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Current Medicinal Chemistry

Author(s): Ghasem Ghasempour, Fahimeh Zamani-Garmsiri, Farhad Shaikhnia, Ali Akbar Soleimani, Syed Reza Hosseini Fard, Janani Leila, Shohreh Teimuri, Najmeh Parvaz, Payam Mohammadi and Mohammad Najafi*

DOI: 10.2174/0929867330666230228120601

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Efficacy and Safety of Alirocumab and Evolocumab as Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors in Familial Hypercholesterolemia: A Systematic Review and Meta-Analysis

Page: [223 - 241] Pages: 19

  • * (Excluding Mailing and Handling)

Abstract

Background: Familial hypercholesterolemia (FH) is a prevalent and potentially fatal illness that causes a substantial elevation in low-density lipoprotein cholesterol (LDL-C).

Objective: The aim of this study was to investigate the effects of monoclonal antibodies alirocumab and evolocumab on LDL-C and other lipid parameters, as well as their safety in familial hypercholesterolemia patients.

Methods: A comprehensive search was done on PubMed/MEDLINE, EMBASE, Web of Science (WOS/ ISI), Scopus, ClinicalTrials (www.ClinicalTrials.gov), and conferences/ congress research papers. Random effect models were used to calculate mean differences (%) and risk ratios (RRs), and confidence intervals (95%).

Results: Ten studies (n=1489 patients) were included in this study. PCSK9 inhibitors decreased the levels of LDL-C by -49.59% (95%CI -55.5%, -43.67%) as compared to placebo. They also didn’t alter the Treatment-Emergent Adverse Event (TEAE) and neuronal events by RR 0.92 (0.75, 1.13) and 1.31 (0.66, 2.59), respectively. PCSK9 inhibitors were effective and safe in treating patients with FH.

Conclusion: There was high-quality evidence showing that monoclonal antibodies (alirocumab & evolocumab) lower LDL-C (GRADE: high), lipoprotein (a) (GRADE: High), triglycerides (TG) (GRADE: High), total cholesterol (GRADE: High), non-high-density lipoprotein cholesterol (non- HDL-C) (GRADE: Moderate), and apolipoprotein B (GRADE: High), and increase the HDL-C (GRADE: High) as well as apolipoprotein A1 (GRADE: High). Comparing PCSK9 inhibitors against placebo, neither TEAE (GRADE: high) nor neuronal events (GRADE: moderate) were changed.

[1]
Pejic, R.N. Familial hypercholesterolemia. Ochsner J., 2014, 14(4), 669-672.
[PMID: 25598733]
[2]
Austin, M.A.; Hutter, C.M.; Zimmern, R.L.; Humphries, S.E. Genetic causes of monogenic heterozygous familial hypercholesterolemia: A HuGE prevalence review. Am. J. Epidemiol., 2004, 160(5), 407-420.
[http://dx.doi.org/10.1093/aje/kwh236] [PMID: 15321837]
[3]
De Castro-Orós, I.; Pocoví, M.; Civeira, F. The genetic basis of familial hypercholesterolemia: Inheritance, linkage, and mutations. Appl. Clin. Genet., 2010, 3, 53-64.
[PMID: 23776352]
[4]
Softanmohammadi, E.; Piran, S.; Mohammadi, A.; Hosseni, B.; Naseri, F.; Shabani, M.; Najafi, M. Serum sdLDL-C and cellular SREBP2-dependent cholesterol levels; is there a challenge on targeting PCSK9? J. Med. Biochem., 2016, 35(4), 410-415.
[http://dx.doi.org/10.1515/jomb-2016-0019] [PMID: 28670193]
[5]
Chen, P.; Chen, X.; Zhang, S. Current status of familial hypercholesterolemia in China: A need for patient FH registry systems. Front. Physiol., 2019, 10, 280.
[http://dx.doi.org/10.3389/fphys.2019.00280] [PMID: 30949068]
[6]
Mytilinaiou, M.; Kyrou, I.; Khan, M.; Grammatopoulos, D.K.; Randeva, H.S. Familial hypercholesterolemia: New horizons for diagnosis and effective management. Front. Pharmacol., 2018, 9, 707.
[http://dx.doi.org/10.3389/fphar.2018.00707] [PMID: 30050433]
[7]
Stone, N.J.; Robinson, J.G.; Lichtenstein, A.H.; Bairey Merz, C.N.; Blum, C.B.; Eckel, R.H.; Goldberg, A.C.; Gordon, D.; Levy, D.; Lloyd-Jones, D.M.; McBride, P.; Schwartz, J.S.; Shero, S.T.; Smith, S.C., Jr; Watson, K.; Wilson, P.W.F. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol., 2014, 63(25), 2889-2934.
[http://dx.doi.org/10.1016/j.jacc.2013.11.002] [PMID: 24239923]
[8]
Kataoka, Y.; Puri, R.; Hammadah, M.; Duggal, B.; Uno, K.; Kapadia, S.R.; Tuzcu, E.M.; Nissen, S.E.; Nicholls, S.J. Frequency-domain optical coherence tomographic analysis of plaque microstructures at nonculprit narrowings in patients receiving potent statin therapy. Am. J. Cardiol., 2014, 114(4), 549-554.
[http://dx.doi.org/10.1016/j.amjcard.2014.05.035] [PMID: 24996554]
[9]
Toth, P.P.; Harper, C.R.; Jacobson, T.A. Clinical characterization and molecular mechanisms of statin myopathy. Expert Rev. Cardiovasc. Ther., 2008, 6(7), 955-969.
[http://dx.doi.org/10.1586/14779072.6.7.955] [PMID: 18666846]
[10]
Silva, M.A.; Swanson, A.C.; Gandhi, P.J.; Tataronis, G.R. Statin-related adverse events: A meta-analysis. Clin. Ther., 2006, 28(1), 26-35.
[http://dx.doi.org/10.1016/j.clinthera.2006.01.005] [PMID: 16490577]
[11]
Navarese, E.P.; Szczesniak, A.; Kolodziejczak, M.; Gorny, B.; Kubica, J.; Suryapranata, H. Statins and risk of new-onset diabetes mellitus: Is there a rationale for individualized statin therapy? Am. J. Cardiovasc. Drugs, 2014, 14(2), 79-87.
[http://dx.doi.org/10.1007/s40256-013-0053-0] [PMID: 24174174]
[12]
Blazing, MA; Giugliano, RP; Cannon, CP; Musliner, TA; Tershakovec, AM; White, JA Evaluating cardiovascular event reduction with ezetimibe as an adjunct to simvastatin in 18,144 patients after acute coronary syndromes: Final baseline characteristics of the IMPROVE-IT study population. Am Heart J, 2014, 168(2), 205-212.
[http://dx.doi.org/10.1016/j.ahj.2014.05.004] [PMID: 25066560]
[13]
Norata, G.D.; Tavori, H.; Pirillo, A.; Fazio, S.; Catapano, A.L. Biology of proprotein convertase subtilisin kexin 9: beyond low-density lipoprotein cholesterol lowering. Cardiovasc. Res., 2016, 112(1), 429-442.
[http://dx.doi.org/10.1093/cvr/cvw194] [PMID: 27496869]
[14]
Fu, T.; Guan, Y.; Xu, J.; Wang, Y. APP, APLP2 and LRP1 interact with PCSK9 but are not required for PCSK9-mediated degradation of the LDLR in vivo. Biochim. Biophys. Acta Mol. Cell Biol. Lipids, 2017, 1862(9), 883-889.
[http://dx.doi.org/10.1016/j.bbalip.2017.05.002] [PMID: 28495363]
[15]
Nozue, T. Lipid lowering therapy and circulating PCSK9 concentration. J. Atheroscler. Thromb., 2017, 24(9), 895-907.
[http://dx.doi.org/10.5551/jat.RV17012] [PMID: 28804094]
[16]
Manniello, M.; Pisano, M. Alirocumab (Praluent): First in the new class of PCSK9 inhibitors. P&T, 2016, 41(1), 28-53.
[PMID: 26766888]
[17]
Kasichayanula, S.; Grover, A.; Emery, M.G.; Gibbs, M.A.; Somaratne, R.; Wasserman, S.M.; Gibbs, J.P. Clinical pharmacokinetics and pharmacodynamics of evolocumab, a PCSK9 inhibitor. Clin. Pharmacokinet., 2018, 57(7), 769-779.
[http://dx.doi.org/10.1007/s40262-017-0620-7] [PMID: 29353350]
[18]
Verhagen, A.P.; de Vet, H.C.W.; de Bie, R.A.; Kessels, A.G.H.; Boers, M.; Bouter, L.M.; Knipschild, P.G. The delphi list. J. Clin. Epidemiol., 1998, 51(12), 1235-1241.
[http://dx.doi.org/10.1016/S0895-4356(98)00131-0] [PMID: 10086815]
[19]
Wan, X.; Wang, W.; Liu, J.; Tong, T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med. Res. Methodol., 2014, 14(1), 135.
[http://dx.doi.org/10.1186/1471-2288-14-135] [PMID: 25524443]
[20]
Barde, P.; Barde, M. What to use to express the variability of data: Standard deviation or standard error of mean? Perspect. Clin. Res., 2012, 3(3), 113-116.
[http://dx.doi.org/10.4103/2229-3485.100662] [PMID: 23125963]
[21]
Egger, M.; Smith, G.D.; Schneider, M.; Minder, C. Bias in meta-analysis detected by a simple, graphical test. BMJ, 1997, 315(7109), 629-634.
[http://dx.doi.org/10.1136/bmj.315.7109.629] [PMID: 9310563]
[22]
Duval, S. The trim and fill method. In: Publication bias in meta-analysis: Prevention, assessment and adjustments; , 2005; pp. 127-144.
[http://dx.doi.org/10.1002/0470870168.ch8]
[23]
Guyatt, G.H.; Oxman, A.D.; Kunz, R.; Vist, G.E.; Falck-Ytter, Y.; Schünemann, H.J. What is “quality of evidence” and why is it important to clinicians? BMJ, 2008, 336(7651), 995-998.
[http://dx.doi.org/10.1136/bmj.39490.551019.BE] [PMID: 18456631]
[24]
Blom, D.J.; Harada-Shiba, M.; Rubba, P.; Gaudet, D.; Kastelein, J.J.P.; Charng, M.J.; Pordy, R.; Donahue, S.; Ali, S.; Dong, Y.; Khilla, N.; Banerjee, P.; Baccara-Dinet, M.; Rosenson, R.S. Efficacy and safety of alirocumab in adults with homozygous familial hypercholesterolemia. J. Am. Coll. Cardiol., 2020, 76(2), 131-142.
[http://dx.doi.org/10.1016/j.jacc.2020.05.027] [PMID: 32646561]
[25]
Ginsberg, H.N.; Rader, D.J.; Raal, F.J.; Guyton, J.R.; Baccara-Dinet, M.T.; Lorenzato, C.; Pordy, R.; Stroes, E. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia and LDL-C of 160 mg/dl or higher. Cardiovasc. Drugs Ther., 2016, 30(5), 473-483.
[http://dx.doi.org/10.1007/s10557-016-6685-y] [PMID: 27618825]
[26]
Kastelein, J.J.P.; Ginsberg, H.N.; Langslet, G.; Hovingh, G.K.; Ceska, R.; Dufour, R.; Blom, D.; Civeira, F.; Krempf, M.; Lorenzato, C.; Zhao, J.; Pordy, R.; Baccara-Dinet, M.T.; Gipe, D.A.; Geiger, M.J.; Farnier, M. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur. Heart J., 2015, 36(43), ehv370.
[http://dx.doi.org/10.1093/eurheartj/ehv370] [PMID: 26330422]
[27]
Moriarty, P.M.; Parhofer, K.G.; Babirak, S.P.; Cornier, M.A.; Duell, P.B.; Hohenstein, B.; Leebmann, J.; Ramlow, W.; Schettler, V.; Simha, V.; Steinhagen-Thiessen, E.; Thompson, P.D.; Vogt, A.; von Stritzky, B.; Du, Y.; Manvelian, G. Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: The ODYSSEY ESCAPE trial. Eur. Heart J., 2016, 37(48), 3588-3595.
[http://dx.doi.org/10.1093/eurheartj/ehw388] [PMID: 27572070]
[28]
Raal, F.; Scott, R.; Somaratne, R.; Bridges, I.; Li, G.; Wasserman, S.M.; Stein, E.A. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: The Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation, 2012, 126(20), 2408-2417.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.112.144055] [PMID: 23129602]
[29]
Raal, F.J.; Honarpour, N.; Blom, D.J.; Hovingh, G.K.; Xu, F.; Scott, R.; Wasserman, S.M.; Stein, E.A. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): A randomised, double-blind, placebo-controlled trial. Lancet, 2015, 385(9965), 341-350.
[http://dx.doi.org/10.1016/S0140-6736(14)61374-X] [PMID: 25282520]
[30]
Raal, F.J.; Stein, E.A.; Dufour, R.; Turner, T.; Civeira, F.; Burgess, L.; Langslet, G.; Scott, R.; Olsson, A.G.; Sullivan, D.; Hovingh, G.K.; Cariou, B.; Gouni-Berthold, I.; Somaratne, R.; Bridges, I.; Scott, R.; Wasserman, S.M.; Gaudet, D. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): A randomised, double-blind, placebo-controlled trial. Lancet, 2015, 385(9965), 331-340.
[http://dx.doi.org/10.1016/S0140-6736(14)61399-4] [PMID: 25282519]
[31]
Stein, E.A.; Gipe, D.; Bergeron, J.; Gaudet, D.; Weiss, R.; Dufour, R.; Wu, R.; Pordy, R. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: A phase 2 randomised controlled trial. Lancet, 2012, 380(9836), 29-36.
[http://dx.doi.org/10.1016/S0140-6736(12)60771-5] [PMID: 22633824]
[32]
Guedeney, P.; Giustino, G.; Sorrentino, S.; Claessen, B.E.; Camaj, A.; Kalkman, D.N.; Vogel, B.; Sartori, S.; De Rosa, S.; Baber, U.; Indolfi, C.; Montalescot, G.; Dangas, G.D.; Rosenson, R.S.; Pocock, S.J.; Mehran, R. Efficacy and safety of alirocumab and evolocumab: A systematic review and meta-analysis of randomized controlled trials. Eur. Heart J., 2022, 43(7), e17-e25.
[http://dx.doi.org/10.1093/eurheartj/ehz430] [PMID: 31270529]
[33]
Marais, A.D.; Blom, D.J.; Firth, J.C. Statins in homozygous familial hypercholesterolemia. Curr. Atheroscler. Rep., 2002, 4(1), 19-25.
[http://dx.doi.org/10.1007/s11883-002-0058-7] [PMID: 11772418]
[34]
Gouni-Berthold, I.; Descamps, O.S.; Fraass, U.; Hartfield, E.; Allcott, K.; Dent, R.; März, W. Systematic review of published Phase 3 data on anti-PCSK9 monoclonal antibodies in patients with hypercholesterolaemia. Br. J. Clin. Pharmacol., 2016, 82(6), 1412-1443.
[http://dx.doi.org/10.1111/bcp.13066] [PMID: 27478094]
[35]
McDonagh, M.; Peterson, K.; Holzhammer, B.; Fazio, S. A systematic review of PCSK9 inhibitors alirocumab and evolocumab. J. Manag. Care Spec. Pharm., 2016, 22(6), 641-653q.
[http://dx.doi.org/10.18553/jmcp.2016.22.6.641] [PMID: 27231792]
[36]
Eslami, S.M.; Nikfar, S.; Ghasemi, M.; Abdollahi, M. Does evolocumab, as a PCSK9 inhibitor, ameliorate the lipid profile in familial hypercholesterolemia patients? A meta-analysis of randomized controlled trials. J. Pharm. Pharm. Sci., 2017, 20, 81-96.
[http://dx.doi.org/10.18433/J36C8N] [PMID: 28459663]
[37]
Li, C.; Lin, L.; Zhang, W.; Zhou, L.; Wang, H.; Luo, X.; Luo, H.; Cai, Y.; Zeng, C. Efficiency and safety of proprotein convertase subtilisin/kexin 9 monoclonal antibody on hypercholesterolemia: A meta-analysis of 20 randomized controlled trials. J. Am. Heart Assoc., 2015, 4(6), e001937.
[http://dx.doi.org/10.1161/JAHA.115.001937] [PMID: 26077586]
[38]
Cao, Y.X.; Liu, H.H.; Li, S.; Li, J.J. A meta-analysis of the effect of PCSK9-monoclonal antibodies on circulating lipoprotein (a) levels. Am. J. Cardiovasc. Drugs, 2019, 19(1), 87-97.
[http://dx.doi.org/10.1007/s40256-018-0303-2] [PMID: 30229525]
[39]
Dicembrini, I.; Giannini, S.; Ragghianti, B.; Mannucci, E.; Monami, M. Effects of PCSK9 inhibitors on LDL cholesterol, cardiovascular morbidity and all-cause mortality: A systematic review and meta-analysis of randomized controlled trials. J. Endocrinol. Invest., 2019, 42(9), 1029-1039.
[http://dx.doi.org/10.1007/s40618-019-01019-4] [PMID: 30762200]
[40]
Karatasakis, A.; Danek, B.A.; Karacsonyi, J.; Rangan, B.V.; Roesle, M.K.; Knickelbine, T.; Miedema, M.D.; Khalili, H.; Ahmad, Z.; Abdullah, S.; Banerjee, S.; Brilakis, E.S. Effect of PCSK9 inhibitors on clinical outcomes in patients with hypercholesterolemia: A meta-analysis of 35 randomized controlled trials. J. Am. Heart Assoc., 2017, 6(12), e006910.
[http://dx.doi.org/10.1161/JAHA.117.006910] [PMID: 29223954]
[41]
Schmidt, AF; Pearce, LS; Wilkins, JT; Overington, JP; Hingorani, AD; Casas, JP PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev, 2017, 4(4), CD011748.
[http://dx.doi.org/10.1002/14651858.CD011748.pub2]
[42]
Ge, X; Zhu, T; Zeng, H; Yu, X; Li, J; Xie, S A systematic review and meta-analysis of therapeutic efficacy and safety of alirocumab and evolocumab on familial hypercholesterolemia. Biomed Res Int., 2021, 2021, 8032978.
[http://dx.doi.org/10.1155/2021/8032978]