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Pharmacological Strategies beyond Statins: Ezetimibe and PCSK9 Inhibitors

Dyslipidemia, highly elevated, low-density lipoprotein (LDL) cholesterol, is a major cardiovascular risk factor. Statins have been proven to effectively reduce the risk of atherosclerotic cardiovascular disease (ASCVD) and are recommended as a first-line therapy for the primary and secondary prevention of ASCVD. However, statins may not be sufficient in decreasing LDL cholesterol levels and pose a significant on-treatment residual risk of major cardiovascular events (i.e., residual cholesterol risk) according to meta-analyses of statin trials. Current guidelines for cholesterol management to achieve additional LDL cholesterol reduction and reduce ASCVD risk recommend two hyperlipidemic agents besides statins. Use of ezetimibe, a cholesterol absorption inhibitor, leads to additional LCL cholesterol reduction and decreased ASCVD risk, when added to statin therapy, without raising significant safety concerns. Furthermore, in combination with a mild-to-moderate statin intensity, ezetimibe is used in situations of statin-associated adverse effects such as myalgia and the combination therapy is relatively safer. Monoclonal antibody of proprotein convertase subtilisin/kexin type 9 (PCSK9), alirocumab, and evolocumab, have been approved to lower LDL cholesterol level. While there are drawbacks to the use of PCSK9 inhibitors, including high cost and adverse events such as injection site reaction, they significantly decreased serum LDL cholesterol levels and thereby ASCVD risks when added to maximally tolerated statin therapy.


INTRODUCTION
Atherosclerotic cardiovascular disease (ASCVD) is still the leading cause of death in the world and dyslipidemia, especially high levels of low density lipoprotein (LDL) cholesterol, are known to be a well-established risk factor. Statins, the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, effectively block the cholesterol synthesis pathway in the liver and decrease serum LDL cholesterol up to 50% from baseline according to their potency. During the past few decades, statins have played a central role in the treatment of dyslipidemia and decrease ASCVD risk by 15%-37%. High-intensity statin therapy additionally lowers LDL cholesterol level and cardiovascular events when compared to moderate intensity statins. 1 However, there is still a residual risk of recurrent ASCVD, along with unmet issues as to how we could optimize the treatment for patients with a higher risk of ASCVD 2 who would benefit from new drug combinations beyond statins. 3 In this review, we will discuss pharmacological strategies for dyslipidemia beyond statins, especially two recommended hyperlipidemic agents, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, by recent guidelines. 4,5

RECENT AMERICAN HEART ASSOCIATION/ AMERICAN COLLEGE OF CARDIOLOGY (AHA/ACC), EUROPEAN SOCIETY OF CARDIOLOGY/EUROPEAN ATHEROSCLEROSIS SOCIETY (ESC/EAS) GUIDELINES AND KOREAN GUIDELINE ON THE MANAGEMENT OF BLOOD CHOLESTEROL FOR SECONDARY PREVENTION
The 2018 AHA/ACC and 2016 ESC/EAS guidelines recognized that the principle of "the lower, the better" in cholesterol management. Many studies suggest that the ideal total cholesterol level is about 150 mg/dL and LDL cholesterol at or below 100 mg/dL. Especially if patients have a history of ischemic heart disease or stroke, the cholesterol level should be lower than 70 mg/dL or a reduction of at least 50% of baseline for secondary prevention. Statins are thus used, and dose escalation is recommended to achieve optimal cholesterol level. 4,5 The adopted Korean guideline for management of dyslipidemia revised in 2018 also recommends a treatment target below 70 mg/dL or a 50% reduction of baseline level in patients with an extremely high cardiovascular risk, such as coronary artery disease, ischemic cerebrovascular disease, and peripheral artery disease. 6 Although high-intensity statins demonstrated a significantly reduced level of LDL cholesterol and cardiovascular events, there is still concern for a "residual cholesterol risk" in patients with ASCVD. Among the pharmacological strategies beyond statins, ezetimibe and an PCSK9 inhibitor are most commonly used as non-statin therapies and have demonstrated additional benefits in lowering LDL cholesterol and reducing residual cardiovascular risks in recent clinical trials [7][8][9][10][11] and are approved by current guidelines. [4][5][6] In patients with a high cardiovascular risk with persistent high LDL cholesterol despite high-intensity statins or maximum tolerated statin dose, ezetimibe is indicated to achieve the treatment goal of LDL cholesterol and secondary prevention. If patients cannot achieve LDL cholesterol targets after maximum tolerable dose statins plus ezetimibe, a PCSK-9 inhibitor can be considered. [4][5][6]

EZETIMIBE
Ezetimibe, by targeting the Niemann-Pick C1-like 1 (NPC1L1) protein, inhibits the absorption of cholesterol from the intestine and thereby reduces LDL cholesterol levels. 12 In clinical studies, ezetimibe as a monotherapy reduces LDL cholesterol in patients with dyslipidemia by 18%. 13 When combined with a statin, ezetimibe provides additional reduction of LDL cholesterol by 15%-20%, leading to a 34%-61% reduction of total LDL cholesterol level. 3 One comprehensive study regarding LDL cholesterol effects of ezetimibe was published in 2015 and involved 27 different trials, 21,671 patients, and ezetimibe add-on therapy. It showed a significant LDL cholesterol-lowering effect when compared to statin monotherapy. 14 A number of clinical trials have demonstrated additional benefits of ezetimibe add-on therapy. 10,15 Among them, a large randomized study, "IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT)," reported that adding ezetimibe to statins decreased LDL cholesterol by 24% and reduced cardiovascular events in patients with acute coronary syndrome. 10 It was a double-blind, randomized trial involving 18,144 patients with acute coronary syndrome. In the trial, the simvastatin-ezetimibe group showed a 2% lower rate of primary end points including cardiovascular death, nonfatal myocardial infarction, hospitalization due to unstable angina, coronary revascularization, and nonfatal stroke, compared to the simvastatin monotherapy group (p<0.05). In a subgroup analysis of IMPROVE-IT, the beneficial cardiovascular effect was consistent regardless of sex or the presence of diabetes. 16,17 Studies reported that ezetimibe has additional benefits in ischemic stroke and cardiovascular-related hospitalization. 18,19 Ezetimibe is well-tolerated and associated with adverse events such as myopathy and abnormalities in liver function tests. In a pre-specified safety analysis and IMPROVE-IT trial, patients who achieved an LDL cholesterol level of <30 mg/dL were compared with those achieving higher LDL cholesterol. There was no significant increase in 9 pre-specified safety outcomes, including myalgia, hepatobiliary events, and neurocognitive disorders. 5,10 Myalgia is one of the most frequent statin-associated side effects, reported in 10%-25% of patients 20,21 and is often a result of statin non-adherence. As statin-associated myalgia is thought to be dose dependent, it seems that an ezetimibe add-on to low-dose statin therapy is a treatment option to achieve a target LDL cholesterol level and decreased cardiovascular risk without adverse effects. 22 In the most recent guidelines, ezetimibe is to be considered in combination with low-dose statins to manage statin-attributed muscle symptoms. 5,22,23 Regarding the effect of ezetimibe on diabetes, a recently published systemic review of randomized controlled trials (RCTs) including 2,440 patients with dyslipidemia reported that ezetimibe did not cause any adverse effects such as increased levels of fasting blood glucose or hemoglobin A1c. Compared with high-dose statin therapy, ezetimibe add-on to low-dose statins may even have beneficial effects on glycemic control. 24 By inhibiting the intestinal cholesterol absorption and the NPC1L1 at the hepatic level, ezetimibe decreases hepatic insulin resistance and improves insulin sensitivity and glycemic control in metabolic syndrome. 25 However, further study is needed for the clarification of ezetimibe's effect on metabolic disease.
Regarding cost-effectiveness, ezetimibe showed favorable results. Pre-specified analysis of the IMPROVE-IT study reported adding ezetimibe to statin in patients with acute coronary syndrome led to a reduction of cardiovascular-related hospitalization and costs compared to a statin placebo. 18 In patients with high cardiovascular risk, ezetimibe may lead to cost savings in the health care system. 18 The recommended ezetimibe dosage is 10 mg daily, regardless of food intake. When used in combination with bile acid sequestrates, it should be taken either 2 hours before or 4 hours after the bile acid sequestrants. 26 Ezetimibe has a favorable drug-drug interaction profile, so that there was no clinically significant interaction between ezetimibe and other drugs used in patients with dyslipidemia, such as statins. 5 Exceptionally, some reports have demonstrated interaction between fibrates and ezetimibe due to competition for the same glu1curonide clearance pathways. 26 Finally, timing of the administration of ezetimibe had no effect on its potency or metabolism. Tables 1 and 2 show a brief summary and clinical trials of ezetimibe.

PCSK-9 INHIBITORS
PCSK9 is a serine protease that plays a major role in cholesterol metabolism in the liver. Circulating PCSK9 binds to the LDL receptors (LDLR) on the liver surface, internalizes LDLR into the lysosome, and enhances their clearance in the hepatocyte so as to prevent the recycling of LDLRs back to the cell surface. [27][28][29] By promoting degradation of LDLR, PCSK9 decreases the clearance of LDL cholesterol from the blood. 30  and decrease LDLRs degradation and increase the surface expression of the LDLRs on liver, which in turn enhance LDLRs recycling and reduce level of serum LDL cholesterol. 31 Although various investigation has been done regarding PCSK9 inhibition, the human data are only available for the monoclonal antibody of PCSK9. The best-studied PCSK9 inhibitors are alirocumab and evolocumab, which are currently Food and Drug Administrationapproved drugs. In a clinical trial involving 77 patients with heterozygous familial hypercholesterolemia, alirocumab reduced LDL cholesterol by 29%-43% with monthly injections of 150-300 mg and by 68% with biweekly injections of 150 mg. 28 Furthermore, the higher doses of alirocumab and biweekly injections of 150 mg showed a significant increase in high-density lipoprotein (HDL) cholesterol and ApoA1 by 6.5% and 8.8%, respectively, and a decrease in ApoB and non-HDL cholesterol. 28 In the Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects (GAUSS) trial, evolocumab dosedependency induced a significant decrease in LDL cholesterol levels from 41%-51% compared to baseline in patients with statin-intolerance. 27 Contrary to bococizumab, the humanized antibody inhibits PCSK9, a recently reported substantive attenuation of a LDL cholesterol-lowering effect due to immunogenicity, 32 evolocumab showed sustained lipid lowering effect to 48 weeks, 33 and alirocumab showed a sustained lipid-lowering effect until 78 weeks; both drugs showed a reduction of major adverse cardiovascular events. 9,33 Recently, large-scale RCTs have been performed for monoclonal antibody therapies that inactivated PCSK9. In the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk (FOURIER) trial, a total of 27,564 patients with ASCVD and suboptimal LDL cholesterol levels despite maximally tolerate statin therapy were enrolled and randomly assigned to receive evolocumab or a placebo. 8 Regarding a primary end point, which was a composite of cardiovascular death, myocardial infarction, stroke, and hospitalization for unstable angina or coronary revascularization, the evolocumab group showed significant risk reduction (p<0.001) compared to placebo with no significant difference in adverse events. The Odyssey Outcomes trial confirmed the benefit of alirocumab to reduce ASCVD risk. 7 The relative risk reduction of 15% was similar to that in the FOURIER trial. While the FOURIER trial enrolled patients with stable ischemic disease, the Odyssey Outcomes trial enrolled patients with recent ACS, which resulted in consistent results in the reduction of all-cause mortalities.
Another PCSK9 inhibitor, inclisiran, a small interfering RNA that silences target RNA and prevents PCSK9 synthesis in the liver, resulted in a decrease in LDL cholesterol up to 53% at day 180 after a second injection. 34 Further study is needed for clarification of the cardiovascular effect of inclisiran, and the Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease (ORION-4) trial, which will include 15,000 participants, is expected to provide evidence for the safety and effectiveness of inclisiran on ASCVD patients.
There are several obstacles to the clinical use of the PCSK9 inhibitor. In a phase 2 trial of alirocumab, even though the adverse events were slightly higher in the alirocumab group, there was no increase in any specific organ systems and no difference in liver and muscle enzymes. One patient terminated the study due to an injection-site reaction. 28 In a phase 2 trial of evolocumab, nasopharyngitis, cough, upper respiratory tract infections, influenza, arthralgia, and injection site reactions were reported. 35 However, in phase 3 trial RCTs, adverse events associated with the PCSK9 inhibitor were variable compared to the placebo except for injection site reactions. [7][8][9]33 A meta-analysis of 35 RCTs, including 45,539 patients, reported no In recent years, the concept of residual cholesterol risk among statin treated patients has emerged and efforts to reduce this risk have been made. Ezetimibe and PCSK9 inhibitors are drugs which have abundant clinical evidence and are frequently used in the clinical field. Recognition that there is still room for improvement in clinical outcomes for patients with dyslipidemia and ACSVD and understanding the optimal indication for dyslipidemia medication beyond statins is needed to achieve clinical benefits.