The following are key points to remember from this review about the mechanism, use, and future of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors:

1. Genetic studies identified gain of function (GOF) PCSK9 mutations as the third causative gene for familial hypercholesterolemia (FH), which prompted extensive investigations into its relationship with the low-density lipoprotein receptor (LDLR) and cholesterol metabolism. Individuals with PCSK9 loss of function (LOF) mutations were found to have lifelong low LDL cholesterol (LDL-C) levels, reduced atherosclerotic cardiovascular disease (ASCVD) risk, and were otherwise healthy. These discoveries led to the development of PCSK9 inhibitors as a therapy to lower LDL-C.
2. PCSK9 inhibits LDLR recycling. The binding of PCSK9 to the LDLR targets LDLR to the lysosome for degradation, preventing LDLR from returning to the surface of the hepatocyte to bind to additional LDL particles. The exact mechanism by which PCSK9 binds to and targets LDLR for degradation remains under investigation.
3. Currently, there are two available antibodies against PCSK9: alirocumab and evolocumab. They are fully human immunoglobulin G subtypes that bind with a 1:1 ratio to circulating PCSK9. Upon the antibody’s binding to PCSK9, PCSK9 is unable to bind to LDLR and cause its degradation. The ultimate result is an accumulation of LDLR on hepatocytes, leading to accelerated clearance of LDL particles, and large decreases in LDL-C levels.
4. The Food and Drug Administration (FDA) has approved both alirocumab and evolocumab as “an adjunct to diet and maximally tolerated statin therapy for treatment of adults with heterozygous FH or clinical ASCVD who require additional lowering of LDL-C.” Evolocumab also has indications from the FDA for treatment of homozygous FH and, based on the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial, “to reduce the risk of myocardial infarction (MI), stroke, and coronary revascularization in adults with established CVD.”
5. Alirocumab is available in 75 mg and 150 mg subcutaneous injections every 2 weeks and 300 mg subcutaneous injection per month. With the 75 mg dose, LCL-C levels decrease 45% to 48%, and with the 150 mg dose, LCL-C levels decrease approximately 60%. Evolocumab is available in 140 mg subcutaneous injections every 2 weeks and 420 mg subcutaneous injection monthly. Both doses lower LDL-C approximately 60%. Both alirocumab and evolocumab lower triglycerides by 10% to 15%, raise HDL cholesterol by 5% to 10%, and lower lipoprotein (a) by 25% to 30%.
6. The GLAGOV (Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound) trial measured the effect of PCSK9 inhibition on atherosclerosis. In this study, 968 patients with coronary artery disease (CAD) were treated with evolocumab or placebo for 1.5 years. LDL-C levels were 36.6 mg/dl in the evolocumab group compared to 93.0 mg/dl in the placebo group. On serial intravascular ultrasound, patients treated with evolocumab showed a greater reduction in percent atheroma volume and plaque regression compared to placebo. The GLAGOV trial demonstrated that LDL-C lowering by adding a PCSK9 inhibitor to statin therapy induced atheroma regression.
7. The FOURIER trial enrolled 27,564 patients with prior ASCVD with an additional high-risk feature who were treated with maximally tolerated statin therapy, but who had LDL-C >70 mg/dl or a non-HDL-C >100 mg/dl. Patients were randomized to evolocumab (either 140 mg every 2 weeks or 420 mg every month, based on patient preference) or placebo. Evolocumab-treated patients had a 59% LCL-C lowering to a median of 30 mg/dl. After an average of 2 years of follow-up, the composite endpoint of CV death, MI, stroke, hospitalization for angina, or revascularization occurred in 9.8% of patients in the evolocumab-treated group versus 11.3% of the placebo group. CV death, MI, or stroke was reduced from 7.4% to 5.9% (p < 0.001).
8. The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) evaluated the effect of alirocumab treatment in patients after acute coronary syndrome treated with maximally tolerated statin therapy. ODYSSEY OUTCOMES randomized 18,924 patients to treatment with either alirocumab or placebo, with a treat-to-target design. In the alirocumab arm, patients received 75 mg of alirocumab every 2 weeks, and the dose was increased to 150 mg every 2 weeks if the LDL-C did not decrease to <50 mg/dl. The composite endpoint of CHD death, nonfatal MI, fatal and nonfatal ischemic stroke, or unstable angina requiring hospitalization occurred in 9.5% of patients receiving alirocumab and 11.1% of patients receiving placebo (p = 0.0003). The secondary endpoints of major CHD event, CV event, MI, or ischemic stroke were significantly reduced.
9. The SPIRE (Studies of PCSK9 Inhibition and the Reduction of Vascular Events) program consisted of two clinical trials (SPIRE-1 and SPIRE-2) that were terminated early. These trials evaluated ASCVD in 27,438 patients randomized to receive bococizumab or placebo. Bococizumab is a humanized monoclonal antibody to PCSK9, which contains 3% of the murine sequence in the antigen-binding complementarity-determining region. LDL-C was significantly lower in the treatment group, and in higher-risk patients with baseline LDL-C >100 mg/dl, major ASCVD events were reduced. The major limitation of SPIRE was the development of antidrug antibodies, which decreased the magnitude and durability of LDL-C reduction. Due to the development of antidrug antibodies, the sponsor terminated the clinical development of bococizumab.
10. Small interfering ribonucleic acid (siRNA) oligonucleotides inhibit hepatic synthesis of PCSK9. These agents currently are not available in clinical practice. In the randomized, double-blind, phase 2 ORION-1 trial, inclisiran, a siRNA that targets PCSK9 messenger RNA, effectively lowered PCSK9 and LDL-C levels in patients with high CV risk. This therapeutic approach lowers PCSK9 levels in plasma, mimicking the state of true PCSK9 deficiency seen in patients with LOF mutations. Further evaluation in large trials is ongoing.
11. Heterozygous FH is an FDA-approved indication for both alirocumab and evolocumab. In heterozygous FH patients, LDL-C reductions were 51% and 61% for evolocumab and alirocumab, respectively. In patients with homozygous FH, evolocumab reduced LDL-C by 31%. Antibodies to PCSK9 were effective in lowering LDL-C in patients with mutations in LDLR and APOB, and in patients with heterozygous PCSK9 GOF mutations.
12. The GAUSS-2 (Global Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2) trial evaluated the safety and efficacy of evolocumab in patients with statin-associated muscle symptoms (SAMS). None of the patients in the evolocumab group discontinued the drug due to muscle-related adverse events (during a 12-week follow-up). The ODYSSEY ALTERNATIVE trial compared alirocumab with ezetimibe and atorvastatin in patients with moderate to high CV risk and SAMS. During a 24-week follow-up, 66% of patients in the atorvastatin and ezetimibe arms and 76% of patients in the alirocumab arm completed the double-blind treatment. In the 2-year open-label alirocumab treatment period, >98% of patients were able to tolerate the study medication.
13. The safety profiles of alirocumab and evolocumab are excellent. The most common adverse reactions are nasopharyngitis and mild injection-site reactions. There are no increases in myalgias or neurocognitive adverse effects. In pooled analyses from phase II and IIIA trials, treatment with human monoclonal anti-PCSK9 antibodies resulted in LDL-C <25 mg/dl in 37% of alirocumab-treated patients and 26% of evolocumab-treated patients. LDL-C <15 mg/dl were reported in 9.4% of alirocumab-treated patients. In FOURIER, there were no associations between LDL-C <15 mg/dl and predetermined safety events. Prospective, objective assessments of neurocognitive function were integrated into phase III clinical outcomes trials (EBBINGHAUS substudy of FOURIER), which showed no significant differences in spatial working memory strategy index of executive function.
14. The cost-effectiveness of PCSK9 inhibitors can be improved by selection of higher-risk patients who received higher absolute benefit in the FOURIER and ODYSSEY OUTCOMES trials. Cost-benefit analyses suggest that in patients with FH, a two-thirds reduction in the cost of PCSK9 inhibitors will make a strong argument for their use compared to other commonly reimbursed treatments.
15. There has been renewed discussion on whether a target LDL-C level should be used in clinical practice. The LDL-C target of <70 mg/dl for high-risk patients was readopted in the 2017 ACC Consensus pathway for use of nonstatin agents. Given the clinical outcomes benefits seen in the PCSK9 inhibitor trials, there is question as to whether there should be an even lower LDL-C target. One can consider for the highest risk patients (such as those post-acute coronary syndrome or with multivessel CAD) an LDL-C target <50 mg/dl. The American Association of Clinical Endocrinologists and American College of Endocrinology guideline recommends an LDL-C level of <55 mg/dl and non-HDL-C of <80 mg/dl in patients with progressive ASCVD and in patients with established ASCVD with diabetes, chronic kidney disease stage 3 or 4, heterozygous FH, or premature ASCVD.

Keywords: Acute Coronary Syndrome, Atherosclerosis, Brain Ischemia, Cholesterol, HDL, Cholesterol, LDL, Coronary Artery Disease, Diabetes Mellitus, Type 2, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Metabolic Syndrome, Myalgia, Myocardial Infarction, Primary Prevention, Plaque, Atherosclerotic, Proprotein Convertases, Receptors, LDL, Renal Insufficiency, Chronic, Stroke, Subtilisins, Triglycerides

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