To evaluate the association of sodium-glucose cotransporter 2 inhibitors (SGLT2i) with diabetic ketoacidosis (DKA) in type 2 diabetes mellitus (T2DM) patients across different subgroups, we searched randomized controlled trials (RCTs) comparing SGLT2i with the control groups among T2DM patients and including DKA as a safety outcome. Pooled risk ratios (RRs) were calculated using random or fixed-effects models, as appropriate. An inverse-variance-weighted Mendelian randomization (MR) analysis was performed to estimate the genetic correlation. Twenty-two trials involving 80,235 patients were included. SGLT2i increased the risk of DKA compared to the control groups (RR 2.32, 95% CI 1.64-3.27). The risk was significantly increased in patients with higher HbA1c levels (> 7.9%) (RR 2.24, 95% CI 1.59-3.14), but not in those with lower HbA1c levels (≤ 7.9%) (RR 1.05, 95% CI 0.49-2.26; interaction P = 0.034). SGLT2i increased DKA risk in chronic kidney disease (CKD) (RR 2.70, 95% CI 1.55-4.71) and high atherosclerotic cardiovascular disease (ASCVD) risk trials (RR 2.46, 95% CI 1.47-4.11) but not significantly in heart failure (HF) trials (RR 1.23, 95% CI 0.51-2.96). Moreover, in the HF trials, SGLT2i consistently did not increase the risk of DKA in any clinical subgroups. Nevertheless, MR analysis still confirmed a genetic association between SGLT2i and the risk of DKA among overall T2DM patients. SGLT2i may increase the risk of DKA in T2DM patients, particularly in patients with higher levels of HbA1c and those with comorbid CKD or at high-risk ASCVD. However, the increased risk was not significant in patients with HF.

Diabetic cardiomyopathy (DbCM) is increasingly prevalent, but intervention targets remain unclear due to the lack of appropriate models and the complexity of risk factors. Here, this work establishes an in vitro assessment system for DbCM function using cardiomyocytes derived from human pluripotent stem cells and engineered heart tissue. This work finds high-fat status in complex diabetes risk factors majorly contributes most to cardiomyocyte death and contractile dysfunction. Notably, PA induced early electrophysiological abnormalities, and lately is associated with cardiac fibrosis, mitochondrial fission, and systolic and diastolic dysfunction at tissue level. Using this in vitro assessment system, this work finds that empagliflozin (EMPA), a first-line glucose-lowering drug, effectively alleviated early PA-induced cardiomyocyte injury. Treatment with EMPA enhanced abnormal diastolic and electrophysiological functions in the PA-hEHT model and significantly reduced endoplasmic reticulum stress, and apoptosis. Furthermore, these promising results are confirmed in a type 2 diabetes mellitus mouse model, reinforcing the potential of EMPA as a therapeutic option to alleviate cardiomyocyte injury under diabetic conditions. These findings suggest that this work has developed an engineered model of diabetic cardiomyopathy that mimics the various stages of lipotoxic myocardial injury and support the use of EMPA as a potential therapeutic option for diabetic or lipotoxic cardiomyopathy.

The high disease burden and bidirectional relationship of chronic kidney disease (CKD), heart failure (HF) and other cardiovascular disease (CVD) necessitate the need for early diagnosis of these diseases. While current screening and detection methods are recommended by CKD and CVD guidelines, their adoption in practice is low. Urine albumin-to-creatinine ratio (uACR) is recognized as a diagnostic marker for CKD and a prognostic marker for CKD progression, HF and CVD outcomes, therefore albuminuria changes have been accepted as a surrogate outcome for kidney and cardiovascular endpoints. Furthermore, clinical trials investigating guideline-directed medical therapies have shown that uACR reductions are accompanied by risk reductions for cardiovascular, HF and other CKD outcomes. However, uACR is not routinely measured in patients at risk of kidney and heart disease, and its utility for detection, risk stratification and prediction models may not be fully appreciated in routine clinical practice. This review will discuss the effectiveness and implications of uACR screening as a method for heart and kidney disease diagnosis and risk assessment.

Clinical trials have established the prognostic benefits of sodium‒glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and heart failure (HF) with preserved ejection fraction (HFpEF), although the underlying mechanisms are not clearly understood. The purpose of this study was to determine the effects of the SGLT2 inhibitor empagliflozin on functional capacity, left ventricular (LV) diastolic function/filling pressure, and cardiac reserves in patients with HFpEF and T2DM.

In the present prospective single-center trial, we enrolled 70 diabetic patients with stable HF according to the New York Heart Association functional class II-III criteria, an LV ejection fraction ≥ 50%, and increased LV filling pressure at rest and/or during exercise (determined by echocardiography). The patients were randomly assigned in an open-label fashion to the empagliflozin group (10 mg a day, n = 35) or the control group (n = 35) for 6 months. Echocardiography (at rest and during exercise), the 6-min walk test distance (6MWD), blood levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), and the profibrotic biomarker sST2 were analysed at baseline and 6 months after randomization. The primary endpoint was the change in the 6MWD, and the secondary endpoints included the change in the left atrial (LA) volume index, early mitral inflow to mitral annulus relaxation velocity (E/e') ratio both at rest and during exercise, key cardiac reserves and biomarkers in the blood from baseline to 6 months.

After 6 months of empagliflozin therapy, the 6MWTD significantly increased, whereas the LA volume index and the E/e' ratio both at rest and during exercise decreased compared with those of the control group (P < 0.05 for all). LV diastolic, LA reservoir and contractile, and chronotropic reserves also improved in the empagliflozin group compared with those in the control group (P < 0.05 for all). Furthermore, treatment with empagliflozin led to improvements in NT-proBNP and ST2 blood levels compared with those in the control group (P < 0.05 for both).

In diabetic patients with HFpEF, empagliflozin treatment improved exercise capacity, which appeared to be the result of favourable effects on LV diastolic dysfunction and key cardiac reserves: LV diastolic, LA reservoir and contractile, and chronotropic. These haemodynamic mechanisms may underline the benefits of SGLT2 inhibitors in large-scale HFpEF trials.

URL: https://www.

gov . Unique Identifier NCT03753087.

To investigate the efficacy and safety of sodium-glucose cotransporter 2 (SGLT-2) inhibitors in patients with heart failure (HF) and type 2 diabetes mellitus (T2DM).

A manual search was conducted in 3 prestigious English databases, Cochrane Library, PubMed, and Web of Science, for studies published within the last decade, from July 2014 to July 2024. The extracted literature was synthesized to analyze the efficacy outcomes, survival prognostic indicators, and safety profiles of SGLT-2 inhibitors in patients with HF and T2DM. The Cochrane bias risk assessment scale was used as a tool to evaluate the quality of the literature, and Review Manager 5.4 software was used to create the bias risk chart. Data analysis and merging were completed with the help of Review Manager 5.4 and Stata 15.0 statistical software.

Twelve studies encompassing 9509 patients were included in the meta-analysis. The results revealed that compared to the control group, the SGLT-2 inhibitor-treated group demonstrated significantly greater reductions in left ventricular end-diastolic volume index [mean difference (MD) = -7.25, 95% confidence intervals [95% CI] (-9.83, -4.67)], brain natriuretic peptide levels [MD = -36.96, 95% CI (-63.51, -10.41)], and N-terminal pro-brain natriuretic peptide [MD = -519.27, 95% CI (-660.77, -377.78)]. Furthermore, the SGLT-2 inhibitor-treated group exhibited significantly higher increases in Kansas City Cardiomyopathy Questionnaire scores [MD = 3.32, 95% CI (3.30, 3.34)], indicating improved quality of life. Additionally, the incidence of adverse events was significantly lower in the SGLT-2 inhibitor-treated group compared to the control group [OR = 0.78, 95% CI (0.69, 0.88)]. The pooled results of the meta-analysis indicated that SGLT-2 inhibitor therapy reduced the risk of cardiovascular death or HF hospitalization by 23%, the risk of cardiovascular death by 19%, and the risk of all-cause mortality by 9%.

SGLT-2 inhibitor therapy significantly reduced the risks of all-cause mortality, cardiovascular death, and hospitalization for HF in patients with HF and T2DM. Additionally, SGLT-2 inhibitors significantly improve cardiac function, decrease the incidence of adverse events, and enhance the quality of life in these patients.

Recent evidence suggests that empagliflozin (EMPA) and metformin (MET) may improve prognosis in heart failure with preserved ejection fraction (HFpEF) patients. This study aims to compare their effects on cardiac structure and function in HFpEF.

Male C57BL/6J mice were fed a high-fat diet with L-NAME for 8 weeks to induce HFpEF, followed by 4 weeks of MET or EMPA treatment. Cardiac structure and function were assessed. Network pharmacology and bioinformatics identified key targets, validated by RT-qPCR and WB.

EMPA-treated mice lost weight, unlike MET-treated ones. MET reduced systolic blood pressure significantly. Both treatments improved glucose tolerance; MET enhanced insulin sensitivity. EMPA increased exercise tolerance by extending exhaustion distance. Both treatments improved diastolic function, reduced heart weight, and attenuated myocardial fibrosis and hypertrophy. Plasma NT-proBNP levels were slightly elevated but not significant. EMPA downregulated HSP90 mRNA and protein expression; both drugs downregulated TGFβ.

MET and EMPA improve cardiac fibrosis, diastolic function, and pulmonary congestion in HFpEF mice. MET acts by downregulating TGFβ, while EMPA affects collagen metabolism and downregulates HSP90 and TGFβ. These findings offer insights into HFpEF treatment.

This clinical consensus statement revisits the role of left ventricular ejection fraction (LVEF) as a measurement of cardiac function, a prognostic marker and a major criterion to classify patients with heart failure, and gives new advice for clinical practice. Heart failure is traditionally classified on the basis of LVEF thresholds and this has major implications for treatment recommendations. However, the reproducibility of LVEF measurement is poor and its prognostic and diagnostic value lessens when it is above 45%, with no relationship with the severity of either cardiac dysfunction or outcomes at higher values. These limitations dictate the need for a more comprehensive approach to classify and assess heart failure focusing more on the trajectory of LVEF rather than to its absolute value. Furthermore, the assessment of LVEF is not required for the initiation of treatments like sodium-glucose cotransporter 2 inhibitors, mineralocorticoid receptor antagonists and diuretics in patients with suspected de novo heart failure and elevated N-terminal pro-B-type natriuretic peptide levels. Future research utilizing advanced imaging techniques and biomarkers which can better characterize myocardial structure, metabolism and performance may facilitate the identification of alternative therapeutic targets and better ways to monitor heart failure therapies across the entire spectrum of LVEF.

This clinical consensus statement revisits the role of left ventricular ejection fraction (LVEF) as a measurement of cardiac function, a prognostic marker and a major criterion to classify patients with heart failure, and gives new advice for clinical practice. Heart failure is traditionally classified on the basis of LVEF thresholds and this has major implications for treatment recommendations. However, the reproducibility of LVEF measurement is poor and its prognostic and diagnostic value lessens when it is above 45%, with no relationship with the severity of either cardiac dysfunction or outcomes at higher values. These limitations dictate the need for a more comprehensive approach to classify and assess heart failure focusing more on the trajectory of LVEF rather than to its absolute value. Furthermore, the assessment of LVEF is not required for the initiation of treatments like sodium-glucose cotransporter 2 inhibitors, mineralocorticoid receptor antagonists and diuretics in patients with suspected de novo heart failure and elevated N-terminal pro-B-type natriuretic peptide levels. Future research utilizing advanced imaging techniques and biomarkers which can better characterize myocardial structure, metabolism and performance may facilitate the identification of alternative therapeutic targets and better ways to monitor heart failure therapies across the entire spectrum of LVEF.

Individuals with heart failure (HF), other forms of cardiovascular disease, or kidney disease are at increased risk for the development and adverse health effects of diabetes. As such, prevention or delay of diabetes is an important treatment priority in these groups. The aim of this meta-analysis was to determine the effect of sodium-glucose co-transporter 2 inhibitors (SGLT2i) on incident diabetes in HF across the spectrum of left ventricular ejection fraction (LVEF) and across the broader spectrum of cardiovascular or kidney disease.

First, the effects of dapagliflozin vs. placebo on new-onset diabetes were assessed in a pooled, participant-level analysis of the DAPA-HF and DELIVER trials. New-onset diabetes was defined as the new initiation of glucose-lowering therapy during follow-up, and time from randomization to new-onset diabetes was evaluated using Cox proportional hazards models. Second, PubMed and Embase were searched to identify large-scale randomized clinical outcomes trials (RCTs) comparing SGLT2i with placebo among adults with cardiovascular or kidney disease. A trial-level meta-analysis was then conducted to summarize the treatment effects of SGLT2i on the incidence of new-onset diabetes.

In the pooled analysis of DAPA-HF and DELIVER including 5623 participants with HF but without diabetes at baseline, dapagliflozin reduced the incidence of new-onset diabetes by 33% [hazard ratio (HR), 0.67; 95% confidence interval (CI), .49-.91; P = .012] when compared with placebo. There was no evidence of heterogeneity across the spectrum of continuous LVEF or key subgroups. Among seven complementary RCTs including 17 855 participants with cardiovascular or kidney disease, SGLT2i reduced the of new-onset diabetes by 26% (HR, 0.74; 95% CI .65-.85; P < .001), with consistent effects across trials.

SGLT2i reduced the incidence of new-onset diabetes among individuals with cardiovascular or kidney disease. These findings suggest that SGLT2i implementation may have an important ancillary benefit on prevention or delay of diabetes in these high-risk populations.

Diabetes mellitus (DM) is a major risk factor for cardiovascular disease, including heart failure (HF). A high proportion of DM patients eventually require cardiac surgery. While the traditional approach to DM therapy focuses on tight glucose control with insulin and oral hypoglycemic agents, novel antidiabetic drugs have emerged over the past two decades that offer not only improved glycemic control but also cardiovascular and renal protection, such as benefits in HF management. The aim of this review is to examine and evaluate the perioperative risk and benefits of novel antidiabetic agents in HF treatment for both DM and non-DM patients undergoing cardiac surgery. We specifically studied glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose cotransporter 2 inhibitors (SGLT2is). Although studies on novel antidiabetic therapy in cardiac surgeries were limited, the results showed all three agents to be safe for use in the perioperative period, with SLGT2i demonstrating the most benefits in HF management for those with or without DM and kidney impairment undergoing cardiac surgery. Future research on larger study populations and using a more rigorous study design is necessary in bridging current knowledge to improve patient outcomes.

Although previous studies have evaluated renal function decline in patients with heart failure (HF), there is limited evidence on long-term renal trajectories, especially in patients with concomitant HF and type 2 diabetes (T2D). This study aims to provide a detailed analysis of renal function decline over an extended follow-up period in a well-characterized cohort of patients with HF and T2D.

This is a post hoc subanalysis of a prospective registry involving ambulatory patients with HF and T2D referred to a specialized HF clinic. The estimated glomerular filtration rate (eGFR) was assessed at baseline and during scheduled follow-up visits every three months using the Chronic Kidney Disease Epidemiology Collaboration formula. Loess curves were plotted for predefined subgroups, and multivariable longitudinal Cox regression analyses were performed to evaluate the associations between eGFR trajectories and all-cause mortality.

A total of 1,114 patients with HF and T2D were included, with a mean age of 69.3 ± 10.3 years, and 68.2% were men. In total, 10,830 scheduled creatinine measurements were analysed, with a mean of 15.8 ± 9.4 measurements per patient. A significant progressive decline in the eGFR was observed, with an average annual rate of - 2.05 (95% CI - 2.11 to - 1.95, p < 0.001) ml/min/1.73 m2. Subgroup analysis indicated that older age, nonischaemic HF aetiology, HFpEF or HFmrEF, poor glycaemic control, and higher baseline eGFRs were associated with a more pronounced decline in renal function. Furthermore, a decrease in the eGFR was independently associated with an increased risk of all-cause mortality.

This study offers novel insights into long-term renal function trajectories in patients with HF and T2D and identifies key clinical factors associated with accelerated renal decline. Future research is warranted to validate these results in larger, more diverse cohorts and to explore potential therapeutic interventions.

The global rise in diabetes prevalence has significantly contributed to the increasing burden of atherosclerotic cardiovascular disease (ASCVD), a leading cause of morbidity and mortality in this population. Diabetes accelerates atherosclerosis through mechanisms such as hyperglycemia, oxidative stress, chronic inflammation, and epigenetic dysregulation, leading to unstable plaques and an elevated risk of cardiovascular events. Despite advancements in controlling traditional risk factors like dyslipidemia and hypertension, a considerable residual cardiovascular risk persists, highlighting the need for innovative therapeutic approaches. Emerging treatments, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, epigenetic modulators, and RNA-based therapies, are showing promise in addressing the unique challenges of diabetes-associated ASCVD. Precision medicine strategies, such as nanoparticle-based drug delivery and cell-specific therapies, offer further potential for mitigating cardiovascular complications. Advances in multiomics and systems biology continue to deepen our understanding of the molecular mechanisms driving diabetes-associated atherosclerosis. This review synthesizes recent advances in understanding the pathophysiology and treatment of diabetes-related atherosclerosis, offering a roadmap for future research and precision medicine approaches to mitigate cardiovascular risk in this growing population.

The goal of this systematic review is to determine the effectiveness of empagliflozin in managing patients with heart failure with preserved ejection fraction (HFpEF) as compared with a placebo.

Web of Science, Cochrane, PubMed, and Scopus databases were searched for articles from 2000 to 2023. Reference lists of articles were manually screened. Trials that recruited patients with HFpEF and reported the effects of empagliflozin were included. Endnote X9 software was used for the study screening process.

1029 non-duplicate articles were identified from the literature and 9 were selected for inclusion in this review. The included papers were all randomized controlled trials (RCTs). According to the findings, empagliflozin reduces the risk of cardiovascular mortality, hospitalization for heart failure, and urgent heart failure visit to the hospital, as compared to placebo treatment. Empagliflozin was also associated with improved quality of life and lower occurrence of severe adverse events. Additionally, there were no significant differences between the treated and placebo groups, regarding the occurrence of adverse events or ability to exercise. The effect of empagliflozin was found to be better in Mineralocorticoid Receptor Antagonists (MRA) non-users and non-diabetic HFpEF patients. The effectiveness of empagliflozin was unaffected by age or gender.

Empagliflozin treatment for HFpEF patients appears to be both safe and efficient when compared to a placebo, according to data of moderate quality.

Cardiovascular diseases represent the principal cause of death and comorbidity among people with diabetes. Ferroptosis, an iron-dependent non-apoptotic regulated cellular death characterized by lipid peroxidation, is involved in the pathogenesis of diabetic cardiovascular diseases. The susceptibility to ferroptosis in diabetic hearts is possibly related to myocardial iron accumulation, abnormal lipid metabolism and excess oxidative stress under hyperglycemia conditions. Accumulating evidence suggests ferroptosis can be the therapeutic target for diabetic cardiovascular diseases. This review summarizes ferroptosis-related mechanisms in the pathogenesis of diabetic cardiovascular diseases and novel therapeutic choices targeting ferroptosis-related pathways. Further study on ferroptosis-mediated cardiac injury can enhance our understanding of the pathophysiology of diabetic cardiovascular diseases and provide more potential therapeutic choices.

Atherosclerosis is a disease of large and medium arteries that can lead to life-threatening cardiovascular and cerebrovascular consequences, such as myocardial infarction and stroke. Moreover, atherosclerosis is a major contributor to cardiovascular-related mortality in individuals with diabetes mellitus. Diabetes aggravates the pathobiological mechanisms that underlie the development of atherosclerosis. Currently available anti-atherosclerotic drugs or strategies solely focus on optimal control of systemic risk factors, including hyperglycaemia and dyslipidaemia, but do not adequately target the diabetes-exacerbated mechanisms of atherosclerotic cardiovascular disease, highlighting the need for targeted, mechanism-based therapies. This Review focuses on emerging pathological mechanisms and related novel therapeutic targets in atherosclerotic cardiovascular disease in patients with diabetes.

Background: SGLT-2 inhibitors (SGLT-2i) and GLP-1 receptor agonists (GLP-1RA) have demonstrated nephro- and cardioprotective effects, but their neuroprotective properties, especially concerning stroke severity, and mechanisms are not unambiguous. We aimed to study the influence of SGLT-2i with different selectivity and GLP-1RA on brain damage volume and neurological status in non-diabetic and diabetic rats and to investigate the underlying mechanisms. Methods: Non-diabetic Wistar rats were divided into five groups (n = 10 each) and received empagliflozin, canagliflozin, or dulaglutide as study drugs and metformin as comparison drug. Control animals were administered 0.9% NaCl for 7 days before stroke. At 48 h after stroke, we assessed neurological deficit, neuronal and astroglial damage markers, and brain damage volume. We also modeled type 2 DM in Wistar rats using the high-fat diet+nicotinamide/streptozotocin method and established similar treatment groups. After 8 weeks, rats were subjected to stroke with further neurological deficit, neuroglial damage markers, and brain necrosis volume measurement. Results: In non-diabetic rats, all the drugs showed an infarct-limiting effect; SGLT-2i and dulaglutide were more effective than metformin. DULA improved neurological status compared with MET and SGLT-2i treatment. All the drugs decreased neurofilament light chains (NLCs) level and neuronal damage markers, but none of them decreased the glial damage marker S100BB. In DM, similarly, all the drugs had infarct-limiting effects. Neurological deficit was most pronounced in the untreated diabetic rats and was reduced by all study drugs. All the drugs reduced NLC level; dulaglutide and empagliflozin, but not canagliflozin, also decreased S100BB. None of the drugs affected neuron-specific enolase. Conclusions: SGLT-2i and GLP-1RA are neuroprotective in experimental stroke. GLP-1RA might be more effective than SGLT-2i as in non-diabetic conditions it influences both brain damage volume and neurological status. All study drugs decrease neuronal damage, while GLP-1RA and highly selective SGLT-2i EMPA, but not low-selective CANA, also have an impact on neuroglia in diabetic conditions.

Heart failure (HF) is a life-threatening condition with severe incapacitating consequences. Many body organs and systems may be affected, which may also hinder the quality of life and finances at the individual and societal levels. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have also emerged as potentially useful drugs in the HF domain and other medical fields, in addition to their glucose-lowering effect. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the authors searched Google Scholar, PubMed, and Scopus websites for SGLT2i and SGLT2i-related terms and their impact on HF events, major adverse cardiovascular events (MACEs), renal composite outcomes, and improvement in the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, involving human adult populations. Two reviewers conducted the literature search, and disagreements were resolved through mutual consensus and input from a third reviewer. A literature search was conducted from 1st February to 20th February 2024. We included studies published after 2018 to focus only on the latest advancements. Randomized controlled trials, observational studies, or systematic reviews of these studies were included in our study. Of the 44 initial articles identified, only 14 met the inclusion and exclusion criteria. The outcomes revealed the superiority of SGLT2i therapeutics over placebo in all four domains mentioned above. A total of 234,509 patients from 11 papers with moderate heterogeneity (P = 0.07; I2 = 42%) evaluating the effect of SGLT2i in comparison to placebo on HF events were considered; of these, 128,477 patients received the intervention drug, and 106,032 individuals were assigned to the control group. The absolute numbers of HF events were 6845 and 8877, respectively. The study showed an overall benefit of SGLT2i in patients with heart failure due to their ability to major adverse cardiovascular events (MACE) in comparison to placebo (OR: 0.92; 95% CI: 0.89-0.96; P < 0.00001). This systematic review confirmed previous findings related to the use of SGLT2i as adjunctive therapy for HF and amelioration of KCCQ scores and as a protective agent against MACE and renal impairment progression.

Empagliflozin (EMPA) is an SGLT-2 inhibitor that can control hyperglycemia. Clinical trials have indicated its cardio-protective effects against cardiac remodeling in diabetes or non-diabetes patients. However, the underlying molecular mechanisms of EMPA's cardio-protective effects remain elusive.

We evaluated whether the EMPA attenuated the pressure-overload-induced cardiac hypertrophy by inhibiting the Wnt/β-catenin pathway. Furthermore, the effects of the EMPA on a mouse model of transverse aortic constriction (TAC) induced cardiac hypertrophy was also evaluated. Mice were administrated with 0.5% CMC-Na as a vehicle or EMPA (10 mg/kg/day, daily, throughout the study) by intragastric gavage.

The in vivo echocardiography and histologic morphological analyses revealed that EMPA attenuated TAC-induced cardiac hypertrophy. Moreover, it also ameliorated TAC-induced cardiac fibrosis and decreased the cell size of the cardiomyocytes in isolated adult cardiomyocytes. Molecular mechanism analysis revealed that the EMPA reduced the TAC-induced enhanced expression of the Wnt/β-catenin pathway in vivo. For in vitro assessments, isolated neonatal rat cardiomyocytes (NRCMs) were treated with Angiotensin II (AngII) and EMPA; the results showed that in the absence of EMPA, the expression of the Wnt/β-catenin pathway was enhanced. In the trans-genetic heterozygous β-catenin deletion mice, EMPA attenuated TAC-induced cardiac remodeling by reducing the Wnt/β-catenin pathway. In addition, molecular docking analysis indicated that EMPA interacts with FZD4 to inhibit the TAC and AngII induced Wnt/β-catenin pathway in cardiomyocytes.

Our study illustrated that EMPA might directly interact with FZD4 to inhibit the TAC and AngII-induced activation of the Wnt/β-catenin pathway to attenuate the adverse cardiac remodeling.

The sodium‒glucose cotransporter-2 (SGLT2) inhibitor empagliflozin (EMPA) has been demonstrated to reduce the risk of cardiovascular mortality or hospitalization for heart failure (HF) in patients. Nevertheless, data concerning the long-term cardiovascular effects in clinically important subgroups are scarce. A prespecified meta-analysis of randomized controlled trials (RCTs) was conducted to assess the long-term effects of EMPA on cardiovascular outcomes in HF patients, regardless of HF type and glycemic status. The assessment included parameters related to left ventricular (LV) remodeling, including the LV volume, the LV mass index (LVMI), the ejection fraction, the systolic blood pressure, and biomarkers. Moreover, the effects of the treatment on exercise capacity and quality of life (QoL) were analyzed. Furthermore, these cardiovascular parameters were evaluated in prespecified subgroups of HF patients, including type of HF, type 2 diabetes status, and duration of therapy. The quantitative meta-analysis was synthesized and analyzed via the statistical software Stata 17.0. The meta-analysis revealed that EMPA administration significantly contributed to a reduction in systolic blood pressure (SBP) (MD = 4.93 mmHg, 95% CI=[-9.67, -0.19]; P < 0.0001) and left ventricular end-diastolic volume (LVEDV) (MD=-18.03 mL, 95% CI=[-25.4, -10.67], P < 0.0001). Furthermore, left ventricular end-systolic volume (LVESV) (MD=-16.09 mL, 95% CI=[-26.94, -5.25]; P < 0.0001) and N-terminal pro-B-type NP (NT-proBNP) (SMD=-0.54, 95% CI=[-0.94, -0.13]; P = 0.01) significantly decreased. These decreases were accompanied by improvements in the 6-minute walk distance (6MWD, SMD = 0.78, 95% CI=[-0.22, -1.79], P = 0.13) and KCCQ score (MD = 1.98, 0.97-2.99; P < 0.0001). The results of the subgroup analysis indicated that EMPA administration was associated with more pronounced benefits in terms of cardiac remodeling, function and exercise capacity for specific populations, including (1) HF with a reduced ejection fraction (HFrEF); (2) the absence of diabetes; and (3) treatment for no less than 6 months. Additionally, EMPA may lead to an increased risk of cardiovascular adverse events (AEs) but is less effective for improving the QoL in HF patients with preserved EF (HFpEF) populations.

Currently, there is no comprehensive systematic review available to comprehensively assess the efficacy and safety of Empagliflozin and other sodium-glucose cotransporter 2 inhibitors in the treatment of heart failure (HF). This study employed a meta-analysis approach to systematically evaluate the therapeutic effects of Empagliflozin in HF patients and its impact on cardiac function.

The keywords including "heart failure," "HF," "cardiac failure," "cardiac disease," "Empagliflozin," and "sodium-glucose cotransporter 2 inhibitors" were utilized to search for relevant clinical studies on Empagliflozin in the treatment of HF in various databases, such as China National Knowledge Infrastructure, Wanfang, VIP Chinese Medical Journal Database, PubMed, MEDLINE, Embase, Cochrane Library, Springer, and Science Direct. The studies included patients with HF who received drug treatment. Data on baseline characteristics and posttreatment outcomes, including HF hospitalization (HHF), cardiovascular mortality, all-cause mortality, estimated glomerular filtration rate changes, Kansas City Cardiomyopathy Questionnaire quality of life (QoL) scores, N-terminal pro-B-type natriuretic peptide, left ventricular ejection fraction, hematocrit, and other relevant indicators were collected. Meta-analysis was conducted using RevMan5.3 to analyze the extracted data.

A total of 15 studies were included in the final analysis, comprising 36,917 patients with HF. Among them, 18,486 patients were in Empagliflozin group, and 18,431 patients were in control (Ctrl) group. The results of the meta-analysis demonstrated that, relative to Ctrl group, Empagliflozin group showed a substantially lower HHF rate, a substantial improvement in estimated glomerular filtration rate changes, a reduced cardiovascular mortality rate, a higher Kansas City Cardiomyopathy Questionnaire QoL score, increased hematocrit values, reduced N-terminal pro-B-type natriuretic peptide changes, and enhanced left ventricular ejection fraction changes. These findings suggest that remarkable improvements in various outcomes compared to the Ctrl group.

The sodium-glucose cotransporter 2 inhibitor Empagliflozin markedly reduces the HHF rate and cardiovascular mortality in HF patients. It also improves patients' QoL, enhances renal function, and increases cardiac function while reducing both, the preload and afterload.

Insulin, a critical hormone in the human body, exerts its effects by binding to insulin receptors and regulating various cellular processes. While nitric oxide (NO) plays an important role in insulin secretion and acts as a mediator in the signal transduction pathway between upstream molecules and downstream effectors, holds a significant position in the downstream signal network of insulin. Researches have shown that the insulin-NO system exhibits a dual regulatory effect within the central nervous system, which is crucial in the regulation of diabetic encephalopathy (DE). Understanding this system holds immense practical importance in comprehending the targets of existing drugs and the development of potential therapeutic interventions. This review extensively examines the characterization of insulin, NO, Nitric oxide synthase (NOS), specific NO pathway, their interconnections, and the mechanisms underlying their regulatory effects in DE, providing a reference for new therapeutic targets of DE.

The prevalence of HF with preserved ejection raction (HFpEF, with EF ≥50%) is increasing across all populations with high rates of hospitalization and mortality, reaching up to 80% and 50%, respectively, within a 5-year timeframe. Comorbidity-driven systemic inflammation is thought to cause coronary microvascular dysfunction and increased epicardial adipose tissue, leading to downstream friborsis and molecular changes in the cardiomyocyte, leading to increased stiffness and diastolic dynsfunction. HFpEF poses unique challenges in terms of diagnosis due to its complex and diverse nature. The diagnosis of HFpEF relies on a combination of clinical assessment, imaging studies, and biomarkers. An additional important step in diagnosing HFpEF involves excluding certain cardiac diagnoses that may be specific underlying causes of HFpEF or may be masquerading as HFpEF and require specific alternative treatment approaches. In addition to administering sodium-glucose cotransporter 2 inhibitors to all patients, the most effective approach to enhance clinical outcomes may involve tailored therapy based on each patient's unique clinical profile. Exercise should be recommended for all patients to improve the quality of life. Glucagon-like peptide-1 1 agonists are a promising treatment option in obese HFpEF patients. Novel approaches targeting inflammation are also in early phase trials.

Heart failure (HF) with preserved ejection fraction (HFpEF) reflects half of all clinical HF yet has few therapies. Obesity and diabetes are now common comorbidities which have focused attention towards underlying myocardial metabolic defects. The profile of a major metabolic pathway, glycolytic intermediates and their regulating enzymes and ancillary pathways, remains unknown.

Endomyocardial biopsies from HFpEF (n = 37) and non-failing controls (n = 21) were assayed by non-targeted or targeted metabolomics and immunoblot to determine glycolytic and ancillary pathway metabolites and protein expression of their regulating enzymes. Glucose and GLUT1 expression were higher in HFpEF, but prominent glycolytic metabolites: glucose-6-phosphate, fructose-1,6-biphosphate (F1,6bP), and 3-phosphoglycerate were reduced by -78%, -91%, and -73%, respectively, versus controls. Expression of their corresponding synthesizing enzymes hexokinase, phospho-fructokinase, and phosphoglycerate kinase were also significantly lower (all p < 0.0005). Pentose phosphate and hexosamine biosynthetic pathway metabolites were reduced while glycogen content increased. Despite proximal reduction in key glycolytic intermediates, pyruvate increased but mitochondrial pyruvate transporter (MPC1) expression was reduced. Pyruvate dehydrogenase converting pyruvate to acetyl-CoA was more activated but some Krebs cycle intermediates were reduced. This HFpEF glycolytic profile persisted after adjusting for body mass index (BMI), diabetes, age, and sex, or in subgroup analysis with controls and HFpEF matched for BMI and diabetes/insulin history. In HFpEF, BMI but not glycated haemoglobin negatively correlated with F1,6bP (p = 7e-5, r = -0.61) and phosphoenolpyruvate (p = 0.006, r = -0.46).

Human HFpEF myocardium exhibits reduced glycolytic and ancillary pathway intermediates and expression of their synthesizing proteins. This combines features reported in HF with reduced ejection fraction and obesity/diabetes that likely exacerbate metabolic inflexibility.

The triglyceride-glucose (TyG) index, proven to be a crucial insulin resistance biomarker (better than the Homeostasis Model Assessment for Insulin Resistance), is simple and non-invasive. Recently, indisputable evidence has shown that the TyG index is strongly associated with cardiovascular disease [CVD, including atherosclerosis, heart failure (HF), and hypertension] prognosis and mortality. Nevertheless, the value of the TyG index in HF patients treated with sodium-glucose cotransporter 2 inhibitors (SGLT2is) has not been systematically evaluated. Therefore, in this review, we summarized the value of the TyG index and its related parameters as markers of CVD, especially HF. Furthermore, we addressed the use of SGLT2is and GLP-1 receptor antagonists in HF patients. Finally, we summarized the mechanism of the "obesity paradox."

To evaluate the efficacy of empagliflozin combined with sacubitril/valsartan in treating hypertensive patients with heart failure (HF), focusing on its effects on blood pressure variability (BPV) and cardiac function.

This retrospective study included 101 patients with hypertension and heart failure with reduced ejection fraction treated at Baoji High-Tech Hospital from October 2021 to October 2023. Patients were divided into two groups: an observation group (n=51), treated with both empagliflozin and sacubitril/valsartan, and a control group (n=50), treated with sacubitril/valsartan alone. We compared the therapeutic effects, BPV (including 24-hour, daytime, and nighttime systolic and diastolic BPV), cardiac function indicators, levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI) before and after treatment, and the incidence of adverse reactions between the groups. Independent risk factors affecting treatment efficacy were also analyzed.

The total effective rate of treatment in the observation group was significantly higher than in the control group (P<0.05). Both groups showed reductions in daytime and nighttime systolic and diastolic BPV after treatment, with the observation group displaying more pronounced improvements (all P<0.05). Enhancements in cardiac ultrasound measurements, NT-proBNP levels, and cTnI levels were more significant in the observation group compared to the control group post-treatment (both P<0.05). There was no significant difference in the incidence of adverse reactions during treatment between the two groups (P>0.05). Age and comorbid diabetes were identified as independent risk factors for poor prognosis, while treatment with empagliflozin combined with sacubitril/valsartan was a protective factor.

Empagliflozin combined with sacubitril/valsartan significantly enhances treatment efficacy in hypertensive patients with heart failure, effectively improves cardiac function and BPV, and demonstrates good safety.

In this paper, we concentrate on updating the clinical research on sodium-glucose cotransporter inhibitors (SGLTis) for patients with type 2 diabetes who have heart failure with a preserved injection fraction, acute heart failure, atrial fibrillation, primary prevention of atherosclerotic cardiovascular disease/cardiovascular disease, and acute myocardial infarction. We searched the data of randomized controlled trials and meta-analyses of SGLTis in patients with diabetes from PubMed between January 1, 2020 and April 6, 2024 for our review. According to our review, certain SGLTis (empagliflozin, dapagliflozin, canagliflozin, and tofogliflozin), but not sodium-glucose cotransporter 1 inhibitor (SGLT1i), exhibit relatively superior clinical safety and effectiveness for treating the abovementioned diseases. Proper utilization of SGLTis in these patients can foster clinical improvement and offer an alternative medication option. However, clinical trials involving SGLTis for certain diseases have relatively small sample sizes, brief intervention durations, and conclusions based on weak evidence, necessitating additional data. These findings are significant and valuable for providing a more comprehensive reference and new possibilities for the clinical utilization and scientific exploration of SGLTis.

Heart failure (HF), especially HF with reduced ejection fraction (HFrEF), presents complex challenges, particularly in the aging population where it often coexists with type 2 diabetes mellitus (T2DM).

To analyze the effect of dapagliflozin treatment on cardiac, renal function, and safety in patients with HFrEF combined with T2DM.

Patients with T2DM complicated with HFrEF who underwent treatment in our hospital from February 2018 to March 2023 were retrospectively analyzed as the subjects of this study. The propensity score matching method was used, and a total of 102 eligible samples were scaled. The clinical efficacy of the two groups was evaluated at the end of the treatment, comparing the results of blood glucose, insulin, cardiac function, markers of myocardial injury, renal function indexes, and 6-min walk test (6MWT) before and after the treatment. We compared the occurrence of adverse effects on the treatment process of the two groups of patients. The incidence of adverse outcomes in patients within six months of treatment was counted.

The overall clinical efficacy rate of patients in the study group was significantly higher than that of patients in the control group (P = 0.013). After treatment, the pancreatic beta-cell function index, left ventricular ejection fraction, and glomerular filtration rate of patients in the study group were significantly higher than control group (P < 0.001), while their fasting plasma glucose, 2-h postprandial glucose, glycosylated hemoglobin, insulin resistance index, left ventricular end-systolic diameter, left ventricular end-diastolic diameter, cardiac troponin I, creatine kinase-MB, N-terminal pro b-type natriuretic peptide, serum creatinine, and blood urea nitrogen were significantly lower than those of the control group. After treatment, patients in the study group had a significantly higher 6MWT than those in the control group (P < 0.001). Hypoglycemic reaction (P = 0.647), urinary tract infection (P = 0.558), gastrointestinal adverse effect (P = 0.307), respiratory disturbance (P = 0.558), and angioedema (P = 0.647) were not statistically different. There was no significant difference between the incidence of adverse outcomes between the two groups (P = 0.250).

Dapagliflozin significantly enhances clinical efficacy, cardiac and renal function, and ambulatory capacity in patients with HFrEF and T2DM without an increased risk of adverse effects or outcomes.

The effect of empagliflozin, a sodium-glucose-co-transporter-2 inhibitor, on risk for myocardial infarction has not been fully characterized.

This study comprised prespecified and post-hoc analyses of the EMPA-REG OUTCOME trial in which 7020 people with type 2 diabetes (T2D) and cardiovascular disease [mostly atherosclerotic (ASCVD)] were randomized to empagliflozin or placebo and followed for a median 3.1 years. We assessed the effect of empagliflozin on total (first plus recurrent) events of centrally adjudicated fatal and non-fatal myocardial infarction (MI) using a negative binomial model with robust confidence intervals (CI) that preserves randomization and accounts for the within-patient correlation of multiple events. Post hoc, we analyzed types of MI: type 1 (related to plaque-rupture/thrombus), type 2 (myocardial supply-demand imbalance), type 3 (sudden-death related, i.e. fatal MI), type 4 (percutaneous coronary intervention-related), and type 5 (coronary artery bypass graft-related). MIs could be assigned to > 1 type.

There were 421 total MIs (including recurrent); 299, 86, 26, 19, and 1 were classified as type 1, 2, 3, 4, and 5 events, respectively. Overall, empagliflozin reduced the risk of total MI events by 21% [rate ratio for empagliflozin vs. placebo, 0.79 (95% CI, 0.620-0.998), P = 0.0486], largely driven by its effect on type 1 [rate ratio, 0.79 (95% CI, 0.61-1.04)] and type 2 MIs [rate ratio, 0.67 (95% CI, 0.41-1.10)].

In T2D patients with ASCVD, empagliflozin reduced the risk of MIs, with consistent effects across the two most common etiologies, i.e. type 1 and 2.

URL: https://www.

gov ; Unique identifier: NCT01131676.

To assess the effect of empagliflozin on patients with comorbid heart failure (HF) and diabetes with or without baseline insulin, and to study the impact of empagliflozin on insulin requirements over time.

We performed a post-hoc analysis of pooled patient-level data from two cardiovascular outcomes trials of empagliflozin in HF (EMPEROR-Reduced and EMPEROR-Preserved trials). We undertook a subgroup analysis stratified by baseline insulin use, including all patients with diabetes. The studied endpoints included the primary composite endpoint of first hospitalization for HF or cardiovascular death, rate of decline of estimated glomerular filtration rate, composite renal outcome and rates of sustained insulin initiation.

Among 4794 patients with diabetes, 1333 (658 in empagliflozin, 675 in placebo) were using insulin at baseline. The treatment effect of empagliflozin on the primary endpoint was consistent irrespective of insulin use [no insulin, hazard ratio 0.74, 95% confidence interval (CI) 0.63-0.86; using insulin, hazard ratio 0.81, 95% CI 0.66-1.00, pinteraction = .49], as was the effect on the rate of decline of the estimated glomerular filtration rate (pinteraction = .75). There was no effect of empagliflozin on the composite renal outcome in patients using or not using insulin (pinteraction = .30). Among patients not using insulin at baseline, those randomized to empagliflozin initiated insulin less frequently throughout the follow-up period compared with those receiving placebo (2.6% vs. 3.8%, odds ratio 0.66, 95% CI 0.50-0.88).

Empagliflozin exerts a consistent benefit on cardiovascular outcomes and renal function decline, irrespective of baseline insulin use, and reduces the need for sustained insulin initiation in patients with HF and diabetes.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been studied in patients with heart failure, type 2 diabetes, chronic kidney disease, atherosclerotic cardiovascular disease, and acute myocardial infarction. Individual trials were powered to study composite outcomes in one disease state. We aimed to evaluate the treatment effect of SGLT2 inhibitors on specific clinical endpoints across multiple demographic and disease subgroups.

In this systematic review and meta-analysis, we queried online databases (PubMed, Cochrane CENTRAL, and SCOPUS) up to Feb 10, 2024, for primary and secondary analyses of large trials (n>1000) of SGLT2 inhibitors in patients with heart failure, type 2 diabetes, chronic kidney disease, and atherosclerotic cardiovascular disease (including acute myocardial infarction). Outcomes studied included composite of first hospitalisation for heart failure or cardiovascular death, first hospitalisation for heart failure, cardiovascular death, total (first and recurrent) hospitalisation for heart failure, and all-cause mortality. Effect sizes were pooled using random-effects models. This study is registered with PROSPERO, CRD42024513836.

We included 15 trials (N=100 952). Compared with placebo, SGLT2 inhibitors reduced the risk of first hospitalisation for heart failure by 29% in patients with heart failure (hazard ratio [HR] 0·71 [95% CI 0·67-0·77]), 28% in patients with type 2 diabetes (0·72 [0·67-0·77]), 32% in patients with chronic kidney disease (0·68 [0·61-0·77]), and 28% in patients with atherosclerotic cardiovascular disease (0·72 [0·66-0·79]). SGLT2 inhibitors reduced cardiovascular death by 14% in patients with heart failure (HR 0·86 [95% CI 0·79-0·93]), 15% in patients with type 2 diabetes (0·85 [0·79-0·91]), 11% in patients with chronic kidney disease (0·89 [0·82-0·96]), and 13% in patients with atherosclerotic cardiovascular disease (0·87 [0·78-0·97]). The benefit of SGLT2 inhibitors on both first hospitalisation for heart failure and cardiovascular death was consistent across the majority of the 51 subgroups studied. Notable exceptions included acute myocardial infarction (22% reduction in first hospitalisation for heart failure; no effect on cardiovascular death) and heart failure with preserved ejection fraction (26% reduction in first hospitalisation for heart failure; no effect on cardiovascular death).

SGLT2 inhibitors reduced heart failure events and cardiovascular death in patients with heart failure, type 2 diabetes, chronic kidney disease, and atherosclerotic cardiovascular disease. These effects were consistent across a wide range of subgroups within these populations. This supports the eligibility of a large population with cardiorenal-metabolic diseases for treatment with SGLT2 inhibitors.

None.

The study aims to provide comprehensive evidence for the selection of agents in type 2 diabetes mellitus (T2DM) patients with cardiovascular risk and summarize the lasted evidence for the cardiovascular effects of sodium glucose cotransporter-2 inhibitor (SGLT2i) in patients with heart failure (HF).

Several online databases were searched. All studies that explored the cardiovascular effects of SGLT2i or glucagon-like peptide 1 receptor agonist (GLP1-RA) were screened and reviewed. A total of 38 studies were included. Compared with GLP1-RA, the use of SGLT2i significantly reduced the risk of cardiovascular death [risk ratio (RR) = 0.59; 95% confidence interval (CI), 0.44-0.58], hospitalization of heart failure (HHF) (RR = 0.77; 95% CI, 0.74-0.80), death from any cause (RR = 0.64; 95% CI, 0.60-0.68), and myocardial infarction (MI) (RR = 0.81; 95% CI, 0.76-0.87). However, SGLT2i significantly increased the risk of stroke (RR = 1.10; 95% CI, 1.04-1.17). Compared with the control group, SGLT2i treatment reduced the risk of cardiovascular death by 14% (RR = 0.86; 95% CI, 0.79-0.94), HHF by 25%, and death from any cause by 9% in patients with HF, regardless of diabetes status.

SGLT2i is associated with a lower risk of cardiovascular death, HHF, death from any cause, and MI in patients with T2DM compared with GLP1-RA. In addition, SGLT2i brought more benefits with respect to the effects of cardiovascular death, HHF, and death from any cause in patients with HF, regardless of diabetes status.

An acute metabolic complication of diabetes mellitus, especially type 1, is diabetic ketoacidosis (DKA), which is due to an increase in blood ketone concentrations. Sodium/glucose co-transporter-2 inhibitor (SGLT2-i) drugs have been associated with the occurrence of a particular type of DKA defined as euglycemic (euDKA), characterized by glycemic levels below 300 mg/dL. A fair number of euDKA cases in SGLT2-i-treated patients have been described, especially in the last few years when there has been a significant increased use of these drugs. This form of euDKA is particularly insidious because of its latent onset, associated with unspecific symptomatology, until it evolves (progressing) to severe systemic forms. In addition, its atypical presentation can delay diagnosis and treatment. However, the risk of euDKA associated with SGLT2-i drugs remains relatively low, but it is essential to promptly diagnose and manage it to prevent its serious life-threatening complications. In this narrative review, we intended to gather current research evidence on SGLT2i-associated euDKA from randomized controlled trials and real-world evidence studies, its diagnostic criteria and precipitating factors.

Although the cardiovascular (CV) benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with diabetes mellitus (DM) are well known, their effects in patients without DM continue to be explored. We provide a meta-analysis of the available evidence. Online databases were searched for randomized controlled trials (RCTs) comparing SGLT2i to placebo/control in patients without DM. The end points of interest were composite CV death/hospitalization for heart failure (HF) with individual components, all-cause death, major adverse CV events, and serious adverse events. Subgroup analysis was performed according to the type of SGLT2i. Pooled odds ratios (OR) and 95% confidence intervals (CI) were generated through a random-effects model. A total of 6 RCTs with 12,984 patients (6,501 in the SGLT2i group and 6,483 in the placebo group) were included, followed over a mean duration of 17.7 months. Four RCTs had patients with HF, 1 with chronic kidney disease, and 1 with myocardial infarction. The mean age was 64 years, 72% of patients were men and mean hemoglobin A1C was 5.7%. As compared with a placebo, SGLT2i treatment was associated with significant reduction in composite CV death or hospitalization for HF (OR 0.77, 95% CI 0.68 to 0.87, p <0.0001), primarily because of a decrease in hospitalization for HF (OR 0.70, 95% CI 0.60 to 0.81, p <0.00001). No significant differences were found pertaining to CV death (OR 0.86, 95% CI 0.74 to 1.01, p = 0.06), all-cause death (OR 0.89, 95% CI 0.71 to 1.11, p = 0.29) and major adverse CV events (OR 0.95, 95% CI 0.68 to 1.32, p = 0.75). Serious adverse events were lower with use of empagliflozin vs placebo. In conclusion, this study shows significant CV benefits in terms of reduction in CV death or hospitalization for HF in patients without DM treated with SGLT2i as compared with placebo. The underlying heterogeneity of patients in terms of co-morbidities (HF, chronic kidney disease, or myocardial infarction) needs to be considered while interpreting the results.

Despite major advances in prevention and medical therapy, heart failure (HF) remains associated with high morbidity and mortality, especially in older and frailer patients. Therefore, a complete, guideline-based treatment is essential, even in HF patients with conditions traditionally associated with a problematic initiation and escalation of the medical HF therapy, such as chronic kidney disease and arterial hypotension, as the potential adverse effects are overcome by the overall decrease of the absolute risk. Furthermore, since the latest data suggest that the benefit of a combined medical therapy (MRA, ARNI, SGLT2i, beta-blocker) may extend up to a LVEF of 65%, further trials on these subgroups of patients (HFmrEF, HFpEF) are needed to re-evaluate the guideline-directed medical therapy across the HF spectrum. In particular, the use of SGLT2i was recently extended to HFpEF patients, as evidenced by the DELIVER and EMPEROR-preserved trials. Moreover, the indication for other conservative treatments in HF patients, such as the intravenous iron supplementation, was accordingly strengthened in the latest guidelines. Finally, the possible implementation of newer substances, such as finerenone, in guideline-directed medical practice for HF is anticipated with great interest.

Heart failure (HF) affects more than 60 million individuals globally. Empagliflozin is currently approved for type 2 diabetes and chronic HF. Clinical trials have demonstrated that empagliflozin reduces the composite end point of hospitalizations for HF and mortality and improves the quality of life irrespective of left ventricular ejection fraction. Empagliflozin is a once-daily medication with minimal drug-drug interactions and does not require titration. Empagliflozin causes mild weight loss and does not significantly reduce blood pressure. Empagliflozin acts as an enabler for other HF drugs by reducing the risk of hyperkalemia. Empagliflozin is also beneficial for chronic kidney disease which exists commonly with HF. This review outlines the pharmacokinetics, pharmacodynamics, safety, and efficacy of empagliflozin in HF across various sub-groups and settings.

Heart failure with mid-range ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) represent over half of heart failure cases but lack proven effective therapies beyond sodium-glucose cotransporter 2 inhibitor and diuretics. HFmrEF and HFpEF are heterogeneous conditions requiring precision phenotyping to enable tailored therapies. This review covers concepts on precision medicine approaches for HFmrEF and HFpEF. Areas discussed include HFmrEF mechanisms, anti-inflammatory and antifibrotic treatments for obesity-related HFpEF, If inhibition for HFpEF with atrial fibrillation, and mineralocorticoid receptor antagonism for chronic kidney disease-HFpEF. Incorporating precision phenotyping and matched interventions in HFmrEF and HFpEF trials will further advance therapy compared to blanket approaches.