PCSK9-directed therapies: an update
Abstract
Purpose of review Two large cardiovascular outcomes trials of monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) demonstrated that therapeutic inhibition of extracellular PCSK9 markedly reduces LDL cholesterol concentration and cardiovascular risk. Several novel strategies to inhibit PCSK9 function are in development. Different mechanisms of action may determine specific properties with potential relevance for patient care. Recent findings For the monoclonal antibodies evolocumab und alirocumab as first-generation PCSK9 inhibitors, follow-up data of up to 8 years of exposure complement the information on efficacy and safety available from outcome trials. For the small-interfering RNA inclisiran as second-generation PCSK9 inhibitor, several phase III trials have been published and a cardiovascular outcome trial has completed recruitment and is ongoing. Third-generation PCSK9 inhibitors encompass, among others, orally available drugs such as MK-0616 and the fusion protein lerodalcibep. Additional strategies to inhibit PCSK9 include vaccination and gene editing. Summary Long-term inhibition of PCSK9 with monoclonal antibodies is safe and conveys sustained cardiovascular benefit. Novel strategies to inhibit PCSK9 function such as orally available drugs, RNA targeting, and one-time treatment with gene editing may further enhance the therapeutic armamentarium and enable novel preventive strategies.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
The second-generation PCSK9 inhibitor, inclisiran, is a small interfering RNA administered by health care professionals biannually during the maintenance phase.
“The second-generation PCSK9 inhibitor, inclisiran, is a small interfering ribonucleic acid (siRNA) administered by health care professionals biannually during the maintenance phase.2”
From Adherence to PCSK9 Inhibitors in Clinical Practice (2026) · cites this paper as [2]
Currently available PCSK9 inhibitors are administered via injection and are typically intended for lifelong use.
“Currently available PCSK9 inhibitors are administered via injection and are typically intended for lifelong use.2”
From Adherence to PCSK9 Inhibitors in Clinical Practice (2026) · cites this paper as [2]
Cites
Mach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimon, L., Chapman, M. J., De Backer, G. G., Delgado, V., Ference, B. A., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz455 · Cited by 8,961 · see citing works
Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease
Sabatine, M. S., Giugliano, R. P., Keech, A. C., Honarpour, N., Wiviott, S. D., Murphy, S. A., Kuder, J. F., Wang, H., Liu, T., Wasserman, S. M., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1615664 · Cited by 6,138 · see citing works
Mach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimon, L., Chapman, M. J., De Backer, G. G., Delgado, V., Ference, B. A., et al. (2019) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2019.08.014 · Cited by 4,854 · see citing works
Self-citationAlirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome
Schwartz, G. G., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1801174 · Cited by 3,634 · cited 1× · see citing works
“…monoclonal antibodies evolocumab and alirocu-mab markedly reduce low-density lipoprotein cholesterol (LDL-C), are well tolerated, and led to a 15% relative reduction of risk for major adverse cardio-vascular events (MACE) in the FOURIER and ODYS-SEY Outcomes trials on top of statin therapy [1,2].”
BackgroundTwo Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol
Ray, K. K., Wright, R. S., Kallend, D., Koenig, W., Leiter, L. A., Raal, F. J., Bisch, J. A., Richardson, T., Jaros, M., Wijngaard, P. L. J., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1912387 · Cited by 1,665 · see citing works
Nicholls, S. J., Puri, R., Anderson, T., Ballantyne, C. M., Cho, L., Kastelein, J. J. P., Koenig, W., Somaratne, R., Kassahun, H., Yang, J., et al. (2016) · JAMA · doi:10.1001/jama.2016.16951 · Cited by 1,178 · see citing works
Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia
Raal, F. J., Kallend, D., Ray, K. K., Turner, T., Koenig, W., Wright, R. S., Wijngaard, P. L. J., Curcio, D., Jaros, M. J., Leiter, L. A., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1913805 · Cited by 818 · see citing works
In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates
Musunuru, K., Chadwick, A. C., Mizoguchi, T., Garcia, S. P., DeNizio, J. E., Reiss, C. W., Wang, K., Iyer, S., Dutta, C., Clendaniel, V., et al. (2021) · Nature · doi:10.1038/s41586-021-03534-y · Cited by 793 · see citing works
Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients
Ridker, P. M., Revkin, J., Amarenco, P., Brunell, R., Curto, M., Civeira, F., Flather, M., Glynn, R. J., Gregoire, J., Jukema, J. W., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1701488 · Cited by 624 · see citing works
Räber, L., Ueki, Y., Otsuka, T., Losdat, S., Häner, J. D., Lønborg, J., Fahrni, G., Iglesias, J. F., van Geuns, R., Ondracek, A. S., et al. (2022) · JAMA · doi:10.1001/jama.2022.5218 · Cited by 616 · see citing works
Nicholls, S. J., Kataoka, Y., Nissen, S. E., Prati, F., Windecker, S., Puri, R., Hucko, T., Aradi, D., Herrman, J. R., Hermanides, R. S., et al. (2022) · JACC. Cardiovascular imaging · doi:10.1016/j.jcmg.2022.03.002 · Cited by 469 · see citing works
Long-term evolocumab in patients with established atherosclerotic cardiovascular disease
O’Donoghue, M. L., Giugliano, R. P., Wiviott, S. D., Atar, D., Keech, A., Kuder, J. F., Im, K., Murphy, S. A., Flores-Arredondo, J. H., López, J. A. G., et al. (2022) · Circulation · doi:10.1161/circulationaha.122.061620 · Cited by 410 · see citing works
Lipid-reduction variability and antidrug-antibody formation with bococizumab
Ridker, P. M., Tardif, J.-C., Amarenco, P., Duggan, W., Glynn, R. J., Jukema, J. W., Kastelein, J. J. P., Kim, A. M., Koenig, W., Nissen, S., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1614062 · Cited by 369 · see citing works
Ray, K. K., Troquay, R. P. T., Visseren, F. L. J., Leiter, L. A., Scott Wright, R., Vikarunnessa, S., Talloczy, Z., Zang, X., Maheux, P., Lesogor, A., et al. (2023) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(22)00353-9 · Cited by 328 · see citing works
Lee, R. G., Mazzola, A. M., Braun, M. C., Platt, C., Vafai, S. B., Kathiresan, S., Rohde, E., Bellinger, A. M., & Khera, A. V. (2022) · Circulation · doi:10.1161/circulationaha.122.062132 · Cited by 249 · see citing works
Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616
Ballantyne, C. M., Banka, P., Méndez, G., Garcia, R., Rosenstock, J., Rodgers, A., Mendizabal, G., Mitchel, Y., & Catapano, A. L. (2023) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2023.02.018 · Cited by 231 · see citing works
Inclisiran and cardiovascular events: a patient-level analysis of phase III trials
Ray, K. K., Raal, F. J., Kallend, D. G., Jaros, M. J., Köenig, W., Leiter, L. A., Landmesser, U., Schwartz, G. G., Lawrence, D., Friedman, A., et al. (2022) · European Heart Journal · doi:10.1093/eurheartj/ehac594 · Cited by 228 · see citing works
Gaba, P., O’Donoghue, M. L., Park, J., Wiviott, S. D., Atar, D., Kuder, J., Im, K., Murphy, S. A., Ferrari, G. M. D., Gaciong, Z. A., et al. (2023) · Circulation · doi:10.1161/circulationaha.122.063399 · Cited by 186 · see citing works
Johns, D. G., Campeau, L., Banka, P., Bautmans, A., Bueters, T., Bianchi, E., Branca, D., Bulger, P. G., Crèvecoeur, I., Ding, F., et al. (2023) · Circulation · doi:10.1161/circulationaha.122.063372 · Cited by 171 · see citing works
Hagström, E., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Danchin, N., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J. W., et al. (2022) · Circulation · doi:10.1161/circulationaha.121.057807 · Cited by 118 · see citing works
Effect of inclisiran on lipids in primary prevention: the ORION-11 trial
Ray, K. K., Kallend, D., Leiter, L. A., Raal, F. J., Koenig, W., Jaros, M. J., Schwartz, G. G., Landmesser, U., Garcia Conde, L., Wright, R. S., et al. (2022) · European Heart Journal · doi:10.1093/eurheartj/ehac615 · Cited by 116 · see citing works
Raal, F., Durst, R., Bi, R., Talloczy, Z., Maheux, P., Lesogor, A., Kastelein, J. J. P., & on behalf of the ORION-5 Study Investigators (2024) · Circulation · doi:10.1161/circulationaha.122.063460 · Cited by 96 · see citing works
de Isla, L. P., Díaz-Díaz, J. L., Romero-Jiménez, M. J., Muñiz-Grijalvo, O., Mediavilla, J. D., Argüeso, R., Muñoz-Torrero, J. F. S., Rubio, P., Álvarez-Baños, P., Ponte, P. H., et al. (2023) · Circulation · doi:10.1161/circulationaha.122.062557 · Cited by 93 · see citing works
PCSK9 Inhibition: Insights From Clinical Trials and Future Prospects
Katzmann, J. L., Gouni‐Berthold, I., & Laufs, U. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.595819 · Cited by 89 · see citing works
Self-citationSafety and Tolerability of Inclisiran for Treatment of Hypercholesterolemia in 7 Clinical Trials
Wright, R. S., Köenig, W., Landmesser, U., Leiter, L. A., Raal, F. J., Schwartz, G. G., Lesogor, A., Maheux, P., Stratz, C., Zang, X., et al. (2023) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2023.10.007 · Cited by 84 · see citing works
Raal, F. J., Fourie, N., Scott, R. S., Blom, D. J., Basson, M. D. V., Kayıkçıoğlu, M., Caldwell, K., Kallend, D. G., Stein, E. A., LIBerate-HeFH Investigators, et al. (2023) · European Heart Journal · doi:10.1093/eurheartj/ehad596 · Cited by 76 · see citing works
Zeitlinger, M. A., Bauer, M., Reindl‐Schwaighofer, R., Stoekenbroek, R. M., Lambert, G. C., Berger–Sieczkowski, E., Lagler, H., Oesterreicher, Z. A., Wulkersdorfer, B., Lührs, P., et al. (2021) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-021-03149-2 · Cited by 59 · see citing works
Improving the sensitivity of in vivo CRISPR off-target detection with DISCOVER-Seq+
Zou, R. S., Liu, Y., Gaido, O. E. R., Konig, M. F., Mog, B. J., Shen, L. L., Avilés-Vázquez, F. J., Marín-González, A., & Ha, T. (2023) · Nature Methods · doi:10.1038/s41592-023-01840-z · Cited by 55 · see citing works
Schwartz, G. G., Szarek, M. J., Bhatt, D. L., Bittner, V., Bujas‐Bobanovic, M., Díaz, R., Fazio, S., Fras, Z., Goodman, S. G., Harrington, R. A., et al. (2023) · European Heart Journal · doi:10.1093/eurheartj/ehad144 · Cited by 49 · see citing works
Goodman, S. G., Steg, P. G., Poulouin, Y., Bhatt, D. L., Bittner, V. A., Diaz, R., Garon, G., Harrington, R. A., Jukema, J. W., Manvelian, G., et al. (2023) · Journal of the American Heart Association · doi:10.1161/jaha.122.029216 · Cited by 44 · see citing works
Pre-Clinical Evaluation of the Nanoliposomal antiPCSK9 Vaccine in Healthy Non-Human Primates
Momtazi‐Borojeni, A. A., Jaafari, M. R., Banach, M., Gorabi, A. M., Sahraei, H., & Sahebkar, A. (2021) · Vaccines · doi:10.3390/vaccines9070749 · Cited by 40 · see citing works
Katzmann, J. L., Cupido, A. J., & Laufs, U. (2022) · Metabolites · doi:10.3390/metabo12010070 · Cited by 40 · see citing works
Self-citationA split and inducible adenine base editor for precise in vivo base editing
Zeng, H., Yuan, Q., Peng, F., Ma, D., Lingineni, A., Chee, K., Gilberd, P., Osikpa, E. C., Sun, Z., & Gao, X. (2023) · Nature Communications · doi:10.1038/s41467-023-41331-5 · Cited by 37 · see citing works
Fowler, A., Rompay, K. K. A. V., Sampson, M. L., Leo, J., Watanabe, J., Usachenko, J. L., Immareddy, R., Lovato, D. M., Schiller, J. T., Remaley, A. T., et al. (2023) · npj Vaccines · doi:10.1038/s41541-023-00743-6 · Cited by 36 · see citing works
Xu, M., Zhu, X., Wu, J., Zhang, Y., Zhao, D., Wang, X., Ding, Y., Cao, Y., Li, C., Hu, W. M., et al. (2022) · BMC Medicine · doi:10.1186/s12916-021-02208-w · Cited by 26 · see citing works
Two decades of vaccine development against atherosclerosis
Moreno‐Gonzalez, M. A., Ortega-Rivera, O. A., & Steinmetz, N. F. (2023) · Nano Today · doi:10.1016/j.nantod.2023.101822 · Cited by 21 · see citing works
Third generation PCSK9-inhibitors
Laufs, U., Blüher, M., & Isermann, B. (2023) · European Heart Journal · doi:10.1093/eurheartj/ehad566 · Cited by 13 · see citing works
Self-citationA new compact adenine base editor generated through deletion of HNH and REC2 domain of SpCas9
Qian, Y., Wang, D., Niu, W., Zhao, D., Li, J., Liu, Z., Gao, X., Han, Y., Lai, L., & Li, Z. (2023) · BMC Biology · doi:10.1186/s12915-023-01644-9 · Cited by 12 · see citing works
Ups and downs in PCSK9 inhibition in the cardiovascular arena: a review
McClintick, D. J., & Giugliano, R. P. (2023) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000897 · Cited by 7 · see citing works
Flagged first, then by citations
2 of the 41 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
A new era in the science and care of kidney diseases
Zoccali, C., Mallamaci, F., Lightstone, L., Jha, V., Pollock, C. A., Tuttle, K. R., Kotanko, P., Więcek, A., Anders, H., Remuzzi, G., et al. (2024) · Nature Reviews Nephrology · doi:10.1038/s41581-024-00828-y · Cited by 36 · see citing works
Zhang, S., Sun, L., Xu, X., Zhang, Y., & Chen, Q. (2024) · BMC Cardiovascular Disorders · doi:10.1186/s12872-024-04321-z · Cited by 22 · see citing works
The 2024 APLAR Consensus on the Management of Lupus Nephritis
Mok, C. C., So, H., Hamijoyo, L., Kasitanon, N., Chen, D., Bae, S., Li, M. T., Navarra, S., Yap, D. Y. H., & Tanaka, Y. (2025) · International Journal of Rheumatic Diseases · doi:10.1111/1756-185x.70021 · Cited by 19 · see citing works
Katsuki, S., Jha, P. K., Aïkawa, E., & Aikawa, M. (2024) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2024.1431398 · Cited by 18 · see citing works
Testa, G., Giannelli, S., Staurenghi, E., Cecci, R., Floro, L., Gamba, P., Sottero, B., & Leonarduzzi, G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252413637 · Cited by 14 · see citing works
“Recent progresses in biological therapies further prompted investigations on alternative anti-PCSK9 strategies, among which are macrocyclic peptides, heparin sulfate mimetic peptides, and anticalin fusion proteins [137,138].”
Liu, H., Zhang, Y., Zhao, Y., Li, Y., Zhang, X., Bao, L., Yan, R., Yang, Y., Zhou, H., Zhang, J., et al. (2025) · Genes · doi:10.3390/genes16010098 · Cited by 13 · see citing works
Advances in Oral Biomacromolecule Therapies for Metabolic Diseases
Jiao, Q., Huang, Y., He, J., & Xu, Y. (2025) · Pharmaceutics · doi:10.3390/pharmaceutics17020238 · Cited by 12 · see citing works
Tang, Y., Lv, D., Tao, Y., & Wang, J. (2025) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2025.1599154 · Cited by 10 · see citing works
Adherence to PCSK9 Inhibitors in Clinical Practice
Blais, J. E., Zhong, W., Li, C. Y. V., Kongkaew, C., & Chan, A. H. Y. (2026) · JACC: Advances · doi:10.1016/j.jacadv.2026.102733 · Cited by 7 · see citing works
Gupta, K., Rawlley, B., Meloche, C., Minhas, A. M. K., Hermel, M., Slipczuk, L. N., Sheikh, S. S., Khoja, A. A., Vaughan, E. M., Dalakoti, M., et al. (2024) · Current Atherosclerosis Reports · doi:10.1007/s11883-024-01218-2 · Cited by 6 · see citing works
Shedding of GPP130 by PC7 and Furin: Potential Implication in Lung Cancer Progression
Prabhala, P., Duval, S., Evagelidis, A., Dévéhat, M. L., Sachan, V., & Seidah, N. G. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26136164 · Cited by 4 · see citing works
Time to Combinatorial Regimens: SGLT2i and PCSK9i in High-Risk Cardio-Oncology Patients
Quagliariello, V., Berretta, M., Bisceglia, I., Iovine, M., Arianna, R., Barbato, M., Canale, M. L., Paccone, A., Inno, A., Scherillo, M., et al. (2025) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0000000000001760 · Cited by 4 · see citing works
Proprotein convertase subtilisin/kexin type 9-inhibition across different patient populations
Stürzebecher, P. E., & Laufs, U. (2024) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000935 · Cited by 3 · see citing works
Self-citationInhibition of PCSK9 with polypurine reverse hoogsteen hairpins: A novel gene therapy approach
López-Aguilar, E., Pacheco-Velázquez, S. C., Busquets, M.-A., Hay, J., Mueller, P. A., Fazio, S., Ciudad, C. J., Noé, V., & Pamir, N. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.116976 · Cited by 3 · see citing works
Choi, J., & Gwon, J. (2025) · Vascular Specialist International · doi:10.5758/vsi.250043 · Cited by 5 · see citing works
PCSK9 inhibitors: a promising lipid-lowering strategy for kidney transplant recipients
Luo, B., Guo, L., & Di, W. (2025) · Renal Failure · doi:10.1080/0886022x.2025.2604881 · Cited by 2 · see citing works
Katzmann, J. L., & Laufs, U. (2026) · Current Atherosclerosis Reports · doi:10.1007/s11883-026-01390-7 · Cited by 2 · see citing works
Self-citationBasak, A. (2025) · Biomolecules · doi:10.3390/biom15040468 · Cited by 3 · see citing works
Protein-binding therapy: a new approach to lower cholesterol
Hegele, R. A. (2025) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(24)00347-4 · Cited by 1 · see citing works
Biologics for cardiovascular diseases: from bench to bedside
Sun, X., Wang, X., Jia, R., Tang, J., Zeng, X. Y., Zhao, F., Zeng, F., Huang, N., Li, J., & Cui, K. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02673-w · Cited by 2 · see citing works
Effects of evolocumab combined with L-carnitine on prognosis of patients after emergency PCI
Wang, L., Mu, L., Yu, P., Gao, G., Zhang, Q., Chen, C., & Zhang, J. (2025) · Current Problems in Surgery · doi:10.1016/j.cpsurg.2025.101969
SAIMSARA (2026) · SAIMSARA Journal · doi:10.62487/saimsarac25dcb0d
- Authors
- Katzmann, J. L., & Laufs, U.
- Affiliations
- University Hospital Leipzig (DE)
- Corresponding author
- Katzmann, Julius L.
- Venue
- Current Opinion in Lipidology
- Published
- 2024-01-19
- Volume
- 35
- Issue
- 3
- Pages
- 117-125
- ISSN
- 0957-9672 (ISSN-L)
- 1473-6535
- OpenAlex
- W4391251010
- Cited by
- 22
- References
- 41
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 6
- FWCI
- 2.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Opinion in Lipidology (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 inhibitors, PCSK9, evolocumab, alirocumab, inclisiran, genome editing, LDL cholesterol lowering, cardiovascular risk reduction, long-term safety, siRNA
- MeSH terms
- Proprotein Convertase 9, PCSK9 Inhibitors, Animals, Antibodies, Monoclonal, Cardiovascular Diseases, Humans
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
