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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 6  |  Issue : 1  |  Page : 12-17

Proprotein convertase subtilisin kexin 9 inhibitors: Current status and future directions


1 Chairman, Department of Cardiology, Dharma Vira Heart Center, Sir Ganga Ram Hospital, New Delhi, India
2 Senior Resident, Department of Cardiology, G. B. Pant Hospital, New Delhi, India

Date of Web Publication26-Dec-2016

Correspondence Address:
JPS Sawhney
Department of Cardiology, Dharma Vira Heart Center, Sir Ganga Ram Hospital, New Delhi - 110 060
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2250-3528.196649

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  Abstract 

The discovery of proprotein convertase subtilisin kexin 9 (PCSK9) has considerably changed the therapeutic options in the field of lipid management. PCSK9 reduces low-density lipoprotein receptor (LDLR) recycling, leading to a decrease of LDL cholesterol (LDL-C) receptors on the surface of hepatocytes and a subsequent increase of circulating LDL-C levels. Among the various approaches to PCSK9 inhibition, human data are only available for inhibition of PCSK9 binding to LDLR by monoclonal antibodies. In Phase II studies, the two most advanced monoclonal antibodies in development (alirocumab and evolocumab) decreased atherogenic lipoproteins very effectively and were well tolerated. Sixty percent to seventy percent of reduction in LDL-C was observed, especially when subcutaneous injections were performed regularly every 2 weeks. No significant side effects were observed, with the exception of injection-site reactions. Three large Phase III programs with the new anti-PCSK9 antibodies are currently underway in patients with acute coronary syndrome and LDL-C inadequately controlled by standard treatments. In this review, we will discuss the effect of PCSK9 inhibition, its current status, and future perspectives.

Keywords: Dyslipidemia, familial hypercholesterolemia, statin intolerance


How to cite this article:
Sawhney J, Bagga S. Proprotein convertase subtilisin kexin 9 inhibitors: Current status and future directions. J Clin Prev Cardiol 2017;6:12-7

How to cite this URL:
Sawhney J, Bagga S. Proprotein convertase subtilisin kexin 9 inhibitors: Current status and future directions. J Clin Prev Cardiol [serial online] 2017 [cited 2018 Dec 10];6:12-7. Available from: http://www.jcpconline.org/text.asp?2017/6/1/12/196649


  Introduction Top


Two decades after the results of the Scandinavian Simvastatin Survival Study first showed that statins effectively improved survival in patients with cardiovascular disease (CVD), thus initiating a revolution in the treatment of dyslipidemia, ezetimibe (EZE) has been the only drug shown to further improve the outcomes for dyslipidemic patients. Research programs of novel compounds were prematurely halted due to safety concerns or a lack of efficacy, and the clinical use of such drugs was often associated with only modest reductions in low-density lipoprotein cholesterol (LDL-C). [1] In addition, current lipid-lowering therapies fail to achieve desired LDL-C levels; intolerance to statin is becoming increasingly common, and increased incidence of new-onset diabetes reduces drug acceptance and compliance in some patient groups. These unmet needs warrant the continuing search for new, potent, and safe lipid-lowering therapies. [2]

Proprotein convertase subtilisin kexin 9 (PCSK9) has received considerable attention in the last decade as a promising therapeutic target in the management of lipid disorders. PCSK9 inhibition offers a novel therapeutic mechanism for the lowering of LDL-C levels. The clinical development of human monoclonal antibodies against PCSK9 has yielded promising results reported in several Phase II clinical studies. [3]

Based on available data, this new therapeutic approach would reinforce the possibility of treating patients who have poorly controlled LDL-C levels with current evidence-based therapies. In addition, PCSK9 inhibitors may reveal themselves to be an alternative for patients intolerant to statin treatment. The impact of the PCSK9 saga might also be particularly important in patients with established CVD who need intensive control of LDL-C levels in the secondary prevention. [3]


  Discovery Top


The ninth member of the proprotein convertase family, PCSK9, was discovered in 2003 and subsequently emerged as a novel target for LDL-C lowering therapy. [4] PCSK9 was recognized to play an important role in LDL-C metabolism after the identification of gain-of-function mutations in two French families with familial hypercholesterolemia (FH) without mutations in other FH-associated genes.

Subsequent experiments revealed that PCSK9 increases levels of LDL-C by reducing the available pool of hepatic LDL receptors (LDLRs). In the absence of PCSK9, the LDLR is recycled back to the plasma membrane. Binding of PCSK9, on the other hand, prevents LDLR recycling and instead targets it for lysosomal degradation [Figure 1]. Large cohort studies have revealed associations between variations in the PCSK9 gene and LDL-C levels and CVD risk. In addition, studies have shown that statin treatment increases PCSK9 levels. The inverse relation between PCSK9 activity levels and LDLRs suggests that PCSK9 inhibition could have a synergistic effect with statins on LDL-C. Therefore, PCSK9 has been identified as a promising target for anti-atherosclerotic drug development. Several strategies have been developed to reduce PCSK9 function, including binding of plasma PCSK9 by monoclonal antibodies reducing PCSK9 expression by silencing RNA, or vaccination against PCSK9. [1]
Figure 1: (a) Proprotein convertase subtilisin kexin 9 mediated degradation of low-density lipoprotein receptor. A complex of low-density lipoprotein cholesterol, low-density lipoprotein receptor, and proprotein convertase subtilisin kexin 9 is internalized into hepatocytes within clathrin-coated pits and subsequently undergoes lysosomal degradation; (b) proprotein convertase subtilisin kexin 9 inhibition. Monoclonal antibodies bound to proprotein convertase subtilisin kexin 9 prevent the association between proprotein convertase subtilisin kexin 9 and low-density lipoprotein receptor. Low-density lipoprotein receptor binds and internalizes low-density lipoprotein cholesterol particles, which are then degraded in the lysosome, whereas the low-density lipoprotein receptor is recycled back to the plasma membrane. LDL = Low-density lipoprotein, LDL-R = Low-density lipoprotein receptor, PCSK9 = Proprotein convertase subtilisin kexin 9

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  Functions of Proprotein Convertase Subtilisin Kexin 9 Top


Role in the regulation of low-density lipoprotein cholesterol concentration

The major function of PCSK9 is the degradation of the LDLR by complex mechanisms: PCSK9 directly interacts with the LDLR both within the cell and at the surface of the plasma membrane. However, evidence indicates that PCSK9 acts on the LDLR primarily as a secreted factor and promotes the reduction of LDLR protein concentrations, mainly in the liver. LDLR protein concentrations are increased in the liver of PCSK9 knockout mice. Secreted PCSK9 binds to the LDLR in a complex with its prosegment and is subsequently internalized together with the LDLR. The binding of PCSK9 to LDLR induces modification of LDLR conformation, avoiding normal recycling of LDLR to the plasma membrane, and enhancing the LDLR lysosomal degradation. As a result, LDLR represents the main route of elimination of PCSK9. However, the mature secreted PCSK9 can be inactivated through cleavage by other proprotein convertases, particularly furin. The mature active form and inactive form of PCSK9 circulate in the bloodstream. [4]

Other functions of proprotein convertase subtilisin kexin 9

In addition to being a key player in cholesterol homeostasis through the regulation of LDLR concentrations, data suggest a role of PCSK9 in triglyceride metabolism and triglyceride accumulation in visceral adipose tissue. The function of PCSK9 in the intestine is not well known. It has been recently reported that PCSK9 can enhance chylomicron secretion and participate in the control of enterocyte cholesterol balance. Beyond effects on lipid metabolism, animal data also suggest a role for PCSK9 in glucose homeostasis, liver regeneration, and susceptibility to hepatitis C virus infection. Although unexpected adverse effects cannot be excluded during PCSK9 inhibition, genetic variants of PCSK9 have given reassuring information. Recently, it has been reported that the absence of PCSK9 can be protective against melanoma invasion in mouse liver, suggesting that a PCSK9 inhibitor may be also useful in therapies against cancer metastasis. However, there is a large need for human data, and until now, PCSK9 inhibitors have been developed to treat hypercholesterolemia and prevent atherosclerosis. [4] It has also been proposed that PSCK9 may play roles in neuronal apoptosis, regulation of sodium channels, nervous system development, septic pathogen lipid transport, and clearance. Furthermore, circulating PCSK9 has been reported to be associated with plasma glucose, body mass index, and blood pressure. [5]


  Targeting Inhibition of Proprotein Convertase Subtilisin Kexin 9 Top


Studies in PCSK9 knockout mice demonstrated a 2- to 3-fold increase in LDLRs and a 25%-50% decrease in circulating cholesterol. This led to the exploration of a number of methods to reduce PCSK9 levels and/or inhibit its function, including both oral and parenteral therapies. Both antisense oligonucleotides and small interfering ribonucleic acids have been studied in preclinical and Phase I human studies. Mimetic peptides, LDLR antagonists, small molecules, and gene-silencing approaches to modulate PCSK9 are in earlier stages of the development. A number of approaches using novel small molecules have been described, including the use of epidermal growth factor-A mimetics to block PCSK9 binding of the LDLR and inhibitors of pro-PCSK9 autoprocessing and/or secretion; unfortunately, the PCSK9-LDLR complex has a relatively flat surface that makes binding by a small molecule inhibitor challenging. However, parenteral monoclonal antibodies (mAbs) have been the most successful strategy to date and are now in late-stage (Phase III clinical trials) testing. [6]

The Food and Drug Administration recently approved two medications, evolocumab and alirocumab. [7] Human data are available for three of these mAbs: alirocumab and evolocumab, two fully human mAbs and RN316/PF04950615, a humanized mAb. [4]

Alirocumab

Alirocumab is a monoclonal antibody that inhibits PCSK9 and shown to reduce LDL-C levels in patients who are receiving statin therapy. [8]

Phase I studies

Three Phase I studies of alirocumab have been performed, two in healthy volunteers and one in patients with hypercholesterolemia. Alirocumab significantly reduced LDL-C by 38%-65% in patients taking atorvastatin and by 57% in patients not taking atorvastatin. Alirocumab induced a maximum lowering of LDL-C within 2 weeks. It seems that the duration of action is longer in participants who are not treated with atorvastatin, suggesting that the statin-stimulated production of PCSK9 might affect the duration of action of therapeutic mAbs. [4]

Phase II studies

Alirocumab was administered subcutaneously in three Phase II randomized double-blind, placebo-controlled trials. The efficacy on atherogenic lipid variables observed with the most efficacious dose is indicated in [Table 1]. [4]
Table 1: Efficacy of alirocumab and evolocumaba


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Seventy-seven patients with heterozygous FH (HeFH) on a stable statin dose with or without EZE therapy were randomized to alirocumab 150 mg, 200 mg, and 300 mg every 4 weeks, or 150 mg every 2 weeks, or placebo every 2 weeks. Alirocumab dose dependently reduced LDL-C by 29%-43% for 150-300 mg injected every 4 weeks and by 68% for 150 mg injected every 2 weeks. Furthermore, with the 150 mg every 2 weeks' dose regimen, more than 80% of patients achieved an LDL-C concentration <70 mg/dL. In addition, the 150 mg every 2 weeks showed significant decreases in apolipoprotein B (ApoB) and non-high-density lipoprotein cholesterol [non-HDL-C; [Table 1] and increases in HDL-C (+6.5% vs. baseline) and apoAI (+8.8% vs. baseline). [4]

In the second Phase II trial, a 12-week study of 183 patients with LDL-C ≥100 mg/dL on stable-dose atorvastatin 10, 20, or 40 mg, dose-dependent and regimen-dependent reductions in LDL-C were observed: The dose of 150 mg every 2 weeks was found to be the most effective (72% reduction in LDL-C); patients receiving 100 and 150 mg every 2 weeks had greater reductions in LDL-C than those receiving 200 and 300 mg every 4 weeks. LDL-C reductions were unaffected by atorvastatin dose with the dose of 150 mg every 2 weeks; ApoB, non-HDL-C, and lipoprotein (a) (Lp[a]) were also significantly reduced [Table 1], and all patients receiving this dose achieved targets of <70 mg/dL, <80 mg/dL, and <100 mg/dL for LDL-C, ApoB, and non-HDL-C, respectively. [4]

In the last Phase II trial, 92 patients with LDL-C ≥100 mg/dL on atorvastatin 10 mg were randomized to receive 8 weeks of the treatment with atorvastatin 80 mg plus alirocumab 150 mg every 2 weeks, atorvastatin 10 mg plus alirocumab 150 mg every 2 weeks, or atorvastatin 80 mg plus placebo every 2 weeks. Adding alirocumab to either atorvastatin 80 mg or atorvastatin 10 mg resulted in a significantly greater LDL-C reduction than that attained with atorvastatin 80 mg alone. Interestingly, the complementary LDL-C reduction was not significantly different between the groups receiving alirocumab added to atorvastatin 80 or 10 mg. All the patients assigned to alirocumab, compared with 52% in the group receiving atorvastatin 80 mg plus placebo, and achieved the target LDL-C <100 mg/dL. Alirocumab also induced significant decreases in ApoB, non-HDL-C, and Lp(a) [Table 1]. [4]

Evolocumab

Evolocumab is a 141.8 kDa, fully human monoclonal immunoglobulin G2 directed against human PCSK9. Evolocumab strongly binds to PCSK9 and prevents circulating PCSK9 from binding to the LDLRs. The inhibition of PCSK9-mediated LDLR degradation enables the LDLRs to recycle back to the liver cell surface. By inactivating PCSK9, evolocumab upregulates LDLRs, resulting in increased catabolism of LDL-C and the consequent reduction of LDL-C levels in the blood. Evolocumab is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or clinical atherosclerotic CVD, who require additional lowering of LDL-C. Evolocumab is also approved as an adjunct to diet and other LDL-lowering therapies for the treatment of patients with homozygous FH (HoFH) who require additional lowering of LDL-C. [7]

Phase I studies

Two Phase I studies have been published. The Phase Ia study is a single ascending subcutaneous or intravenous dose in healthy participants. Single doses (7-420 mg administered subcutaneously; or 21 mg or 420 mg administered intravenously in a 1-h infusion) of evolocumab induced dose-dependent reductions in LDL-C by up to 64% compared with placebo. The Phase Ib study enrolled seven hypercholesterolemic cohorts of participants receiving stable statin therapy (five cohorts receiving low-to-moderate statin doses, one receiving high-dose statins, and one with HeFH) in multiple ascending subcutaneous doses with different dosing intervals (1-4 weeks). Evolocumab reduced mean LDL-C concentrations by up to 75% versus placebo at the end of the dosing interval. [4]

Phase II studies

The efficacy of evolocumab administered subcutaneously was evaluated in four 12-week Phase II randomized placebo-controlled (or EZE-controlled) trials. The main efficacy results for atherogenic lipid variables obtained with the most efficacious doses are summarized in [Table 1]. [4]

167 HeFH patients on stable statin therapy (with or without EZE) and LDL-C ≥100 mg/dL were randomized to evolocumab 350 mg every 4 weeks, 420 mg every 4 weeks or placebo, evolocumab decreased LDL-C by 43.8% in the 350 mg group and 56.4% in the 420 mg group (vs. placebo). Significant reductions were also observed for ApoB, non-HDL-C, and Lp(a) concentrations [Table 1]. Seventy percent of patients receiving 350 mg, and 89% of those receiving 420 mg achieved LDL-C <100 mg/dL; 44% and 65% patients achieved LDL-C <70 mg/dL. [4]

In the LAPLACE-TIMI57 trial, 631 patients with LDL-C ≥85 mg/dL on stable statin therapy (with or without EZE) were randomized into eight groups: six treatment arms with evolocumab at 70, 105, and 140 mg every 2 weeks or evolocumab at 280, 350, or 420 mg every 4 weeks; and two control groups receiving placebo every 2 weeks or every 4 weeks. Evolocumab induced dose-dependent significant reductions in LDL-C (41.8%-66.1% with every 2 weeks' regimen and 41.8%-50.3% with every 4 weeks regimen). The effects on other atherogenic lipoproteins observed with the most efficacious doses (140 mg every 2 weeks and 420 mg every 4 weeks) are listed in [Table 1]. Overall, 93.5% of patients receiving evolocumab 140 mg every 2 weeks, and 71.8% of patients receiving evolocumab 420 mg every 4 weeks achieved the target LDL-C <70 mg/dL. In a complementary analysis of LAPLACE-TIMI57 trial, evolocumab significantly reduced Lp(a) by up to 32%. [4]

The GAUSS trial investigated the efficacy and safety of evolocumab in 160 statin-intolerant patients.

Treatment arms included evolocumab at 280 mg, 350 mg and 420 mg every four weeks; a combined treatment group was given evolocumab at 420 mg every four weeks plus ezetimibe 10 mg; and a control group received placebo subcutaneously every four weeks plus ezetimibe 10 mg. Versus baseline, evolocumab induced a significant dose-dependent decrease in LDL-C from 40.8% to 50.7%. Furthermore, the combination of evolocumab and EZE induced an almost additive 63% reduction in LDL-C. [4]

The last Phase II study (MENDEL) was a monotherapy trial evaluating the efficacy of evolocumab in 406 patients with LDL-C ≥100 mg/dL. The treatment groups were identical to those for LAPLACE-TIMI57, with a complementary group receiving EZE 10 mg. The dose-dependent reductions in LDL-C (37.3%-47.2% with evolocumab every 2 weeks and 43.6-52.5% with evolocumab every 4 weeks) appeared similar to those observed in the LAPLACE-TIMI57 trial with every four regimens, but smaller than those observed with every 2-week regimen. These data suggest that every 4-week regimen could be recommended without statin therapy and raises the question of the best regimen for those on statin therapy. [4]

Finally, the efficacy of evolocumab in the rare population of HoFH patients has been tested in a pilot study conducted in eight patients (two receptor negative and six receptor defective). Evolocumab 420 mg every 2 weeks and every 4 weeks decreased LDL-C by 26.3 and 19.3%, respectively, in receptor-defective patients, with no reduction in receptor-negative patients. These preliminary results need to be confirmed in a larger trial. [4]


  Ongoing Trials Top


Three large Phase III programs with the new PCSK9 antibodies are currently ongoing: the PROFICIO programs with evolocumab, the ODYSSEY program with alirocumab, and the bococizumab program (SPIRE 1 and 2). Two large trials - FOURIER with evolocumab and ODYSSEY-OUTCOMES with alirocumab - are ongoing in patients hospitalized following with acute coronary syndrome (ACS) inadequately controlled LDL-C on evidence-based treatment. [3]

The main objective of these studies is to evaluate the effect of PCSK9 inhibition on the occurrence of cardiovascular events (composite endpoint of coronary heart death, nonfatal myocardial infarction, fatal and nonfatal stroke, and unstable angina requiring hospitalization) in patients with ACS. [3]


  Safety of the Monoclonal Antibodies Inhibiting Proprotein Convertase Subtilisin Kexin 9 Top


Overall, the mAbs tested so far have been generally safe and well tolerated, with no major safety issues from completed Phase I and II studies. In each of the Phase I studies for alirocumab and evolocumab, no serious adverse events were reported, and no evidence of drug-related adverse events was observed. [4]

In all of the Phase II studies, alirocumab was generally well tolerated over the treatment period (8-12 weeks). Injection-site reactions were the most common adverse events in two of the Phase II trials but were generally mild in severity and transient. However, in the Phase II study assessing alirocumab for the treatment of FH, one patient in the 300 mg dose every 4-week group discontinued treatment after the first dose due to injection-site reaction and generalized pruritus. In another Phase II trial, one patient receiving atorvastatin 80 mg plus alirocumab 150 mg every 2 weeks discontinued treatment due to a hypersensitivity reaction and rash occurring 12 days after the second injection of mAb. There was a single case of cutaneous leukocytoclastic vasculitis reported in one patient, 9 days after initiation of alirocumab 300 mg. The patient responded rapidly to withdrawal of the drug and initiation of steroid therapy. [4]

Evolocumab was also generally well tolerated throughout the Phase II trials, with a similar incidence of drug-related adverse events across treatment groups and no evidence of a relationship between the incidence of any adverse event and evolocumab dose. Small numbers of serious adverse events occurred, but none was considered related to the treatment. Injection-site reactions were generally infrequent and mild. In the specific trial conducted in statin-intolerant patients, myalgia was the most common treatment-emergent adverse event, but the frequency was low (3% in the placebo, evolocumab at 350 and 420 mg groups; 20% in the evolocumab 420 mg/EZE group); two patients in the evolocumab 350 mg group had creatine kinase concentrations greater than 10 times the upper normal limit during the study. [4]

Finally, antibodies against alirocumab and evolocumab were detected at low titer in some patients. The use of fully human mAbs, such as alirocumab and evolocumab, will reduce the risk of immunosensitivity reactions. [4]


  Future Perspectives Top


Although injections might not be particularly attractive for lifelong treatment, this approach would provide a valuable option for patients who suffer from the side effects of statins or for high-risk patients who need to achieve stringent LDL-C target level as recommended by the European guidelines. For example, patients with FH started with LDL-C levels ≈3-4 times higher than the general population.

Although low PCSK9 levels or their genetic deficiency appears to be safe on the basis of available data, the impact of PCSK9 inhibition in individuals with genetically normal PCSK9 has yet to be clarified. [3]

A number of important questions will need to be resolved before the approval of these new agents. Long-term efficacy and safety trials are critical as patients will probably need lifelong treatment. Even if antidrug antibodies were rare in Phase II trials, experience with other mAbs suggests that the development of antidrug antibodies could reduce clinical efficacy and increase the incidence of adverse events. Two large Phase III programs are ongoing: the PROFICIO program with evolocumab and the ODYSSEY program with alirocumab. Systematic monitoring of antibody development and adverse events will be needed in these programs. As suggested by the reduced incidence of events in healthy patients with PCSK9 loss-of-function (LOF) mutations, the cardiovascular benefit in relation to the lowering effect of atherogenic lipoproteins will need to be evaluated in specific cardiovascular outcome trials. Additional studies will also be needed to obtain a better understanding of the physiological role of PCSK9 and the effect of PCSK9 inhibition in other populations, such as patients with mixed hyperlipidemia, diabetes, or renal impairment. [4]

Moreover, the place of PSCK9 inhibitors needs to be defined in comparison with other strategies that are either available or under development to reduce the residual risk linked to atherogenic lipoproteins. Undoubtedly, a PCSK9 inhibitor combined with statin therapy will be more effective than EZE and resins in terms of LDL-C lowering. [4]

The use of a PCSK9 inhibitor combined with a low statin dose also seems an attractive strategy to avoid the side effects associated with high statin doses. The statin-fenofibrate combination therapy is only useful for high-risk patients with high triglycerides and low HDL-C on statin therapy. For this specific category of patients, the efficacy of PCSK9 inhibition still needs to be established. Among the new classes of agents that reduce LDL-C under development, the use of lomitapide (a microsomal transfer protein inhibitor) and mipomersen (an ApoB antisense oligonucleotide) will be limited to the rare population of patients with HoFH while the putative benefit of new cholesteryl ester transfer protein inhibitors, such as anacetrapib and evacetrapib, remains controversial. Among the candidate populations for PCSK9 inhibition, HeFH should be considered as a priority. High-risk patients with documented statin intolerance are also candidates for PCSK9 inhibition. Other medical needs are high-risk patients not at goal on maximum lipid-lowering therapy, but the cost/benefit ratio will be an important issue. [4]


  Conclusion Top


The discovery of PCSK9 has considerably changed the therapeutic reality in the lipid field . PCSK9 is a key player in LDL metabolism, mainly by enhancing degradation of LDLR in the liver. The reduced incidence of CVD in patients with PCSK9 LOF mutations provides a strong rationale for the development of PCSK9 inhibitors. Their remarkable efficacy in reducing LDL-C and the possible synergistic effects with statins, combined with a favorable safety profile and tolerability, provides these drugs with the potential to revolutionize the treatment of patients at high risk of CVD. Large clinical trials with long-term follow-up are currently assessing their impact on clinical outcomes, especially in term of CVD events reduction. Despite their safety, there are some concerns about the potential side effects of lowering LDLC and PCSK9 to "unphysiological" levels. Nevertheless, since the discovery of statin treatment, it has been a long time since a new therapy could be shown to reduce cholesterol levels so efficiently.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Stoekenbroek RM, Kastelein JJ, Huijgen R. PCSK9 inhibition: The way forward in the treatment of dyslipidemia. BMC Med 2015;13:258.  Back to cited text no. 1
    
2.
Tavori H, Giunzioni I, Fazio S. PCSK9 inhibition to reduce cardiovascular disease risk: Recent findings from the biology of PCSK9. Curr Opin Endocrinol Diabetes Obes 2015;22:126-32.  Back to cited text no. 2
    
3.
Gencer B, Lambert G, Mach F. PCSK9 inhibitors. Swiss Med Wkly 2015;145:w14094.  Back to cited text no. 3
    
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Farnier M. PCSK9: From discovery to therapeutic applications. Arch Cardiovasc Dis 2014;107:58-66.  Back to cited text no. 4
    
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Rallidis LS, Lekakis J. PCSK9 inhibition as an emerging lipid lowering therapy: Unanswered questions. Hellenic J Cardiol 2016;57:86-91.  Back to cited text no. 5
    
6.
Giugliano RP, Sabatine MS. Are PCSK9 inhibitors the next breakthrough in the cardiovascular field? J Am Coll Cardiol 2015;65:2638-51.  Back to cited text no. 6
    
7.
Henry CA, Lyon RA, Ling H. Clinical efficacy and safety of evolocumab for low-density lipoprotein cholesterol reduction. Vasc Health Risk Manag 2016;12:163-9.  Back to cited text no. 7
    
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Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99.  Back to cited text no. 8
    


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