Abstract

Statins are widely used lipid-lowering drugs that are relatively well-tolerated and have an established safety profile. However, statin therapy has been reported to increase the risk of developing new-onset type 2 diabetes mellitus (NOD2). Although this side effect is rare, research on this topic is still ongoing. This bibliometric study was performed to provide an overview of the dynamics of research on statin-associated NOD2 and insulin resistance from the initial report to the year 2022. Original articles related to statin-associated NOD2 and insulin resistance were selected and retrieved from the Web of Science database. A quantitative analysis of publication trends, the contributions of different countries and funding agencies, and the most highly cited articles were then tabulated. The citation networks and the co-occurrence analysis of keywords of the included articles were illustrated with VOSviewer. A total of 271 research articles were included and analysed. The years 2012 to 2016 were prolific in research on statin-associated NOD2 and insulin resistance, followed by a decreasing trend in publications on this topic in many countries, particularly from 2020 to 2021. However, researchers from South Korea and China seem to have had a continued interest in this research area and the trend in publications increased again in 2022. Based on this trend, it is predicted that the number of pertinent articles in the coming years will be maintained or will continue to rise. The co-occurrence analysis of keywords showed that ``atorvastatin'' occurred more often than other statins. Among the thematic areas of research on statin-associated NOD2 and insulin resistance that were identified in this study were ``heterogeneity'', ``peripheral glucose uptake and insulin sensitivity'', ``tissue inflammation and oxidative stress'' and ``targeted tissues''. This is the first bibliometric study to predict the trends and provide an overview of the progress of research on statin-associated NOD2 and insulin resistance.

Introduction

Statins are lipid-lowering drugs widely used in the primary prevention of atherosclerotic cardiovascular disease. Their benefits in reducing cardiovascular mortality and morbidity are remarkable1. Despite their established safety profile, statins have been reported to enhance the risk of developing new-onset type 2 diabetes mellitus (NOD2) and worsen glucose control in patients with diabetes2, 3, 4. Although an earlier meta-analysis of 112 randomized controlled trials and 64 cohort studies concluded that the overall prevalence of the side effects of statins, including impaired glucose tolerance, was not significant, it revealed the high heterogeneity between studies5, making the conclusions uncertain. The risk of developing NOD2 is influenced by co-morbidities and genetic variations1, whereas it was reported that the type of statins used might not significantly alter the risk5. Based on a more recent systematic review and meta-analysis involving 67 randomized controlled trials enrolling a total of 25,481 individuals, statins minimally but significantly increase diabetic indexes in individuals with adequate or altered glycemic control. The diabetogenic effect of statins does not seem to be determined by the type or dosage of statin prescribed6. Studies have suggested that statins can increase insulin resistance while reducing insulin sensitivity and secretion from pancreatic β-cells7, 8. A recent molecular study using skeletal muscle tissues from patients receiving statins demonstrated that statins aggravated the risk of insulin resistance in the muscle tissues9.

Globally, many studies investigating the effects of statin therapy on the development of NOD2 have been conducted. However, bibliometric analysis of the progress of research into statin-associated NOD2 and insulin resistance has not previously been carried out. Bibliometric analysis can provide an overview of overall research trends and may also identify potential future directions for a particular field of study10. The current analysis aimed to portray: 1) the global output of research into statin-associated NOD2 and insulin resistance over a period of 30 years, with a prediction of the trend of future studies; 2) the presence of any bibliographic factors that may influence the research on statin-associated NOD2 and insulin resistance, such as countries and funding agencies; 3) the countries/regions that have contributed the most to this field of study; 4) the most cited articles on statin-associated NOD2 and insulin resistance and the citation networks; and 5) a co-occurrence analysis of keywords related to this research area. It is important to declare that this bibliometric study does not challenge the use of statins in any way, but rather illustrates the research dynamics of statin-associated NOD2 and insulin resistance over recent decades.

Methods Search strategy

A search was conducted on September 14, 2023 in the Web of Science (WoS) database using the following search string: ((TS=(hydroxymethylglutaryl-coa reductase inhibitors)) OR TS=(statins)) OR TS=(statin)) OR TS=(pitavastatin)) OR TS=(rosuvastatin)) OR TS=(pravastatin)) OR TS=(lovastatin)) OR TS=(simvastatin)) OR TS=(atorvastatin)) OR TS=(fluvastatin)) AND ((TS=(new onset diabetes mellitus)) OR TS=(insulin resistance)) OR TS=(insulin-resistant)) OR TS=(impaired fasting blood glucose)) OR TS=(impaired fasting blood sugar)) OR TS=(pre-diabetic)) OR TS=(non-diabetic)), with a time span ranging from 1991 to 2022.

Data collection

The search retrieved 2757 articles, which were then screened for inclusion criteria by two independent investigators (H.N.S. and H-S.H.): any discrepancies were solved by consensus. Only original articles, written in English and covering both clinical and experimental studies, were included. Those articles that were included reported on the association of statins with new-onset diabetes mellitus, the association of statins with disease progression in pre-existing diabetes mellitus, the association of statins with the prediction of insulin resistance, consisting of changes in fasting insulin levels, fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), and the homeostatic model assessment of insulin resistance (HOMA-IR) or β-cell function (HOMA-B), which is a marker of basal insulin secretion by pancreatic β-cells. Review articles, editorials, letters, meeting abstracts, book chapters, errata, articles unrelated to statin-associated NOD2 or insulin resistance, articles involving a combination of statins with other medications that focused on the effect of the other medications rather than the statins, articles involving compounds without a separated statin group, articles on the effects of statins on lipid profiles and liver enzymes without statin-associated NOD2 or insulin-resistant indicators, and articles on the effects of statins on pre-existing diabetes mellitus without disease progression were excluded.Figure 1 illustrates the flow chart of the article retrieval process. Based on the inclusion and exclusion criteria, only 271 documents were included in the analysis.

Bibliometric analysis

The data analysis procedure was adapted from Wong et al.10 and was divided into two parts. First, the publication trends (global research output), the countries/regions and funding agencies that have contributed the most to this field of study, and the most cited articles were quantitatively analysed. This analysis was meant to illustrate the impacts and productivity of this field of study. Secondly, the full citation records of the selected documents were exported from the WoS into “.txt” files for the construction of a bibliometric network, which is a citation analysis by documents to demonstrate the relationships among articles that received high levels of citation and a co-occurrence analysis of keywords to determine the research focus. VOSviewer software (Centre for Science and Technology Studies, Leiden University, Netherlands) was used to map these bibliometric networks.

× Figure 1 . Flow chart of the article retrieval process . Figure 1 . Flow chart of the article retrieval process . × Figure 2 . The number of original articles related to statin-associated new-onset diabetes mellitus and insulin resistance . Figure 2 . The number of original articles related to statin-associated new-onset diabetes mellitus and insulin resistance . × Figure 3 . Citation analysis of documents with more than 50 citations per document related to statin-associated new-onset diabetes mellitus and insulin resistance . Node size represents the number of citations while the colors represent the publication year. Among the top 15 most cited documents with node labels not visible in the figure but connected with other documents are Caparros-Martin et al . (2017) 11 , Cederberg et al . (2015) 12 , Koh et al. (2005) 13 , Koh et al . (2010) 14 , Koh et al . (2009) 15 , Henriksbo et al . (2014) 14 , Sathyapalan et al . (2009) 16 and Abe et al . (2008) 17 . Figure 3 . Citation analysis of documents with more than 50 citations per document related to statin-associated new-onset diabetes mellitus and insulin resistance . Node size represents the number of citations while the colors represent the publication year. Among the top 15 most cited documents with node labels not visible in the figure but connected with other documents are Caparros-Martin et al . (2017) 11 , Cederberg et al . (2015) 12 , Koh et al. (2005) 13 , Koh et al . (2010) 14 , Koh et al . (2009) 15 , Henriksbo et al . (2014) 14 , Sathyapalan et al . (2009) 16 and Abe et al . (2008) 17 . × Figure 4 . Network visualization of the co-occurrence analysis of keywords related to the research on statin-associated new-onset diabetes mellitus and insulin resistance . The colors in the map represent the clusters–“heterogeneity” (in blue), “peripheral glucose uptake and insulin sensitivity” (in red), “tissue inflammation and oxidative stress” (in green), and “targeted tissue” (in yellow). Figure 4 . Network visualization of the co-occurrence analysis of keywords related to the research on statin-associated new-onset diabetes mellitus and insulin resistance . The colors in the map represent the clusters–“heterogeneity” (in blue), “peripheral glucose uptake and insulin sensitivity” (in red), “tissue inflammation and oxidative stress” (in green), and “targeted tissue” (in yellow).

Table 1.

Top 10 funding agencies involved in research on statin-associated new-onset diabetes mellitus and insulin resistance

Funding agencies Record count Percentage National Institutes of Health (NIH) USA 19 7.01% United States Department of Health Human Services 19 7.01% National Natural Science Foundation of China 10 3.69% Canadian Institutes of Health Research 7 2.58% Pfizer Inc. 7 2.58% Fundacao De Amparo A Pesquisa Do Estado De São Paulo Fapesp 6 2.21% AstraZeneca plc 5 1.85% Research Council of Finland 5 1.85% Conselho Nacional De Desenvolvimento Cientifico E Tecnologico 4 1.48% Coordenacao De Aperfeicoamento De Pessoal De Nivel Superior Capes 4 1.48%

Table 2.

Top 10 most productive countries for publishing articles on statin-associated new-onset diabetes mellitus and insulin resistance

Countries/ regions Total publication H-index Citations 1992-1997 1998-2002 2003-2007 2008-2012 2013-2017 2018-2022 Number of documents USA 48 26