We implemented a systematic literature search through the Web of Science Core Collection (WoSCC) database using the following strategy: TS = (“proprotein convertase subtilisin/kexin type 9 inhibitor*” OR “pcsk9 inhibitor*” OR “proprotein convertase subtilisin/kexin type 9 inhibition*” OR “pcsk9 inhibition”) AND LA=(English), from 1999 to December 31, 2022. The results showed that the first article on PCSK9 inhibitors was published in 2007. A total of 2421 records were retrieved. We then excluded 1349 literature studies on review articles, meeting abstracts, editorial material, letters, early access, news items, corrections, proceeding papers, book chapters, data papers, and reprints. The final search yielded 1072 papers. The procedure for searching was presented in Figure 2A .

The retrieved literature data were exported and then imported into CiteSpace software (version 6.2. R2) for further analysis and processing (39). Information extracted from each study included authors, keywords, affiliations, countries and regions, publication years, publication titles, and funding agencies. The visual maps drawn by CiteSpace consist of nodes and connections. Nodes typically denote specific items like authors, nations, or institutions, and their size and color indicate the amount and type of items accordingly. The number of connections between nodes shows how frequently items are co-cited or collaborated upon. The higher a node’s centrality, the more impact it has in the field, as centrality is a measure of importance in a relationship network. We also use Microsoft Excel (version 2019) and Graphpad software (version 9.4.1) for drawings.

The number of publications reveals the trend and rate of research development in a certain field. As shown in Figure 2B , the annual volume of literature in this field was less than 30 before 2016; it grew rapidly from 2016 onward, with 175 papers published by 2022. Similar to the number of publications, the citation volume of literature has also grown rapidly year by year. It’s worth noting that the number of articles published in 2022 was lower than in 2021; this could be because of the coronavirus disease 2019 (COVID-19) epidemic, which temporarily shifted the focus of scientific research. As shown in Table 2 , the main research areas include cardiac cardiovascular systems (422, 39.37%), pharmacology pharmacy (226, 21.08%), and peripheral vascular disease (132, 12.31%), etc. For journal ranking, most papers related to PCSK9 inhibitors were published in the following journals: Journal of Clinical Lipidology (66, 6.16%), Atherosclerosis (45, 4.2%), Journal of the American College of Cardiology (31, 2.89%), Circulation (25, 2.33%), and Journal of the American Heart Association (25, 2.33%). In terms of funding, Amgen grants supported the most research (200, 18.66%), followed by two major pharmaceuticals, Regeneron (126, 11.75%) and Sanofi (103, 9.61%).

According to the WoSCC database, among the 89 countries or regions involved in the PCSK9 inhibitors field, the country with the highest volume of publications is the United States (507, 47.29%), followed by England (163, 15.21%), Canada (133, 12.41%), Italy (131, 12.22%), and France (128, 11.94%) ( Table 2 ). Through CiteSpace screening, Figure 3 visualizes the outputs and links across countries. Among the top 10 countries in output ranking ( Table 2 ), France, the United States, and Germany have the highest centrality, denoting their important role in the field of PCSK9 inhibitors. Further, from 2007 through 2022, the publications with the strongest bursts of citations in countries were analyzed. In Figure 4 , the blue segment represents the timeline, while the red line represents the citation burst duration. The top 6 countries for the strongest citation bursts ( Figure 4A ) include the United States of America (USA) (2007–2016), Canada (2008–2013), South Africa (2012–2015), Germany (2013–2014), Scotland (2014–2018), and Thailand (2019–2020). Among these countries, the USA (16.13) showed the highest burst strength and longest duration. According to the WoSCC database, the top 5 institutions for article output in the field of PCSK9 inhibitor research ( Table 3 ) are Harvard University (128, 11.94%), Amgen Inc. (114, 10.63%), Brigham & Women’s Hospital (107, 9.98%), Harvard Medical School (94, 8.77%), and Imperial College London (83, 7.74%). In the collaboration network ( Figure 5A ) and centrality ranking ( Figure 5B ) drawn by CiteSpace, the three institutions with the highest centrality are Ben Gurion Univ Negev (0.4), Imperial College London (0.35), and Leiden Univ (0.14), respectively, indicating their important position in the field, although some of them have relatively fewer publications. In addition, we conducted an analysis of citation bursts from various institutions over the past fifteen years ( Figure 4B ). Among these, the top-ranked institutions for citation bursts include: Univ Witwatersrand (5.79), Univ Amsterdam (5.73), and Harvard Univ (4.74), representing the highest research heat in the early years. In recent years, the Univ Paris, Harvard Med Sch, Icahn Sch Med Mt Sinai, and Inst Cardiovasc Rosario have also shown high enthusiasm for research.

According to the WoSCC database, Table 4 enumerates the top 6 authors with the highest number of publications in the field of PCSK9 inhibitors: Sabatine MS (51, 4.76%), Giugliano RP (46, 4.29%), Wasserman SM (38, 3.54%), Mach F (31, 2.89%), Jukema JW (29, 2.71%), and Somaratne R (29, 2.71%). In the ranking of centrality ( Table 4 ), the top-ranked authors included: Wasserman SM (0.07), Cannon CP (0.06), Catapano AL (0.06), Blom DJ (0.06), Banach M (0.05), and Ballantyne CM (0.05). Figure 4C presents a list of the top 20 authors for citation bursts over the past 15 years. The two authors with the highest burst strength are Somaratne R (9.13) and Wasserman SM (8.61), who are much higher than the other authors.

Highly cited references indicate that the academic quality and impact of the paper are widely recognized. Highly cited references can reflect hotspots in the field and are the focus of researchers. Table 5 shows the 10 most frequently cited literatures in terms of PCSK9 inhibitors. More than half of these 10 literatures were about clinical trials of PCSK9 mAbs, and almost all were published in the New England Journal of Medicine. The first-, fourth-, seventh-, and eighth-ranked literature examined the effect of evolocumab on LDLc and the risk of cardiovascular events, whereas the second- and third-ranked literature examined the effect of alirocumab on LDLc and the risk of cardiovascular events. The top 30 references, based on the citation bursts with the highest strength, are shown in Figure 6A . The article “Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome”, published in 2018, wins the strongest citation burst. This article has a burst intensity of 52.31, and its heat might continue.

The top 10 journals according to the number of citations are shown in Table 6 . The New England Journal of Medicine (864) was the most cited journal, followed by Circulation (747), the Journal of the American College of Cardiology (739), the European Heart Journal (674), the Lancet (632), the Atherosclerosis (624), the Jama-Journal of the American Medical Association (565), the Journal of Clinical Lipidology (442), the American Journal of Cardiology (367), and the Journal of Lipid Research (345). The 2021 impact factor for these journals ranged from 3.133 to 202.731, with 60% of journals having an impact factor exceeding 20. Through journal citation reports (JCR) partition analysis, Q1 accounts for 90%. In addition, we also constructed a dual map overlay of journals on PCSK9 inhibitors ( Figure 7 ) to describe the subject distribution of journals. The left part of the figure shows the citing journals, while the right part shows the cited journals. Three main citation pathways are shown in this figure. The two green citation lines indicate that research in Molecular, Biology, Genetics journals and Health, Nursing, Medicine journals is frequently cited by Medicine, Medical, Clinical journals. The orange citation line indicates that research in Molecular, Biology, Genetics journals is frequently cited by Molecular, Biology, Immunology journals.

The keywords are the core and main points of a paper and can reflect the hotspots and fronts of a certain field. Table 7 and Figure 8A show the co-occurrence analysis of keywords. The keywords with a high frequency of co-occurrence include “low density lipoprotein” (391), “familial hypercholesterolemia” (305), “pcsk9 inhibitor” (265), “pcsk9” (230), “efficacy” (221), “safety” (187), “risk” (164), “cholesterol” (159), “cardiovascular disease” (158), and “monoclonal antibody” (149). The keyword centrality ranking ( Table 7 ) shows that “apolipoprotein b” (0.13), “atorvastatin” (0.11), “expression” (0.11), “cholesterol” (0.1), and “ldl receptor” (0.09) have higher centrality than other keywords, indicating that these keywords are the core of the PCSK9 inhibitors field. We further conducted the keyword cluster timeline using CiteSpace. Keyword clusters refer to groups consisting of keywords with similar research topics. A total of ten clusters are generated as shown in Figure 8B : “familial hypercholesterolaemia”, “hepg2 cell”, “pcsk9-monoclonal antibodies”, “rapid reduction”, “cognitive function”, “pcna guideline”, “secondary prevention”, “reducing low-density lipoprotein cholesterol”, “lowering therapy”, and “drug-target mendelian randomization study”. Circles denoted keywords in the keyword clustering timeline, and the number of occurrences was closely correlated with the circle’s diameter; the purple axis indicated 2007-2022. Meanwhile, we present the top 25 keywords in the field of PCSK9 inhibitors that have had the strongest citation bursts within the past 15 years ( Figure 6B ). Notably, “monoclonal antibody” (15.55) has the strongest citation bursts, followed by “reducing lipid” (11.07), “ldl receptor” (9.73), “pcsk9” (9), “evolocumab amg 145” (8.46), and “randomized trial” (8.07). As can be seen from Figure 6B , “apolipoprotein b”, “ldl receptor”, “mice”, “secreted pcsk9”, “mutation”, “degradation”, “triglyceride transfer protein”, and “familial hypercholesterolemia” were the earliest keywords in the field of PCSK9 inhibitors and were therefore the subjects of interest to researchers in the early years. Moreover, “insight”, “coronary”, “outcome”, and “inflammation” are at the forefront of the current PCSK9 inhibitor research field and are in a period of explosion.

In this study, the literature related to PCSK9 inhibitors was analyzed using CiteSpace quantitative analysis software. Publications, nations, organizations, writers, keywords, literature, journals, and other objects were all subjected to a quantitative evaluation. From the number of publications ( Figure 2B ), very few PCSK9 inhibitor-related articles existed before 2012. The possible reason is that researchers have focused mainly on animal models and the mechanism of the decrease in LDLc caused by PCSK9 deficiency (40–45). Since 2012, with the continuous development of clinical trials of PCSK9 mAbs (46–50), the output of papers in this field has also been increasing year by year. Given the large number of clinical trials of PCSK9 mAbs demonstrating efficacy and safety for lipid lowering (51–53), the US Food and Drug Administration and the European Medicines Agency approved evolocumab and alirocumab, two PCSK9 mAbs, in 2015 for LDLc lowering, particularly in patients with familial hypercholesterolemia (FH). Thus, the number of publications has grown rapidly since 2015. In 2019, with the release of the results of phase 3 trials of inclisiran (54), a PCSK9 siRNA, this field is gaining more attention, even though the paper output is tempered by the outbreak of COVID-19.

As can also be seen in Table 5 , multiple heavyweight papers were published in 2015, all of which were published in the New England Journal of Medicine or the Lancet. These articles, including the two most frequently cited ones (Sabatine MS, 2017 and Schwartz GG, 2018), are almost exclusively large clinical trials of PCSK9 mAbs, indicating that clinical trials of PCSK9 inhibitors have received significant attention from researchers and also demonstrating their strong interest and recognition in the clinical application of PCSK9 inhibitors. In addition, two of the top 10 articles were about dyslipidemia management guidelines, demonstrating the important role of guidelines in guiding clinical and scientific research work. As we can see from Table 2 , the USA, England, Canada, Italy, and France are the five countries with the largest number of published articles. Notably, the number of publications for American academics was almost the sum of the number of publications from the other four countries. The top five institutions by number of publications include Harvard University, Amgen Inc., Brigham & Women’s Hospital, Harvard Medical School, and Imperial College London, with four institutions located in the United States and one in England. In a similar vein, four of the top five funding organizations are American, and one is French. Consistent with the countries citation bursts intensity ( Figure 4A ), the United States undoubtedly holds a leading position in the field of PCSK9 inhibitors due to excellent research institutions and sufficient financial support. In the cooperation network of countries ( Figure 3 ), there is close cooperation and communication between developed countries, such as France, the United States, Germany, and so on. It is worth noting that although China is the only Asian country in the top 10 ranking for the number of publications ( Table 2 ), there is little cooperation between China and other countries. And there were not many high-quality studies published in top journals in China. Further analysis of countries bursts ( Figure 4A ) show that South Africa and Thailand exhibit research enthusiasm in this area, in addition to developed countries such as Europe and the United States. The relatively lagging biomedical industry may be the reason why developing countries such as China have published fewer papers in this field. In addition, the use of PCSK9 inhibitors is particularly constrained in underdeveloped countries by the high expenditures associated with research and development (R&D) and clinical trials. China has abundant biological resources and a huge market demand. With the government’s support, gradually increased R&D input, and enhanced cooperation and communication with other countries, it is believed that China will also achieve high-quality research in this field in the future. Four American authors, one Swiss author, and one Dutch author make up the top-ranked authors for the number of published articles ( Table 4 ). Sabatine MS and Giugliano RP work at Brigham and Women’s Hospital. Wasserman SM and Somaratne R are both employed by Amgen. Mach F works at the University of Geneva. Jukema JW is from Leiden University Medical Center. It is worth mentioning that two professors, Sabatine MS and Giugliano RP, who have been long dedicated to the research of PCSK9 inhibitors in clinical trials since 2012 and have continuously presented high-quality papers to date, have made important contributions to the clinical applications of PCSK9 inhibitors. The top-ranked author for centrality is Wasserman SM from Amgen ( Table 4 ), who has also been involved in a large number of clinical trials of PCSK9 inhibitors, undoubtedly having a profound impact on the development of this field. Overall, our results demonstrate consistency among high-yield countries, institutions, authors, and funding agencies. Developed countries such as the United States and Western European countries have been leading the way in the study of PCSK9 inhibitors. In addition, developing countries such as China should enhance their exchanges and cooperation with other countries to advance this field.

Journal and cited journal ranking analysis helps researchers select the most appropriate journal for their manuscript (55, 56). Table 2 displays the relative number of PCSK9 inhibitor-related publications published in many medical journals. The Journal of Clinical Lipidology (Q1, IF=5.365) leads the pack, followed by Atherosclerosis (Q1, IF=6.847), the Journal of the American College of Cardiology (Q1, IF=27.203), Circulation (Q1, IF=39.918), and the Journal of the American Heart Association (Q2, IF=6.106). This result suggests that high-quality journals favor relevant studies on PCSK9 inhibitors. Of the ranking of cited journals ( Table 6 ), 90% are high impact Q1 international journals. Among these journals, the New England Journal of Medicine and Journal of the American College of Cardiology focus more on the related clinical studies of PCSK9 inhibitors, while the Journal of Lipid Research et al. emphasize the early basic research in the PCSK9 field. This means that the field of PCSK9 inhibitors is currently relatively mature, either in basic or clinical studies. Moreover, the dual journal map overlay ( Figure 7 ) reveals that “molecular, biology, genetics” are frequently cited in “medicine, medical, clinical” demonstrating that current PCSK9 inhibitor research is increasingly concentrated on clinical translation.

Keywords help understand the focus and evolution of specific research areas. Based on the keyword co-occurrence analysis, keyword timeline, and citation bursts, we believe that the research focuses of PCSK9 inhibitors mainly include the following aspects: lipid-lowering mechanisms of PCSK9 inhibitors, PCSK9 mAbs and related clinical trials.

The study employs a rigorous approach to comprehend and analyze a substantial amount of data and presents the accumulated scientific findings and subtle evolutionary trends in the area of PCSK9 inhibitors in a visually appealing manner. To our knowledge, this is the first study to analyze the trends in PCSK9 inhibitor research over the past 15 years using the bibliometric tool CiteSpace. Our research aims to lay a solid foundation for future development in this field by assisting clinicians and researchers in quickly obtaining an overview of knowledge in this field and identifying knowledge gaps; identifying potential future research directions and initiating new research ideas; and finally, positioning their expected contributions to the field (123).

However, the present study also has some limitations. First, we only conducted a literature search in the WoSCC database, and relevant studies from other databases may have been missed. Second, only English-language publications were included in our study, so articles published in other languages were missed. These two limitations may lead to biased results.