Hypertension Journal

Show Contents

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors:Ready to Target Atherosclerotic Cardiovascular Diseasebeyond Statins
  JOHTN
CARDIOVASCULAR THERAPEUTICS
Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors:
Ready to Target Atherosclerotic Cardiovascular Disease
beyond Statins
1Prabhash C Manoria, 2Nidhi Mishra
1Director and Chief, 2Assistant Professor
1Department of Cardiology, Manoria Heart & Critical CareHospital, Bhopal, Madhya Pradesh, India
2Department of Biochemistry, Mahaveer Institute of MedicalSciences & Research, Bhopal, Madhya Pradesh, India
Corresponding Author: Prabhash C Manoria, E-5/103, AreraColony, Bhopal - 462016, Madhya Pradesh, India
Phone: +919893042229
e-mail: pmanoria@rediffmail.com
 
ABSTRACT
Dyslipidemia contributes to 50% of atherogenic cardiovascularevents (CVEs). Statins decrease low-density lipoproteincholesterol (LDL-C) on an average of 1 mmol and this is transformedinto 20 to 25% reduction in CVE. Proprotein convertasesubtilisin/kexin type 9 (PCSK9) fully humanized monoclonalantibodies (MoAbs) decrease LDL-C by another 1 to 1½ mmolon top of statins and this decreases CVE by another 20%.Therefore, the era has come when we are able to minimize thedyslipidemia-related atherogenic risk to a very great extent.The PCSK9 MoAbs require 12 to 26 injections per year. Inclisiran,which is a small interfering ribonucleic acid (siRNA),has shown to decrease LDL-C consistently for 6 months aftera single injection. It is therefore emerging as a very importantcompetitor to PCSK9 MoAbs. The future ongoing trials will tellus more about this molecule.
Keywords: Alirocumab, Proprotein convertase subtilisin/kexintype 9 inhibitors evolocumab, Small interfering ribonucleic acid.
How to cite this article: Manoria PC, Mishra N. ProproteinConvertase Subtilisin/Kexin Type 9 Inhibitors: Ready to TargetAtherosclerotic Cardiovascular Disease beyond Statins. HypertensJ 2017;3(3):147-153.
Source of support: Nil
Conflict of interest: None
 
 

INTRODUCTION

Dyslipidemia is a major modifiable risk factor for atheroscleroticCVD (ASCVD). As per the World HealthOrganization, 50% of CVEs are attributed to dyslipidemia(Graph 1) and the rest 50% is related to nonlipid atherogenicrisk factors.

Figure 1 shows the evolution of lipid guidelinesduring the last 29 years ever since Adult TreatmentPanel-1 (ATP-1) came into existence in 1987.

Among lipids, LDL-C and nonhigh-density lipoproteincholesterol (HDL-C) are the principal targets. Apolipoprotein B (ApoB) is also a target but usually itis not utilized due to lack of facilities for estimating it,and an idea about its level is obtained from non-HDL-C.All trials of HDL-C elevation on top of statins have beennegative and there is no evidence-based target for it. Infact, HDL-C is fallen angel.
 
Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors:Ready to Target Atherosclerotic Cardiovascular Diseasebeyond Statins
Graph 1: Relation of lipid to coronary heart disease

For several years LDL-C goal < 70 has been recommendedfor the very high risk group. The Lipid Associationof India has slashed down this goal to < 501 andthe American Association of Clinical Endocrinologists(AACE) guidelines 20172 to < 55 mL/dL (Tables 1 and 2).The goals for non-HDL-C are 30 mg/dL more than theLDL-C goal.

TRIGLYCERIDES

Triglycerides (TGs) may be playing an important rolein Indian dyslipidemia but this has not been properlyinvestigated in the Indian context. Data on TGs show thatlow TG levels with loss of function mutation ApoC3)3 andangiopoietin-like protein 4 (ANGPTL4)4 are associatedwith decreased coronary heart disease, so increased TGlevels are associated with increased cardiovascular andall-cause mortality. But we do not have any randomizedcontrolled trial which has shown benefit of lowering TGon top of statins. The Action to Control CardiovascularRisk in Diabetes (ACCORD) trial,5 which tested efficacyof fibrates on top of statins in diabetic patients, failed to show any benefit. Diabetologists often use fibrates basedon subgroup analysis of the ACCORD trial5 and metaanalysisof fibrate trials but the problem with this data isthat subgroup analysis of ACCORD trial in patients withraised TG >204 mg/dL and low HDL-C < 34 mg/dL didshow a benefit but subgroup analysis is only hypothesisgenerating and the finding needs to be confirmed in alarge randomized trial which is nonexistent at the presentstate of time. Likewise, in the meta-analysis of fibratetrials,6 these drugs were not used on top of statins in alltrials. It is important to realize that it is ApoB particleswhich enter the vessel wall and not TG per se. The risk ofatherosclerosis is related to the number of atherogenic particles and each atherogenic lipoprotein particle containsa single molecule of ApoB. Therefore, the concentrationof ApoB provides a direct measure of the number ofcirculating atherogenic particles. In most hypertriglyceridemic(HyperTG) patients including diabetics, LDLparticles make up 85 to 90% of total ApoB particles andthe contribution of very low density lipoprotein is only10 to 15%. Fibrates lower LDL particles by only about10% and therefore fibrates at most may only play a minorrole. The Quebec cardiovascular study also showed thatif there is HyperTG with normal ApoB levels, there is noincrease in odds ratio of ischemic heart disease (IHD)but if there is HyperTG with increased ApoB levels, the odds ratio of IHD are significantly increased. Dietaryintake of fish and omega-3 fish oil is associated withreductions in the risks of total mortality, sudden death,and CAD through various mechanisms of action otherthan lowering of LDL-C.

Hypertension Journal, July-September, Vol 3, 2017 147

Prabhash C Manoria, Nidhi Mishra

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors:Ready to Target Atherosclerotic Cardiovascular Diseasebeyond Statins
Fig. 1: Evolution of lipid treatment guidelines during last 29 years after ATP-1

Table 1: Treatment goals for LDL-C and non-LDL-C as per Lipid Association of India
Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors:Ready to Target Atherosclerotic Cardiovascular Diseasebeyond Statins
*After an initial adequate nonpharmacological intervention for at least 3 months

Table 2: American association of clinical endocrinologists guidelines 2017
Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors:Ready to Target Atherosclerotic Cardiovascular Diseasebeyond Statins
DM: Diabetes mellitus; *High: DM but no other major risk and/or age < 40; **Very high: DM + major ASCVD risk(s) (HTN, Fam Hx,low HDL-C, smoking, CKD3,4); +++Extreme: DM plus established clinical CVD

 
 
148

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors

Table 3: Drugs for treatment of dyslipidemia
Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors:Ready to Target Atherosclerotic Cardiovascular Diseasebeyond Statins
#Available only in India, not approved by the FDA; +Under evaluation

Besides statins, several other drugs are used for thetreatment of dyslipidemia. The drugs utilized for modulatingdyslipidemia are outlined in Table 3.

Statins are the first line agents for targeting dyslipidemia.The Cholesterol Treatment Trialists (CTT) MetaanalysisCollaboration has shown that high-intensitystatins on an average decrease LDL-C by 1 mmol andthis reduction is seen across the range of LDL-C and thistranslates into reduction of CVE by 20 to 25% approximatelyirrespective of baseline LDL-C.

We have already witnessed the revolutionary era ofstatins for last 30 years and indeed statins have emergedas uncontested king for lipid management. We havevoluminous data on statins and they are class IA recommendationfor primary as well as secondary preventionof coronary artery disease. They are highly effectivedrugs and have minimal side effects. The year 2015came with breaking news when two PCSK9 inhibitors,evolocumab and alirocumab, were approved for clinicaluse by the European Medicines Agency (EMA) andUnited States Food and Drug Administration (USFDA).With this a new era has started in lipid management.The PCSK9 inhibitors decrease LDL-C by another 1 to 1½mmol and this is expected to decrease CVE by another20 to 25% as per the analysis of Further CardiovascularOutcomes Research with PCSK9 Inhibition in Subjectswith Elevated Risk (FOURIER), Studies of PCSK9 Inhibitionand the Reduction of Vascular Events (SPIRE),and Mendelian randomization study. Therefore, withcombination of both drugs the dyslipidemia-relatedatherogenicity can be minimized to a great extent.The effect of reduction in LDL-C on CVEs is shown inTable 4.
 
Table 4: Effect of LDL-C reduction on atherogenic CVEs
Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors:Ready to Target Atherosclerotic Cardiovascular Diseasebeyond Statins

NONSTATIN DRUGS

In selected high-risk patients, such as those withexisting ASCVD or patients with familial hypercholesterolemia(FH) not achieving LDL goals, use ofnonstatins may be considered if maximally toleratedstatin therapy has not shown >50% reduction in LDL-Cfrom baseline.

Ezetimibe is the first nonstatin medication that shouldbe considered in most of such patient scenarios, givenits safety and tolerability, though modest efficacy, whenadded to moderate-dose statin as shown in the IMPROVEIT Trial.7

Bile acid sequestrants (BASs) may be considered assecond-line therapy for patients in whom ezetimibe isnot tolerated, but they should be avoided in patients withTGs >300 mg/dL.

Familial Hypercholesterolemia

For patients with homozygous hypercholesterolemiathe goals are difficult to achieve. Statins, and nonstatinsdrugs, including ezetimibe, BASs, are utilized.The new drugs like lomitapide8 and mipomersen9 areused if necessary. Low-density lipoprotein-apheresisis approved for heterozygous FH.

The PCSK9 inhibitors, like evolocumab and alirocumab,may be considered if the goals of therapy havenot been achieved on maximally tolerated statin andezetimibe in FH. The PCSK9 inhibitors are also used inhigh-risk patients with clinical ASCVD.

Hypertension Journal, July-September, Vol 3, 2017 149

Prabhash C Manoria, Nidhi Mishra

What is PCSK9?

Proprotein convertase subtilisin/kexin type 9 is a proteinthat regulates LDL-C levels in the blood by regulatinglow-density lipoprotein receptors (LDL-R). It is secretedfrom the liver, goes into the blood, circulates back to liver,and directly binds to LDL-R increasing their degradationand thereby reducing the rate at which LDL-C isremoved from circulation10 and thus increasing LDL-Clevels in blood. Thus, PCSK9 is an important regulator ofLDL metabolism. The PCSK9 is also affected by geneticmutation. There are two types of mutation: Loss of functionmutation which results in decrease in LDL-C andprovides atheroprotection; the gain of function mutation11causes FH and predisposes to ASCVD.

Both statins and ezetimibe12 increase secretion ofPCSK9, which could attenuate their efficacy by reducingthe amount of cholesterol cleared from circulation. Thisexplains the limitation of statin therapy and may be thebest explanation regarding the classic rule of 6 observedwith statin therapy. This rule refers to the fact that everytime the statin dose is doubled, there is only an approximately6% complementary decrease in LDL-C levels.Therefore, the combination of PCSK9 inhibition with astatin would be a sensible and logical approach and willcause a dramatic decrease in LDL-C levels.

Proprotein Convertase Subtilisin/Kexin
Type 9 Inhibition


PCSK9 inhibition is now a validated therapeutic optionfor modulating LDL-C after the results of the FOURIERtrial in 2017. Its inhibition can be achieved by MoAbs,gene silencing, and small peptides.13 The MoAbs arecommonly used to inhibit PCSK9. Both evolocumab andalirocumab have been approved for clinical use in 2015by EMA and USFDA.

Evolocumab

This has already been approved for clinical use and isavailable commercially as 1 mL pen containing 140 mg.It is given in doses of 140 mg biweekly/420 mg monthlysubcutaneously. It was tested in the Program to ReduceLDL-C and Cardiovascular Outcomes (PROFICIO) GlobalProgram, which had 14 trials and roughly 30,000 patients.Most of the trials have been completed and the resultsof FOURIER were presented in 2017. Most of these trialshave shown significant reduction in LDL-C by 40 to 60%on top of statins. There is also consistent and robustreduction in other lipoproteins. The lipoprotein Lp(a) isreduced by approximately 25%, TG and non-HDL-C arealso decreased. The HDL-C and Apo-A1 are increased.The drug is used in the doses of 120 mg biweekly or420 mg monthly subcutaneously.

 
Interestingly, when both statins and PCSK9 MoAbsare combined together, they decrease LDL to very lowlevels, as low as 25 mg/dL in a substantial number ofcases. Two questions automatically erupt out of this. Isvery low LDL-C safe and is it powered to produce incrementalbenefits on top of statins? The answer to bothquestions is yes because the FOURIER trial14 has provedboth safety and efficacy of evolocumab. We had safetydata from earlier trials also, like Open-Label Study ofLong-Term Evaluation against LDL Cholesterol (OSLER),Evaluation of Cardiovascular Outcomes after an AcuteCoronary Syndrome during Treatment with Alirocumab(ODYSSEY) long-term trials. In FOURIER study, LDL-Cdecreased from median baseline value 92 to 30 mg/dL,i.e., approximately by 60% (p < 0.001), 42% had LDL-C< 25 mg/dL. Despite such low levels of LDL-C, there wasno evidence of muscle or liver toxicity, diabetogenicityor neurocognitive decline. The dedicated substudy,Evaluating PCSK9 Binding antiBody Influence oNcoGnitive HeAlth in High cardiovascUlar Risk Subjects(EBBINGHAUS), also confirmed lack of neurocognitivedecline with its use. The side effects which were morecommon with evolocumab were injection site reactions,2.1% (evolocumab) vs 1.6% (placebo). Upper respiratorytract infections, nasopharyngitis, flu, back pain wereobserved in small number of patients. However, longtermuse of these agents in future will further clarifyregarding their safety.

We had the initial efficacy data from the OSLER andODDYSEY long-term, and recently from the FOURIERtrial. The OSLER trial showed 53% relative risk reduction(RRR) in the composite endpoint of death, myocardialinfarction (MI), unstable angina hospitalization, coronaryrevascularization, stroke, transient ischemic attack, orcongestive heart failure hospitalization [heart rate (HR)= 0.47; 95% confidence interval (CI) 0.28-0.78, p = 0.003]and the post hoc analysis of long-term ODYSSEY showeda 48% RRR reduction in mean adverse cardiac events (HR= 0.52; CI 0.31-0.90; p = 0.02). This year the FOURIER trialshowed a statistically significant 15% risk reduction in theprimary endpoint of CV death, MI, stroke, hospitalizationfor unstable angina, and revascularization (HR = 0.85;95% CI, 0.79-0.92, p < 0.001). The secondary endpoint ofCV death and stroke showed a statistically significantreduction of 20% reduction (HR = 0.80; 95% CI, 0.73-0.88,p < 0.001) (Graph 2).

The curves are divergent so that the risk reductionat 2 years translated to number needed to treat of 74 toprevent CVD, MI, stroke but at 3 years it decreased to 50.It seems that the future is brighter than the present, andlong-term follow-up may lead to more fruitful results. Thetarget of < 70 for the high-risk patients has been scrappedby the FOURIER trial. There was no J curve, so lower is better is also validated for very low LDL. The reductionin primary and key secondary endpoint was consistentacross all key subgroups, including age, sex, differenttypes of CVD, intensity of statin therapy, dosing regimenof evolocumab, and baseline LDL levels, including thosewith the lowest quartile of LDL-C starting at 74 mg/dL inwhom evolocumab reduced LDL down to 22 mg/dL. TheFOURIER trial showed reduction in MI by 27%, p ≤ 0.001,stroke by 21%, p = 0.01, and coronary revascularizationby 22%, p ≤ 0.001. There was no significant decrease inall-cause or CV mortality.
 
150

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors:Ready to Target Atherosclerotic Cardiovascular Diseasebeyond Statins
Graphs 2A and B: Primary and secondary efficacy endpoint in the FOURIER trial

Alirocumab

This is approved for clinical use in the United States andis commercially available as 1 mL pen containing 75 or150 mg. It is given in doses of 75 mg biweekly or 150 mgsubcutaneously. It was evaluated in ODYSSEY GlobalProgram, which included 11 trials and roughly has 22,000patients. Most of the trials have been completed exceptODYSSEY outcome trial in post ACS patients, the resultsof which are keenly awaited.

 
Bococizumab

The SPIRE 1 and 2 with bococizumab was prematurelyterminated because of the presence of neutralizing antibodyin 29% and antidrug antibodies in 48% of patientstaking the drug. This is because bococizumab is a partiallymurine MoAb unlike evolocumab and alirocumab,which are fully humanized MoAbs. The incidence ofantidrug antibody and neutralizing antibody to variousPCSK9 MoAbs is mentioned in Table 5.

Although both SPIRE I and SPIRE II trials were prematurelyterminated, the SPIRE II which had LDL-C >100 mg/dL showed a reduction in CVEs by 21% at12 months, hinting that the drug is also useful for primary prevention. The SPIRE I trial which enrolled cooperativelylower risk population (LDL-C > 70) did not showany benefit.

Hypertension Journal, July-September, Vol 3, 2017 151

Prabhash C Manoria, Nidhi Mishra

Table 6: Indications of PCSK9
Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors:Ready to Target Atherosclerotic Cardiovascular Diseasebeyond Statins

The current indications of PCSK9 MoAbs are outlinedin Table 6.

Given the lack of long-term safety and efficacy dataon these agents, they are not recommended for use forprimary prevention except in patients with FH. The dataof PCSK9 for primary prevention like high-risk diabeticsare yet to evolve out.

Future Developments in PCSK9 Inhibition

Despite exciting results of FOURIER trials, the trialistsrealized two problems with PCSK9 MoAbs, i.e., the drugrequires 12 to 26 injections per year and adherence datawith PCSK9 MoAbs showed no substantial improvementover statins. Due to this, attempts were made to exploreother ways of inhibiting PCSK9. Inhibiting the synthesisof PCSK9 by siRNA (inclisiran) targeted to PCSK9 showedsustained reduction of LDL-C >50% (Graph 3) lasting for6 months (mean LDL reduction of 52.6% at 180 days and48% of patients had LDL-C below 50 mg/dL).15 The sideeffects are seen only in minority of patients and includecough, musculoskeletal pain, nasopharyngitis, headache,backache, and diarrhea.

After the exciting results of this molecule, the FDAhas cleared Phase III trials for inclisiran. It seems that inclisiran may emerge as a strong competitor for evolocumaband alirocumab in future.

 
CONCLUSION

Dyslipidemia is a major modifiable risk factor for ASCVD.Statin trials have validated LDL-C; the lower is better andthey decrease lipid-related CVEs by 20 to 25%. The newdrug PCSK9 MoAbs has validated that further lowering ofLDL-C as low as 25 mg/dL produces incremental benefitwith incredible safety as shown in the FOURIER trial. Ittherefore seems that the goal of LDL-C will be furtherslashed down in future.

REFERENCES
  1. Iyengar SS, Puri R, Narasingan SM, Wangnoo SK, Mohan V,Mohan JC, Misra A, Sriram U, Dalal JJ, Gupta R, et al. LAIExpert Consensus Statement on Management of Dyslipidemiain Indians 2016. JAPI 2016 Mar;64:7-52.
  2. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L,Bloomgarden ZT, Bush MA, Dagogo-Jack S, DeFronzo RA,Einhorn D, Fonseca VA, et al. Consensus statement by theAmerican association of clinical endocrinologists and Americancollege of endocrinology of the comprehensive type 2diabetes management algorithm - 2017 executive summary.Endocr Pract 2017 Feb;23(2):207-227.
  3. TG and HDL Working Group of the Exome SequencingProject, National Heart, Lung, and Blood Institute; Crosby J,Peloso GM, Auer PL, Crosslin DR, Stitziel NO, Lange LA,Lu Y, Tang ZZ, Zhang H, et al. Loss-of-function mutations inAPOC3, triglycerides, and coronary disease. N Engl J Med2014 Jul;371(1):22-31.
  4. Folsom AR, Peacock JM, Demerath E, Boerwinkle E. Variationin ANGPTL4 and risk of coronary heart disease: theatherosclerosis risk in communities study. Metabolism 2008Nov;57(11):1591-1596.

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors:Ready to Target Atherosclerotic Cardiovascular Diseasebeyond Statins
Graph 3: ORION-1 trial showing effect of inclisiran on LDL-C
 
152

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors

  1. The ACCORD Study Group. Effects of combination lipidtherapy in type 2 diabetes mellitus. N Engl J Med 2010Apr;362(17):1563-1574.
  2. Lee M, Saver JL, Towfighi A, Chow J, Ovbiagele B. Efficacyof fibrates for cardiovascular risk reduction in persons withatherogenic dyslipidemia: a meta-analysis. Atherosclerosis2011 Aug;217(2):492-498.
  3. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA,Theroux P, Darius H, Lewis BS, Ophuis TO, Wouter Jukema J,et al; for the IMPROVE-IT Investigators. Ezetimibe added tostatin therapy after acute coronary syndromes. N Engl J Med2015 Jun;372:2387-2397.
  4. Neef D, Berthold HK, Gouni-Berthold I. Lomitapide foruse in patients with homozygous familial hypercholesterolemia:a narrative review. Expert Rev Clin Pharmacol 2016Mar;9(5):655-663.
  5. Stein EA, Dufour R, Gagne C, Gaudet D, East C, Donovan JM,Chin W, Tribble DL, McGowan M. Apolipoprotein B synthesisinhibition with mipomersen in heterozygous familialhypercholesterolemia: results of a randomized, doubleblind,placebo-controlled trial to assess efficacy and safetyas add-on therapy in patients with coronary artery disease.Circulation 2012 Nov;126(19):2283-2292.

 
  1. Yamamoto T, Lu C, Ryan RO. A two-step binding mode ofPCSK9 interaction with the low density lipoprotein receptor.J Biol Chem 2011 Feb;286(7):5464-5470.
  2. Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K,Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D,et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.Nat Genet 2003 Jun;34(2):154-156.
  3. Ason B, Tep S, Davis HR Jr, Xu Y, Tetzloff G, Galinski B,Soriano F, Dubinina N, Zhu L, Stefanni A, et al. Improvedefficacy for ezetimibe and rosuvastatin by attenuating theinduction of PCSK9. J Lipid Res 2011 Apr;52(4):679-687.
  4. Marais DA, Blom DJ, Petrides F, Goueffic Y, Lambert G. Proproteinconvertase subtilisin/kexin type 9 inhibition. CurrOpin Lipidol 2012 Dec;23(6):511-517.
  5. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD,Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, et al;for the FOURIER Steering Committee and Investigators.Evolocumab and clinical outcomes in patients with cardiovasculardisease. N Engl J Med 2017 May:376:1713-1722.
  6. Ray KK, Landmesser U, Leiter AL, Kallend D, Dufour R,Karakas M, Hall T, Troquay RP, Turner T, Visseren FL, et al.Inclisiran in patients at high cardiovascular risk with elevatedLDL cholesterol. N Engl J Med 2017 Apr;376:1430-1440.

Hypertension Journal, July-September, Vol 3, 2017 153