SGLT2 Inhibitors Research Articles

Efficacy and safety of of SGLT2 ihibtors in post mi patients: a systematic review and meta-analysis of RCTs

Abstract Introduction Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have demonstrated a decrease in cardiovascular (CV) events, especially in diabetic patients. However, it remains unclear whether the early administration of SGLT2is confers cardioprotective benefits following acute myocardial infarction (AMI). Purpose Our objective is to explore the in-hospital and long-term prognoses of patients presenting with AMI who are treated with SGLT2is compared to non-SGLT2is users. Methods We conducted comprehensive searches across PubMed, CENTRAL, WOS, Scopus, and EMBASE until October 2023. Pooled data were reported using risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, along with a 95% confidence interval (CI). This systematic review and meta-analysis is registered with PROSPERO. Results We included 14 studies with a total of 37,038 patients. Compared to non-SGLT-2 inhibitors, SGLT-2 inhibitors were associated with a decreased incidence of major adverse cardiovascular events (MACE) (RR: 0.60 with 95% CI [0.45, 0.82], P< 0.01), all-cause mortality (RR: 0.67 with 95% CI [0.55, 0.81], P< 0.01), heart failure (RR: 0.68 with 95% CI [0.57, 0.80], P< 0.01), stroke (RR: 0.67 with 95% CI [0.45, 0.99], P= 0.04), increased left ventricular ejection fraction (MD: 2.45 with 95% CI [0.81, 4.09], P< 0.01), and decreased left ventricular end-systolic volume (MD: -5.72 with 95% CI [-10.76, -0.67], P= 0.03). Conclusion SGLT-2 inhibitors significantly decrease MACE, all-cause mortality, heart failure, left ventricular ejection fraction, and left ventricular end-systolic volume in myocardial infarction patients.Figure 1Figure 2

Activation of fibroblast growth factor 21 by Canagliflozin reduces high-fat diet associated obesity-related cardiac injury: a translational study from bench to bedside

Abstract Aims/hypothesis Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are indicated for the treatment of type 2 diabetes, and evidence shows that they may confer a cardioprotective effect to reduce the incidence of cardiovascular conditions in obese type 2 diabetes patients. The mechanisms underlying this effect remain unclear, but an SGLT2i, canagliflozin (CANA), has been reported to increase levels of fibroblast growth factor-21 (FGF21) and enhance activation of its downstream target proteins. We thus aimed to study whether the effect on FGF21 by CANA can reduce obesity-related cardiac injury. Methods 1) Animal study: Sixteen-week-old normal diet and high-fat diet male mice were treated with or without 30 mg/kg CANA once a day for 24 weeks, and were subsequently examined for body weight, blood glucose levels, adipose tissue changes, lipid accumulation in the liver, and cardiac function. 2) Cell study: An in vitro study that treated H9c2 cardiomyocyte cells cultured in a simulated high-lipid environment containing palmitic acid (PA) with FGF21 recombinant protein was also conducted to examine protein expression profiles. Furthermore, the effect of CANA on FGF21 expression. 3) Human clinical trial: A randomized double-blinded control trial (NCT 05764811) was performed to test effect of CANA on MRI liver fibrosis scores of obese type 2 diabetes patients (n = 40). Results 1) High-fat diet mice treated with CANA for 24 weeks had lower average body weight than untreated controls (34 g vs. 40 g, p < 0.001). In addition, CANA treatment stimulated FGF21 protein production in liver tissue and plasma at higher levels for both normal diet and high-fat diet mice, and reduced expression levels of proteins associated with fibrosis and apoptosis. 2) H9c2 cardiomyocyte culture studies suggested that a simulated high-lipid environment with PA caused higher expression of apoptotic proteins, but the addition of FGF21 recombinant protein significantly reduced apoptosis signalling. 3) MRI before and after 4 weeks of CANA treatment in obese type 2 diabetes patients showed a significant reduction in liver fibrosis scores for those receiving CANA treatment. Conclusion CANA treatment stimulated FGF21 protein expression and reduced fibrosis and apoptosis signalling protein expression. Moreover, reductions in liver fibrosis scores were observed in obese type 2 diabetes patients treated with CANA. Taken together, this suggests that CANA-induced FGF21 expression may exert a cardioprotective effect against fibrosis and apoptosis and can potentially reduce the risk of obesity-related cardiac injury.

Implementation of sodium-glucose co-transporter 2 inhibitors in patients with heart failure through a new digital strategy (EMAIL-HF): a randomised clinical trial study design

Abstract Introduction Delayed implementation of new medical discoveries remains a global healthcare challenge and is mainly due to the complexity of cross-institutional patient care. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors is the latest medical discovery in heart failure (HF) and have recently been added to clinical guidelines as they have proven to reduce the risk of adverse cardiovascular outcomes in patients with HF across the ejection fraction spectrum. Whether a new digital strategy can optimise and accelerate the implementation of SGLT2 inhibitors in patients living with HF is of great importance for public health. Purpose To evaluate whether a new and streamlined digital strategy can optimise and accelerate the implementation of SGLT2 inhibitors in patients with HF. Design and methods: The trial is a multicentre, parallel group, register-based randomised clinical study, evaluating the effect and potential of a new digital strategy to implement new guideline therapies to patients living with a chronic disease, specifically SGLT2 inhibitors to patients with HF (figure 1). The setup employs data from nationwide health registers and official digital letters to inform patients about the new therapy option and invite them to have their eligibility evaluated by a HF specialist and start therapy. A total of ~10,000 patients with HF across the ejection fraction spectrum (with and without diabetes), who have not yet been started on SGLT2 inhibitors, are identified through Danish nationwide health registers, and randomised 1:1 to receive the digital letter (figure 2). The primary outcome is the proportion of patients redeeming a prescription of a SGLT2 inhibitor within six months. Secondary outcome is a composite HF endpoint consisting of all-cause death or HF hospitalisation. Other outcome measures are renal failure, stroke and myocardial infarction, safety outcomes, adherence to therapy and proportion of vulnerable patient groups initiating therapy including immigrants, elderly, frail patients, patients with lower socioeconomic level and lower educational level. A total of 4689 patients have been randomised (February 2024) and data will be presented in 2025. Conclusions The trial will determine the efficacy and safety of a new and streamlined digital strategy to implement SGLT2 inhibitors to patients with chronic HF. The setup has the potential to be used in a broad spectrum of patients living with chronic diseases and is expected to be highly cost-effective.Figure 1.Study hypothesisFigure 2.Study design

Dapagliflozin enhances arterial and venous compliance during exercise in heart failure with preserved ejection fraction

Abstract Background Systemic arterial compliance and venous capacitance are typically impaired in patients with heart failure with preserved ejection fraction (HFpEF), contributing to hemodynamic congestion with stress. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce hemodynamic congestion and improve clinical outcomes in patients with HFpEF, but the mechanisms remain unclear. Purpose This study tested the hypothesis that SGLT2i dapagliflozin would improve systemic arterial compliance and venous capacitance during exercise in patients with HFpEF. Methods In this secondary analysis from the RCT trial, patients with HFpEF underwent invasive hemodynamic exercise testing at baseline and following treatment for 24 weeks with dapagliflozin or placebo. Patients were required to display pulmonary capillary wedge pressure (PCWP) ≥25 mmHg during exercise at the time of baseline evaluation. Radial artery pressure (BP) was measured continuously using a fluid-filled catheter with transformation to aortic pressure, central hemodynamics were measured using high-fidelity micromanometers, and stressed blood volume was estimated (eSBV) from hemodynamic indices fit to a comprehensive cardiovascular model. Results A total of 37 patients completed the study and were included in this analysis (21 dapagliflozin and 16 placebo). Patients were predominantly women (24/37, 65%) and older (mean age 67 years). There was no statistically significant effect of dapagliflozin on resting BP, but dapagliflozin reduced systolic BP during peak exercise (estimated treatment difference [ETD], -18.8 mmHg, 95% CI: -33.9 to -3.7, P=0.016) (Figure 1A). Dapagliflozin improved exertional total arterial compliance (TAC) index (ETD, 0.06 mL/mmHg/m2, 95% CI: 0.003 to 0.11, P=0.039) (Figure 1B) and aortic root characteristic impedance (ETD, -2.6 mmHg/ml*sec, 95% CI: -5.1 to -0.03, P=0.048) during peak exercise, with no significant effect on systemic vascular resistance. Dapagliflozin reduced eSBV at rest and during peak exercise (ETD, -292 mmHg, 95% CI: -530 to -53, P=0.018) (Figure 1C), and improved venous capacitance evidenced by a decline in ratio of eSBV to total blood volume (ETD, -7.3%, 95% CI -13.3 to -1.3, P=0.020). Each of these effects of dapagliflozin during peak exercise were also observed during matched 20W exercise intensity. Improvements in TAC index and eSBV were correlated with decreases in body weight, and reduction in systolic BP with treatment was correlated with the change in eSBV during exercise (r=0.40, P=0.019) (Figure 2A). Decreases in BP were correlated with reduction in PCWP during exercise (r=0.56, P<0.001) (Figure 2B). Conclusion In patients with HFpEF, treatment with dapagliflozin improved systemic arterial compliance and venous capacitance during exercise, while reducing aortic characteristic impedance, suggesting a reduction in arterial wall stiffness. These vascular effects may partially explain the clinical benefits with SGLT2i in HFpEF.

Human epicardial adipose tissue-derived factors promote atrial endothelial dysfunction: role of pro-inflammatory cytokines and AT1R/NADPH oxidases/SGLT2 pro-oxidant pathway

Abstract Introduction Epicardial adipose tissue (EAT) has been suggested to contribute to left atrium dysfunction via paracrine mechanisms to induce endothelial dysfunction, pro-arrhythmogenic and pro-remodeling responses thereby favoring atrial fibrillation (AF) onset. Recently, sodium-glucose co-transporter2 inhibitors (SGLT2i) have been shown to reduce AF incidence, EAT volume, differentiation and inflammation, however, the underlying mechanisms are unknown. Purpose This study investigates the impact of human EAT-derived mediators on atrial endothelial cell function and, if so, to characterize the role of SGLT2 using the inhibitor empagliflozin (EMPA). Methods Epicardial and subcutaneous adipose tissues (SAT) were collected from 70 cardiac patients at a university hospital. Conditioned medium (CM, 24 h) from fats were applied to porcine atrial endothelial cells (AECs, first passage) for 24 h. Histology of tissues was assessed by haematoxylin and eosin staining, protein expression by Western blot analysis or immunofluorescence staining, mRNA levels by RT-qPCR, formation of reactive oxygen species (ROS) and nitric oxide (NO) by fluorescent probes, and pro-inflammatory cytokine levels by ELISA. Results Compared to SAT, EATs were more vascularized with increased infiltration of M1-like macrophages, expression of proinflammatory cytokines (IL-1ß, IL-6, TNF-α), markers of ECs VCAM-1 and eNOS, fibrosis TGF-β, NADPH oxidases NOX-1 and SGLT1/2. These effects were associated with a pro-oxidant response that was inhibited by neutralizing Abs directed against IL-1ß or IL-6, and by inhibition of either NOS, NADPH oxidases, ACE, AT1R or SGLT2. Levels of SGLT2 and ROS in EATs were higher in AF compared to non-AF patients and progressively increasing with age. CM of EATs showed higher concentrations of IL-1ß, IL-6, TNF-α and MCP-1 than that of SAT. Exposure of AECs to CM of EATs increased the level of oxidative stress that was positively correlated to the level of pro-inflammatory cytokines, and reduced basal and bradykinin-induced NO formation that was prevented by EMPA. It also resulted in upregulation of p53 and SGLT2 expression, and nuclear translocation of NF-kB by CM of the top quartile inflamed EATs but not by the lowest quartile of EATs or SATs, prevented by EMPA. Conclusion The findings indicate that compared to SATs, the EATs showed higher in situ expression and release of pro-inflammatory cytokines that contributed to oxidative stress involving the AT1R/NADPH oxidases/SGLT2 pro-oxidant pathway. CMs of inflamed EATs induced AECs dysfunction, oxidative stress and activation of NF-kB involving pro-inflammatory cytokines and SGLT2. Thus, SGLT2i appear as an interesting strategy to decrease EAT inflammation and improve endothelial function contributing to prevent cardiac remodeling and fibrotic responses.

Effects of empagliflozin on myocardial transcriptome in rats with aortic stenosis-induced heart failure

Abstract Introduction Aortic stenosis (AS) represents one of the most prevalent valvular heart diseases and an important cause of heart failure. Currently, no medical therapies influence the natural history of aortic stenosis. Although sodium glucose co-transporter 2 inhibitors (SGLT2i) have improved cardiovascular outcomes in heart failure patients with both reduced and preserved ejection fraction, their action mechanisms are not clear. Transcriptome analysis present great potential to identify biomarkers of disease and to gain insight into disease pathophysiology. In this study, we analyzed myocardial mRNA profile in aortic stenosis rats treated with empagliflozin. Methods Eighteen weeks after supra-aortic banding surgery, male Wistar rats were divided into 3 groups: Sham (n=15); aortic stenosis (AS, n=27); AS+empagliflozin (AS-EMP, n=27). Empagliflozin (10 mg/kg/day) was added to rat chow for 8 weeks. Transcriptome of left ventricle (LV) myocardium was studied by RNA-sequencing (sample size: 5 per group). Differential gene expression was analyzed in R environment using the DESeq2 package. Genes were considered differentially expressed (DEG) when they exhibited a log2 fold change (log2FC) higher than 1 (upregulated) or lower than -1 (downregulated), coupled with an adjusted p-value below 0.05. Functional enrichment analysis using gene ontology was performed by the online tool Enrich. Statistical analysis: ANOVA and Tukey. Results AS-EMP had lower LV diastolic diameter (Sham 8.39±0.57; AS 9.80±0.53*; AS-EMP 9.08±0.87# mm; p<0.05: * vs Sham; # vs AS), left atrium diameter (Sham 5.68±0.40; AS 9.67±1.00*; AS-EMP 8.97±1.36*# mm; p<0.05: * vs Sham; # vs AS), and LV mass (Sham 0.85±0.11; AS 2.19±0.27*; AS-EMP 1.76±0.34*# g; p<0.05: * vs Sham; # vs AS) than AS. A total of 1246 differentially expressed genes were identified, comprising 663 upregulated genes (70 genes in AS vs SHAM; 593 in AS-EMP vs AS) and 583 downregulated genes (35 genes in AS vs SHAM; 548 in AS-EMP vs AS). Most of the differentially expressed genes were enriched in processes such as extracellular matrix and structure organization, signal transduction regulation, and substrate-dependent cell migration (AS vs SHAM), as well as myocardial contraction, negative regulation of programmed cell death, and mitochondrial membrane organization (AS-EMP vs AS). The main upregulated genes were Loxl1, Mfap4, Postn, Col8a1, Pi16, and Nppa in AS vs SHAM; and Mxra8, Zfta, Pnisr, Thoc1, and Ralbp1 in AS-EMP vs AS comparison. The main downregulated genes were Mxra8, Ralbp1, and Tubgcp6 in AS vs SHAM; and Itgb5, Ltbp2, Tmem109, Plec, and Rorc in AS-EMP vs AS comparison. Conclusion We identified myocardial genes and biological processes that are potentially involved in aortic stenosis-induced heart failure. Empagliflozin attenuates cardiac remodeling and modulates myocardial genes involved with myocyte contraction, apoptosis, and mitochondrial organization in aortic stenosis rats.

The effects of SGLT2 inhibitors on right ventricle functions in heart failure patients: update meta-analysis of the current literature

Abstract Background There is some discrepancy in the present studies concerning the effect of sodium-glucose cotransporter type 2 (SGLT2) inhibitors on right ventricular (RV) functions in heart failure (HF) patients. The current meta-analysis was focused on determining the impact of SGLT2 inhibitors on RV functions in such individuals. Methods Two independent investigators searched PubMed, Google Scholar, and the Cochrane Library for articles of interest. To analyze heterogeneity, Higgins' I2 as well as prediction intervals and Egger's test were utilized to assess heterogeneity. The Newcastle-Ottawa standard ratings approach was used to assess the quality of observational studies. The Robin-I risk of bias algorithm was used to assess the bias risks of randomized studies. Results This meta-analysis evaluated 8 studies in total. Over the follow-up time frame, patients who used SGLT-2 inhibitors had substantially lower systolic pulmonary artery pressure (sPAP) and higher TAPSE values (mean difference (MD) = 1.30 [0.78;1.82], p =0.002 and MD =-5.39 [-7.88; -2.89], p=0.003, respectively). There was no significant difference in RVS’ values between follow-up and baseline (MD=1.38 [-1.35;3.80], p=0.169). However, as compared to the baseline period, fractional area contraction (FAC) values were substantially larger at the end of the follow-up period (MD=5.40 [3.74;7.07], p=0.015). Conclusion To the best of our knowledge, this is the first meta-analysis assessing the impact of SGLT2 inhibitors on RV function in HF patients. Our findings suggest that SGLT2 inhibitors may improve RV performance in HF patients.

Differences in the optimization of pharmacological treatment in patients with heart failure and reduced ejection fraction and advanced chronic kidney disease

Abstract Introduction Chronic kidney disease is very prevalent in patients with HF, makes their treatment difficult and worsens their prognosis, especially when it is advanced CKD (glomerular filtration rate <30 mL/min/m2). Renal insufficiency increases the risk of drug intolerance and an increase in serious side effects, which can lead to underuse, with consequent negative effects on patient prognosis. Purpose To analyze in a contemporary registry of HF patients followed in specialized HF units in Spain the achievement of dose targets for the most used drugs in HF with reduced ejection fraction (HFrEF) and the impact of advanced CKD. Methods We analyzed 914 patients with HFrEF consecutively included between 2019 and 2021 in the registry of the SEC-Excelente-IC quality accreditation program of the Spanish Society of Cardiology in 45 centers. We evaluated the proportion of patients treated with ACEI, ARA, ARNI, MRA, beta-blockers and SGLT2 inhibitors at the registry inclusion visit, the causes of non-prescription, and the achievement of the maximum dose recommended in the ESC clinical practice guidelines or the maximum tolerated dose in these patients, comparing the GFR groups, greater or less than 30 ml/min/m2. Results Of the 914 patients, 8.9% had a GFR<30 mL/min/m2. Their age was 76.9±9.7 years, 39.7% women, mean LVEF 32.8±9-6%. Patients with GFR<30 received in a significantly lower proportion all HF drugs except diuretics, ARBs and potassium chelators: sacubitril-valsartan 30.5% vs 59.2%; MRAs 31.7 vs 77.8%; SGLT2 inhibitors 34.1 vs 52.9% (p<0.001; Figure 1). The main reason for non-use was intolerance/contraindication for beta-blockers and "other" for the rest of the drugs (Figure 1). The proportion of patients in whom the maximum recommended, or maximum tolerated dose was reached was low in both groups, less than 40-50% for all drugs except MRA. There were no significant differences between the two groups in relation to the degree of renal dysfunction, although there was a tendency for the recommended doses to be obtained more frequently in the group with lower GFR (Figure 2). Conclusions In our contemporary cohort of real-life patients with HFrEF and advanced CKD, the use of recommended drugs for HF was significantly lower than in those patients with better renal function. However, where they were used, maximum recommended or tolerated doses were achieved in a higher proportion of patients. This indicates that with adequate selection it is possible to achieve the objectives proposed by the clinical practice guidelines in this complex group of patients.

Use of new antidiabetic drugs in patients with cardiovascular diseases - real life data

Abstract Introduction and aim Cardiovascular diseases (CVD) are among the most common and significant complications of type 2 diabetes mellitus (T2DM). Despite significant therapeutic progress in the prevention of CVD, T2DM remains a leading cause of major adverse cardiac events (MACE). Patients with T2DM and clinical manifestations of atherosclerotic CVD, or those at high risk of developing it, should receive cardioprotective and nephroprotective medications such as GLP-1 receptor agonists (GLP-1) and SGLT-2 inhibitors (SGLT2). This study aims to determine to what extent patients undergoing treatment at the general practitioner (GP) level comply with the recommendations. Methodology Retrospectively, in the period January 2022 to September 2023, records in the EHR were reviewed in the five GP offices. For all patients ( ≥18 years) with DMT2, all demografic as well as data on chronic therapy, stage of chronic kidney disease (CKD), presence of any cardiovascular (CV) risk factors and/or history of cardiovascular diseases (CVD), and the therapy applied were observed. Results A total of 6,941 patients' data were reviewed, out of which 483 (6.96%) had a diagnosis of DMT2. Table 1. shows the characteristics of the study population. Table 2. presents the values of HbA1c according to the criteria of good, acceptable, and poor DMT2 control, as well as the CKD stage by eGFR. Among the associated comorbidities, the most common was arterial hypertension, observed in 79.5% of the participants, followed by obesity in 28.2%. In terms of the applied therapy, the majority of participants were on metformin (76.8%). There were no significant differences in body mass index (BMI) and glycemic control between the group with and without CVD. However, compared to the group without CVD, patients with both DMT2 and CVD had a higher frequency of SGLT2 inhibitors (27% vs. 18.5%) [chi²=4.336, df=1, p=0.032] and GLP-1 receptor agonists (10.7% vs. 4.6%) [chi²=6.336, df=1, p=0.012] use, but a lower frequency of metformin (67.9% vs. 81.2%) [chi²=10.510, df=1, p=0.001]. Discussion According to current guidelines, all patients with CVD and CKD should have SGLT2 inhibitors and/or GLP-1 receptor agonists in their therapy. Comparing our study with the CAPTURE study, our patients were older and had slightly fewer associated CVD (38.7% vs. 32.9%). According to the CAPTURE study, less than 25% of patients with DMT2 in therapy have an antidiabetic medication with proven cardiovascular benefit, while in our sample, this was the case for 31.4% of the participants. This suggests that progress is being made, but it is still insufficient. Conclusion Over the past decade, there has been a rapid increase in knowledge regarding the appropriate treatment and management of risk factors in the population of individuals with DMT2. Although new insights are continuously incorporated into guidelines, our study shows that implementation in practice lags.

Impact of SGLT2 inhibitor dapagliflozin on myocardial protein profile in rats with long-standing Type 1 diabetes mellitus

Abstract Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial effects on the cardiovascular system in diabetes mellitus (DM) patients. However, as most trials have focused on Type 2 DM, the impact of SGLT2 inhibitors on Type 1 DM remains unclear. Objective To investigate the effects of long-term treatment with SGLT2 inhibitor dapagliflozin on the left ventricular (LV) proteome in Type 1 DM rats. Methods Male Wistar rats were divided into three groups: Control (C, n=7); Diabetes (DM, n=6); and Diabetes treated with Dapagliflozin (DM+DAPA, n=8) for 30 weeks. Diabetes was induced by streptozotocin (40 mg/kg). Dapagliflozin was added to chow at 5 mg/kg/day. Label-free mass spectrometry was used to assess LV proteome using a nanoAcquity UPLC-Xevo QTof MS system and ProteinLynx Global Server (PLGS) software. Cytoscape software, Cluster Marker, and Cluego plugins were used for bioinformatic analysis. Statistical analysis: ANOVA and Tukey or Kruskal-Wallis and Dunn. Results Dapagliflozin increased body weight (C 574±43; DM 339±31*; DM+DAPA 413±30*# g; p<0.05: * vs C; # vs DM) and reduced glycemia [C 108 (101–111); DM 554 (529–562)*; DM+DAPA 343 (237–416)*# mg/dL; p<0.05: * vs C; # vs DM]. One rat died in C and two in DM+DAPA. A total of 252 differentially expressed proteins were identified. Most proteins identified in the networks were downregulated in DM vs C and upregulated in DM+DAPA vs DM. Six proteins related to energy metabolism (Atp5j, P21571; CKm, P00564; Ak1, P39069; Atp5h, P31399; Mdh1, O88989; and Idh2, P56574), four involved in myocyte excitation-contraction (Act1, P68065; Casq2, P51868; SERCA1, Q64578; and SERCA2a, P11507), and two associated with oxidative stress (Sod1, P07632; and Sod2, P07895) were upregulated in DM+DAPA x DM. Comparing DM with C, the KEEG Pathway with the highest percentage of gene associations for upregulated proteins was related to gap junction (25.6%), necroptosis (25.6%), and fatty acid degradation (25.6%), and for downregulated proteins was related to Alzheimer disease (27.3%), cardiac muscle contraction (25%) and glycolysis/gluconeogenesis (13.6%). Comparing DM+DAPA with DM, the KEEG Pathway with the highest percentage of gene associations for upregulated proteins was related to Parkinson disease (18.3%), cardiac muscle contraction (14.2%), citrate acid cycle (9.47%), necroptosis (8.88%), and cGMP-PKG signaling (7.10 %), and for downregulated proteins was related to ketone bodies synthesis and degradation (100%). Conclusion Dapagliflozin is safe and prevents changes in the expression of proteins related to energy metabolism, cardiac muscle contraction, and oxidative stress in Type 1 diabetes mellitus rats. These results offer new insights into the cardioprotective mechanisms of dapagliflozin in Type 1 diabetes mellitus.

Clinical characteristics and treatment patterns of new users of dapagliflozin for heart failure with reduced ejection fraction: an observational study programme across 12 countries (EVOLUTION HF)

Abstract Background Clinical trials have shown that dapagliflozin, a sodium–glucose cotransporter-2 inhibitor (SGLT-2i), reduces cardiovascular mortality and worsening heart failure (HF). Adoption of new therapies has historically been slow despite robust evidence. Furthermore, treatment profiles of patients in real-world settings are scarce. Purpose EVOLUTION HF is a multinational study programme that aims to describe clinical characteristics and treatment patterns among patients initiating dapagliflozin for HF with reduced ejection fraction (HFrEF) in routine clinical practice. Methods The EVOLUTION HF primary data study programme consists of prospective, observational, descriptive studies of new users of dapagliflozin for HFrEF in 12 countries (Italy, Portugal, UK and the Central and Eastern Europe and Baltic [CEEBA] region [Bulgaria, Croatia, Estonia, Hungary, Latvia, Lithuania, Poland, Romania and Slovenia]). Patients with type 1 diabetes or prior SGLT-2i treatment were excluded. Clinical characteristics were obtained from electronic health records. A total of 2170/2555 (85%) patients were enrolled from November 2021 to November 2023; 1736 patient profiles were assessed using descriptive statistics in this interim analysis. Results In total, 256, 228, 125 and 1127 new dapagliflozin users were analysed from Italy, Portugal, the UK and the CEEBA region, respectively (Table 1). Across the 12 countries, mean patient age in the studies was 65–70 years. Patients were predominantly male (67–76%) and generally had HF with an ischaemic aetiology (35–56%) and New York Heart Association functional class II (52–85%). Mean left ventricular ejection fraction in the studies was 29–32% and estimated glomerular filtration rate was 61–77 mL/min/1.73m². Hypertension and atrial fibrillation were common comorbidities. Mean time between HF diagnosis and dapagliflozin initiation in the studies was 23–52 months. Background therapy included angiotensin receptor-neprilysin inhibitors (36–72%), angiotensin receptor blockers (4–12%) and angiotensin-converting enzyme inhibitors (9–33%). At 6 and 12 months after dapagliflozin initiation, respectively, treatment discontinuation rates across the CEEBA region were 5.22% (59/1131) and 4.66% (50/1072). Conclusions The EVOLUTION HF primary data study programme provides novel insights into clinical characteristics and treatment patterns in patients with HFrEF initiating dapagliflozin in real-world practice across a broad European population. At dapagliflozin initiation, a large proportion of patients were receiving other HF therapeutics, suggesting dapagliflozin is one of the later therapies to be initiated. Indeed, this study identified a substantial delay (23–52 months) in dapagliflozin initiation following HF diagnosis. Treatment discontinuation rates following dapagliflozin initiation were also low, reinforcing the findings of the EVOLUTION HF secondary data studies.

Advancing care in type 2 diabetes and atherosclerosis: assessing pharmacist-led strategies in England's primary care - a retrospective observational study

Abstract Background Type 2 diabetes (T2D) mellitus is a complex multi-system disorder with a tendency to develop complications. ‘Persistence to therapy’ plans affect almost 50% of all people with T2D, leading to suboptimal glycaemic and cardiovascular (CVD) risk factor control. The interplay between T2D and established atherosclerotic cardiovascular disease (ASCVD) underscores the need for a comprehensive, multidisciplinary approach to care that addresses both glycaemic control and CVD risk factors. Purpose This study retrospectively analysed pharmacist-led interventions in patients living with T2D and established ASCVD in general practices in a large UK city. Methods A retrospective pre-post observational study was conducted using electronic health record data from men and women diagnosed with T2D and ASCVD. Participants attended an independent prescribing pharmacist-led clinic within 21 general practices. The practices operated linked and comprehensive electronic health records systems, facilitating access to high-quality longitudinal data that align with study objectives. Results A total of 380 patients received pharmacist-led interventions. Comparisons of pre-intervention and post-intervention data revealed a significant decrease in HbA1c levels (73.7 ± 10.7 mmol/mol vs 67.2 ± 8.5 mmol/mol, p < 0.01), systolic blood pressure (132 ± 10.2 mmHg vs 125.9 ± 9.9 mmHg, p < 0.01), and diastolic blood pressure (76.8 ± 5.9 mmHg vs 72.4 ± 5.0 mmHg, p < 0.001). Additionally, total cholesterol levels significantly reduced from 4.4 ± 0.7 mmol/L to 3.9 ± 0.7 mmol/L (p < 0.001). The proportion of patients achieving the triple target of HbA1c (≤58 mmol/mol), BP (≤140/80 mmHg), and total cholesterol (≤5 mmol/L) increased significantly from 2.4% before the intervention to 23.4% afterward (p < 0.001). The initiation of the sodium-glucose co-transporter 2 inhibitors (SGLT2i) therapies was the most common prescribing intervention (67%). Conclusions Pharmacist-led interventions in a general practice setting significantly improved several critical diabetes and CVD risk related outcomes. These findings underscore the potential benefits of integrating pharmacist-led care models into the management of T2D, particularly for patients with concurrent ASCVD and adopting an individualised, evidence-based approach to prescribing interventions.

Assessing the practicality of a novel heart failure therapeutic score (QUAD Score) for drug optimisation in heart failure with a reduced ejection fraction

Abstract Introduction The 4 pillars of drug treatment for heart failure with a reduced ejection fraction (HFrEF) [Angiotensin-converting enzyme inhibitors (ACEi)/Angiotensin receptor–neprilysin inhibitors (ARNi), β-blockers (BB), Mineralocorticoid receptor antagonists (MRA), and Sodium-glucose cotransporter 2 inhibitors (SGLT2i)], are recommended by international HF guidelines to improve patient outcomes. Treatment inertia remains a challenge with non-prescription or sub-optimal dosing of these therapies. We developed a pragmatic HFrEF treatment score (QUAD score) (Figure 1) to prompt initiation and/or titration of sub-optimally dosed foundational therapies. Patients are categorized as poor (<8), good (8-14), and excellent (15-24) based on the dose and number of foundational drugs prescribed. This study aims to assess the practical utility of the QUAD score and its influence on treatment optimization. Methods Unwarned prescribing HCPs were approached consecutively in person, within clinical settings. Participants were told the questions were part of a research project and they provided verbal consent. Responses were anonymous and no patients were involved; therefore, verbal consent was considered proportionate and reasonable. HCPs were given an information sheet describing the QUAD score (Figure 1). They were then presented with 3 hypothetical clinical scenarios of haemodynamically stable and uncomplicated HFrEF patients with uncalculated poor, good and excellent QUAD scores. They were asked to calculate the QUAD score and if they proposed any changes to treatment. Time was recorded using a stopwatch and proposed changes were recorded. They were then invited to answer a series of follow-on questions. Results Between September 2023 and February 2024, there were 70 respondents. 71% (50) were doctors and 29% (20) allied HCPs. 83% (58) placed patients in the correct treatment grade in at least one scenario. 62.9% (44) did so for all three scenarios (Figure 2) with numerically more HCPs compared to doctors (80% vs 56% p=0.06).The median (IQR) time in seconds required to calculate the QUAD score for clinical scenarios 1,2 and 3 was 158 (100-234), 86 (54-122) and 83 (53-119) respectively. In response to the calculated QUAD score, 94.3% (66), recommended drug treatment optimisations. On a 5-point Likert scale (1 -poor, 5- excellent), 77.1% of participants rated the QUAD score ≥3 for ease of use, and 88.6% rated ≥3 as an incentive for treatment optimization. Conclusion We demonstrated the rapid clinical usability of the QUAD Score in a cohort of unselected prescribing HCPs, with a decremental calculation time with each presented clinical scenario. HCPs were also motivated to achieve further HF drug therapy optimization based on the calculated score. We conclude that the QUAD Score as a HFrEF drug therapy score may have a role in addressing treatment inertia however, it needs validation against clinically relevant outcomes in a larger cohort of HFrEF patients.

Systolic plood pressure response to ASi BI 690517 with and without empagliflozin in CKD

Abstract Background and Aims: BI 690517 is a highly selective aldosterone synthase inhibitor (ASi) in clinical development for CKD treatment. Coadministration of BI 690517 with a sodium-glucose cotransporter-2 inhibitor may provide additive efficacy and also mitigate risk of hyperkalaemia. This multinational, randomised, dose-finding, Phase II trial (NCT05182840) investigated the efficacy and safety of BI 690517, given alone or in combination with empagliflozin (EMPA), for albuminuria reduction in people with CKD and with or without type 2 diabetes.1 Here, we present a secondary analysis for effects on systolic blood pressure (SBP). Method Adults with CKD receiving a maximally tolerated dose of a renin-angiotensin system inhibitor were randomised (R1) 1:1 to receive background EMPA 10 mg or placebo (PBO-EMPA) during an 8-week run-in. They were then re-randomised (R2) 1:1:1:1 to receive BI 690517 (3 mg, 10 mg, or 20 mg) or PBO-ASI for 14 weeks, in addition to their assigned EMPA or PBO-EMPA therapy. Participants had mean baseline SBP ≥110 and ≤160 mmHg. Elevated blood pressure (BP) was defined as SBP ≥140 mmHg or DBP ≥90 mmHg and receiving ≥2 classes of anti-HTN medication. Changes in SBP from R2 baseline to Week 14 were analysed to assess BI 690517 effects with and without EMPA use. Results Of 714 people randomised at R1, 586 were randomised at R2, and the treated set consisted of 583 people. Demographics and clinical characteristics were similar between dose groups.1 At R2 baseline, 169 (29.0%) people had elevated BP. Mean SBP was 142.7 mmHg in the elevated BP group versus 129.2 mmHg in the non-elevated BP group. Treatment with BI 690517 consistently reduced SBP with reductions that were comparable in people with and without elevated BP (p-value for interaction not significant) (Table). Conclusions In people with CKD, BI 690517 reduced SBP in people with and without elevated BP.(Table)

Guideline-directed medical therapy titration for heart failure with ischaemic aetiology and its effect on cardiac remodelling and cardiovascular mortality-from a real world perspective

Abstract Background Contemporary Heart Failure (HF) pharmacological treatment has been reshaped by several landmark trials in recent years, and available evidence strongly encourages treatment up-titration to target doses. Recent literature regarding treatment sequencing demonstrated positive effects of up-titration on major outcomes regardless of HF aetiology. Purpose We investigated a contemporary Heart Failure with Reduced Ejection Fraction (HFrEF) patient cohort and ischaemic aetiology and sought to understand the effects both in terms of echocardiographic remodelling and upon mortality for cardiovascular (CV) causes of contemporary ESC guideline-directed medical therapy (GDMT) on a real-world level. Methods We retrospectively analysed data of consecutive patients with HFrEF and ischaemic genesis followed in our tertiary HF clinic between January 2019 and January 2022. Eligible patients were stratified into two groups: patients treated or not with full doses of ESC GDMT [including angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) or angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i)]. Results Overall, 203 patients (mean age 70.1±12.3 years, 165 males) were included into the analysis. Over a mean follow-up of 1223±221.2 days, 115 (56.6) patients achieved the full recommended doses of each drug. Patients with an unsuccessful up-titration had higher end-diastolic volume at transthoracic echocardiography (p for difference at first and second follow-up <0.001; figure 1, panel A), lower left ventricular ejection fraction (40.1±4.3% vs 44.3±7.8 and 38.7±4.9% vs 42.3±5.6% at the first and second follow-up, respectively) and higher CV mortality rates compared to those treated with the maximal doses (figure 1, panel B). Conclusions Up-titration of pharmacotherapy in our real-world cohort of patients with HFrEF and ischaemic aetiology demonstrated a positive effect both on pivotal echocardiographic parameters and on CV mortality. Our data suggest that timely identification and referral of patients with coronary artery disease who fail to achieve complete positive remodelling after an acute event (or during chronic disease course) for HF contemporary treatment implementation should be envisaged.Figure 1

Effects of empagliflozin on cardio-renal interaction in heart failure with reduced ejection fraction: results from in-vivo experiments and the CINNAMON-study

Abstract Background Heart failure is often accompanied by renal dysfunction, which indicates a pathophysiological connection between the heart and kidneys. Empagliflozin, a SGLT2 inhibitor, showed beneficial effects on both cardiovascular and renal endpoints. Mechanistically, however, it is unclear whether the empagliflozin-dependent renal protection is mediated via the inhibition of renal SGLT2 or rather indirectly via improved cardiac function. Interestingly, in the EMPEROR trials, there was a significant interaction of empagliflozin-dependent kidney protection with systolic contractile dysfunction. We hypothesized that Empagliflozin treatment ameliorates heart failure in response to chronic pressure overload in mice leading to improved renal function. We correlated these findings with data from our prospective, single-armed trial. Methods Transverse aortic constriction (TAC) or sham surgery was performed in C57BL/6J (wildtype, WT) and SGLT2 deficient mice (SGLT2-/-). Animals received either Empagliflozin (10 mg/kg bodyweight) or vehicle by daily oral gavage. Cardiac function was evaluated by echocardiography and kidney function by transdermal FITC-Sinistrin measurement (GFR), urinary albumin/creatinine ratio (UACR) and Siriusred fibrosis staining. Results After 10 weeks, echocardiography confirmed TAC induced pressure-overload, leading to reduced left ventricular ejection fraction (LVEF) and diastolic dysfunction. Empagliflozin attenuated changes in LVEF (Fig. A) and improved diastolic dysfunction (data not shown). Interestingly, at 10 weeks, TAC reduced GFR, increased UACR and tended to increase renal fibrosis, which was attenuated by empagliflozin (Fig. B, C and D). To test if direct inhibition of SGLT2 in the heart and kidney is mechanistically involved, TAC surgery was repeated in SGLT2-deficient mice (SGLT2-/-). In fact, exposure to TAC resulted in comparable reduction of LVEF in SGLT2-/- mice and Empagliflozin prevented this deterioration similar to WT mice (Fig. E vs. A). Surprisingly, Empagliflozin also prevented GFR deterioration 10 weeks after TAC in mice lacking SGLT2 (SGLT2-/-) with comparable magnitude as in WT mice (Fig. F), suggesting that the reno-protective effect of Empagliflozin was independent from renal SGLT2 inhibition. The effect of empagliflozin on the heart and kidney was also investigated in patients with HF (prospective, single-arm CINNAMON-study, DRKS00031101). After 180 days of Empagliflozin treatment (10 mg), there was a significant improvement in LVEF, NT-proBNP levels and KCCQ-12 Scores (Fig. G-I) and the effects on UACR and GFR are subject of investigation. Conclusion This is the first study investigating the role of SGLT2 in Empagliflozin-dependent kidney protection of mice that develop heart failure after TAC. Importantly, empagliflozin treatment prevented deterioration of LVEF and GFR independent of the presence of SGLT2 in mice and improved cardiac markers and quality of life in patients.

Diuretic therapy strategies in decompensated acute heart failure: a systematic review and network metanalysis

Abstract Background Congestion in acute heart failure (AHF) is treated with furosemide, mainly in continuous infusion (furosemide continuous, FC) or iv boluses, and combination of different diuretics. Randomized controlled trials (RCTs) only compared the efficacy and safety of some diuretic strategies with discordant results. Purpose To provide a comprehensive synthesis of the effects of diuretic regimens in AHF. Methods The PubMed, EMBASE, SCOPUS and Cochrane databases were searched for phase III RCTs until July 31st, 2023, evaluating diuretics without any other intervention in patients admitted for AHF, with randomization within 48 hours, no run-in period and/or need of clinical stabilization. The arms assigned to iv boluses or undefined schemas of furosemide/loop diuretic (LD) were grouped together as "furosemide bolus" (FB). The endpoints were weight loss over 24 hours (WL), worsening renal function (WRF), total urine output (tUO) and net urine output (nUO) over 24 hours, hypokalemia (hypoK), and hyponatremia (hypoNa). Heterogeneity was estimated by Thompsons’ I2 statistics, and odds ratios (OR) with 95% confidence intervals were calculated by means of a random-effects model with inverse variance weighting. A leave-one-out analysis, an analysis limited to studies with specified mode of furosemide/LD administration, and an analysis of measures of congestion/decongestion were also carried out. Results Twenty-five RCTs were selected, for a total of 7,095 patients with mean age 69.2±11.1 years and mean LVEF 38.1±12.7%. In subjects treated with furosemide/LD, the mean furosemide equivalent dose was 154.7±53.0 mg/24 hours. Heterogeneity was moderate-to-high (37.3%-66.0% across the study endpoints). FC, FB plus tolvaptan, FB plus sodium-glucose cotransporter inhibitor (SGLT2i), and FB plus thiazide were associated with greater WL than FB (Figure 1A). The combination of FB and thiazide or SGLT2i also portended higher odds of WRF than FB alone, as did the combination of FB and acetazolamide (Figure 1B). tUO was greater with FC (OR 2.77 [1.98-3.88]), FB plus tolvaptan (OR 1.69 [1.22-2.35]), and FB plus SGLT2i (OR 1.95 [1.16-3.28]) than with FB, and nUO was greater with FC (OR 1.50 [1.06-2.13]) and FB plus tolvaptan (OR 1.76 [1.06-2.92]) than with FB. Compared with FB, hypoK was more frequent with FB and thiazide (OR 1.68 [1.29-2.19]), while there was a trend for less hypoK events with FB plus tolvaptan (OR 0.86 [0.69-1.08]). No differences in hypoNa rates were found. Sensitivity analyses were consistent with the main one. Thirteen (52%) and 14 (56%) studies had published information about symptoms and signs of congestion, respectively, and 6 (24%) adopted pre-specified scoring systems. Conclusions FC and most combination diuretic regimens have greater efficacy than FB in promoting WL and diuresis, but at the cost of WRF and hyoK, especially when thiazide is used. Congestion has inconsistently been evaluated in RCTs of diuretic therapy in AHF.

Tubulointerstitial injury in proteinuric chronic kidney diseases

Proteinuria is an independent risk factor for chronic kidney disease progression and cardiovascular diseases. Apart from its prognostic role, the load of proteins that pass across the disrupted glomerular capillary wall trigger multiple pathophysiologic processes. These include, among others, intratubular complement activation and excessive proximal tubular reabsorption of filtered proteins, especially albumin and albumin-bound free fatty acids, which can set off several pathways of cellular damage. The activation of these pathways can cause apoptosis of proximal tubular cells and paracrine effects that incite the development of interstitial inflammation and fibrosis, ultimately leading to irreversible kidney injury. In this review, we provide a comprehensive overview of the current understanding on the mechanisms underlying the tubular toxicity of ultrafiltered proteins in the setting of proteinuric chronic kidney diseases. The acquired knowledge is expected to be instrumental for the development of novel therapeutic classes of medications to be tested on top of standard of care with optimized renin-angiotensin-aldosterone blockade and sodium-glucose cotransporter-2 inhibition, in order to further improve the clinical outcomes of patients with proteinuric chronic kidney diseases.

Efficacy and safety of dapagliflozin in non-diabetic patients with primary anterior ST-elevation myocardial infarction initiated in early hospital period

Abstract Background The effectiveness of SGLT2 inhibitors has been proven in all types of chronic heart failure (HFpEF, HFmrEF, and HFrEF), regardless of the presence of diabetes mellitus. There are still no clear recommendations regarding the timing of SGLT2 inhibitor administration after myocardial infarction (MI) and its influence on prognosis. It can be assumed that it is appropriate to consider the possibility that, if started quickly after the presentation of acute MI, SGLT inhibition might enhance outcomes in patients. Objective This study aims to investigate the efficacy and safety of the SGLT2 inhibitor Dapagliflozin in primary anterior ST-segment elevation myocardial infarction (STEMI) initiated in early hospital period, irrespective of heart failure manifestation. Methods The study includes 124 non-diabetic patients with primary anterior STEMI who underwent primary PCI and had left ventricular ejection fraction (LV EF) ≤45% and NT-proBNP > 900 pg/ml at symptom onset within 24 hours, regardless of heart failure symptom manifestation. Patients with cardiogenic shock were excluded. 62 patients received standard medical treatment including beta-blockers, ACE inhibitors (Control group), while the other 62 patients were administered the SGLT2 inhibitor Dapagliflozin 10 mg once a day during the first 48 hours of inpatient treatment, in addition to standard therapy (Dapa group). All patients were followed up for one year. Echocardiography was performed during the first 24 hours. Echocardiography and NT-proBNP were repeated at the end of the year. The primary endpoint was the one-year heart failure hospitalizations and secondary endpoints included one year cardiovascular mortality and changes in NT-proBNP, plasma creatinine and glycosylated hemoglobin levels. Results The study shows a significant difference in heart failure hospitalization between the groups. In the Control group, it was 25.8%, and in the Dapa group, it was 8.1% (p = 0.008). Initially, there were no significant changes in NT-proBNP levels; 1152.2 ± 222.4 pg/ml in the Control group and 1197.3 ± 279.8 pg/ml in the Dapa group (p= 0.33). At the end of a year, NT-proBNP increased in the Control group (1827.4 ± 317.8 pg/ml), whereas in the Dapa group, it significantly decreased (613.5 ± 215.6 pg/ml) (p < 0.01). One-year cardiovascular mortality in the Control and Dapa groups was 9.7% and 4.8%, respectively(p=0.491). Other blood markers did not differ, and side effects were comparable during the in-hospital period as well as at the end of the year. Conclusion Early administration of Dapagliflozin among non-diabetic patients with primary anterior STEMI is associated with a significant decreasing of heart failure hospitalization rate and NT-proBNP level. Additionally, early administration of dapagliflozin does not impact on safety indicators.

Comparison of ventricular tachyarrhythmias in HF patients on dapagliflozin versus empagliflozin

Abstract Background Ventricular tachycardia (VT) and ventricular fibrillation (VF) are devastating tachyarrhythmias that can cause sudden cardiac death in patients with heart failure (HF) if not anticipated or treated promptly. Although post-hoc analysis in DAPA-HF showed promise in their benefit, Sodium-glucose transport protein 2 inhibitors (SGLT2i) have not yet been evaluated for their effect on these tachyarrhythmias. This retrospective analysis aims to compare the 2 most commonly used SGLT2i agents, dapagliflozin and empagliflozin, and the incidence of VT in patients with HF. Methods The TriNetX Research network was used for this study. The two initial patient cohorts were created using ICD-10 codes and medication codes from the TriNetX platform. Both cohorts consisted of patients over age 60 with a history of heart failure and either VF or VT. One cohort was on treatment with dapagliflozin and the other with empagliflozin. The cohorts were balanced by propensity score matching and the greedy nearest neighbor algorithm for age, gender, race, ethnicity, hyperkalemia, and the current use of spironolactone, amiodarone, metoprolol, and carvedilol, resulting in 9,841 patients in each arm. The cohorts were then evaluated for the development of VF or VT over the subsequent five years as well as all-cause mortality. Additional cohorts were created to evaluate dapagliflozin vs empagliflozin in diabetics, nondiabetics, and patients with ejection fractions less than 35% Results Dapagliflozin was associated with an increased risk of ventricular arrhythmia in heart failure patients compared to empagliflozin (46.0% vs. 40.8%, RR 1.13, 95% CI (1.09,1.16), P value < 0.0001). It was also associated with higher mortality at five years (RR 1.10, 95% CI (1.03,1.18), P value 0.0034). Conclusions In comparisons between dapagliflozin and empagliflozin in heart failure patients with previously documented ventricular arrhythmias, empagliflozin had 13% less risk of recurrence of ventricular arrhythmias. Secondarily, the empagliflozin cohort also exhibited lower all-cause mortality (14.8% vs 16.3%) at five years from starting the drug. Our analysis does not disprove findings in DAPA-HF, but rather may support the potential class effect of SGLT2 inhibitors in their ability to suppress VT.(1) Importantly, the overall incidence of ventricular tachyarrhythmias is high in both cohort, given we selected a high-risk population. Notably, our documented recurrence rate is similar to past reports of recurrence after VT ablation, the gold standard for treatment of VT. (2) SGLT2 inhibitors have shown clear benefit in multiple placebo-controlled studies in terms of heart failure outcomes like mortality and readmission, but their effect on arrhythmias is one more additional benefit this class may have. (3) Given these associations, empagliflozin may be a more favorable options for HF patients who have already had VT or VF.