Reduction of low-density lipoprotein cholesterol by monoclonal antibody inhibition of PCSK9
Open accessAbstract
Published phase I and II trials with two fully human monoclonal antibodies to PCSK9 have provided comprehensive evidence that inhibiting PCSK9 is a very effective method to reduce low-density lipoprotein cholesterol (LDL-C). In all populations studied so far, whether on statins or LDL-C-reducing diet alone, with or without a genetic defect in the LDL receptor, and in subjects intolerant to statins, the LDL-C reductions have been large and consistent. Even the most efficacious statin, rosuvastatin, at its highest dose has not achieved such reductions. The clinical trials have established that monoclonal antibody therapy targeted to PCSK9 may be administered subcutaneously every two or four weeks. Current data suggest these drugs will provide an effective therapeutic option for LDL-C reduction and that, if proven safe in phase III trials, they will be as important to LDL-C control, and likely to cardiovascular disease risk reduction, as statins have been over the past three decades.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
PCSK9 inhibitors reduce LDL-C by 50-60% in a variety of patient groups, including those identified as statin intolerant.
“Studies have consistently shown large LDL-C reductions of 50–60% in a variety of patient groups,64,65 including those identified as statin intolerant,66–68”
PCSK9 has become a therapeutic target for potently reducing LDL-C in humans.
“First identified in 2003 and shown to be related to autosomal-dominant hypercholesterolaemia, PCSK9 has become a therapeutic target for potently reducing LDL-C in humans.64,65”
PCSK9 inhibitors have a very low rate of muscle symptoms.
“with a very low rate of muscle symptoms”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Expert Panel on Detection, E. (2001) · JAMA: The Journal of the American Medical Association · doi:10.1001/jama.285.19.2486 · Cited by 26,011 · see citing works
Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein
Ridker, P. M., Danielson, E., Fonseca, F. A. H., Genest, J., Gotto, A. M., Kastelein, J. J. P., Koenig, W., Libby, P., Lorenzatti, A. J., MacFadyen, J. G., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0807646 · Cited by 6,674 · see citing works
Cholesterol Treatment Trialists' (CTT) Collaboration (2010) · The Lancet · doi:10.1016/s0140-6736(10)61350-5 · Cited by 6,550 · see citing works
Rosuvastatin to Prevent Vascular Events in Men and Women With Elevated C-Reactive Protein
Ridker, P. M., Danielson, E., Fonseca, F. A. H., Genest, J. J., Gotto, A. M., Kastelein, J. J. P., Köenig, W., Libby, P., Lorenzatti, A. J., MacFadyen, J. G., et al. (2009) · Obstetrical & Gynecological Survey · doi:10.1097/01.ogx.0000344393.60303.0a · Cited by 3,641 · see citing works
ESC/EAS Guidelines for the management of dyslipidaemias
Reiner, Ž., Catapano, A. L., De Backer, G., Graham, I., Taskinen, M.-R., Wiklund, O., Agewall, S., Alegria, E., Chapman, M. J., Durrington, P., et al. (2011) · European Heart Journal · doi:10.1093/eurheartj/ehr158 · Cited by 3,549 · see citing works
Sequence Variations in <i>PCSK9,</i> Low LDL, and Protection against Coronary Heart Disease
Cohen, J. C., Boerwinkle, E., Mosley, T. H., & Hobbs, H. H. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa054013 · Cited by 3,181 · see citing works
Mutations in PCSK9 cause autosomal dominant hypercholesterolemia
Abifadel, M., Varret, M., Rabès, J.-P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., et al. (2003) · Nature Genetics · doi:10.1038/ng1161 · Cited by 2,985 · see citing works
Bruckert, E., Hayem, G., Dejager, S., Yau, C., & Bégaud, B. (2005) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-005-5686-z · Cited by 1,226 · see citing works
Seidah, N. G., Benjannet, S., Wickham, L., Marcinkiewicz, J., Jasmin, S. B., Stifani, S., Basak, A., Prat, A., & Chrétien, M. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0335507100 · Cited by 1,191 · see citing works
Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and inlivers of parabiotic mice
Lagace, T. A., Curtis, D. E., Garuti, R., McNutt, M. C., Park, S. W., Prather, H. B., Anderson, N. N., Ho, Y. K., Hammer, R. E., & Horton, J. D. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29383 · Cited by 681 · see citing works
Decreased plasma cholesterol and hypersensitivity to statins in mice lacking <i>Pcsk9</i>
Rashid, S., Curtis, D. E., Garuti, R., Anderson, N. N., Bashmakov, Y., Ho, Y. K., Hammer, R. E., Moon, Y.-A., & Horton, J. D. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501652102 · Cited by 679 · see citing works
Effect of a Monoclonal Antibody to PCSK9 on LDL Cholesterol
Stein, E. A., Mellis, S., Yancopoulos, G. D., Stahl, N., Logan, D., Smith, W. B., Lisbon, E., Gutierrez, M., Webb, C., Wu, R., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1105803 · Cited by 664 · see citing works
Self-citationZhao, Z., Tuakli-Wosornu, Y., Lagace, T. A., Kinch, L. N., Grishin, N. V., Horton, J. D., Cohen, J. C., & Hobbs, H. H. (2006) · The American Journal of Human Genetics · doi:10.1086/507488 · Cited by 628 · see citing works
Maxwell, K. N., & Breslow, J. L. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402133101 · Cited by 613 · see citing works
Stein, E. A., Gipe, D., Bergeron, J., Gaudet, D., Weiss, R., Dufour, R., Wu, R., & Pordy, R. C. (2012) · The Lancet · doi:10.1016/s0140-6736(12)60771-5 · Cited by 575 · see citing works
Self-citationMcKenney, J. M., Koren, M. J., Kereiakes, D. J., Hanotin, C., Ferrand, A.-C., & Stein, E. A. (2012) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2012.03.007 · Cited by 507 · see citing works
Self-citationRaal, F. J., Scott, R. C., Somaratne, R. M., Bridges, I. M., Li, G., Wasserman, S. M., & Stein, E. A. (2012) · Circulation · doi:10.1161/circulationaha.112.144055 · Cited by 502 · see citing works
Self-citationAtorvastatin with or without an Antibody to PCSK9 in Primary Hypercholesterolemia
Roth, E. M., McKenney, J. M., Hanotin, C., Asset, G., & Stein, E. A. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1201832 · Cited by 459 · see citing works
Self-citationLambert (2012) · doi:10.1194/jlr.r026658 · Cited by 448 · see citing works
Sullivan, D., Olsson, A. G., Scott, R., Kim, J. B., Xue, A., Gebski, V., Wasserman, S. M., & Stein, E. A. (2012) · JAMA · doi:10.1001/jama.2012.25790 · Cited by 447 · see citing works
Self-citationGiugliano, R. P., Desai, N. R., Kohli, P., Rogers, W. J., Somaratne, R. M., Huang, F., Liu, T., Mohanavelu, S., Hoffman, E. B., McDonald, S. T., et al. (2012) · The Lancet · doi:10.1016/s0140-6736(12)61770-x · Cited by 425 · see citing works
Maxwell, K. N., Fisher, E. A., & Breslow, J. L. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409736102 · Cited by 415 · see citing works
Chan, J. C. Y., Piper, D. E., Cao, Q., Liu, D., King, C., Wang, W., Tang, J. T., Liu, Q., Higbee, J., Xia, Z., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903849106 · Cited by 410 · see citing works
Koren, M. J., Scott, R. C., Kim, J. B., Knüsel, B., Liu, T., Lei, L., Bolognese, M. A., & Wasserman, S. M. (2012) · The Lancet · doi:10.1016/s0140-6736(12)61771-1 · Cited by 364 · see citing works
The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population
Hooper, A. J., Marais, A. D., Tanyanyiwa, D. M., & Burnett, J. R. (2006) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2006.08.039 · Cited by 363 · see citing works
Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia
Leren, T. (2004) · Clinical Genetics · doi:10.1111/j.0009-9163.2004.0238.x · Cited by 256 · see citing works
Effects of AMG 145 on Low-Density Lipoprotein Cholesterol Levels
Dias, C. S., Shaywitz, A. J., Wasserman, S. M., Smith, B. P., Gao, B., Stolman, D., Crispino, C., Smirnakis, K. V., Emery, M. G., Colbert, A., et al. (2012) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2012.08.986 · Cited by 230 · see citing works
Self-citationStein, E. A., Stender, S., Mata, P., Sager, P. T., Ponsonnet, D., Melani, L., Lipka, L., Suresh, R., Maccubbin, D., & Veltri, E. P. (2004) · American Heart Journal · doi:10.1016/j.ahj.2004.03.052 · Cited by 159 · see citing works
Self-citationPotential of Proprotein Convertase Subtilisin/Kexin Type 9 Based Therapeutics
Stein, E. A., & Swergold, G. D. (2013) · Current Atherosclerosis Reports · doi:10.1007/s11883-013-0310-3 · Cited by 84 · see citing works
Self-citation
Flagged first, then by citations
1 of the 30 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- Gumbiner B, Joh T, Udata C, et al. 2012. Effects of 12 weeks of treatment with RN316 (PF-04950615), a humanized IgG2 a monoclonal antibody binding proprotein convertase subtilisin kexin type 9, in hypercholesterolemic subjects on high-and maximal-dose statins. Circulation 126(23):2782 (Abstr.)
Cited by
Sorted by citations
Stroes, E. S., Thompson, P. D., Corsini, A., Vladutiu, G. D., Raal, F. J., Ray, K. K., Roden, M., Stein, E., Tokgözoğlu, L., Nordestgaard, B. G., et al. (2015) · European Heart Journal · doi:10.1093/eurheartj/ehv043 · Cited by 1,443 · see citing works
“First identified in 2003 and shown to be related to autosomal-dominant hypercholesterolaemia, PCSK9 has become a therapeutic target for potently reducing LDL-C in humans.(64,65) Clinical development of human monoclonal antibodies has progressed very rapidly, with the most advanced being evolocumab, alirocumab, and boc…”
Self-citationNair, J. K., Willoughby, J. L. S., Chan, A., Charisse, K., Alam, M. R., Wang, Q., Hoekstra, M., Kandasamy, P., Kel’in, A. V., Milstein, S., et al. (2014) · Journal of the American Chemical Society · doi:10.1021/ja505986a · Cited by 1,141 · see citing works
Wiegman, A., Gidding, S. S., Watts, G. F., Chapman, M. J., Ginsberg, H. N., Cuchel, M., Ose, L., Averna, M., Boileau, C., Borén, J., et al. (2015) · European Heart Journal · doi:10.1093/eurheartj/ehv157 · Cited by 891 · see citing works
Self-citationGender differences in the effects of cardiovascular drugs
Tamargo, J. L., Rosano, G. M. C., Walther, T., Duarte, J., Niessner, A., Kaski, J., Ceconi, C., Drexel, H., Kjeldsen, K. P., Savarese, G., et al. (2016) · European Heart Journal - Cardiovascular Pharmacotherapy · doi:10.1093/ehjcvp/pvw042 · Cited by 319 · see citing works
Lipid management in patients with chronic kidney disease
Ferro, C. J., Mark, P. B., Kanbay, M., Sarafidis, P. A., Heine, G. H., Rossignol, P., Massy, Z. A., Mallamaci, F., Valdivielso, J. M., Małyszko, J., et al. (2018) · Nature Reviews Nephrology · doi:10.1038/s41581-018-0072-9 · Cited by 275 · see citing works
The Multifaceted Biology of PCSK9
Seidah, N. G., & Prat, A. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnab035 · Cited by 232 · see citing works
Sex- and Gender-Based Pharmacological Response to Drugs
Mauvais‐Jarvis, F., Berthold, H. K., Campesi, I., Carrero, J. J., Dhakal, S., Franconi, F., Gouni‐Berthold, I., Heiman, M. L., Kautzky‐Willer, A., Klein, S. L., et al. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000206 · Cited by 194 · see citing works
“Numerous, large-scale studies indicate that statins and PCSK9 inhibitors also effectively prevent secondary coronary events in both sexes (Baigent et al., 2010; Kostis et al., 2012; Stein and Raal, 2014; Fulcher et al., 2015; Collins et al., 2016).”
BackgroundWatts, G. F., Chan, D. C., Somaratne, R. M., Wasserman, S. M., Scott, R. C., Marcovina, S. M., & Barrett, P. H. R. (2018) · European Heart Journal · doi:10.1093/eurheartj/ehy122 · Cited by 151 · see citing works
“This could entail an impact of evolocumab and atorvastatin on LDLR activity and/or decrease competition of Lp(a) particles for clearance by this receptor.(4,10,16,17) Other hepatic receptors could mediate the catabolism of Lp(a), including VLDL and plasminogen receptors,(10,31,32) but their exact roles remain to be in…”
BackgroundBouhairie, V. E., & Goldberg, A. C. (2015) · Cardiology Clinics · doi:10.1016/j.ccl.2015.01.001 · Cited by 128 · see citing works
Seidah, N. G., Abifadel, M., Prost, S., Boileau, C., & Prat, A. (2016) · Pharmacological Reviews · doi:10.1124/pr.116.012989 · Cited by 119 · see citing works
“As will be discussed later, thesemAbsarenows.c. administered toFHpatients that are either statin-resistant or statin-intolerant to reduce their LDL-c levels (Stein and Raal, 2014; Seidah, 2015).”
BackgroundFactorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism
Watts, G. F., Chan, D. C., Dent, R. E., Somaratne, R. M., Wasserman, S. M., Scott, R. C., Burrows, S., & Barrett, P. H. R. (2016) · Circulation · doi:10.1161/circulationaha.116.025080 · Cited by 94 · see citing works
Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies
Seidah, N. G., Prat, A., Pirillo, A., Catapano, A. L., & Norata, G. D. (2019) · Cardiovascular Research · doi:10.1093/cvr/cvz003 · Cited by 89 · see citing works
The LXR–Idol Axis Differentially Regulates Plasma LDL Levels in Primates and Mice
Hong, C., Marshall, S. M., McDaniel, A. L., Graham, M., Layne, J. D., Cai, L., Scotti, E., Boyadjian, R., Kim, J., Chamberlain, B. T., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.10.001 · Cited by 87 · see citing works
“Statins, which act indirectly through SREBP, and antibodies directed against PCSK9, which are in late-stage clinical development, increase LDLR (Stein and Raal, 2014; Young and Fong, 2012).”
BackgroundKent, S. T., Rosenson, R. S., Avery, C. L., Chen, Y.-D. I., Correa, A., Cummings, S. R., Cupples, L. A., Cushman, M., Evans, D. S., Gudnason, V., et al. (2017) · Circulation: Cardiovascular Genetics · doi:10.1161/circgenetics.116.001632 · Cited by 86 · see citing works
“African Americans.(10) CHD and stroke events have been adjudicated by review of medical”
InfluentialTavori, H., Rashid, S., & Fazio, S. (2015) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2014.12.017 · Cited by 86 · see citing works
“effective in lowering LDL-C levels (8).”
Shim, J., Al-Mashhadi, R. H., Sørensen, C. B., & Bentzon, J. F. (2015) · The Journal of Pathology · doi:10.1002/path.4646 · Cited by 75 · see citing works
“Animal models of atherosclerosis, especially genetically modified mouse models [1], have enabled many discoveries of disease mechanisms [2], but treatment of atherosclerosis still relies on the old discovery that low-density lipoproteins (LDLs) are central instigators of the disease, and the successful development of…”
BackgroundWatts, G. F., Chan, D. C., Pang, J., Ma, L., Ying, Q., Aggarwal, S., Marcovina, S. M., & Barrett, P. H. R. (2020) · Metabolism · doi:10.1016/j.metabol.2020.154221 · Cited by 68 · see citing works
Walley, K. R., Francis, G. A., Opal, S. M., Stein, E. A., Russell, J. A., & Boyd, J. H. (2015) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201505-0876ci · Cited by 58 · see citing works
Self-citationMarais, A. D., Kim, J. B., Wasserman, S. M., & Lambert, G. C. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.07.004 · Cited by 53 · see citing works
Butkinaree, C., Canuel, M., Essalmani, R., Poirier, S., Benjannet, S., Asselin, M.-C., Roubtsova, A., Hamelin, J., Marcinkiewicz, J., Chamberland, A., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.647180 · Cited by 52 · see citing works
Monoclonal antibodies: From magic bullet to precision weapon
Aboul-Ella, H., Gohar, A., Ali, A. A., Ismail, L. M., Mahmoud, A. E. E.-R., Elkhatib, W. F., & Aboul-Ella, H. (2024) · Molecular Biomedicine · doi:10.1186/s43556-024-00210-1 · Cited by 55 · see citing works
“…disease therapy [12], such as cardiovascular disease (CVD) [13, 14], chronic respiratory syndromes (CRS) [15], autoimmune diseases [16, 17], diabetes [18, 19], which are the most incriminated causes of global mortality, elevated lower density lipoprotein (LDL) level [20], and cancers [21–34].”
BackgroundThe PCSK9 revolution and the potential of PCSK9-based therapies to reduce LDL-cholesterol
Seidah, N. G. (2017) · Global Cardiology Science and Practice · doi:10.21542/gcsp.2017.2 · Cited by 51 · see citing works
Research methods for animal models of atherosclerosis (Review)
Zhang, Y., Fatima, M., Hou, S., Bai, L., Zhao, S., & Liu, E. (2021) · Molecular Medicine Reports · doi:10.3892/mmr.2021.12511 · Cited by 46 · see citing works
“Recently, the proprotein convertase subtilisin/kexin type 9 (PCSK9)‐adeno‐associated virus (AAV) mice have been used as a rapid, versatile and cost‐effective animal model for atherosclerosis research (39).”
New developments in proprotein convertase subtilisin–kexin 9's biology and clinical implications
Seidah, N. G. (2016) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000295 · Cited by 43 · see citing works
Lipid Metabolism and Emerging Targets for Lipid-Lowering Therapy
Gaudet, D., Drouin‐Chartier, J., & Couture, P. (2017) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2016.12.019 · Cited by 43 · see citing works
PCSK9: from biology to clinical applications
Blanchard, V., Khantalin, I., Ramin‐Mangata, S., Chemello, K., Nativel, B., & Lambert, G. C. (2018) · Pathology · doi:10.1016/j.pathol.2018.10.012 · Cited by 45 · see citing works
New Therapies for Reducing Low-Density Lipoprotein Cholesterol
Stein, E. A., & Raal, F. J. (2014) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2014.08.008 · Cited by 42 · see citing works
Self-citationImbalzano, E., Ilardi, F., Orlando, L., Pintaudi, B., Savarese, G., & Rosano, G. M. C. (2023) · European Heart Journal - Cardiovascular Pharmacotherapy · doi:10.1093/ehjcvp/pvad019 · Cited by 40 · see citing works
Statin-associated muscle symptoms: position paper from the Luso-Latin American Consortium
Sposito, A. C., Faria‐Neto, J. R., de Carvalho, L. S. F., Lorenzatti, A. J., Cafferata, A., Elikir, G. D., Esteban, E., Villegas, E. C. M., Bodanese, L. C., Rodrigo Alonso, K., et al. (2016) · Current Medical Research and Opinion · doi:10.1080/03007995.2016.1252740 · Cited by 38 · see citing works
Scolaro, B., Kim, H. S. J., & de Castro, I. A. (2016) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2016.1235546 · Cited by 37 · see citing works
“Phase II trials showed that PCSK9 inhibitors, particularly monoclonal antibodies, reduce LDL-C by between 60 and 70%, even in the presence of background statin therapy (Norata et al., 2014; Stein and Raal, 2014).”
BackgroundGenetic testing in cardiovascular diseases
Arndt, A.-K., & MacRae, C. A. (2014) · Current Opinion in Cardiology · doi:10.1097/hco.0000000000000055 · Cited by 34 · see citing works
“Unau 0268-4705 2014 Wolters Kluwer Health | Lippincott Williams & Wilk with plasma cholesterol measurements and the empiric nature of subsequent management [42], is likely to become much more prevalent if PCSK9 inhibitors demonstrate efficacy [43].”
BackgroundWeider, E., Susan‐Resiga, D., Essalmani, R., Hamelin, J., Asselin, M.-C., Nimesh, S., Ashraf, Y., Wycoff, K. L., Zhang, J., Prat, A., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.717736 · Cited by 34 · see citing works
“Healthy diets and exercise are highly recommended to lower LDLc in patients with high baseline levels.”
BackgroundInfluentialAnacetrapib reduces (V)LDL cholesterol by inhibition of CETP activity and reduction of plasma PCSK9
van der Tuin, S. J. L., Kühnast, S., Berbée, J. F. P., Verschuren, L., Pieterman, E. J., Havekes, L. M., van der Hoorn, J. W. A., Rensen, P. C. N., Jukema, J. W., Princen, H. M. G., et al. (2015) · Journal of Lipid Research · doi:10.1194/jlr.m057794 · Cited by 33 · see citing works
Susan‐Resiga, D., Girard, E., Kiss, R. S., Essalmani, R., Hamelin, J., Asselin, M.-C., Awan, Z. A., Butkinaree, C., Fleury, A., Soldera, A., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.769430 · Cited by 33 · see citing works
Seidah, N. G., Chrétien, M., & Mbikay, M. (2018) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000484 · Cited by 31 · see citing works
Lambert, G. C., Chatelais, M., Petrides, F., Passard, M., Thedrez, A., Rye, K., Schwahn, U., Gusarova, V., Blom, D. J., Sasiela, W. J., et al. (2014) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2014.07.995 · Cited by 30 · see citing works
“I read with great interest the editorial by Fuster (1), detailing both expanded recommendations to address the global burden of cardiovascular disease and the necessity for evaluating implemented recommendations by measuring outcomes.”
BackgroundResultPCSK9 Antibodies for the Treatment of Hypercholesterolemia
Gouni‐Berthold, I., & Berthold, H. K. (2014) · Nutrients · doi:10.3390/nu6125517 · Cited by 30 · see citing works
“Moreover, they were shown to decrease apoB, total cholesterol (TC) and non-high-density lipoprotein cholesterol (non-HDL-C) concentrations to a degree similar to that of LDL-C [21].”
BackgroundDjebli, N., Martinez, J.-M., Lohan, L., Khier, S., Brunet, A., Hurbin, F., & Fabre, D. (2017) · Clinical Pharmacokinetics · doi:10.1007/s40262-016-0505-1 · Cited by 29 · see citing works
Lipid-Lowering Drug Therapy for CVD Prevention: Looking into the Future
Stein, E. A., & Raal, F. J. (2015) · Current Cardiology Reports · doi:10.1007/s11886-015-0659-8 · Cited by 28 · see citing works
Self-citationNew developments in atherosclerosis: clinical potential of PCSK9 inhibition
Tavori, H., & Giunzioni, I. (2015) · Vascular Health and Risk Management · doi:10.2147/vhrm.s74692 · Cited by 28 · see citing works
Non-statin Treatments for Managing LDL Cholesterol and Their Outcomes
Turner, T. A., & Stein, E. A. (2015) · Clinical Therapeutics · doi:10.1016/j.clinthera.2015.09.004 · Cited by 28 · see citing works
“rties of evolocumab: changes in PCSK9 and LDL-C with permission.(15) PCSK9, proprotein convertase”
BackgroundSelf-citationHenne, K. R., Ason, B. L., Howard, M., Wang, W., Sun, J., Higbee, J., Tang, J., Matsuda, K. C., Xu, R., Zhou, L., et al. (2015) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.114.221242 · Cited by 28 · see citing works
“Clinically, anti-PCSK9 mAbs have shown promise as monotherapy, in combination with other treatments such as statins (Robinson et al., 2014), which are known to increase PCSK9 expression (Careskey et al., 2008), or as treatment in statin-intolerant populations (Stroes et al., 2014).”
BackgroundUsing Human ‘Experiments of Nature’ to Predict Drug Safety Issues: An Example with PCSK9 Inhibitors
Jerome, R. N., Pulley, J. M., Roden, D. M., Shirey-Rice, J. K., Bastarache, L. A., Bernard, G. R., Ekstrom, L. B., Lancaster, W. J., & Denny, J. C. (2017) · Drug Safety · doi:10.1007/s40264-017-0616-0 · Cited by 28 · see citing works
“Since the discovery of this protein in 2003 [3], the work of understanding its function and developing agents that target PCSK9 has progressed at a rapid pace, with the first human subject being treated with a PCSK9 monoclonal antibody (mAb) in 2009 [4].”
BackgroundTargeting low‐density lipoprotein cholesterol with PCSK9 inhibitors
Scherer, D. J., Nelson, A. J., Psaltis, P. J., & Nicholls, S. J. (2017) · Internal Medicine Journal · doi:10.1111/imj.13451 · Cited by 27 · see citing works
Sarkar, S. K., Foo, A. C. Y., Matyas, A., Asikhia, I., Kosenko, T., Goto, N. K., Vergara‐Jaque, A., & Lagace, T. A. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.010221 · Cited by 26 · see citing works
“Therapeutic monoclonal antibodies that target PCSK9 and prevent its binding to LDLR lower LDL-C by up to 70% in hypercholesterolemic patients, clearly establishing circulating PCSK9 as a central regulator of hepatic LDLR expression and plasma LDL-C levels (7, 8).”
BackgroundPirro, M., Bianconi, V., Francisci, D., Schiaroli, E., Bagaglia, F., Sahebkar, A., & Baldelli, F. (2017) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13273 · Cited by 24 · see citing works
“PCSK9 inhibition is currently considered an effective strategy for lowering plasma LDL-C levels [64, 65], but its impact on HCV infection has not been explored so far in clinical trials.”
BackgroundAlirocumab: PCSK9 inhibitor for LDL cholesterol reduction
Tavori, H., Melone, M., & Rashid, S. (2014) · Expert Review of Cardiovascular Therapy · doi:10.1586/14779072.2014.954551 · Cited by 21 · see citing works
“Phase II data indicate that 4-week dosing with 300 mg will produce similarly low LDL-c (50% reduction) compared with half the amount at 2 weeks (70% reduction), but the former may be a more cost-efficient regime [54,64].”
BackgroundPCSK9 Inhibitors: Clinical Relevance, Molecular Mechanisms, and Safety in Clinical Practice
Ferrari, F., Stein, R., Motta, M. T., & Moriguchi, E. H. (2019) · Arquivos Brasileiros de Cardiologia · doi:10.5935/abc.20190029 · Cited by 22 · see citing works
Bouhairie, V. E., & Goldberg, A. C. (2016) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2015.09.001 · Cited by 21 · see citing works
PCSK9 antibodies: A new class of lipid-lowering drugs
Gouni‐Berthold, I. (2015) · Atherosclerosis Supplements · doi:10.1016/j.atherosclerosissup.2015.02.003 · Cited by 20 · see citing works
Češka, R., Latkovskis, G., Владиславович, Е. М., Freiberger, T., Lalic, K. S., Mitchenko, O., Paragh, G., Petrulionienė, Ž., Pojskić, B., Rašlová, K., et al. (2019) · Current Atherosclerosis Reports · doi:10.1007/s11883-019-0797-3 · Cited by 18 · see citing works
Novel Oral Nano-hepatic targeted anti-PCSK9 in hypercholesterolemia.
Salaheldin, T., Godugu, K., Bharali, D., Fujioka, K., Elshourbagy, N., & Mousa, S. (2021) · Nanomedicine: Nanotechnology, Biology and Medicine · doi:10.1016/j.nano.2021.102480 · Cited by 16 · see citing works
Modeling cholesterol metabolism and atherosclerosis
Auley, M. T. M. (2021) · WIREs Mechanisms of Disease · doi:10.1002/wsbm.1546 · Cited by 16 · see citing works
Kehinde, I. O., Akawa, O. B., Adewumi, A. T., Rabbad, A. H., & Soliman, M. E. S. (2024) · Journal of Cellular Biochemistry · doi:10.1002/jcb.30581 · Cited by 15 · see citing works
“29,30 2 | METHODOLOGY 2.1 | Retrieval and preparation of proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) protein PCSK9 receptor co ‐ crystallized with compound 16 (063), was attained from the RCSB Protein Data Bank (accession code, 6U26).”
InfluentialTran-Dinh, A., Levoye, A., Lambert, G., Louedec, L., Journé, C., Meilhac, O., & Amarenco, P. (2014) · Stroke · doi:10.1161/strokeaha.114.005958 · Cited by 13 · see citing works
“25g/L).(3) A relationship between low LDL-C levels and the risk of hemorrhagic transformation (HT) after ischemic stroke has been suggested.”
BackgroundLi, Z., Fan, K., Suo, C., Gu, X., Zhu, C., Wei, H., Chen, L., Gao, P., & Sun, L. (2025) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjaf001 · Cited by 12 · see citing works
“…type 9 (PCSK9) is known to bind to the EGF precursor homology domain A (EGF-A) of LDLR and promote its lysosomal degradation, and monoclonal antibodies block the interaction between PCSK9 and EGF-A, significantly reducing plasma LDL-C levels (Zhang et al., 2007 ; Stein and Raal, 2014 ).”
Lipid-Modifying Drugs: Pharmacology and Perspectives
Xu, R.-X., & Wu, Y. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-981-15-2517-9_5 · Cited by 12 · see citing works
Assaying Low-Density-Lipoprotein (LDL) Uptake into Cells
Loregger, A., Nelson, J. K., & Zelcer, N. (2017) · Methods in molecular biology · doi:10.1007/978-1-4939-6875-6_5 · Cited by 11 · see citing works
“Recently, antibodies that target PCSK9 and thereby increase hepatic LDLR levels and LDL clearance have shown strong LDL-lowering potency [11, 12], and are being currently introduced into clinical practice [13].”
BackgroundStein, E. A. (2016) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000242 · Cited by 10 · see citing works
Self-citationThe efficacy of anti-PCSK9 antibodies: Results from recent trials
Gouni‐Berthold, I. (2017) · Atherosclerosis Supplements · doi:10.1016/j.atherosclerosissup.2017.05.030 · Cited by 10 · see citing works
“These antibodies do not contain any mouse protein compone nts, thus they are very likely to avoid many of the side-effects associated with prior gene ration antibodies [6].”
PCSK9 Inhibitors and Their Role in high-risk Patients in Reducing Ldl Cholesterol Levels: Alirocumab
Dahagam, C., Goud, A., Abdelqader, A., Hendrani, A. D., Feinstein, M. J., Qamar, A., Joshi, P. H., Swiger, K. J., Byrne, K., Quispe, R., et al. (2016) · Future Cardiology · doi:10.2217/fca.15.88 · Cited by 10 · see citing works
Novel Therapies for Low-Density Lipoprotein Cholesterol Reduction
Toth, P. P. (2016) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2016.05.028 · Cited by 9 · see citing works
Semenkovich, C. F., Goldberg, A. C., & Goldberg, I. J. (2016) · Elsevier eBooks · doi:10.1016/b978-0-323-29738-7.00037-x · Cited by 10 · see citing works
The PCSK9 revolution and the potential of PCSK9-based therapies to reduce LDL-cholesterol
Seidah, N. G. (2015) · Global Cardiology Science and Practice · doi:10.5339/gcsp.2015.59 · Cited by 7 · see citing works
Statins, PCSK9 inhibitors and cholesterol homeostasis: a view from within the hepatocyte
Sniderman, A. D., Kiss, R. S., Reid, T., Thanassoulis, G., & Watts, G. F. (2017) · Clinical Science · doi:10.1042/cs20160872 · Cited by 7 · see citing works
Lu, X. (2019) · Current Drug Targets · doi:10.2174/1389450120666190214141626 · Cited by 6 · see citing works
Posttranslational Processing of Secretory Proteins
Seidah, N. G., & Guillemot, J. (2016) · doi:10.1002/9781118760369.ch9 · Cited by 6 · see citing works
Satyam, S. M., El-Tanani, M., Patni, M. A., Rehman, A., Irshad, S. M., Raheem, R., Junais, E., John, A. A., Rassal, R. Y., Kumari, R., et al. (2026) · BMC Cardiovascular Disorders · doi:10.1186/s12872-026-05515-3 · Cited by 5 · see citing works
“Monoclonal PCSK9 antibodies bind circulating PCSK9 proteins which blocks their interaction with LDLR receptors [11].”
PCSK9 Inhibitors and Their Role in high-risk Patients in Reducing Ldl Cholesterol Levels: Evolocumab
Dahagam, C., Goud, A., Abdelqader, A., Hendrani, A. D., Feinstein, M. J., Qamar, A., Joshi, P. H., Swiger, K. J., Byrne, K., Quispe, R., et al. (2016) · Future Cardiology · doi:10.2217/fca.15.89 · Cited by 5 · see citing works
The Essence of Lipoproteins in Cardiovascular Health and Diseases Treated by Photodynamic Therapy
Wańczura, P. M., Aebisher, D., Iwański, M. A., Myśliwiec, A., Dynarowicz, K., & Bartusik‐Aebisher, D. (2024) · Biomedicines · doi:10.3390/biomedicines12050961 · Cited by 5 · see citing works
“In addition, it was noted that alirocumab reduced total cholesterol, ApoB, non-HDL-C, and Lp(a) without influence from the dose of baseline statin [74].”
BackgroundPCSK9 Inhibitors: The Next Frontier in Low-Density Lipoprotein Lowering
Jialal, I., & Patel, S. B. (2015) · Metabolic Syndrome and Related Disorders · doi:10.1089/met.2015.1503 · Cited by 5 · see citing works
Bibliometric analysis of monoclonal antibodies for atherosclerosis
Ma, J., Zhao, K., Zhu, Y., Wen, X., Huang, J., Wei, X., & Zhao, Z. (2023) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2023.2266926 · Cited by 5 · see citing works
“14 These therapeutics also exhibit the capacity to reduce lipoprotein A and triglyceride levels.”
BackgroundThe Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Atherosclerosis Development
Chaulin, A. M., Степановна, К. Л., Aleksandrov, A., Mazaev, A., Grigorieva, E., & Адылбековна, Н. Д. (2019) · Bulletin of Science and Practice · doi:10.33619/2414-2948/42/15 · Cited by 4 · see citing works
Targeting Protein–Protein Interactions Perspective
Chung, C., & Hann, M. M. (2020) · Wiley eBooks · doi:10.1002/9781118681121.ch20 · Cited by 4 · see citing works
PCSK9 inhibition: A promise fulfilled?
Solaru, K. W., Mohan, C., & Rocco, M. B. (2016) · Cleveland Clinic Journal of Medicine · doi:10.3949/ccjm.83.s2.05 · Cited by 3 · see citing works
One-Shot, One Cure With Genome Editing for Dyslipidemia
Gupta, R. M. (2014) · Circulation Cardiovascular Genetics · doi:10.1161/circgenetics.114.000958 · Cited by 2 · see citing works
Fazio, S., & Tavori, H. (2014) · Circulation Research · doi:10.1161/circresaha.114.304575 · Cited by 2 · see citing works
Monthly PCSK9 inhibitors: The CHOICE for prolonged duration of effect
de Carvalho, L. S. F., & Yoshida, H. (2016) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2016.09.013 · Cited by 1 · see citing works
Schaefer, J., & Jackson, S. (2016) · Springer eBooks · doi:10.1007/978-3-319-29514-5_8 · Cited by 1 · see citing works
Update on PCSK9 Inhibitors and New Therapies
Stein, E. A., & Raal, F. J. (2016) · US Endocrinology · doi:10.17925/use.2016.12.01.18 · Cited by 1 · see citing works
“An unexpected effect has been a robust and consistent reduction in lipoprotein(a) (Lp[a]) of 25% to 30% seen with both alirocumab and evolocumab.(42) Table 1: US Food and Drug Administration-approved indications, dosing and LDL-C reductions for Alirocumab (Praluent®) and Evolocumab (Repatha®)21,22,43”
BackgroundSelf-citationThe Genetic and Proteomic Detereminants of the Risk of Coronary Artery Disease
Almontashiri, N. A. M. (2015) · uO Research (University of Ottawa) · doi:10.20381/ruor-6541 · Cited by 1 · see citing works
“robust LDL-C reductions by preventing degradation of the LDL-receptor (26,27,217,260).”
BackgroundRussell, J. A., & Walley, K. R. (2015) · F1000Research · doi:10.12688/f1000research.6565.1
Critical role of cholesterol transfer protein in atherosclerosis development
Dorovsky, D. A., & Zagayko, A. L. (2016) · Ukrainian biopharmaceutical journal · doi:10.24959/ubphj.16.78
“Accumulating evidence shows that PCSK9 inhibition is a beneficial strategy of reducing cholesterol-enriched LDL both in clinical and preclinical studies [25, 32].”
BackgroundToth, P. P. (2018) · Contemporary cardiology · doi:10.1007/978-3-319-97622-8_3
Schaefer, J., & Jackson, S. (2022) · Springer eBooks · doi:10.1007/978-3-031-06731-0_8
Molecular targets in dyslipidemia: Therapeutic potential of plant molecules
Martins, M. D. C. D. C. E., Macedo, J. L., Abreu, L. L. D. C., & Amorim, J. A. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-27370-4.00018-4
PCSK9 in critical illness – It’s not all about lipids
Crossley, E., Silversides, J. A., O’Kane, C. M., & Hamilton, P. (2025) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1177/00045632251395579
“These prevent its interaction with the EGFR-A domain of the LDLR. 36,37 40 Long-term trials (alirocumab: 78 weeks and evolocumab: 52 weeks) have demonstrated that both mAbs are safe and well-tolerated, with minor side effects of oropharyngeal pain, nasopharyngitis, rhinorrhoea, and injection site…”
- Authors
- Stein, E. A., & Raal, F.
- Affiliations
- University of Cincinnati (US)
- University of the Witwatersrand (ZA)
- Venue
- Annual Review of Medicine
- Publisher
- Annual Reviews
- Published
- 2014-01-14
- Volume
- 65
- Issue
- 1
- Pages
- 417-431
- ISSN
- 0066-4219 (ISSN-L)
- 1545-326X
- OpenAlex
- W2105872402
- Cited by
- 89
- References
- 30
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 5 · 2020: 4 · 2019: 5 · 2018: 5 · 2017: 11 · 2016: 20 · 2015: 17 · 2014: 12
- FWCI
- 3.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Annual Review of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- PCSK9 inhibition, monoclonal antibodies, LDL cholesterol lowering, LDL receptor, statin intolerance, rosuvastatin, cardiovascular disease risk reduction, hypercholesterolemia
- MeSH terms
- Proprotein Convertase 9, Animals, Antibodies, Monoclonal, Anticholesteremic Agents, Apolipoproteins B, Humans, Hypercholesterolemia, Cholesterol, LDL, Serine Endopeptidases, Lipoprotein(a), Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, Proprotein Convertases, Molecular Targeted Therapy, Antibodies, Monoclonal, Humanized
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
