FNLA PAUL E. ZIAJKA, MD, PhD, FNLA Clinical Professor of Medicine Director Jefferson University Hospital Florida Lipid Institute Philadelphia, PA Winter Park, FL Diplomate, American Board of Clinical Lipidology Diplomate, American Board of Clinical Lipidology routine process of care. This report was REPATHA (evolocumab) now is indicated generated independently from industry as follows: sponsorship to assist clinical lipidologists • to reduce the risk of myocardial Discuss this article at to ensure access to care for those patients infarction, stroke and coronary www.lipid.org/lipidspin who require additional LDL-C lowering revascularization in adults with in anticipation of lowering cardiovascular established cardiovascular disease.1 events. The Committee expects to provide • as an adjunct to diet, alone or future reports with additional updates as in combination with other lipid- more clinical data becomes available. lowering therapies (e.g., statins, COMMITTEE NOTE TO MEMBERS OF ezetimibe), for treatment of adults THE NATIONAL LIPID ASSOCIATION: Clinical Overview and Indications for with primary hyperlipidemia At the request of the NLA President, the PCSK9 Inhibitors (including heterozygous familial NLA Board of Directors, the Science and Alirocumab and evolocumab are both hypercholesterolemia [HeFH]) to Policy Council, the Practice Management proprotein convertase subtilisin-kexin type reduce low-density lipoprotein Council and the Health Quality and 9 (PCSK9) inhibitors that were approved cholesterol (LDL-C).1 Research Committee, it is with pleasure in the United States in 2015 by the U.S. • as an adjunct to diet and other LDL- that the 2017-18 NLA Therapeutics Food and Drug Administration (FDA). The lowering therapies (e.g., statins, Committee presents a Special Report on alirocumab prescribing information (PI) ezetimibe, LDL apheresis) in how to best incorporate PCSK9 Inhibitors most recently was updated in September patients with homozygous familial into routine clinical lipid practice by 2017 and the evolocumab PI most recently hypercholesterolemia (HoFH) who integrating best available evidence into the was updated in December 2017. require additional lowering of LDL-C.1 16 LipidSpin • Volume 16, Issue 3 • September 2018 PRALUENT (alirocumab) now is treatment LDL-C ≥190 mg/dL, and the age, gender and ethnicity]; Lipoprotein(a) indicated as an adjunct to diet and presence of either uncontrolled ASCVD [Lp(a)] ≥50 mg/dL using an isoform- maximally tolerated statin therapy for the risk factors, key additional high-risk insensitive assay, high-sensitivity C-reactive treatment of adults with HeFH or clinical markers, or genetic confirmation of FH, protein [hs-CRP] ≥2 mg/L or chronic kidney atherosclerotic cardiovascular disease who and on-treatment LDL-C ≥70 mg/dL or disease [CKD] including albumin/creatinine require additional lowering of LDL-C. non-HDL-C ≥100 mg/dL on maximally ratio ≥30 mg/g). tolerated statin ± ezetimibe. Strength: B, 2017 Recommendations of the NLA Quality: Moderate Safety of PCSK9 Inhibitors Expert Panel on Treatment with PCSK9 Alirocumab and evolocumab have been inhibitors3 3c. PCSK9 inhibitor therapy may be in general use in the United States since Atherosclerotic Cardiovascular Disease considered to further reduce LDL-C in FDA approval in mid-2015. Their approval (ASCVD) patients ages 18 to 39 years with pre- was based on clinical trials of safety and 1. PCSK9 inhibitor therapy should be treatment LDL-C ≥190 mg/dL, and the efficacy that involved several thousand considered for ASCVD risk reduction presence of either uncontrolled ASCVD patients, including studies of at least 1-year in patients with stable atherosclerotic risk factors, key additional high-risk exposure.1,2 cardiovascular disease, particularly in markers, or genetic confirmation of FH, those with additional ASCVD risk factors, and on-treatment LDL-C ≥100 mg/dL or Both agents are considered biologic on maximally tolerated statin therapy ± non-HDL-C ≥130 mg/dL on maximally therapies because they are injectable, fully ezetimibe, with on-treatment LDL-C ≥70 tolerated statin ± ezetimibe. Strength: E, human monoclonal antibodies. As with all mg/dL or non-high-density lipoprotein Quality: Low injectable proteins, there is the potential cholesterol (HDL-C) ≥100 mg/dL. Strength for immunogenicity and a host response. A, Quality: High 3d. PCSK9 inhibitor therapy may be Alirocumab and evolocumab represent considered to further reduce LDL-C in fourth-generation Immunoglobulin G 2. PCSK9 inhibitor therapy may be patients with HoFH, either of unknown (IgG) monoclonal antibodies that are fully considered to further reduce LDL-C genotype or those known to be LDL human, thus greatly reducing the potential in patients with progressive ASCVD receptor defective, on maximally tolerated for therapy-associated anti-drug antibodies on maximally tolerated statin therapy statin therapy ± ezetimibe with LDL-C (ADA) or neutralizing antibodies (NAbs) ± ezetimibe, and on-treatment LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL. developing in treated patients.4 ≥70 mg/dL or non-HDL-C ≥100 mg/dL. Strength B, Quality: Moderate Strength B, Quality: Moderate Screening assays for ADAs and NAbs are Very high risk/statin intolerance available and were used in the clinical LDL-C ≥190 mg/dL (including polygenic pre-approval trials. These assays vary hypercholesterolemia, HeFH, HoFH and 4. PCSK9 inhibitor therapy may be considerably in sensitivity and specificity the homozygous FH phenotype) considered to further reduce LDL-C in and can be used to detect antibodies that selected very-high-risk patients who bind to the paratope of the IgG therapies. 3a. PCSK9 inhibitor therapy may be meet the definition of statin intolerance Because of differences in handling, disease considered to further reduce LDL-C (as previously defined by the NLA Statin states, concomitant medications, and in patients ages 40 to 79 years with Expert Panel) and who require substantial collection variables, etc., comparison of pre-treatment LDL-C ≥190 mg/dL, no additional atherogenic cholesterol ADA occurrence rates between agents not uncontrolled ASCVD risk factors, or other lowering, despite the use of other lipid- studied together may be misleading.5 key additional high-risk markers, and lowering therapies. Strength C, Quality: on-treatment LDL-C ≥100 mg/dL or non- Low Across 10 placebo- and active- (ezetimibe) HDL-C ≥130 mg/dL on maximally tolerated controlled trials with alirocumab of at least statin therapy +/- ezetimibe. Strength B, *Including history of uncontrolled high 24-week duration, ADAs were detected in Quality: Moderate blood pressure, diabetes, current cigarette 4.8% of patients on alirocumab compared smoking or family history of premature to 0.6% on placebo. NAbs were detected 3b. PCSK9 inhibitor therapy may be ASCVD; or additional high-risk markers in 1.2% in patients on alirocumab vs. 0% considered to further reduce LDL-C in (coronary calcium ≥ 300 Agatston units in placebo; however, NAbs with transient patients ages 40 to 79 years with pre- [or ≥ 75th percentile for the patient’s or continued loss of efficacy were only Official Publication of the National Lipid Association 17 noted in 0.3% of patients on alirocumab. can differ notably in their absorption, than placebo, include: nasopharyngitis, ADA and NAbs generally were transient in distribution, metabolism and excretion, upper respiratory tract infection, influenza, most patients, and about half of cases that all monoclonal antibodies share common back pain and injection-site reactions.2 developed antibodies did so after 12 weeks pharmacokinetic and pharmocodynamic With alirocumab, similarly reported adverse of therapy. Only low titers of these ADAs properties. They typically are removed by events include: nasopharyngitis, injection- were detected in the trials and disappeared target-mediated clearance with PCSK9 site reactions and influenza.1 when the studies were concluded. The or by non-saturable proteolytic pathways development of ADAs, however, was through the reticuloendothelial system. Muscle-related adverse events with associated with a notably greater likelihood They are not thought to be glucuronidated evolocumab were reported in 6.4% of of injection-site reactions compared to or metabolized by the cytochrome patients (vs. 6% in placebo) in pre-approval the absence of ADAs (10.2% vs. 5.9%, P-450 system and do not interfere with clinical trials and were comparable in the respectively). Overall, clinically determined drug transporters such as permeability Further Cardiovascular Outcomes Research allergic reactions were reported in 8.6% glycoprotein (P-gp) or organic-anion- with PCSK9 Inhibition in Subjects with of patients on alirocumab vs. 7.8% with transport polypeptides (OATP). There Elevated Risk
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