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. 2024 Sep 25;86(11):6602–6618. doi: 10.1097/MS9.0000000000002592

Glucagon-like peptide-1 agonists in cardiovascular diseases: a bibliometric analysis from inception to 2023

Abinash Mahapatro a, Ali Bozorgi b, Sri UJ Obulareddy c, Shika M Jain d, Rohan Reddy Korsapati e, Aroon Kumar f, Kristina Patel g, Saman Soltani Moghadam h, Arash Arya i, Abdulhadi Jameel Alotaibi j, Mohammad-Hossein Keivanlou h, Soheil Hassanipour h, Maryam Hasanpour h, Ehsan Amini-Salehi h,*
PMCID: PMC11543192  PMID: 39525800

Abstract

Background:

In recent years, glucagon-like peptide-1 (GLP-1) agonists have garnered increasing attention for their potential cardiovascular benefits beyond glycemic control in patients with diabetes. Understanding the research landscape surrounding GLP-1 agonists and cardiovascular diseases (CVDs) is crucial for informing clinical practice and guiding future research endeavors. This bibliometric analysis aimed to comprehensively assess the scholarly output and trends in this field, shedding light on the evolving landscape of GLP-1 agonists’ role in cardiovascular health.

Methods:

The publications concerning GLP-1 agonists in CVDs were gathered from the Web of Science Core Collection, and visualizations were created utilizing Excel 2019, Cite Space, and VOS viewer software.

Results and Conclusion:

Using bibliometric and visual methods, the research hotspots and trends regarding GLP-1 agonists in cardiovascular diseases were pinpointed. Additionally, a thriving interest in GLP-1 agonists research within cardiovascular medicine was observed, with a notable surge in publications from 2016 onwards. The analysis revealed that the United States and China are the leading contributors, accounting for over 50% of the total publications. The University of Copenhagen and the University of Toronto emerged as the most prolific institutions in this field. Co-citation analysis highlighted the influential role of landmark clinical trials, such as the LEADER, ELIXA, and EXSCEL. Keyword trend analysis identified the emergence of newer GLP-1 agonists, such as tirzepatide and semaglutide, as well as a growing focus on topics like ‘healthy obesity’ and chronic kidney disease. These findings suggest that the research landscape is evolving, with a focus on expanding the therapeutic applications of GLP-1 agonists beyond glycemic control. Overall, this bibliometric analysis provided insights into the current state and future directions of research on GLP-1 agonists and their impact on cardiovascular health, guiding future research endeavors, and informing clinical practice.

Keywords: bibliometric analysis, cardiovascular diseases, diabetes mellitus, glucagon-like peptide-1, trend

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Introduction

Highlights

  • GLP-1 agonists are renowned for their potential role in the treatment of diabetes mellitus; however, they have also garnered attention for their cardiovascular benefits.

  • To date, numerous studies have explored the potential of GLP-1 agonists in cardiovascular disorders. Nonetheless, there exists a need for a bibliometric analysis to comprehensively assess the scholarly output and trends in this field, thereby shedding light on the evolving landscape of GLP-1 agonists’ role in cardiovascular health.

  • Our bibliometric study yielded compelling results, indicating an interest in GLP-1 agonists research within cardiovascular medicine. Additionally, recent studies have underscored emerging topics in GLP-1 research in CVDs, including investigations into new drugs such as tirzepatide and semaglutide, as well as explorations into heart failure with preserved ejection fraction (HFpEF) and kidney outcomes.

In the landscape of metabolic disorder treatments, glucagon-like peptide-1 (GLP-1) agonists have emerged as a significant class of therapeutic agents, offering a multifaceted approach in managing conditions such as type 2 diabetes mellitus (T2DM) and obesity1–4. These agents mimic the action of the endogenous hormone GLP-1, enhancing glucose-dependent insulin secretion, suppressing glucagon secretion, and slowing gastric emptying5,6. Beyond their glycemic benefits, GLP-1 agonists have garnered attention for their potential protective effects on the cardiovascular system and their role in the management of hepatic diseases, such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH)7–14.

Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, presenting a significant public health challenge15–21. The intricate relationship between metabolic disorders and cardiovascular health has been well-documented, with conditions like T2DM and obesity significantly increasing the risk of developing CVDs22–28. In this context, treatments that address metabolic dysfunctions while also offering cardiovascular protective effects are of paramount importance. Recent studies and clinical trials have highlighted the potential of GLP-1 agonists in reducing cardiovascular risk factors, making them an area of keen interest for researchers and clinicians alike29–33.

The increasing trend of utilizing GLP-1 agonists in the management of CVDs is reflective of a broader shift towards integrative therapeutic strategies that encompass a wide range of metabolic and cardiovascular benefits34. This trend underscores the need for comprehensive evaluations of the efficacy, safety, and mechanisms of action of these agents, particularly in populations with complex comorbidities such as hepatic diseases.

Bibliometric studies serve as a powerful tool in this evaluative process, providing insights into the structure, dynamics, and evolution of scientific research35. By systematically analyzing publication patterns, citation networks, and thematic evolutions within the scientific literature, bibliometric analyses can uncover the impact, trends, and gaps in the current body of knowledge. This methodological approach allows for a quantitative assessment of research activity and influence, facilitating a deeper understanding of the scientific landscape surrounding specific research areas36–38.

This study aimed to conduct a comprehensive bibliometric analysis of the literature surrounding GLP-1 agonists, with a specific focus on their application in managing CVDs. By mapping out the research trajectory, identifying key contributors, and assessing the thematic and methodological trends within this field, this study sought to elucidate the current state of knowledge and pinpoint areas where further research is needed.

Methods

Data collection

To carry out our research on the impact of GLP-1 agonists on cardiovascular diseases, we selected the Web of Science Core Collection as our principal database for inquiry, conducting our search on 19 February 2024. This database is distinguished by its comprehensive compilation of information, encompassing more than 12 000 reputable journals39–41. To maximize the search’s efficiency, we crafted an elaborate search strategy that integrated a variety of keywords, as detailed in Table S1 (Supplemental Digital Content 1, http://links.lww.com/MS9/A604).

We did not impose any restrictions regarding the timeframe for the studies considered. Initially, we identified 1968 articles. Subsequently, through the exclusion of conference proceedings, letters, editorials, book chapters, prepublication articles, and studies not relevant to our focus, we refined our selection to 1697 pertinent studies.

Data analysis

All the relevant documents sourced from the Web of Science Core Collection were converted to Microsoft Excel 2019, and plain text formats and analyzed using VOS viewer and Cite Space. VOS viewer stands out as a powerful tool for scientometric network analysis, established by the Center for Science and Technology Studies at Leiden University, Netherlands. This software excels in providing visual insights and generating maps based on network data, facilitating an understanding of the relationships within academic literature. It is adept at constructing network diagrams that represent various academic entities such as publications, journals, authors, research institutions, countries, and keywords, connecting them through different types of links like cocitation, co-occurrence, citation, and bibliographic coupling.

VOSviewer offers three distinct types of visualization maps: network, overlay, and density visualizations, each serving a unique analytical purpose42. The foundational concept behind the software’s design is cooccurrence clustering, which signifies the relatedness of items within the network. This approach allows for the identification of correlations of varying strengths and directions. By analyzing the clustering of these relationships based on intensity and direction, one can discern distinct groups within the data. Although primarily utilized for bibliometric analyses, VOS viewer’s capabilities extend to the creation of a wide range of web data maps. Its most notable attribute is the generation of high-quality visual graphics, making it exceptionally suitable for large-scale academic and scientific visual analyses36,43.

Cite Space software, developed by Professor Chen Chaomei at Drexel University, leverages Java programming language to offer citation visualization analysis grounded in scientometrics and data visualization principles. This innovative tool illuminates the structure, dynamics, and distribution patterns of scientific knowledge through advanced data mining techniques, comprehensive information analysis, and the generation of detailed knowledge maps. By providing a visual representation of citation networks, Cite Space facilitates an understanding of the evolving landscape of scientific research, highlighting key trends, pivotal studies, and emerging fields within the vast expanse of scholarly communication44.

Biblioshiny is a user-friendly web application featuring a graphical interface for the Bibliometrix R software, designed to simplify bibliometric analysis. It enables comprehensive evaluations and performs various functions, such as network analysis, descriptive data analysis, and visualization of bibliometric networks45.

Results

Search strategy and study selection

The Web of Science database was searched on 19 February 2024, and a total of 1973 articles were identified. After removing irrelevant articles, a total of 1686 articles were selected for this bibliometric analysis. The keywords used in the search included ‘Major Adverse Cardiac Events’, ‘Cardiac Events, Adverse’, ‘Heart Diseases’, ‘Heart Failure’, ‘Cardiac Failure’, ‘Hypertension’, ‘Ischemic Heart Disease’, ‘Exenatide’, ‘Liraglutide’, ‘Dulaglutide’, ‘Semaglutide’, ‘Albiglutide’, and ‘Tirzepatide’. The study selection process and the detailed search strategy are presented in Figure 1.

Figure 1.

Figure 1

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Study selection.

Publication trends

The volume of publications within a specific timeframe is indicative of the evolving dynamics of research within this domain. As illustrated in Figure 2, from 2005 to 2023, there was a noticeable trend in the increase of studies dedicated to GLP-1 agonists within the field of cardiovascular research. The period from 2005 to 2015 witnessed a modest output of articles, suggesting that the exploration of GLP-1 agonists in cardiovascular science was at its early stages. However, between 2016 and 2019, there was a significant surge in scholarly contributions. Although there was a slight decline in 2020, the period from 2021 to 2023 experienced a marked and sustained increase in scholarly articles, peaking at 247 publications in 2023 alone. This trend highlights the growing interest and acknowledgment among researchers of the significant potential of GLP-1 agonists in cardiovascular health.

Figure 2.

Figure 2

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Trends of papers published regarding GLP-1 agonists and cardiovascular studies over the past 23 years.

Distribution of countries, regions, and institutions

A total of 1686 articles from 89 countries were published on the topic. Figure 3 shows the country's collaborations globally. The United States led with the highest number of publications, contributing 694 articles (41.16%), followed by China with 257 articles (15.24%), England with 199 articles (11.80%), Denmark with 191 articles (11.32%), and Canada with 167 articles (9.90%). The combined contributions from the United States and China accounted for more than half of the total publications. Among institutions, the University of Copenhagen and the University of Toronto were tied for the highest number of publications, each with 83 articles (4.92%), followed by Novo Nordisk with 62 articles (3.67%), Harvard Medical School with 51 articles (3.02%), and the University of Glasgow with 47 articles (2.78%). Table 1 presents the top 10 countries and institutions ranked by their contribution to the field in terms of the number of publications. Figures 4A and B imply that research on GLP-1 agonists conducted by the nations and organizations could have been pivotal in the field of cardiovascular studies. In this context, each node symbolizes a country/institution, with the node’s size reflecting the volume of published articles. The connections between nodes denote collaborations, with thicker connections indicating stronger collaborative ties. There exists a strong linkage between the USA and both Canada and England, as well as between China and the USA, and also between England and Denmark. Centrality demonstrates the impact of a country within the field. The analysis revealed that India exhibited the highest centrality score at 0.26, followed by Austria at 0.12, Portugal at 0.11, and the USA at 0.10 (Fig. 5).

Figure 3.

Figure 3

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Countries collaboration in the world.

Table 1.

Leading countries and institutions in the field of GLP-1 agonists in cardiovascular disease.

Number Country Number of publications Number of links Institution Number of publications Number of links
1 United States 694 72 University of Copenhagen 83 47
2 China 257 60 University of Toronto 83 55
3 England 199 66 Novo Nordisk 62 37
4 Denmark 191 65 Harvard Medical School 51 51
5 Canada 167 64 The University of Glasgow 47 51
6 Italy 159 67 Eli Lilly and Company 41 28
7 Germany 123 63 Duke University 39 48
8 Japan 99 62 University of Washington 38 40
9 Scotland 76 61 University of North Carolina 36 39
10 Sweden 72 63 University of Oxford 32 33
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Figure 4.

Figure 4

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A: Geographical spread of publications across various institutions B: Geographical spread of publications across various nations.

Figure 5.

Figure 5

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Counties with high centrality in the world.

Journals and co-cited academic journals

The analysis unveiled that 520 scientific journals have disseminated research on GLP-1 agonists in the context of cardiovascular diseases. Notably, ‘Diabetes Obesity and Metabolism’ led in publications with 116 articles, accounting for 6.88% of the total, followed by ‘Cardiovascular Diabetology’ with 74 articles (4.38%), ‘Diabetes Therapy’ with 36 articles (2.13%), ‘Diabetes Care’ with 25 articles (1.48%), and ‘Diabetes Research and Clinical Practice’ also with 25 articles (1.48%). Table 2 presents the top 10 journals ranked by their contribution to the field in terms of the number of publications.

Table 2.

Leading journals and co-cited journals in the field of GLP-1 agonists in cardiovascular disease.

Number Journal name Number of publications Impact factor JCR Co-citation journal Citation Impact factor JCR
1 Diabetes, Obesity and Metabolism 116 5.8 Q1 The New England Journal of Medicine 7579 158.5 Q1
2 Cardiovascular Diabetology 74 9.3 Q1 Diabetes Care 6709 16.2 Q1
3 Diabetes Therapy 36 3.8 Q2 The Lancet 4230 168.9 Q1
4 Diabetes Care 25 16.2 Q1 Diabetes, Obesity and Metabolism 3699 5.8 Q1
5 Diabetes Research and Clinical Practice 25 5.1 Q2 Circulation 2959 37.8 Q1
6 Nutrition, Metabolism & Cardiovascular Diseases 21 3.9 Q2 Diabetes 2566 7.7 Q1
7 Postgraduate Medicine 18 4.2 Q2 Diabetologia 2175 8.2 Q1
8 Diabetologia 17 8.2 Q1 Jama 1900 120.7 Q1
9 Biochemical and Biophysical Research Communications 16 3.1 Q2 The Lancet Diabetes and Endocrinology 1805 44.5 Q1
10 The Lancet Diabetes and Endocrinology 16 44.5 Q1 Cardiovascular Diabetology 1579 9.3 Q1
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Cocitation analysis serves as a tool to uncover the interconnectedness among scholarly articles, illustrating how a journal’s influence within a specific research domain can be determined by its frequency of cocitation. This approach highlights the relational dynamics between publications, providing insights into the scholarly impact and thematic relevance of journals in the field. From our cocitation assessment, we identified 6898 journals that were cocited, with 10 of these journals being cited over 1500 times each. The ‘New England Journal of Medicine’ emerged as the most cited journal with 7579 citations, followed by ‘Diabetes Care’ with 6709 citations, ‘Lancet’ with 4230 citations, ‘Diabetes, Obesity and Metabolism’ with 3699 citations, and ‘Circulation’ with 2959 citations. Table 2 presents the top 10 leading co citied journals ranked by their contribution to the field. Figure 6 represents the density visualization plot of the co-cited journal. Figure 7 displays the journals’ production over time.

Figure 6.

Figure 6

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The density plot of the leading journals in the field of GLP-1 agonists in cardiovascular disease.

Figure 7.

Figure 7

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Journals’ production over time in the field of GLP-1 agonists in cardiovascular disease.

The dual-map overlay representing journal relationships showcases the citation dynamics, with citing journals positioned on the left and cited journals on the right. The visualization, highlighted in Figure 8, revealed three primary citation trajectories, marked by two green paths and one yellow path. The dual-map overlay illustrated that research articles from Health/Nursing/Medicine journals received significant citations from publications in the Medicine/Medical/Clinical sector. Additionally, works published in Molecular/Biology/Genetics journals were frequently cited by both Molecular/Biology/Immunology and Medicine/Medical/Clinical journals. This mapping highlights the interconnectedness and impact of these fields on one another, underscoring the cross-disciplinary nature of scientific research and its dissemination.

Figure 8.

Figure 8

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The dual-map overlay of journals on GLP-1 agonists in cardiovascular diseases.

This mapping highlights the interdisciplinary character of scientific research and its dissemination by highlighting the relationships between and effects of several domains on one another.

Authors and cocited authors

A total of 10 005 authors have contributed to the domain of GLP-1 agonists and cardiovascular diseases. Notably, John B. Buse led with the highest number of published papers (n=30, 1.77%), followed by Lawrence A. Leiter (n=26, 1.54%), Adrian F. Hernandez (n=24, 1.42%), Hertzel Gerstein (n=22, 1.30%), and Michael A. Nauck (n=20, 1.18%).

In terms of citations, John B. Buse also maintained the lead with an impressive count of 12 839, followed by Bernard Zinman (n=7576), Steven P. Marso (n=7380), Michael A. Nauck (n=6353), and Neil Poulter (n=6063).

Moreover, the results of co-authorship analysis indicated a robust collaboration among authors within this field. Hertzel Gerstein, Lawrence A. Leiter, Lars Ryden, Matthew Riddle, and John B. Buse emerged as key collaborators, significantly contributing to advancements in this domain. Figure 9 showcases the co-authorship network among contributing authors in this field.

Figure 9.

Figure 9

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Co-authorship visualization on GLP-1 agonists in cardiovascular diseases.

When two or more authors are cited together, they are referred to as cocited authors. Among 30 525 co-cited authors, 94 individuals stood out with over 100 citations each. Steven P. Marso emerged as the most cocited author with a count of 1036 citations, followed by Hertzel Gerstein (n=807), Michael A. Nauck (n=628), Daniel Drucker (n=625), and Bernard Zinman (n=619). These authors’ frequent cocitations highlight their significant contributions and influence within the field. Table 3 represents the top 10 leading authors and cocited authors.

Table 3.

Top 10 leading authors and co-cited authors.

Number Author with high number of publications Number of publications Author with high number of citations Number of citations The most co-cited authors Number of citations
1 John B. Buse 30 John B. Buse 12839 Steven P. Marso 1036
2 Lawrence A. Leiter 26 Bernard Zinman 7576 HC Gerstein 807
3 Adrian F. Hernandez 24 Steven P. Marso 7380 Michael A. Nauck 628
4 Hertzel Gerstein 22 Michael A. Nauck 6353 Daniel Drucker 625
5 Michael A. Nauck 20 Neil Poulter 6063 Bernard Zinman 619
6 Rury Holman 19 Peter Rossing 5208 Julio Rosenstock 611
7 Subodh Verma 19 Richard M. Bergenstal 5115 John B. Buse 589
8 Naveed Sattar 19 Johannes F E Mann 5093 Rury R Holman 581
9 Darren McGuire 18 Apostolos Tsapas 5077 Ralph A. DeFronzo 388
10 Robert John Mentz 17 Kirstine Brown-Frandsen 5032 Marc A Pfeffer 387
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Cited and cocited references

The cocitation analysis uncovers that when two references are cited together within another article’s bibliography, it forms a cocitation link between those references. From a total of 48 622 identified co-cited references, 46 were cited at least 100 times, as depicted in Figure 10A. This study further narrowed down to the top 10 cited references. Out of 1686 included studies, 116 were cited at least 100 times by other scholars, as shown in Figure 10B. Table 4 provides a detailed list of the top 10 cited and cocited references in this area, offering insights into the most influential works and their interconnections. Figure 11 shows the top 25 papers with citation burst.

Figure 10.

Figure 10

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A: Co-cited references network visualization. B: Most cited articles network visualization.

Table 4.

Top 10 cited and co-cited references.

Number Title of most cited paper Doi Published year Title of most co-cited paper Doi Published year
1 Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes 10.1056/NEJMoa1603827 2016 Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes 10.1056/NEJMoa1603827 2016
2 Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) 10.2337/dci18-0033 2018 Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome 10.1056/nejmoa1509225 2015
3 Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome 10.1056/NEJMoa1509225 2015 Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes 10.1056/nejmoa1612917 2017
4 Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial 10.1016/S0140-6736(19)31149-3 2019 Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes 10.1056/nejmoa1611925 2017
5 Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes 10.1056/NEJMoa1612917 2017 Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial 10.1016/s0140-6736(19)31149-3 2019
6 A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management 10.1056/NEJMoa1411892 2015 Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial 10.1016/s0140-6736(18)32261-x 2018
7 Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial 10.1016/s0140-6736(18)32261-x 2018 Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus 10.1056/nejmoa1307684 2013
8 Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials 10.1016/S2213-8587(19)30249-9 2019 Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes 10.1056/nejmoa1501352 2015
9 Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes 10.1056/NEJMoa1607141 2016 Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes 10.1056/nejmoa1305889 2013
10 Management of obesity 10.1016/S0140-6736(16)00271-3 2016 Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes 10.1056/nejmoa1504720 2015
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Figure 11.

Figure 11

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Top papers with citation burst time in the field of GLP-1 agonists in cardiovascular disease.

Keyword trends

In our analysis, we identified a total of 4624 keywords across the included studies. Through cooccurrence keyword analysis, we found that ‘liraglutide’ (n=708), ‘exenatide’ (n=301), ‘obesity’ (n=235), ‘heart failure’ (n=235), and ‘glycemic control’ (n=224) emerged as the most frequently repeated keywords. Moreover, the overlay visualization plot revealed that keywords such as ‘tirzepatide’, ‘semaglutide 2.4 mg’, ‘HFpEF’, ‘kidney outcomes’, and ‘finerenone’ are recent keywords with a higher average publication year, indicating their prominence in the field of GLP-1 agonists in cardiovascular disease (Fig. 12). Figure 13 showed the keywords’ frequency overtime.

Figure 12.

Figure 12

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Overlay visualization of the co-occurrence keywords.

Figure 13.

Figure 13

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Keywords’ frequency overtime in the field of GLP-1 agonists in cardiovascular diseases.

Cluster analysis

The cluster analysis conducted within the research domain of GLP-1 agonists and their impact on cardiovascular diseases has led to a significant classification, identifying 12 distinct clusters. Initially, the focus was primarily on the available therapeutic options and their anti-inflammatory properties. However, recent trends have shifted attention towards emerging hotspots within this field. Notably, topics such as ‘healthy obesity’, ‘oral semaglutide’, ‘cardiovascular outcomes’, and ‘chronic kidney disease’ have gained prominence, marking them as current areas of intense research interest (Fig. 14).

Figure 14.

Figure 14

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Time line cluster analysis.

Discussion

Continued high levels of blood sugar cause harm to the microvasculature, resulting in complications like retinopathy, neuropathy, and nephropathy in patients with T2DM. Notably, chronic hyperglycemia is also identified as a contributor to cardiovascular (CV) risk. Moreover, T2DM frequently coincides with obesity, dyslipidemia, hypertension, and inflammation, all of which are standalone CV risk factors. Consequently, T2DM substantially elevates the risk of CVDs by two to five times46–50.

Interestingly, following conflicting outcomes in extensive trials examining the impact of glucose reduction on CVD risks, current consensus suggests that lowering glucose might not be significantly crucial for preventing CVD in T2DM. Contemporary guidelines advise healthcare providers to lower glucose levels for microvascular disease prevention but emphasize a personalized evaluation of CVD risk factors. Notably, managing blood pressure, lipids, and, if necessary, antiplatelet therapy are emphasized. Despite these interventions, substantial CVD risk persists, underscoring the imperative for novel treatment approaches to effectively address and prevent CVD in individuals with T2DM51–53.

The identification of GLP-1 receptors (GLP-1Rs) on cardiomyocytes has generated significant interest among clinicians and researchers regarding potential cardiovascular advantages associated with GLP-1 and GLP-1-based therapies. Initial clinical trials have indicated potential positive impacts of GLP-1 and its therapies on factors such as cholesterol levels, blood pressure, microcirculation, and low-grade inflammation54–65. Notably, larger randomized CV outcome trials have provided substantial evidence that GLP-1 receptor agonists effectively decrease CVDs in patients with T2DM29,64,66–70.

The bibliometric analysis presented in this study highlighted an increasing trajectory of research interest in GLP-1 agonists, particularly within the realm of cardiovascular health, over the past two decades. This surge in scholarly publications, especially notable from 2016 onwards, reflects a broader recognition within the scientific community of the potential benefits these agents may offer in cardiovascular disease management and prevention.

Innovative clinical trials highlighting the cardiovascular benefits of GLP-1 agonists were reported in 2016. The SUSTAIN-6 experiment was a randomized controlled trial (RCT) that included 3297 individuals with type 2 diabetes mellitus and was published in the New England Journal of Medicine in 2016. For 104 weeks, participants were randomly assigned to receive either a placebo or 0.5 mg or 1.0 mg of semaglutide once a week. This experiment showed that semaglutide recipients had a significantly lower rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke than the placebo group in individuals with type 2 diabetes who were at high cardiovascular risk66. The LEADER study, another noteworthy trial, was also published in the New England Journal of Medicine in 2016. Nine thousand three hundred forty patients with type 2 diabetes mellitus participated in this study, and the results indicated that patients receiving liraglutide had a lower rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke than patients receiving placebo67. On the other hand, the NHLBI trial, which was reported in JAMA in 2016, assessed 300 hospitalized patients who had low left ventricular ejection fraction (LVEF) and heart failure. According to this study, these patients’ posthospitalization clinical stability did not improve when liraglutide was used71. Together, these studies demonstrated the potential cardiovascular advantages of GLP-1 agonists, especially liraglutide and semaglutide, for individuals with type 2 diabetes. The results caused further investigation and debate on the usage of these drugs to lower cardiovascular risks.

Several factors may contribute to heightened interest in GLP-1 agonists. First, the pathophysiological understanding of CVDs has evolved significantly, with increasing recognition of the role of inflammation, metabolic dysregulation, and insulin resistance in the progression of these conditions72–74. GLP-1 agonists, initially developed for the treatment of type 2 diabetes, have shown promise in addressing these underlying mechanisms, offering a novel therapeutic angle for CVD management75.

Moreover, pivotal clinical trials conducted during this period have played a crucial role in shaping the research landscape. Studies such as the LEADER and SUSTAIN-6 have demonstrated the efficacy of GLP-1 agonists in reducing adverse cardiovascular events in individuals with type 2 diabetes66,67. These findings have spurred further investigation into the mechanisms of action, optimal use, and potential benefits of GLP-1 agonists beyond glucose regulation.

The slight decline in publications observed in 2020 might be attributed to the global shift in research priorities due to the COVID-19 pandemic, which impacted various fields of scientific inquiry. Nonetheless, the rebound in scholarly output from 2021 to 2023 underscores the resilience and sustained interest of the cardiovascular research community in exploring GLP-1 agonists. The peak in publications in 2023 could also reflect the culmination of long-term research projects initiated in response to earlier clinical findings, alongside the increasing availability of GLP-1 agonists as therapeutic options.

Our investigation indicated a significant concentration of scholarly publications emanating from Europe and North America, highlighting an imbalance in the distribution of academic resources predominantly in favor of developed nations. This trend is mirrored in the formation of numerous research collectives within these regions. Among these, groups led by Professor John B. Buse stand out as prominent clusters in their field. Professor Buse has played a pivotal role in numerous guideline and international consensus panels, steering several extensive multicenter, prospective, randomized controlled trials, and systematic reviews focusing on GLP1RA’s impact on cardiovascular outcomes76–78.

Dr. Lawrence A. Leiter holds several prestigious positions, including the directorship of the Lipid Clinic, the role of associate director at the Clinical Nutrition and Risk Factor Modification Centre, and associate scientist at the Li Ka Shing Knowledge Institute, all at St. Michael’s Hospital in Toronto. Previously, he led the Division of Endocrinology and Metabolism at the same institution. As a professor affiliated with the Departments of Medicine and Nutritional Sciences at the University of Toronto, Dr Leiter is deeply involved in research. His work focuses on clinical trials aimed at the prevention of atherosclerosis, particularly in relation to diabetes, and extends to exploring dietary and pharmacological strategies for managing diabetes mellitus, hyperlipidemia, hypertension, and obesity66,79–81.

Adrian F. Hernandez, a cardiologist within the Division of Cardiology at Duke University Medical Center, specialized in heart failure research. He has also made significant contributions to various randomized controlled trials, playing a pivotal role in this critical research area64,71.

Based on bibliometric analysis, it was found that there was a significant level of collaboration among multiple institutions located in different countries. The shift towards collaborative and interdisciplinary research has played a pivotal role in evolving this dynamic field. Collaboration among authors and institutions has facilitated a rich exchange of ideas, resources, and expertise. Such partnerships have accelerated the pace of discovery, enabling the execution of large-scale clinical trials and comprehensive studies that span across disciplines. The integration of knowledge from endocrinology, cardiology, pharmacology, and molecular biology, fostered by these collaborative efforts, has been instrumental in advancing our understanding of how GLP-1 agonists can be beneficial for cardiovascular health.

Our examination of cocited references revealed that the LEADER trial stood in the top position, followed by the ELIXA trial in second place and the EXCEL trial in third. The REWIND trial came in fifth, while the Harmony trial was ranked sixth. These are all critical studies investigating the impact of GLP-1 agonists on cardiovascular outcomes. Authored by esteemed experts across various cardiology and endocrinology research centers, these seminal papers have been published in prestigious journals64,67,68,82,83.

Additionally, the fourth most cocited reference is the CANVAS study, which evaluated the effects of canagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor. The seventh most cited reference was the SAVOR-TIMI trial, examining the impact of Saxagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, on diabetic patients84,85. These findings underscore the expanding literature on the outcomes associated with SGLT2 and DPP-4 inhibitors, in conjunction with GLP-1 agonists.

The bibliometric analysis of keyword trends highlighted ‘tirzepatide’ and ‘semaglutide 2.4 mg’ as the most current keywords, with ‘healthy obesity’ and ‘chronic kidney disease (CKD)’ emerging as the latest clusters. A landmark study by Garvey et al., from the SURMOUNT-2 trial, marks the first investigation of tirzepatide in adults with obesity and type 2 diabetes. This 72-week trial study demonstrated that tirzepatide, administered once weekly at doses of 10 mg and 15 mg, significantly reduced body weight while maintaining a safety profile consistent with other incretin-based weight management therapies86. In parallel, the STEP trials investigating semaglutide have yielded noteworthy results; particularly, the recently published STEP 5 trial revealed that in adults who are overweight (with at least one weight-related comorbidity) or obese, semaglutide treatment facilitated significant weight loss over a period of 104 weeks when compared to placebo87.

The idea of metabolically healthy obesity (MHO) suggests that there exists a subset of obese people who do not exhibit the typical cardio-metabolic risk factors often found in obese individuals with dysfunctional adipose tissue and insulin resistance, a condition referred to as metabolic syndrome or the metabolically unhealthy obesity (MUO) phenotype. Those with MHO seem to have better functioning adipose tissue and exhibit greater insulin sensitivity88.

Recent studies have highlighted the promising role of the new GLP-1 agonist drug, Tirzepatide, in managing MHO. Recognized increasingly as a critical risk factor, MHO is linked to the development of cardiovascular diseases, cerebrovascular conditions, and peripheral artery disease. Furthermore, individuals with MHO are at heightened risk of transitioning to a metabolically unhealthy phenotype. Tirzepatide has demonstrated remarkable efficacy, showcasing significant benefits such as weight reduction and notable improvements in key metabolic markers including hemoglobin A1c, fasting serum glucose, and triglyceride/lipoprotein levels. These outcomes suggest that Tirzepatide holds considerable potential in aiding individuals who are either metabolically healthy obese or overweight, reducing their risk of adverse cardiovascular events and preventing the shift towards a metabolically unhealthy status89.

The presence of CKD in the context of GLP-1 agonist research is noteworthy, given the established cardiovascular benefits of these agents in individuals with type 2 diabetes, a common precursor to both CKD and cardiovascular diseases90–92. This cluster’s emergence points to an expanding interest in the renal outcomes associated with GLP-1 agonist therapy, reflecting a broader understanding of the cardiorenal axis in metabolic diseases. The exploration of GLP-1 agonists in CKD patients may offer valuable insights into their potential to slow the progression of renal decline and mitigate cardiovascular risk93–96. This is particularly relevant given the increased cardiovascular morbidity and mortality associated with CKD97. GLP-1 agonists have emerged as promising therapeutic agents in the management of patients with CKD, particularly those with advanced stages. While their impact on cardiovascular outcomes in CKD patients with an estimated glomerular filtration rate (eGFR) below 30 has been less pronounced, they exhibit notable renal protective effects. Studies such as the LEADER, ELIXA, REWIND, and SUSTAIN-6 trials have consistently demonstrated benefits in renal outcomes among patients with relatively fair kidney function, with a significant reduction in parameters such as new-onset macroalbuminuria and decline in eGFR66,67,98,99. These effects are attributed to various mechanisms, including the reduction of oxidative stress-induced autophagy, endothelial dysfunction, and local inflammation. Additionally, GLP-1 agonists have been shown to enhance natriuresis and potentially protect the kidneys via the sodium-hydrogen exchanger 3 (NHE3) pathway100–102. Moreover, despite previous trials excluding patients with advanced CKD, recent studies have started to shed light on the renal protective effects of GLP-1 agonists even in this population. The findings suggest a delay in the progression to end-stage renal disease (ESRD) and a slower decline in kidney function, as evidenced by a significant difference in the time to initiation of dialysis between GLP-1 agonist-treated patients and those receiving other antidiabetic agents66,67. However, the exact mechanisms underlying these renal protective effects in advanced CKD remain unclear and warrant further investigation. Nevertheless, these findings hold promise for improving the management and prognosis of CKD patients, especially those with type 2 diabetes, by offering a potential therapeutic avenue that not only addresses glycemic control but also mitigates renal complications.

Similar to our study, other bibliometric research has also assessed GLP-1 agonists. Dagli et al. conducted a similar bibliometric analysis focused specifically on Semaglutide as a GLP-1 agonist. Their study examined publication trends from 2014 to 2022, revealing a steady rise in research output, peaking in 2022. They identified key authors, institutions, and research themes related to Semaglutide efficacy in glycemic control and broader diabetes management implications103.

In contrast, our analysis examined a broader landscape of GLP-1 agonists and their cardiovascular applications, spanning a longer timeframe from 2005 to 2023. We observed a more gradual increase in publications from 2005 to 2015, followed by a significant surge from 2016 to 2019. This suggests the field has evolved, with growing recognition of the cardiovascular benefits of GLP-1 agonists beyond just their antidiabetic effects.

Additionally, Shou et al., analyzed GLP-1 agonist publications from 2005 to 2021, reporting a similar trajectory to our findings. They noted a gradual increase until 2012, a slight dip, and then a substantial surge from 2016 to 2020, peaking in 2020. This corroborates the trends we observed in our analysis, indicating a sustained and intensifying research interest in this area over the past decade104.

The differences in our findings compared to previous studies can be attributed to the broader scope of our analysis, which encompasses the entire GLP-1 agonist class and its cardiovascular applications, rather than focusing on a single agent. This allowed us to capture the dynamic evolution of the research landscape and the changing emphasis on the cardioprotective properties of these therapies.

This bibliometric study provided a comprehensive examination of the research landscape surrounding GLP-1 agonists and their impact on cardiovascular diseases. The search strategy, which spanned multiple decades without any time restriction, ensured that the analysis captured the full breadth and evolution of this field. The utilization of well-established bibliometric tools, such as VOS viewer and Cite Space, further strengthened the reliability of findings. The multifaceted approach, incorporating analyses of publication trends, geographical distributions, influential journals, key authors, landmark citations, and thematic developments, offered a multidimensional perspective on the state and future directions of this research domain. The integration of both quantitative and visual techniques allowed for the clear identification of research hotspots, collaborative networks, and emerging areas of interest. However, the study was not without its limitations. The reliance on the Web of Science Core Collection as the sole data source may have limited the inclusion of relevant publications indexed in other scholarly databases. Additionally, the search strategy, while comprehensive, may have excluded some studies that did not explicitly mention ‘GLP-1 agonists’ or ‘cardiovascular diseases’ in the title, abstract, or keywords. Integrating qualitative methods, such as manual review of a sample of publications or expert interviews, could have provided additional contextual understanding of the research dynamics and emerging themes.

Conclusions

GLP-1 agonists have emerged as a cornerstone in the therapeutic management of patients with T2DM, gaining prominence for their cardioprotective properties. These benefits have sparked a surge in research and publications focused on the cardioprotective effects of GLP-1 agonists, witnessing a significant increase over the past two decades. Numerous trials investigating these effects have been conducted, yielding results that have been featured in prestigious journals. This research has been characterized by a collaborative effort among authors from various institutions and countries, highlighting the global interest and effort in understanding and leveraging the benefits of GLP-1 agonists for patients with T2DM.

Recent studies have concentrated on innovative GLP-1 agonists such as tirzepatide and semaglutide 2.4 mg, which represent the latest advancements in this field. The exploration of these medications extends to new frontiers in diabetes management, including their impact on individuals with ‘healthy obesity’ and CKD, areas that have attracted considerable research attention. These developments underscore the evolving landscape of T2DM treatment, where the focus is not only on glucose control but also on addressing the broader cardiovascular and renal complications associated with the disease. The continuous exploration of GLP-1 agonists and their multifaceted benefits marks a significant stride toward comprehensive management strategies for patients with type 2 diabetes mellitus.

Ethical approval

Since we conducted a bibliometric study, we did not have any human or animal subjects and our study did not require an ethical approval.

Consent

Since we did not have any human or animal subject, conducting this section is not applicable.

Source of funding

There is no funding for the present study.

Author contribution

A.M. and E.A.S.: provided the research idea; E.A.S. and S.H.: designed the study; E.A.S. and S.O.: performed the analysis; M.H.K. and S.J.: conducted the search strategy; A.M. and R.R.K.: designed the illustrations. All authors contributed to drafting the manuscript.

Conflicts of interest disclosure

The authors declare no competing interest.

Research registration unique identifying number (UIN)

The current study is a bibliometric study and UIN is not applicable for this study.

Guarantor

Ehsan Amini-Salehi (MD), Guilan University of Medical Sciences, 41448-95655, Rasht, Iran. Tel.: +98 1315535116, fax: +98 1315534951. E-mail: ehsanaminisalehi1998@gmail.com

Data availability statement

Data from the study can be provided by the corresponding author on reasonable request.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Supplementary Material

ms9-86-6602-s001.docx (13.2KB, docx)
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Acknowledgement

The authors acknowledge BioRender since some of the illustrations are created with BioRender.com

Footnotes

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, www.lww.com/annals-of-medicine-and-surgery.

Published online 25 September 2024

Contributor Information

Abinash Mahapatro, Email: abinashmahapatro23@gmail.com.

Ali Bozorgi, Email: alibozorgi.md@gmail.com.

Sri U.J. Obulareddy, Email: sobulareddy@uams.edu.

Rohan Reddy Korsapati, Email: RohanReddy.Korsapati@rockets.utoledo.edu.

Aroon Kumar, Email: aroonkp37@gmail.com.

Kristina Patel, Email: Kmpatel06@gmail.com.

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Ehsan Amini-Salehi, Email: ehsanaminisalehi1998@gmail.com.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Data from the study can be provided by the corresponding author on reasonable request.

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