Knowledge domain and emerging trends in empagliflozin for heart failure: A bibliometric and visualized analysis

Abstract

Objective:

Empagliflozin (EMPA), a sodium-glucose cotransporter 2 inhibitor (SGLT2i), is recommended for all patients with Heart failure (HF) to reduce the risk of Cardiovascular death, hospitalization, and HF exacerbation. Qualitative and quantitative evaluation was conducted by searching relevant literatures of EMPA for Heart Failure from 2013 to 2022, and visual analysis in this field was conducted.

Methods:

The data were from the Web of Science Core Collection database (WOSCC). The bibliometric tools, CiteSpace and VOSviewer, were used for econometric analysis to probe the evolvement of disciplines and research hotspots in the field of EMPA for Heart Failure.

Results:

A total of 1461 literatures with 43861 references about EMPA for Heart Failure in the decade were extracted from WOSCC, and the number of manuscripts were on a rise. In the terms of co-authorship, USA leads the field in research maturity and exerts a crucial role in the field of EMPA for Heart Failure. Multidisciplinary research is conducive to future development. With regards to literatures, we obtained 9 hot paper, 93 highly cited literatures, and 10 co-cited references. The current research focuses on the following three aspects: EMPA improves left ventricular remodeling, exert renal protection, and increases heart rate variability.

Conclusion:

Based on methods such as bibliometrics, citation analysis and knowledge graph, this study analyzed the current situation and trend of EMPA for Heart Failure, sorted out the knowledge context in this field, and provided reference for current and future prevention and scientific research.

Introduction

Empagliflozin (EMPA), a sodium-glucose cotransporter 2 inhibitor (SGLT2i), is recommended for all patients with Heart failure (HF) who have been treated with ACE-I/ARNI, β-blockers, and MRA, regardless of diabetes, to reduce the risk of Cardiovascular (CV) death, hospitalization, and HF exacerbation in HF patients (1–4). The EMPEROR-Reduced trial found that EMPA reduced the composite primary end point of CV death or HF hospitalization by 25% in patients with NYHA class II-IV symptoms (1) and reduced eGFR decline in individuals. Similarly, EMPA reduced the combined risk of CV death or hospitalization due to HF with a preserved ejection fraction, regardless of diabetes (4). It is also associated with improved quality of life (5, 6). The natriuretic/diuretic properties of EMPA may provide additional benefits regarding reduce congestion and the need for circulatory diuresis (7, 8). In patients with HF with reduced ejection fraction (EF), EMPA reduced the risk and total number of inpatient and outpatient exacerbations of HF events, ameliorate renal endpoints (9), and decrease CV and all-cause death (10), with benefits seen early after treatment initiation and sustained for the duration of double-blind therapy (11).

Changes in cardiac metabolism and ion homeostasis are precursors and drivers of cardiac remodeling and the development of HF. EMPA exerts direct and acute effects on cardiac ion homeostasis by inhibiting the cardiac Na⁺/H⁺ exchanger (NHE) and reducing intracellular Na⁺ and Ca²⁺ (12, 13). Subsequent studies showed for the first time that EMPA had acute specific metabolic effects in isolated type II diabetic db/db mouse hearts, namely, decreased lactate production of labeled glucose and increased α-ketoglutarate synthesis of labeled palmitate, which appeared to be mediated by NHE-1 inhibition (14).

In addition to cardiovascular benefits, EMPA slowed the estimated rate of decline in GFR in double-blind treatment, and the risk of a composite renal outcome was lower in the EMPA group than in the placebo group. Comparing measurements taken at the beginning and end of the trial after discontinuation of EMPA and placebo, the estimated decrease in GFR was greater in the placebo group than in the EMPA group. These observations are consistent with the benefits observed with SGLT2 inhibitors in type 2 diabetic patients who are largely free of HF. Thus, the positive effect of EMPA on renal function in patients with diabetes, HF, and patients with both conditions is evident (1).

Bibliometrics analysis can systematically deal with the original manuscripts of relevant research fields, track current research hotspots and general trends, reveal landmark literatures in this field and obtain clearer and more intuitive results (15–17). CiteSpace and VOSviewer, series of user-friendly bibliometrics analysis software, make the analyzer easy to operate. In this paper, using literature metrology method combing these documents, determine the influential countries, institutions, scholars, journals, and landmark theory, is to summarize the basic situation, provide references for study in the field of EMPA for HF.

Materials and methods

Data retrieval and collection

The following category was used to retrieve literature from WOSCC: (Topic = Empagliflozin and Heart Failure). There were no language, publication date, and document type restrictions in the selection of the articles. To avoid data bias, the plain text files containing full record and cited references were exported in the text as download_^***.txt in under a day (August 10, 2022). In ClinicalTrials.gov¹, a database of privately and publicly funded clinical studies conducted around the world, we performed a combination search of “Empagliflozin” and “Heart Failure” for clinical trials focused on intervention therapy. Then the retrieval results were analyzed comprehensively according to the stage of the experiment.

Data analysis

Figure 1A shows a flowchart of the scientometric analysis. We used the WOSCC database for most of the analyses including Publications, Citations, Web of Science Categories, Journal, Country/Region, Affiliations, Authors, hot papers, and highly cited literatures.

FIGURE 1

VOSviewer (Version 1.6.17) was utilized for the analysis of countries, organizations, and authors. Based on network visualization, VOSviewer divides countries, organizations, or authors into diverse clusters and colors them in the light of the temporal progression of their occurrence, superimposing time on the network of co-occurrence countries, organizations, or authors. The data about country cooperation was converted into GML format by VOSviewer and imported into Scimago Graphica Beta software (Version 1.0.18) to demonstrate geographical distribution and country cluster.

The software CiteSpace (Version 5.8.R3 64-bit) was used for the analysis of co-cited reference and keywords. In the co-occurrence graph, the circle size represents the number of co-citations, and the centrality and burstiness was strikingly marked by the purple and red in the outer ring of the node, respectively. Key points in CiteSpace are nodes with a centrality of more than 0.1. Long-likelihood ration algorithm was used for keywords cluster analysis based on co-occurrence. In the cluster map, the ones surrounded by boxed represent the same cluster. Cluster names are displayed based on the cluster scale.

Results

Time distribution map of literatures

It can be seen from Figure 1B that in the decade, the amount of literature published in the field of EMPA for HF showed a rise and peaked in 2021. At present, just 8 months into 2022, the analysis of posts is not included yet. This citation analysis of the 1461 papers on EMPA for HF resulted in a grand total of 43861 times cited in the past 10 years, with a mean of 30.02 citations per paper and h-index of 84. H-index is an important indicator of a researchers’ scientific output (18). The times of citations increased year by year from 1 in 2013 to 14754 in 2021 (Based on the uptrend, citations are likely to continue to break through in 2022). The initial database search yielded 1461 articles, which comprise nine different document types (Figure 1C) including Articles (724 papers, 49.555%), Review Articles (450 papers, 30.801%), Meeting Abstracts (133 papers, 9.103%), Editorial Materials (100 papers, 6.845%), Early Access (47 papers, 3.217%), etc.

The analysis of clinical trials

To date, EMPA has 42 clinical trials for HF worldwide and the exact distribution is shown in Figure 1D. Of the 42 trials, 21 have been completed, 11 are recruiting patients, 7 have not yet started recruitment, 2 have been terminated by slow enrollment (ClinicalTrials.gov Identifier: NCT03152552) and outbreak involvement (ClinicalTrials.gov Identifier: NCT03554200), and 1 has unknown information (ClinicalTrials.gov Identifier: NCT03271879). Of the 21 completed trials, 10 submitted final findings and all of them had positive effects, as detailed in Table 1. The number of enrolled patients ranged from 23 to 5988, all of whom were over 18 years old and of both sexes. EMPA was used in two specifications: 10 and 25 mg, with 10 mg being the majority and placebo being used as the control drug. The main outcome measures were NT-proBNP, Left Ventricle-End Systolic/Diastolic Volume (LV-EDV/ESV), 6-Min-Walking-Test (6MWT), Kansas City Cardiomyopathy Questionnaire (KCCQ) score, CV death, hospitalization rate, all-cause mortality, and renal function related indicators. The KCCQ, a self-administered questionnaire designed to evaluate physical limitations, symptoms (frequency, severity, and changes over time), social limitations, self-efficacy, and quality of life in patients with HF, incorporates the following domains: symptom burden, symptom frequency, and physical limitation (19). The KCCQ questionnaire has 23 items and 12 items. The KCCQ-12 is a shorter version of the original 23-item test tool, and its credibility has been verified in clinical trials (20).

A series of clinical trials have demonstrated that EMPA improves hemodynamics in patients with HF, rapidly reducing pulmonary artery pressure that is amplified over time and appears to be independent of loop diuresis management (21–23). In the EMPA-REG OUTCOME trial, EMPA reduced CV risk events and influenced mortality and hospitalization in patients with HF independent of its hypoglycemic effect. In addition, the effect of EMPA on exercise capacity in patients with HF did not differ according to LVEF (24–28). In the EMPULSE trial (29), the initiation of EMPA in hospitalized patients with acute HF produced clinical benefits, improved KCCQ scores regardless of the extent of symptom impairment at baseline, and improved symptoms, physical limitations, and quality of life, with benefits seen as early as 15 days and maintained up to 90 days. EMPA resulted in significant reductions in body weight and serum urate, and when combined with loop diuretics, a significant increase in 24-h urine volume but no increase in urinary sodium. It is hypothesized that EMPA’s role as an osmotic diuretic and its effect on natriuretic may underlie the CV and renal benefits (30, 31).

Web of science disciplines and journals

Table 2 shows the top 15 disciplines. The top three subjects covered by all included literature are Cardiac Cardiovascular Systems (713 papers, 48.802%), Endocrinology Metabolism (352 papers, 24.093%), and Pharmacology Pharmacy (175 papers, 11.978%). The remaining subjects are in order Medicine General Internal (141 papers, 9.651%), Peripheral Vascular Disease (134 papers, 9.172%), Urology Nephrology (54 papers, 3.696%), Medicine Research Experimental (44 papers, 3.012%), Biochemistry Molecular Biology (38 papers, 2.601%), Cell Biology (18 papers, 1.232%), Multidisciplinary Sciences (17 papers, 1.164%), Health Care Sciences Services (16 papers, 1.095%), Toxicology (14 papers, 0.958%), Chemistry Multidisciplinary (12 papers, 0.821%), Chemistry Medicinal (10 papers, 0.684%), and Geriatrics Gerontology (10 papers, 0.684%).

Regarding the number of published papers, Circulation is the most published journal with 86 articles, with IF of 39.918 and JCR of Q1, followed by Cardiovascular Diabetology (71 articles, IF₂₀₂₁ = 8.949, Q1), European Journal Of Heart Failure (67 articles, IF₂₀₂₁ = 17.349, Q1), Diabetes Obesity Metabolism (54 articles, IF₂₀₂₁ = 6.408, Q1), European Heart Journal (39 articles, IF₂₀₂₁ = 35.855, Q1), Journal Of The American College Of Cardiology (35 articles, IF₂₀₂₁ = 27.203, Q1), Esc Heart Failure (31 articles, IF₂₀₂₁ = 3.612, Q2), Diabetologia (27 articles, IF₂₀₂₁ = 10.46, Q1), Heart Failure Reviews (25 articles, IF₂₀₂₁ = 4.654, Q2) and New England Journal Of Medicine (24 articles, IF₂₀₂₁ = 176.079, Q1) (Table 3).

The analysis of co-authorship–Countries/regions, research institutions and influential scholars

In terms of publication numbers, USA is the country with the highest number of publications, accounting for 37 percent of the total, followed by the Germany (286 papers, 19.576%), Canada (213 papers, 14.579%), England (208 papers, 14.237%), Japan (135 papers, 9.24%), China (133 papers, 9.103%), Italy (121 papers, 8.282%), Greece (114 papers, 7.803%), France (110 papers, 7.529%), and Netherlands (107 papers, 7.324%) (Table 4 and Figure 2A). Figure 2B shows geographical distribution of all contributing countries. Of these top 15 countries/regions, ten from Europe, two are from Asia, two from North America and one from Oceania. The total citations, total link strength and h-index ranked first in the USA, which were 28,404, 1,194, and 70 respectively, suggesting that the USA is relatively mature in the field of EMPA for HF. As shown in Figure 2C, 51 countries met the threshold, and 3 clusters were generated, among which the largest clusters were 21 countries, which are represented by red, green, and blue. In Figure 2D, the more purple the color, the earlier the study, and the redder the later the study. It shows that the USA, Canada, and Germany were studied earlier. China, Mexico, and Turkey appear later, around 2021.

FIGURE 2

The three institutions with the largest number of publications were from University of Toronto, Boehringer Ingelheim and Saint Michaels Hospital Toronto, accounting for 11.567, 10.678, and 8.966% of the total reports respectively, will in Table 5 and Figure 3A. Six of the top 15 published research institutions are in the USA, five are in Germany, while two are in Canada. University of Toronto is the research institution with the most total citations, with an API of 134.19 and an h-index of 44, followed by Harvard University and Saint Michaels Hospital Toronto. Figure 3B shows the connections between institutions. Nodes represent the number of publications issued by institutions, and lines represent the connections between institutions. Three clusters are formed with red, blue, and green respectively. As can be seen from the time superposition chart of institutions (Figure 3C), the study of University of Toronto started earlier, while Charite Universitatsmedizin Berlin appeared later, around the end of 2020.

FIGURE 3

With regards to authors, Butler J from the University of Mississippi was the most prolific, followed by Anker SD from Charite Universitatsmedizin Berlin and Inzucchi SE from Yale University. Of the top 15 authors, eight are from the USA and Germany, evenly split. Inzucchi SE from Yale University have the most citations of 1,0007 and the highest h-index of 26 on the field of EMPA for HF (Table 6 and Figure 3D). Figure 3E shows the connections between authors. Nodes represent the number of publications issued by authors, and lines represent the connections between authors. Three clusters are formed with red, blue, and green respectively. The clustering formed by Zinman B, Fitchett D, and Mcguire DK appeared earliest. Since then, many scholars have conducted in-depth research (Figure 3F).

The analysis of reference—Hot papers, highly cited literatures, and co-cited reference

Hot papers

Hot papers were those published in the past 2 years and received enough citations in November/December 2021 to be in the top 0.1% of papers in an academic field in a subject area. There were nine hot papers (1, 4, 10, 32–37) in total, and all of them were highly cited (Table 7). The types of documents are all articles, and all of them are published in the journal with JCR of Q1, most of which were New England Journal of Medicine (IF₂₀₂₁ = 176.079, Q1). The above nine hot papers included two meta-analyses, and the results showed that SGLT2 inhibitors were associated with a reduced risk of major adverse CV events and renal outcomes (36), as well as a reduced combined risk of CV death or hospitalization due to HF in patients with or without diabetes (4). The results were confirmed in another study (10). Three other trials (1, 32, 35), all of which looked at the effects of SGLT2i (EMPA, dapagliflozin, and sotagliflozin) on the kidneys, were also positive.

Highly cited literatures

As of November/December 2021, these highly cited literatures received enough citations to place it in the top 1% of the academic field based on a highly cited threshold for the field and publication year. A total of 93 highly cited literatures were detected in the database in this research field, with the highest citation frequency of 4753. Among them, the above nine hot papers were all among the highly cited articles. Therefore, the top 15 highly cited literatures excluding the hot papers are shown in Table 8. With regards to the document type, 12 were articles and 3 were review. The publication time of highly cited literatures was generally from 2015 to 2019. Among the top 15 highly cited literatures, only one described the underlying mechanism of EMPA in the treatment of HF, involving in vivo experiments in animals (12). Elevated cardiac cytoplasmic Na⁺([Na⁺]_c) and Ca²⁺([Ca²⁺]_c) concentrations and decreased mitochondrial Ca²⁺([Ca²⁺]_m) concentrations are driving factors for HF and cardiac death (38, 39). Previous studies (40, 41) have shown that chronic NHE inhibition prevents or attenuates HF in animal models. Ventricular myocytes of rabbits and rats were acutely isolated, and the activities of [Na⁺]_c, [Ca²⁺]_c, [Ca²⁺]_m and NHE were measured by fluorimetric assay. The results showed that EMPA had a direct effect on the heart by injuring myocardial NHE flux, reducing myocardial [Na⁺]_c and [Ca²⁺]_c, and enhancing [Ca²⁺]_m, independent of SGLT2 activity (12). Thus, it is hypothesized that the beneficial CV effects of EMPA are at least partially attributable to NHE inhibition, and it is appropriate to complement the mechanistic studies of EMPA in the treatment of HF.

Co-cited references

The analysis of co-cited references reveals that there are two references in the list of the third citation article, and then the two references form a co-citation relationship. Figures 4A–D respectively represents the citations, centrality, and burst intensity of co-cited literature. The blue line in the figure represents the time axis of the existence of included literatures, and the red line represents the period of the strongest emergence of corresponding literatures. In the co-occurrence diagram of co-cited literatures, the line between nodes means that two literatures appear in the reference of the same article. The more the line is, the articles have certain similarity in content. Nodes represent the citations of literature, purple outside nodes represents the centrality of literature, and red represents the intensity of highlighting. According to the intensity of burst, the top 10 literatures are shown in Table 9.

FIGURE 4

The first article named “Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes,” which written by Zinman B and published in the New England Journal of Medicine (IF₂₀₂₁ = 176.079) in 2015, is the first study to provide evidence that antidiabetic agents reduce CV events (42). In the EMPA-REG OUTCOME trials, a total of 7020 patients with T2DM were randomized to receive either 10 or 25 mg of EMPA daily or placebo. Compared with placebo, EMPA significantly reduced the risk of death from CV causes, non-fatal myocardial infarction, or non-fatal stroke. The results were surprising; In contrast to other CV risk reducing interventions, such as lowering LDL-C (43) and Blood Pressure (44), CV death was significantly reduced by 38% (P = 0.001). The separation of Kaplan–Meier curves for CV mortality and HF hospitalization observed during the first 3 months of the trial suggests that the treatment mechanism for EMPA has an early and profound effect on the risk of death or HF (42). Another article titled “Heart Failure Outcomes with Empagliflozin in patients with Type 2 Diabetes at High Cardiovascular Risk: Results of the EMPA-Reg OUTCOME^® Trial,” written by Fitchett D, published in the European Heart Journal (IF₂₀₂₁ = 35.855) in 2016, highlighting the strength 13.9, also reported these findings from the same randomized controlled trial (ClinicalTrials.gov Identifier: NCT01131676).

Keywords analysis and visualization

Our analysis of the co-occurrence diagram was used to see which were the main directions and hotspots of EMPA for HF research, as well as to understand how its themes and topics developed and changed over time. The keyword co-occurrence diagram of 386 nodes and 768 links was obtained by running CiteSpace (Figure 5A). The node size represents the frequency of keywords. The centrality of keywords was calculated by “Node-compute Node Centrality” in CiteSpace, and the top 10 keywords in frequency and centrality were summarized.

FIGURE 5

As previous studies (45), based on keyword co-occurrence graph, the keyword clustering analysis was carried out (Figure 5B). The evaluation diagram was mainly judged from the clustering effect and reliability. Modularity Q = 0.7799, the closer Q value was to 1, the better the clustering result of the network was, and Q value > 0.3 indicated that the clustering structure was significant. Silhouette S = 0.91, which measured network homogeneity. When Silhouette was more closely to 1, the more homogenous the Silhouette would be. An S value > 0.5 was considered reasonable and an S value > 0.7 was considered convincing (46). The cluster information is exported in “Summary Table/Whitelists” on the cluster menu bar of CiteSpace, and the key information was displayed in Table 10. A total of 16 clusters were formed in this study. The smaller the number, the larger the cluster size was. #0 sglt2 inhibitor was the largest cluster, followed by #1 lv remodeling, #2 diabetes mellitus, #3 cardiorenal syndrome, #4 chronic heart failure, #5 clinical trial, #6 cardiac function, #7 heart failure, #8 dpp-4 inhibitors, #9 mellitus, #10 preserved ejection fraction, #11 empagliflozin, #12 sodium-glucose co-transporter 2 inhibitors, #13 heart rate variability, #14 cardiomyocyte relaxation and contraction, and #15 glomerular hyperfiltration.

Discussion

Different from traditional review, bibliometrics analysis can systematically deal with the original manuscripts of relevant research fields, track current research hotspots and general trends, reveal landmark literatures in this field, and obtain clearer and more intuitive results. CiteSpace and VOSviewer, series of user-friendly bibliometrics analysis software, make the analyzer easy to operate. In addition, we use other graphics software, such as Scimago Graphica, to make the data more visible.

The WOSCC system is the most famous database of scientific publications regarding many investigations. According to the literature screening strategy mentioned earlier, 1461 literatures about EMPA for HF in the decade were extracted from WOSCC, with a total of 43861 references, and the number of manuscripts was on a rise. Compared with the h-index, the mean number of citations per paper is a superior indicator of scientific quality, in terms of both accuracy and precision (47). As shown in the geographical distribution map of all contributing countries, most of the research comes from developed countries, and the Americas, Asia and Europe are heavily published and closely linked. Africa has few publications and few contacts with other countries, which suggests that countries should further break regional barriers for academic exchanges.

In the WOSCC database, there are 45 disciplines involved in the field of EMPA for HF and the top 15 are summarized in Table 2. Among them, multidisciplinary research shows an outbreak trend in the current research stage, which is conducive to future development. Most of the JCR in the top 15 journals are Q1/Q2, and seven articles had an IF (an index of the quality of articles included in the journal) of more than 10, with the highest score of 176.079, and four of them scored 5–10, suggesting that the quality of articles written by scholars in this field is high and can provide better guidance for new researchers.

Based on keywords co-occurrence, clustering and burstiness studies, the current research focuses on the following three aspects: EMPA improves left ventricular remodeling, exert renal protection, and increases heart rate variability (HRV).

Empagliflozin improves left ventricular remodeling

Acute or chronic myocardial injury results in metabolic disorders followed by cardiomyocyte death. The remaining viable myocardium copes with cell loss through the development of cardiomyocyte hypertrophy and fibrosis in the interstitial space (48, 49). A reduction in contractile force activates neurohormonal compensatory mechanisms designed to maintain systemic perfusion, such as the sympathetic and renal angiotensin systems. Structural changes in the left ventricular (LV) occurred over time, including an increase in ventricular volume, a shift to the right of the end-diastolic pressure-volume relationship (EDPVR), and a development of sphericity (50–52). These anatomical alterations are accompanied by alterations in gene expression, metabolic substrate preference and utilization, and extracellular matrix composition (53–55). These structural, biochemical, and molecular changes are collectively known as ventricular remodeling.

Ventricular remodeling, first described in animal models of LV stress and injury, occurs progressively after large myocardial infarction and in patients with dilated cardiomyopathy. Ventricular remodeling refers to changes in ventricular structure, associated with increased volume and changes in ventricular structure, which are driven by pathological cardiomyocyte hypertrophy, cardiomyocyte apoptosis, myofibroblast proliferation, and interstitial fibrosis at the histological level (56–58). LVEF, the most used clinical measure of cardiac function, is more affected by the degree of LV remodeling than any other factor. Other more precise remodeling measures, such as LV volume and mass, have received greater attention in clinical trials than in clinical practice, but these measures are more closely associated with prognostic and therapeutic effects than LVEF (59). Numerous studies have shown that LV volume measurements at a single time point and over time are of great value in predicting clinical outcomes in patients with HF. A recent meta-analysis of HF trials showed that LV volume stood out among surrogate measures and was strongly associated with the impact of specific drug or device treatment on patient survival. These findings confirm the importance of ventricular remodeling in advancing the pathophysiology of HF and support the role of ventricular remodeling measures in clinical studies of new treatments for HF (60).

EMPATROPISM trial, a pioneer trial to be published first, demonstrated a reduction in LV volumes, regression in LV mass, improvement in LVEF, amelioration in LV sphericity (61). Moreover, EMPA also improved peak oxygen consumption (62), the gold-standard parameter evaluating exercise capacity. EMPA also reduced LV interstitial fibrosis and aortic stiffness (63). The pioneering results of EMPATROPISM have been subsequently confirmed by other independent trials such as SUGAR-DM (64) and eMPIRE-HF (62). In the EMPA-HEART trial (61), the mean LV mass in the regression of body surface area after 6 months was 2.6 g/m² in the EMPA group and 0.01 g/m² in the placebo group (P = 0.01), with a significant reduction in the EMPA group, which is presumed to have a positive effect on CV outcomes.

The results were verified in animal experiments. Researchers used LAD ligation to establish a model of HF after MI in female Yorkshire pigs and randomly assigned them to either EMPA or placebo for 2 months. Myocardial injury was subsequently detected using cardiac magnetic resonance and three-dimensional (3D) Echocardiography. The LV end-systolic and end-diastolic diameters of EMPA treated pigs were significantly reduced, indicating a significant mitigation in LV dilatation. LV mass was significantly reduced in EMPA treated pigs and the degree of sphericity of the heart was lower than in control pigs, as indicated by the lower 3D-LV sphericity index, thus indicating reduced structural changes in the treated arm. Further CMR results showed that the improvement of LV remodeling in the EMPA group was associated with an increase in LVEF 2 months after treatment (65). Santos-Gallego demonstrated that the improvement in LVEF is due to a switch in myocardial metabolism. EMPA induces a shift in myocardial metabolism away from glucose-inefficient glucose toward the consumption of free fatty acid and ketone bodies, which enhances cardiac energetics (66, 67). The circumference of porcine cardiomyocytes treated with EMPA was smaller than that in the control group, indicating that there was less compensatory hypertrophy at the cellular level in the EMPA group (68). Increased interstitial myocardial fibrosis (IMF) causes diastolic dysfunction. Collagen deposition was reduced in EMPA-treated pigs versus controls, and levels of hydroxyproline, an essential amino acid found only in collagen and thus an indirect marker of IMF, were lower in the EMPA group. IMF was reduced as the treated group exhibited stiffer Type-1 collagen and reduced expression of the pro-fibrotic cytokine TGF-B gene, as well as reduced TGF-B activity (68). This suggests that EMPA can ameliorate IMF, thereby improving ventricular remodeling.

Reno protective effects of empagliflozin

In the EMPEROR-Reduced Trial, EMPA slowed the progression of eGFR reduction compared with placebo (69, 70). EMPA resulted in a similar placebo-adjusted reduction in the urinary albumin-to-creatinine ratio (UACR) over a mean period of 3.1 years, regardless of Obstructive Sleep Apnea status at baseline (71). EMPA has moderate diuretic and natriuretic effects that ameliorate OSA symptoms by reducing fluid retention in the pleural cavity (72) and rostral fluid transfer to the legs (73), as well as affecting kidney sodium handling (74). Moreover, EMPA induces natriuresis, which enhances the diuretic effect of loop diuretics (8), but does seems only to be maintained in the acute phase (30). It is this acute natriuretic effect which explains the quick benefits of EMPA in acute heart failure within the first days (75).

Brenner (76) proposed that glomerular hyperfiltration with glomerular capillary hypertension is the pathogenesis of renal disease, among which glomerular hyperfiltration has been considered as a potential risk factor for Diabetic nephropathy (DN) (77). SGLT2i reduce glomerular hyperfiltration, thereby preventing the progression of DN, which may in turn reduce CV risk, including HF. Although EMPA have shown significant renal and CV benefits in humans in clinical trials (42, 78), the mechanism of action is not fully understood but is attributable, at least in part, to a reduction in intraglomerular hypertension and hyperfiltration. Single-nephron GFR (SNGFR) in spontaneously diabetic Ins2^+/Akita mice was significantly higher than in control groups, reflecting glomerular hyperfiltration, which was ameliorated in EMPA treatment (79).

Hyperuricemia is common in HF and is an independent predictor of advanced disease severity and increased mortality. In the EMPEROR-reduced trial, EMPA induced a rapid and sustained reduction of serum uric acid levels and of clinical events related to hyperuricemia and gout (80). Diabetes mellitus is a risk factor for nephrolithiasis. In an observational study involving 24,290 individuals with T2DM taking SGLT2 inhibitors, Kristensen et al. reported that SGLT2 inhibitor use was associated with a 49% lower risk of nephrolithiasis compared with GLP-1 receptor agonists (81). In EMPA-REG OUTCOME trial, compared with placebo, EMPA therapy was associated with an approximate 40% reduced risk of urinary tract stone events. The underlying mechanisms are unknown but may involve altered lithogenic profile of the urine (82).

Progressive decline in renal function often leads to chronic cardiac dysfunction and CV events. HF is a common complication in patients with chronic kidney disease (CKD), and this process is defined as type 4 cardiorenal syndrome. Trials have shown that SGLT2i treatment significantly improves the outcome of HF, reducing the length of hospitalization for this complication in CKD patients by 30–40% (83). Indeed, treatment with EMPA in diabetic adipose rats improved systemic endothelial function (84). These effects are thought to be mediated probably through increased endothelial viability, reduced senescence, and inflammation, and reduced oxidative damage in the nitric oxide (NO)/cycloguanosine monophosphate signaling cascade, rather than upregulation of endothelial NO synthase expression (84).

Juni et al. (85) provide an interesting mechanistic insight into how uremia impinges on the interaction between endothelial cells and cardiomyocytes and highlight the critical role of cardiac microvascular endothelium in the cardiac benefits of EMPA treatment (Figure 6). The researchers used a co-culture model of human cardiac microvascular endothelial cells (CMECs) and rat ventricular cardiomyocytes. The results showed that CMECs positively affected the relaxation and contraction of cardiomyocytes mainly through endoderm-derived NO. They demonstrated that uremic serum impairs endothelium mediated enhancement of cardiomyocyte function and that EMPA counteracts the deleterious effects of uremic serum on CMECs, leading to restoration of cardiomyocyte function (86).

FIGURE 6

Arterial stiffness, a surrogate marker of renal and CV clinical outcomes, is influenced by activation of the renin angiotensin aldosterone system (RAAS) and sympathetic nervous system (SNS) and inhibition of NO (87, 88), increases under the influence of ambient hyperglycemia and can be ameliorated by strict glycemic control (89–91), which may help improve BP control and reduce the risk of CV complications (92–94). Traditional oral hypoglycemic agents (liraglutide or glibenclamide) do not improve arterial stiffness parameters, and a significant proportion of patients develop hypertension as the duration of diabetes increases (95, 96). In an 8-week, open-label, prospective clinical trial (NCT01392560) (97), the novel oral hypoglycemic agents, EMPA, could significantly reduce the parameters of vascular sclerosis, including radial augmentation Index, various sclerosis Index and aortic augmentation index. They suggest that the physiological mechanism of reduced arterial stiffness may be related to a variety of factors, including BP lowering, diuretic effects, altered neurohormone activation, improved glycemic control, and weight loss (Figure 6) (98–103).

Empagliflozin increases heart rate variability

Heart rate variability is a non-invasive ECG parameter that assesses sympathetic vagal balance at the sinoatrial level, but its physiological interpretation is still under discussion (104–106). In patients with HF, when short-term or 24-h recordings were analyzed, reduced HRV was consistently observed and explained primarily because of sympathetic and reduced vagal modulation of sinus node (104). For the time domain, the following indexes were calculated according to the recommended values (104): mean n-n interval (SDNN), root mean square difference of successive N–N intervals (RMSSD), Standard deviation of all 5-min mean normal RR intervals (SDANN), Mean RR interval for 24 h (mean NN) and proportion of differences between adjacent N–N intervals of > 50 ms (PNN50). In an 8-week, open-label, prospective clinical trial (NCT01392560) (97), EMPA increased RMSSD and SDNN, but not statistically significant. In the EMBODY trial (107), SDNN (101.1S vs. 112.8S, P < 0.01), SDANN (81.0S vs. 92.7S, P = 0.02), and RMSSD (34.2S vs. 40.7S, P = 0.01) were significantly higher after 24 weeks of EMPA versus baseline.

Limitations

There are some limitations in this paper. We analyze all the articles on EMPA for HF from the WOSCC database, but due to differences in text quality, the credibility of the analysis may be low. With the continuous updating of WOSCC literature, the number of literatures obtained is different from the actual number of literatures, and the cited times and H-index will also change accordingly.

Conclusion

The research progress, hotspots, and frontier in this field in the decade were elucidated by us through information visualization technology. The publications of manuscripts were on a rise. With regards to country, USA leads the field in research maturity. The scholars, institutions, and representative literature that play an important role in this area have been identified. The current research focuses on the following three aspects: EMPA improves LV remodeling, exert renal protection, and increases HRV.

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