The effects of sodium-glucose co-transporter 2 inhibitors (SGLT-2i) on dementia risk have not been assessed in the Chinese population. We aimed to assess the association between the use of SGLT-2i and dementia incidence in a mainland Chinese population.

A target trial of SGLT-2i vs. dipeptidyl peptidase 4 inhibitors (DPP-4i) was emulated, with cohorts of type 2 diabetes mellitus patients who were new users of SGLT-2i or DPP-4i being assembled using the Yinzhou Regional Health Care Database. Inverse probability of treatment weighting (IPTW) was applied to control potential confounding, and a Cox model was used to estimate the hazard ratio (HR) of the association between the use of SGLT-2i and incident dementia.

The final cohort included 47 335 new users of DPP-4i or SGLT-2i. In the primary analysis, the incidence of dementia was 500.2 and 347.5 per 100 000 person-years in users of DPP-4i and SGLT-2i, respectively. SGLT-2i use was associated with a reduced risk of incident dementia after adjusting for potential confounding using IPTW, with an HR of 0.74 (95% CI, 0.60-0.93). The results were generally consistent in various subgroup analyses and sensitivity analyses.

The use of SGLT-2i is associated with a decreased risk of dementia incidence in the study population in mainland China.

Individuals with prediabetes have a higher risk of cardiovascular events and diabetes mellitus. Therefore, the prevention or delay of prediabetes progression to diabetes via lifestyle modification and medications is an important measure to reduce morbidity and mortality in this population. Based on the American Diabetes Association (ADA) guidelines, metformin is the only recommended drug for prediabetes. A growing body of evidence has shown the beneficial effects of sodium-glucose transporter 2 (SGLT-2) inhibitors in prediabetes. These drugs offer cardiovascular mortality benefits over metformin. This review aimed to summarize current evidence about the clinical effects of SGLT-2 inhibitors in prediabetes.

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.

Excess salt intake is not only an independent risk factor for heart failure, but also one of the most important dietary factors associated with cardiovascular disease worldwide. Metabolic reprogramming in cardiomyocytes is an early event provoking cardiac hypertrophy that leads to subsequent cardiovascular events upon high salt loading. Although SGLT2 inhibitors, such as canagliflozin, displayed impressive cardiovascular health benefits, whether SGLT2 inhibitors protect against cardiac hypertrophy-related metabolic reprogramming upon salt loading remain elusive.

To investigate whether canagliflozin can improve salt-induced cardiac hypertrophy and the underlying mechanisms.

Dahl salt-sensitive rats developed cardiac hypertrophy by feeding them an 8% high-salt diet, and some rats were treated with canagliflozin. Cardiac function and structure as well as mitochondrial function were examined. Cardiac proteomics, targeted metabolomics and SIRT3 cardiac-specific knockout mice were used to uncover the underlying mechanisms.

In Dahl salt-sensitive rats, canagliflozin showed a potent therapeutic effect on salt-induced cardiac hypertrophy, accompanied by lowered glucose uptake, reduced accumulation of glycolytic end-products and improved cardiac mitochondrial function, which was associated with the recovery of cardiac expression of SIRT3, a key mitochondrial metabolic regulator. Cardiac-specific knockout of SIRT3 not only exacerbated salt-induced cardiac hypertrophy but also abolished the therapeutic effect of canagliflozin. Mechanistically, high salt intake repressed cardiac SIRT3 expression through a calcium-dependent epigenetic modifications, which could be blocked by canagliflozin by inhibiting SGLT1-mediated calcium uptake. SIRT3 improved myocardial metabolic reprogramming by deacetylating MPC1 in cardiomyocytes exposed to pro-hypertrophic stimuli. Similar to canagliflozin, the SIRT3 activator honokiol also exerted therapeutic effects on cardiac hypertrophy.

Cardiac mitochondrial dysfunction caused by SIRT3 repression is a critical promotional determinant of metabolic pattern switching underlying salt-induced cardiac hypertrophy. Improving SIRT3-mediated mitochondrial function by SGLT2 inhibitors-mediated calcium handling would represent a therapeutic strategy against salt-related cardiovascular events.

Initially described as a benign acute cardiomyopathy, Takotsubo syndrome has been linked to elevated mortality rates. Emerging evidence suggests that unresolved myocardial inflammation may contribute to this adverse prognosis. This study aimed to evaluate the incremental prognostic utility of C-reactive protein (CRP) in conjunction with the InterTAK prognosis score for stratifying long-term mortality in Takotsubo syndrome.

A retrospective analysis was conducted from a multicentre registry encompassing 307 patients diagnosed with Takotsubo syndrome between 2008 and 2020. Patients were stratified into quartiles based on the InterTAK prognosis score. The discriminatory potential of CRP in predicting long-term mortality was assessed. The primary endpoint was defined as all-cause mortality within 1 year.

A stepwise increase of CRP at discharge that corresponds to INTERTAK quartiles was observed: 9.5 mg/L (25th percentile) in the first quartile, 15.8 mg/L (median) in the second quartile, 25.3 mg/L (75th percentile) in the third quartile and 41.2 mg/L (maximum) in the fourth quartile. Receiver operating-characteristic curves analysis revealed that CRP value at discharge was predictive of 1 year mortality (area under the curve = 0.81; 95% confidence interval = 0.68-0.90) with an optimal threshold set at 33 mg/L (sensitivity: 65%; specificity: 87%). When considering the InterTAK score, the incorporation of CRP at discharge with a cut-off of 33 mg/L exhibited a significant enhancement in the prediction of 1 year mortality in 'intermediate' risk (25% vs. 1%; P = 0.008) or 'very high' risk (40% vs. 10%; P = 0.02) patients.

In Takotsubo syndrome, the persistence of inflammatory burden at hospital discharge emerged as an independent predictor of 1 year mortality, augmenting the predictive capacity of the conventional InterTAK prognosis score.

Cardiac remodelling is a key determinant of worse cardiovascular outcome in patients with heart failure (HF) and reduced ejection fraction (HFrEF). It affects both the left ventricle (LV) structure and function as well as the left atrium (LA) and the right ventricle (RV). Guideline recommended medical therapy for HF, including angiotensin-converting enzyme inhibitors/angiotensin receptors II blockers/angiotensin receptor blocker-neprilysin inhibitors (ACE-I/ARB/ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA) and sodium-glucose transport protein 2 inhibitors (SGLT2i), have shown to improve morbidity and mortality in patients with HFrEF. By targeting multiple pathophysiological pathways, foundational HF therapies are supposed to drive their beneficial clinical effects by a direct myocardial effect. Simultaneous initiation of guideline directed medical therapy (GDMT) through a synergistic effect promotes a 'reverse remodelling', leading to a full or partial recovered structure and function by enhancing systemic neurohumoral regulation and energy metabolism, reducing cardiomyocyte apoptosis, lowering oxidative stress and inflammation and adverse extracellular matrix deposition. The aim of this review is to describe how these classes of drugs can drive reverse remodelling in the LV, LA and RV and improve prognosis in patients with HFrEF.

The prevalence of early-onset type 2 diabetes (EOD) is rapidly increasing. This study intends to screen for early cardiovascular abnormalities in patients newly diagnosed with EOD and evaluate the cardiovascular risk across cluster phenotypes.

A total of 400 patients ≤ 40 years old with newly diagnosed type 2 diabetes were enrolled from the START cohort (the Study of The newly diAgnosed eaRly onset diabeTes). Cluster classification was performed using the K-means method based on age, BMI, HbA1c, HOMA2-β, HOMA2-IR, and GAD antibodies. Echocardiography and carotid ultrasound were performed within 3 months of diabetes diagnosis. Carotid ultrasound abnormalities included intimal thickening and plaque formation, while echocardiography assessed changes in cardiac structure and systolic/diastolic function. Cluster-specific partitioned polygenic scores (pPS) were used to validate our findings from a genetic perspective.

Carotid artery abnormalities were detected in 26.3% of patients, and echocardiography abnormalities were observed in 20.0%. Patients with severe insulin resistant diabetes (SIRD) had the highest incidence of carotid artery abnormality (40.0%). After adjusting for relevant risk factors, fasting C-peptide levels were significantly associated with a 1.247-fold increase in the risk of carotid artery abnormalities. Left atrial enlargement was more prevalent in the SIRD (16.7%) and mild obesity-related diabetes (MOD) (18.5%) classifications. A high proportion of patients with SIRD had abnormal left ventricular geometry (36.1%). Increases in BMI, fasting C-peptide level and HOMA2IR were accompanied by a further increase in left atrial enlargement risk by 1.136-, 1.781- and 1.687-fold respectively. The pPS for lipodystrophy was higher in the EOD group with plaque formation, and showed a significant linear correlation with the ratio of the left atrial anteroposterior diameter to body surface area (LAAP/BSA) (R = 0.344, p < 0.001).

Heart and carotid artery abnormalities are common in patients with early-onset T2DM at the time of diagnosis. Patients with obesity and insulin resistance are at higher risk for cardiovascular abnormalities. Cluster classification based on clinical characteristics enables more accurate identification of patients at increased risk of cardiovascular complications at an early stage.

Heart failure (HF), which falls outside of the historical macrovascular or microvascular categorizations of diabetes complications, has been overlooked for long time in diabetic patients, despite its increasing prevalence and mortality. As originally stated in the Framingham studies, diabetes is associated with an increased risk of HF. Subsequent studies not only corroborated these findings but also identified HF as the most frequent first onset of cardiovascular involvement. The paramount role of proper management of common modifiable risk factors such as hypertension, obesity, dyslipidemia and smoking, became rapidly clear. Conversely, the impact of intensive glycemic control was more contentious. A large meta-analysis of randomized controlled trials reported a lack of effect of strict glycemic control as compared to standard care on HF-related outcomes. The considerable heterogeneity of the effect estimate and the higher risk conferred by thiazolidinediones suggested that mechanism of action of antidiabetic drugs played a key role. Furthermore, the safety concerns of pioglitazone led Food and Drug Administration to release a guidance for drug manufacturers stating that cardiovascular risk should be comprehensively evaluated during drug development. Surprisingly, in just a few years, large cardiovascular outcome trials established the beneficial cardiovascular effects of sodium-glucose cotransporter 2 inhibitors. These effects were consistent regardless diabetes and ejection fraction. Therefore, scientific community started to question the glucose-lowering and diuretic properties of sodium-glucose cotransporter 2 inhibitors as the unique mechanisms for improved outcomes. A plenty of preclinical and clinical studies identified several mechanisms besides glucose-lowering effects. However, these mechanistic studies focused on animal models and patients with established HF. If the same mechanisms account for beneficial effects in patients at risk for or with pre-HF is unknown. Grubić Rotkvić et al published an interesting work adding data in early stages HF.

SGLT-2 inhibitors, initially developed for type 2 diabetes, demonstrate profound cardiorenal and metabolic benefits. This review synthesizes evidence from clinical trials and mechanistic studies to elucidate their roles in cardiovascular diseases, chronic kidney disease, and non-alcoholic fatty liver disease. Key findings include a notable reduction in cardiovascular death/heart failure hospitalization, a marked decrease in heart failure hospitalization risk, and significant improvements in renal and hepatic outcomes. Emerging mechanisms, such as autophagy induction, ketone utilization, and anti-inflammatory effects, underpin these benefits. Ongoing trials explore their potential in non-diabetic populations, positioning SGLT-2 inhibitors as transformative agents in multisystem disease management.

Coronary microembolization (CME) often occurs as a serious complication during or after percutaneous coronary intervention (PCI), leading to an impairment in heart function, inflammation, and cell death. Dapagliflozin (DAPA) has been shown to have cardioprotective effects. However, its role and exact mechanism in CME remains unclear.

A preclinical CME model was developed via the administration of microspheres into the left ventricle. In an in vitro model, the CME-created microenvironment was observed by using lipopolysaccharide (LPS) with hypoxic induction on H9C2 cardiomyocytes. Before developing both experimental models, DAPA or the sirtuin 1 (SIRT1) inhibitor "EX-527" was administered. Echocardiography, histological examination, and molecular and immunological assays were carried out to assess the levels of cardiac tissue or cardiomyocyte damage, inflammation, and apoptosis.

Heart dysfunction and tissue damage caused by CME can be alleviated by pre-treatment with DAPA, which also reduces myocardial inflammation and apoptosis. Moreover, both experimental studies have depicted that DAPA can upregulate the SIRT1 level and downregulate the acetylation and phosphorylation levels of nuclear factor kappa-B (NF-κB) p65. This effect inhibits the induction of NF-κB signaling and mitigates cardiomyocyte damage. However, DAPA's cardioprotective effect was reversed when co-treated with EX-527.

DAPA reduces myocardial damage caused by CME by suppressing myocarditis and apoptosis via the SIRT1/NF-κB axis.

In recent years, new drugs for the treatment of type 2 diabetes (T2D) have been proposed, including glucagon-like peptide 1 (GLP-1) agonists or sodium-glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors. Over time, some of these agents (in particular, GLP-1 agonists and SGLT2 inhibitors), which were initially developed for their glucose-lowering actions, have demonstrated significant beneficial pleiotropic effects, thus expanding their potential therapeutic applications. This review aims to discuss the mechanisms, pleiotropic effects, and therapeutic potential of GLP-1, DPP-4, and SGLT2, with a particular focus on their cardiorenal benefits beyond glycemic control.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) reportedly decreased the new-onset atrial arrhythmias in patients with type-2 diabetes (T2DM) or heart failure (HF). This study examined the impact of SGLT2is on catheter ablation for atrial fibrillation (AF) in HF patients without T2DM.

Persistent AF (PeAF) and HF (N-terminal prohormone of brain natriuretic peptide, NT-proBNP ≥400 pg/ml) patients without T2DM undergoing catheter ablation were prospectively enrolled (n = 102). SGLT2is were prescribed from ≥1 month prior to the procedure and were continued during the follow-up in 51 patients (SGLT2i[+]) but not prescribed in 51 patients (SGLT2i[-]). Left atrial pressure (LAP) was measured via the sheath placed in the LA before starting catheter ablation. The event-free rate of early and 1-year atrial-arrhythmia recurrence were compared between SGLT2i[+] and SGLT2i[-].

There was no significant difference in baseline characteristics between SGLT2i[+] and SGLT2i[-]. SGLT2i[+] significantly decreased average LAP compared to SGLT2i[-] (9.3 ± 4.8 mmHg vs. 12.1 ± 6.6 mmHg, p < 0.01); normalized LAP to systemic blood pressure also decreased in SGLT2i[+] (0.11 ± 0.05 vs. 0.15 ± 0.07, p < 0.01). The serum NT-proBNP levels at the enrollment were unchanged between the two groups but SGLT2i[+] had lower values on the day of catheter ablation (p = 0.06) and at 1 month after the procedure (p < 0.01) than SGLT2i[-]. SGLT2i[+] had significantly higher event-free rate of early (92 % vs. 60 %, p < 0.01) and 1-year (89 % vs. 75 %, p < 0.05) atrial-arrhythmia recurrence than SGLT2i[-].

Periprocedural SGLT2i treatment decreased LAP and improved the outcomes of catheter ablation for PeAF in HF patients without T2DM.

The etiology of diabetic kidney disease (DKD) is multifaceted, with hyperglycemia, inflammation, oxidative stress, and fibrosis recognized as key contributors to renal damage in individuals with DKD. Clinical evidence suggests that dapagliflozin not only reduces blood glucose levels but also demonstrates superior efficacy in ameliorating pancreatic islet cell injury while preserving cardiac and renal function. However, the precise underlying mechanism has been poorly elucidated in the current literature. In this study, a DKD rat model was established by administering a single intraperitoneal injection of streptozotocin (STZ) to investigate the renoprotective properties of dapagliflozin and its underlying mechanisms. The findings of this study indicate that dapagliflozin enhanced pancreatic islet cell function, lowered blood glucose levels, and significantly reduced biochemical markers and renal pathological damage in DKD rats. Dapagliflozin also exerted anti-inflammatory, antioxidant, and antifibrotic effects by inhibiting the activation of the p38 MAPK/NF-κB pathway, enhancing the activity of the SIRT1/Akt/GSK-3β/Nrf2/HO-1 signaling pathway, and inhibiting the over-activation of the TGF-β1/Smad2/3 signaling pathway. These effects led to a reduction in renal injury and improved renal function in DKD rats.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been associated with lower rates of cardiac arrhythmias in post hoc analyses. The real-world effect on cardiac arrhythmias is incompletely defined.

The purpose of this study was to determine the effects of SGLT2i on cardiac arrhythmias in a real-world, hospitalized population.

A retrospective cohort study was performed in South Australia, Australia. Patients (n = 882) with type 2 diabetes mellitus (T2DM) on oral diabetic therapy (33.6% females, median age 62.3 years) who received SGLT2i (for T2DM) were identified through public hospital admissions from 2011-2019. Patients were matched with 3282 contemporaneous controls with T2DM who did not receive SGLT2i. Baseline characteristics were adjusted using inverse probability treatment weighting. The primary outcome was incidence of atrial arrhythmias. Secondary outcomes included incidence of ventricular arrhythmias and cardiac arrest at 2 years.

All-cause mortality was higher in the SGLT2i group (hazard ratio [HR] 2.02, 95% confidence interval [CI] 1.55-2.63, P <.001) despite propensity matching, highlighting the greater unmeasured comorbidity burden of the SGLT2i-treated group. Despite this, SGLT2i treatment was associated with fewer atrial arrhythmias (HR 0.17, 95% CI 0.07-0.41, P <.001) at 2 years. The relationship between SGLT2i use and ventricular arrhythmias (HR 0.25, 95% CI 0.06-1.03, P = .055) and cardiac arrest (HR 0.82, 95% CI 0.20-3.45, P = .796) did not reach statistical significance.

In this real-world, comorbid inpatient cohort, SGLT2i treatment was associated with a lower incidence of atrial arrhythmias. Prospective randomized trials evaluating SGLT2i as specific atrial fibrillation pharmacotherapy are underway.

Studies of sodium-glucose cotransporter-2 (SGLT2) inhibitors assessing kidney outcomes among Asians with type 2 diabetes in a clinical setting are limited. We assessed the association of SGLT2 inhibitors with kidney and safety outcomes in a diverse multiethnic Asian population with type 2 diabetes in a clinical setting.

Retrospective cohort study.

Patients with type 2 diabetes from multi-institutional SingHealth Diabetes Registry in Singapore.

Initiators of SGLT2 inhibitors between 2014 to 2018 with a median follow-up duration of 25.6 months (interquartile range, 17.9-31.4).

Composite kidney outcome (≥40% estimated glomerular filtration rate [eGFR] decline or incident kidney failure with replacement therapy [KFRT]), its components, rate of eGFR change, amputation, and acute kidney injury (AKI).

Propensity scores for SGLT2 inhibitors initiation were developed, with 1:1 matching with initiators of other antidiabetic drugs. Cox proportional hazards and linear mixed effect models were employed.

After matching, there were 4,254 patients newly initiated on either SGLT-2 inhibitors or other glucose-lowering drugs (2,127 in each group). The mean age was 63.4 (SD 9.2) years, with 48.6% women. In total, 67.8% of participants were Chinese, 11.9% Indian, 15.6% Malay, and 4.7% others. Initiating SGLT2 inhibitors was associated with lower risks of composite kidney outcome (hazard ratio [HR], 0.39; 95% CI, 0.31-0.48) and ≥40% reduction in eGFR from baseline (HR, 0.38; 95% CI, 0.31-0.48). SGLT2 inhibitor initiation was also associated with a slower eGFR decline among the intention-to-treat population (n = 1,888, difference in slope: 2.67 mL/min per 1.73 m2 per year; 95% CI, 1.90-3.43). No significant association with amputation was found, though SGLT2 inhibitors were associated with reduced AKI risk.

Potential informed presence bias and residual and unmeasured confounding.

SGLT2 inhibitors significantly benefit kidney outcomes in multiethnic Asians with type 2 diabetes, highlighting their role in preventing kidney complications.

Sodium-glucose cotransporter-2 (SGLT2) inhibition and lactation result in the excretion of large amounts of glucose in urine or milk and are associated with a lower risk of cardiovascular events. The respective mechanisms behind this association with cardiovascular protection are not clear. This review compares the contribution of noninsulin-mediated glucose transport during pharmacologic inhibition of SGLT2 with noninsulin-mediated glucose transport during lactation in terms of the implications for the cardiometabolic health of parous women. The search topics used to obtain information on SGLT2 inhibitors included mechanisms of action, atherosclerosis, and heart failure. The search topics used to obtain information on lactation included cardiovascular health and milk composition. Subsequent reference searches of retrieved articles were also used. Active treatment with SGLT2 inhibitors affects glucose and sodium transport in the kidneys and predominantly protects against hospitalization for heart failure soon after the onset of therapy. Active lactation stimulates glucose transport into the mammary gland and improves subclinical and clinical atherosclerotic vascular disease years after delivery. Both SGLT2 inhibitors and lactation have effects on a variety of glucose transporters. Several mechanisms have been proposed to explain the cardiometabolic benefits of SGLT2 inhibition and lactation. Learning from the similarities and differences between both processes will advance our understanding of cardiometabolic health for all people.

Diabetic kidney disease (DKD) is a prevalent complication of diabetes mellitus (DM), and its incidence is increasing alongside the number of diabetes cases. Effective treatment and long-term management of DKD present significant challenges; thus, a deeper understanding of its pathogenesis is essential to address this issue. Chronic inflammation and abnormal cell death in the kidney closely associate with DKD development. Recently, there has been considerable attention focused on immune cell infiltration into renal tissues and its inflammatory response's role in disease progression. Concurrently, ferroptosis-a novel form of cell death-has emerged as a critical factor in DKD pathogenesis, leading to increased glomerular filtration permeability, proteinuria, tubular injury, interstitial fibrosis, and other pathological processes. The cardiorenal benefits of SGLT2 inhibitors (SGLT2-i) in DKD patients have been demonstrated through numerous large clinical trials. Moreover, further exploratory experiments indicate these drugs may ameliorate serum and urinary markers of inflammation, such as TNF-α, and inhibit ferroptosis in DKD models. Consequently, investigating the interplay between ferroptosis and innate immune and inflammatory responses in DKD is essential for guiding future drug development. This review presents an overview of ferroptosis within the context of DKD, beginning with its core mechanisms and delving into its potential roles in DKD progression. We will also analyze how aberrant innate immune cells, molecules, and signaling pathways contribute to disease progression. Finally, we discuss the interactions between ferroptosis and immune responses, as well as targeted therapeutic agents, based on current evidence. By analyzing the interplay between ferroptosis and innate immunity alongside its inflammatory responses in DKD, we aim to provide insights for clinical management and drug development in this area.

Adults with type 2 diabetes mellitus (T2DM) are at an increased risk for certain brain or psychiatric disorders, as are those with or without chronic kidney disease or heart failure. Whether sodium-glucose cotransporter 2 (SGLT2) inhibitors are associated with these diseases is unclear.

This systematic review and meta-analysis aimed to investigate the effects of SGLT2 inhibitors on nervous system disorders.

We searched PubMed, ClinicalTrials.gov, and Web of Science for randomized, double-blind placebo-controlled trials of at least ≥24 weeks. We used Mantel-Haenszel statistical method, risk ratio (RR), and 95% confidence interval (CI) to dichotomous variables.

We included 52 publications/trials covering 111 376 participants (SGLT2 inhibitors 62 192; Placebo 49 184). Sodium-glucose cotransporter 2 inhibitors had no significant effect on ischaemic stroke (RR = 0.97; 95% CI = 0.87-1.09; P = 0.64), cerebrovascular accident (RR = 1.05; 95% CI = 0.91-1.22; P = 0.50), dementia (RR = 1.29; 95% CI = 0.78-2.12; P = 0.32), carotid artery occlusion/carotid artery stenosis (RR = 1.18; 95% CI: 0.92-1.53; P = 0.20), haemorrhagic stroke (RR = 0.84; 95% CI = 0.62-1.12; P = 0.23), and transient ischaemic attack (RR = 0.97; 95% CI = 0.82-1.15; P = 0.73) compared to placebo. No significant heterogeneity was observed. However, SGLT2 inhibitors showed slight effects to reduce the risk of Parkinson's disease (major heart failure subgroup). Empagliflozin and dapagliflozin significantly increased the risk of syncope (RR = 1.65; 95% CI = 1.15-2.38; P < 0.01) and carotid artery occlusion/carotid artery stenosis (RR = 1.65; 95% CI = 1.04-2.61; P = 0.03), respectively.

No significant effect of SGLT2 inhibitors on nervous system disorders was observed. There was reduced risk for Parkinson's Disease observed in some specific populations. In addition, the risks of empagliflozin and dapagliflozin concerning syncope and carotid artery occlusion/carotid artery stenosis are worth attention.

I am delighted to present this Special Issue, which focuses on the latest advancements in the optimal medical therapy for heart failure [...].

This study aimed to evaluate the cardiorenal effect of combining sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) when compared with monotherapy of either agent in patients with type 2 diabetes (T2D).

PubMed, Web of Science, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrial.gov were systematically searched from inception to June 2024. Eligible studies included randomised controlled trials and observational studies assessing that compared with SGLT2i or GLP-1RA monotherapy, the risk of cardiorenal outcomes in patients with T2D who treated with combination therapy. Pooled relative risk (RR) and 95% confidence intervals (CIs) were computed in random-effects model.

In all, five RCTs, 10 post hoc analyses and one observational study were included. The reduced risk of the composite cardiovascular outcome was observed in patients receiving combination therapy of SGLT2i and GLP-1RA when compared with SGLT2i monotherapy (RR = 0.57, 95% CI 0.38-0.86, p = 0.008) or GLP-1RA monotherapy (RR = 0.77, 95% CI 0.65-0.91, p = 0.002). Likewise, the composite renal adverse events were less frequent in patients receiving combination therapy of SGLT2i and GLP-1RA when compared with SGLT2i monotherapy (RR = 0.69, 95% CI 0.59-0.82, p < 0.001) or GLP-1RA monotherapy (RR = 0.66, 95% CI 0.53-0.83, p < 0.001). Compared with GLP-1RA monotherapy, the combination therapy of SGLT2i and GLP-1RA was associated with lower risks of heart failure-related outcomes (RR = 0.63, 95% CI 0.51-0.77, p < 0.001) and all-cause mortality (RR = 0.66, 95% CI 0.50-0.88, p = 0.004) in patients with T2D.

The cardiorenal benefits might be magnified with the combination therapy of SGLT2i and GLP-1RA when compared with monotherapy of either agent. Further investigations are needed to validate the findings.

Right ventricular failure (RVF) is a clinical syndrome resulting from structural and functional changes in the right ventricle (RV), leading to inadequate blood flow to the pulmonary circulation and elevated systemic venous pressures. Factors modulating RV function include afterload, preload, contractility, and interventricular dependency. The pathophysiology of RVF involves complex interactions, such as maladaptive hypertrophy, metabolic reprogramming, inflammation, fibrosis, apoptosis, and endothelial dysfunction. Therapeutic strategies are limited for RVF, as basic and clinical research has historically focused mainly on the left ventricle. Novel pharmacological interventions targeting metabolism, calcium homeostasis, oxidative stress, extracellular matrix remodeling, endothelial function, and inflammation are needed to address RVF effectively. This review explores the etiology, mechanisms, and pathophysiology of RVF, drugs directly targeting the RV myocardium, the intricate biological processes between RV and pulmonary vascular remodeling, surgical and device therapies, and future perspectives on managing RVF.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to lower the risk of re-hospitalization and cardiovascular mortality among heart failure (HF) patients. Nevertheless, the impact of these agents on ventricular arrhythmias (VAs) has not been thoroughly investigated. To assess the beneficial impact of SGLT2 inhibitors on VAs in patients at various stages of HF, a systematic review and meta-analysis of randomized controlled trials involving SGLT2 inhibitors in this patient population was performed.

A comprehensive search of the PubMed, Embase, Ovid, ProQuest, Scopus, and Cochrane databases was performed for clinical trials published up to November 21, 2024. The primary outcomes of interest were incidences of VAs and sudden cardiac death (SCD) between the groups receiving SGLT2 inhibitors and the control drugs. For the outcomes observed in the populations of the included trials and in specific subgroups, hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled and meta-analysed across the analyses.

A total of 23 randomized trials (22 placebo-controlled trials and 1 active-controlled trial) involving 74,380 patients (37,372 receiving SGLT2 inhibitors and 37,008 in the control group) were included. The analysed SGLT2 inhibitors included canagliflozin, dapagliflozin, empagliflozin, bexagliflozin, sotagliflozin, and ertugliflozin. The participants were non-advanced HF patients, including at-risk for HF, pre-HF, and symptomatic HF, with follow-up duration ranging from 12 to 296 weeks. Compared with the control, treatment with SGLT2 inhibitors was associated with significantly reduced risk of VAs (risk ratio (RR) 0.85, 95% confidence interval (CI) 0.74-0.98; P = 0.02) and SCD (RR 0.79, 95% CI 0.64-0.98; P = 0.03). Subgroup analyses indicated that longer follow-up (≥ 1 year) taking SGLT2 inhibitors can still reduce the risk of VAs (RR 0.79, 95% CI 0.65-0.96; P = 0.02) and SCD (RR 0.80, 95% CI 0.65-0.99; P = 0.04).

SGLT2 inhibitors have beneficial effects on lowering risks of VAs and SCD in patients with type 2 diabetes, cardiovascular diseases, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), and heart failure with mildly reduced ejection fraction (HFmrEF), with longer follow-up duration reinforcing these findings. However, future prospective trials are needed to verify the effects of SGLT2 inhibitors on VAs and SCD.

PROSPERO (CRD42024601914).

Uric acid (UA) is mainly synthesized in the liver, intestine, and vascular endothelium and excreted by the kidney (70 %) and intestine (30 %). Hyperuricemia (HUA) occurs when UA production exceeds excretion. Many studies have found that elevated UA is associated with diabetic microvascular complications (DMC), including diabetic retinopathy (DR), diabetic nephropathy (DN), and diabetic peripheral neuropathy (DPN). In addition, too high or too low UA levels will promote the occurrence and development of chronic diseases, but the relationship between UA and diabetic microvascular complications (DMC) is not clear. Therefore, the rational treatment of UA in patients with diabetes is essential. In this review, we summarize and discuss the mechanism and treatment of UA and DMC and may provide potential advice for rational drug selection.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class initially designed and approved for treatment of diabetes mellitus, have been shown to exert pleiotropic metabolic and direct cardioprotective and nephroprotective effects that extend beyond their glucose-lowering action. These properties prompted their use in two frequently intertwined conditions, heart failure and chronic kidney disease. Their unique mechanism of action makes SGLT2i an attractive option also to lower the rate of cardiac events and improve overall survival of oncological patients with preexisting cardiovascular risk and/or candidate to receive cardiotoxic therapies. This review will cover biological foundations and clinical evidence for SGLT2i modulating myocardial function and metabolism, with a focus on their possible use as cardioprotective agents in the cardio-oncology settings. Furthermore, we will explore recently emerged SGLT2i effects on hematopoiesis and immune system, carrying the potential of attenuating tumor growth and chemotherapy-induced cytopenias.

Dapagliflozin (DAPA), a sodium-glucose co-transporter 2 inhibitor, has been shown to reduce cardiovascular mortality among patients with chronic heart failure. We aimed to evaluate the impact on a worsening renal function (WRF) by adding DAPA as compared to standard decongestive therapy with loop diuretics alone.

We enrolled 114 consecutive acute decompensated heart failure (ADHF) patients with a left ventricular ejection fraction (LVEF) of less than 50%. The patients were prospectively randomized to be assigned either to DAPA group who received DAPA at a dose of 10 mg once daily within 24 h after admission or conventional therapy group (CON group) who received loop diuretics alone. All patients were adjusted by increasing or decreasing the loop diuretic by 10 mg to maintain a 1-2 mL/kg/h urine output. The primary endpoint was the incidence of WRF, which was defined as an increase in the serum creatinine of ≥0.3 mg/dL from baseline. The median age of the patients was 77 [interquartile range (IQR): 64, 85] years, 35% were female and the median LVEF was 33 [IQR: 28, 38] %. There was no significant difference in the incidence of WRF between the two groups (16.1%, n = 9 vs. 12.1%, n = 7, P value = 0.54). The total dose of loop diuretics through day 7 was lower in the DAPA group than CON group (184 ± 79.5 mg vs. 214 ± 66.5 mg, P value = 0.03).

This randomized prospective trial revealed the addition of DAPA within 24 h after admission reduced the diuretic dose without WRF.

Contrast-induced acute kidney injury (CI-AKI) is a prevalent cause of hospital-acquired renal impairment in patients undergoing intervention. Limited clinical trials explore SGLT2 inhibitors' effects on CI-AKI. This study aimed to assess the short-term effect of empagliflozin- an SGLT2 inhibitor- in reducing CI-AKI incidence in PCI patients regardless of diabetes. This research conducted a double-blind randomized clinical trial involving 121 patients undergoing PCI referred to Ghaem Hospital, Mashhad, Iran from 2022 to 2023. Participants were randomly assigned to receive empagliflozin (10 mg daily) or a placebo, starting one day before PCI and continuing for two days post-procedure. Renal function parameters such as estimated glomerular filtration rate (eGFR), creatinine, cystatin C, and urea were evaluated. After the intervention, empagliflozin users exhibited a significant reduction in mean cystatin C levels compared to the placebo users across all age groups (< 50 years, 50-60 years, and > 60 years). Patients older than 60 showed significant improvements in mean changes of eGFR with empagliflozin. Patients with eGFR > 60 and 45 < eGFR < 60 had a significant increase in eGFR in the empagliflozin group. Mean changes in cystatin C levels were significantly reduced with empagliflozin in all eGFR levels (> 60, 45-60, and < 45). There was no significant difference in urea and creatinine levels between the two groups. Empagliflozin notably decreases CI-AKI incidence in PCI patients by improving renal function parameters such as eGFR and cystatin C. These benefits were observed across various age groups, particularly in middle-aged and elderly, and those with varying renal function levels.

Background and Objectives: Insulin resistance (IR) is a key factor involved in the development of type 2 diabetes (T2D). Besides its role in the pathogenesis of T2D, insulin resistance is associated with impairment of glycemic control, reduced achievement of glycemic targets, and increases in cardiovascular risk and diabetes complications, being thus a negative prognosis factor. Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are therapies for T2D which demonstrated, besides glycemic control, improvements of biomarkers traditionally associated with IR and inflammation. This study aimed to evaluate the impact of SGLT2i treatment on IR and inflammation biomarkers in patients with T2D. Materials and Methods: In a retrospective study, 246 patients with T2D treated with SGLT2i for a median of 5 years were evaluated regarding IR (estimated glucose disposal rate-eGDR, triglyceride/glucose index, triglyceride/HDLc index) and inflammation biomarkers (neutrophils to lymphocyte ratio, platelets to lymphocytes ratio and C-reactive protein) before and after intervention with SGLT2i. Results: After a median 5 years of SGLT2i treatment, patients with T2D had a higher eGDR (6.07 vs. 5.24 mg/kg/min; p < 0.001), lower triglyceride/HDLc ratio (3.34 vs. 3.52, p < 0.001) and lower triglyceride/glucose index (9.23 vs. 9.58; p < 0.001). The inflammation biomarkers decreased after SGLT2i therapy: C-reactive protein (3.07 mg/L vs. 4.37 mg/L), NLR (0.68 vs. 0.72; p < 0.001), and PLR (115 vs. 122; p < 0.001). Intervention with SGLT2i also improved the biomarkers associated with diabetes complications and cardiovascular risk: HbA1c (7.1% vs. 8.4%; p < 0.001), body mass index (30.0 vs. 31.5 kg/m2; p < 0.001) and urinary albumin to creatinine ratio (4.75 vs. 11.00 mg/g; p < 0.001). Conclusions: Treatment with SGLT2i in patients with T2D leads to decreases in IR and inflammation. These mechanisms may partially explain the additional cardiovascular and renal risk reductions associated with SGLT2i therapy, alongside the improvements in glycemic control, in patients with T2D.

Previous studies demonstrated that diabetes remission can occur during intensive intervention and in real-world settings. However, the impact of diabetes remission in real-world settings on the incidence of cardiovascular disease (CVD) remains unclear.

This retrospective cohort study included 299,967 individuals aged 20-72 years who underwent multiple checkups between 2008 and 2020 and completed ≥ 3 years of follow-up. Patients were divided into four groups according to changes in glycated hemoglobin levels and the use of diabetes medications during the 1-year baseline period: diabetes mellitus (DM)+/no remission, DM+/remission, DM-/no progression, and DM-/progression. The risk of CVD was evaluated using multivariable Cox regression analysis.

The median follow-up period was 5.0 years. The rates of CVD in the DM+/no remission, DM+/remission, DM-/no progression, and DM-/progression groups were 7.96, 4.76, 1.99, and 5.47 per 1000 person-years, respectively. Compared with DM+/no remission, DM+/remission reduced the risk of CVD [hazard ratio (HR) = 0.71, 95% confidence interval (CI) = 0.57-0.89]. Meanwhile, the HR for CVD in the DM+/remission group was 0.75 (95% CI = 0.56-0.99) for change in BMI ≤ 0%, versus 0.66 (95% CI = 0.45-0.96) for change in BMI > 0%.

In a real-world setting without intensive intervention, diabetes remission decreased the risk of CVD by approximately 30% regardless of changes in BMI, suggesting that diabetes remission can prevent CVD without weight loss in routine care and emphasizing the importance of achieving remission.

Traditionally viewed as a passive player in circulation, the right ventricle (RV) has become a pivotal force in hemodynamics. RV failure (RVF) is a recognized complication of primary cardiac and pulmonary vascular disorders and is associated with a poor prognosis. Unlike treatments for left ventricular failure (LVF), strategies such as adrenoceptor signaling inhibition and renin-angiotensin system modulation have shown limited success in RVF. This review aims to reassure about the progress in RVF treatment by exploring the potential of contemporary therapies for heart failure, including angiotensin receptor and neprilysin inhibitors, sodium-glucose co-transporter 2 inhibitors, and soluble guanylate cyclase stimulators, which may be beneficial for treating RV failure, particularly when associated with left heart failure. Additionally, it examines novel therapies currently in the pipeline.

Over the past decade, a new wave of RVF therapies has emerged, both pharmacological and device-centered. Novel pharmacological interventions targeting metabolism, calcium homeostasis, oxidative stress, extracellular matrix remodeling, endothelial function, and inflammation have shown significant promise in preclinical studies. There is also a burgeoning interest in the potential of epigenetic modifications as therapeutic targets for RVF. Undoubtedly, a deeper understanding of the mechanisms underlying RV failure, both with and without pulmonary hypertension, is urgently needed. This knowledge is not just a theoretical pursuit, but a crucial step that could lead to the development of pharmacological and cell-based therapeutic options that directly target the RV and pulmonary vasculature, aligning with the principles of precision medicine.

This article explores the cardiovascular effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM), with a particular focus on their impact on lipid profiles. As evidence grows of the cardiovascular benefits of SGLT2i beyond glucose control, it is essential to better understand their effects on lipoproteins and their impact on cardiovascular disease.

SGLT2i have shown significant cardiovascular benefits in patients with type 2 diabetes mellitus, beyond their role in lowering blood glucose. Studies indicate that SGLT2i reduce major adverse cardiovascular events by impacting factors such as blood pressure, body weight, and arterial stiffness. However, their effects on lipid profile remain complex and somewhat inconsistent. Some research points to modest increases in LDL cholesterol, while others report shifts toward less atherogenic lipid profile, including reductions in triglycerides and small, dense LDL particles, and increases in HDL-C. SGLT2i represent a significant advancement in managing diabetes and associated cardiovascular risks, with benefits such as triglyceride reduction and HDL-C increase. While their impact on LDL-C remains controversial and varies across studies, the reduction of small, dense LDL particles may mitigate negative effects. This article highlights the need for future research to better understand the specific mechanisms behind lipid modulation.

Sodium/glucose co-transporter 2 (SGLT2) inhibitors have transformed heart failure (HF) treatment, offering sympatholytic effects whose mechanisms are not fully understood. Our previous studies identified Cyclic GMP-AMP synthase (cGAS)-derived neuroinflammation in the Subfornical organ (SFO) as a promoter of sympathoexcitation, worsening myocardial remodeling in HF. This research explored the role of central SGLT2 in inducing endothelial cGAS-driven neuroinflammation in the SFO during HF and assessed the impact of SGLT2 inhibitors on this process.

Hypertensive HF was induced in mice via Angiotensin II infusion for four weeks. SGLT2 expression and localization in the SFO were determined through immunoblotting and double-immunofluorescence staining. AAV9-TIE-shRNA (SGLT2) facilitated targeted SGLT2 knockdown in SFO endothelial cells (ECs), with subsequent analyses via immunoblotting, staining, and co-immunoprecipitation to investigate interactions with cGAS, mitochondrial alterations, and pro-inflammatory pathway activation. Renal sympathetic nerve activity and heart rate variability were measured to assess sympathetic output, alongside evaluations of cardiac function in HF mice.

In HF model mice, SGLT2 levels are markedly raised in SFO ECs, disrupting mitochondrial function and elevating oxidative stress. SGLT2 knockdown preserved mitochondrial integrity and function, reduced inflammation, and highlighted the influence of SGLT2 on mitochondrial health. SGLT2's interaction with cGAS prevented its ubiquitination and degradation, amplifying neuroinflammation and HF progression. Conversely, Empagliflozin counteracted these effects, suggesting that targeting the SGLT2-cGAS interaction as a novel HF treatment avenue.

This study revealed that SGLT2 directly reduced cGAS degradation in brain ECs, enhancing neuroinflammation in the SFO, and promoting sympathoexcitation and myocardial remodeling. The significance of the central SGLT2-cGAS interaction in cardiovascular disease mechanisms is emphasized.

Type 2 diabetes mellitus (T2D) has acquired epidemic proportions worldwide. In recent years, new oral glucose-lowering drugs (OGLD) have emerged that improve the cardiovascular-kidney-metabolic control in T2D people.

To compare the baseline clinical-biological characteristics among T2D people to whom had added-on dapagliflozin (DAPA group) or another OGLD (SOC group) second-line hypoglycaemic therapies among the AGORA study population.

This is a multicentre cross-sectional observational study of the baseline characteristics of T2D people recruited through competitive sampling among 46 primary care health centres in Spain for the AGORA study. The inclusion and exclusion criteria of participants, and justification of the sample size are reported. After verifying the data necessary to be evaluated and informed consent, 317 subjects were included to the DAPA group and 288 to the SOC group. Both categorical and continuous variables were analysed and compared with the usual statistics. Cohen's d was used to assess the standardised difference in means.

Six hundred and five patients with T2D were assessed (mean age 63.5 [SD±8.1] years, 61.8% men), whom 17.4% were smokers, 47.6% had obesity, 74.8% hypertension, 87.3% dyslipidaemia, and 41.7% reported physical inactivity, with no significant differences between both comparison groups. The mean (SD) evolution time of T2D was 10.1 (5.6) years. Most baseline clinical-biological characteristics at recruitment were similar in both groups. However, DAPA group was younger (2.9 years), and had lower systolic blood pressure (SBP) (2.8mmHg), higher body weight (BW) (3.7kg), and higher glycated haemoglobin A1c (HbA1c) (0.3%) than SOC group. Only 11.5% of participants had poor glycaemic control (HbA1c>8%) at recruitment, 54.9% had good glycaemic control (HbA1c<7%), being significantly lower in the DAPA group (47.3%) than in the SOC group (63.4%). The percentage of T2D patients with high vascular risk (VR) was 46.3%, and 53.7% with very high VR, being significantly higher in the DAPA group (57.4%) than in the SOC group (49.6%).

Most baseline cardiovascular-kidney-metabolic characteristics were similar in T2D patients whom had added dapagliflozin on second-line hypoglycaemic therapy as those whom had added-on another OGLD. However, patients whom had added-on dapagliflozin had higher VR, lower SBP, higher BW, and slightly worse HbA1c control. Future research is necessary to explain the causes of these differences in cardiometabolic control.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have significantly impacted the management of diabetic kidney disease (DKD) and heart failure (HF), providing benefits beyond glycemic control. This review examines the mechanisms through which SGLT2is provide renal and cardiovascular protection and assesses their clinical efficacy.

By inducing glucosuria and natriuresis, SGLT2is alleviate multiple complications induced by chronic hyperglycemia. Moreover, SGLT2is reduce albuminuria, improve tubular function, and modulate erythropoiesis. Additionally, they mitigate inflammation and fibrosis by decreasing oxidative stress and downregulating proinflammatory pathways. Clinical trials have demonstrated significant reductions in renal and cardiovascular events among patients with type 2 diabetes mellitus. A comprehensive review of the literature was conducted through PubMed, highlighting the effects of SGLT2is and the results of major clinical trials involving SGLT2is.

SGLT2is play a crucial role in the management of DKD and HF by addressing multiple pathogenic pathways. Currently, SGLT2is are included in clinical guidelines for DKD and HF management, and their benefits extend to nondiabetic populations. Further research is needed to explore SGLT2is' multifaceted mechanisms and potential applications across diverse patient populations and different disease etiologies.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors provide cardiovascular and kidney benefits to patients with heart failure (HF) and/or chronic kidney disease (CKD), regardless of diabetes status and left ventricular ejection fraction (LVEF). Despite robust data demonstrating the efficacy of SGLT-2 inhibitors in both ambulatory and hospital settings, real-world evidence suggests slow and varied adoption of SGLT2 inhibitors among patients hospitalized for HF. Barriers to implementation of SGLT2i may include clinicians' concerns regarding potential adverse events such as diabetic ketoacidosis (DKA), volume depletion, and symptomatic hypoglycemia; or concerns regarding physiologically expected reductions in eGFR. Guidelines lack specific, practical safety data and definitive recommendations regarding in-hospital initiation and continuation of SGLT2i in patients hospitalized with HF. In this review, we discuss the safety of in-hospital SGLT2 inhibitor initiation based on recent trials and highlight the clinical implications of their early use in patients hospitalized for HF.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) show a cardioprotective effect in heart failure and myocardial infarction, pathologies often associated with low-grade inflammation. This cross-sectional study aims to investigate whether low-grade inflammation regulates SGLT2 expression and function in human vasculature, heart, and endothelial cells (ECs).

Human internal thoracic artery (ITA), left ventricle (LV) specimens, and cultured porcine coronary artery ECs were used. Expression of target molecules was assessed using RT-qPCR, western blot analysis, and immunofluorescence staining, and the generation of reactive oxygen species (ROS) and nitric oxide (NO) using fluorescent probes. The function of SGLT2 was investigated using empagliflozin and SGLT1 or 2 siRNA. SGLT2 mRNA and protein levels in ITA and LV specimens were correlated with the level of low-grade inflammation, markers of the angiotensin system, and EC activation. SGLT2 staining was observed in the ITA endothelium and smooth muscle, the coronary microcirculation, and cardiomyocytes. Elevated ROS formation in high SGLT2-expressing specimens was reduced by inhibition of the angiotensin system, SGLT2, and TNF-α. Exposure of ECs to IL-1ß, IL-6, and TNF-α led to an increase in SGLT1 and SGLT2 mRNA and protein expression, up-regulation of components of the angiotensin system, enhanced ROS and decreased NO formation, and activation of NF-κB. The stimulatory effect of TNF-α was prevented by N-acetylcysteine and inhibition of the angiotensin system, SGLT2 but not SGLT1, and NF-κB.

Low-grade inflammation is closely associated with SGLT2 expression in human vasculature and heart, and this response contributes to a feedforward mechanism with the AT1R/NADPH oxidase pathway to cause eNOS-NO/ROS imbalance.

Background: The current review aims to present the beneficial effects of SGLT2 inhibitors (dapagliflozin and empagliflozin) on several hemodynamic parameters such as blood pressure, filtration pressure at the level of the glomerular capillaries, and the improvement of the preload and afterload of heart muscle. In order to stop chronic kidney disease (CKD) from progressing, SGLT2 inhibitors have become an important disease-modifying treatment. Materials and methods: Recent clinical studies have shown the success of these drugs in treating heart failure, reducing the risk of cardiovascular events, hospitalization, and mortality. Results: The hemodynamic effects of SGLT2 inhibitors include a diuretic effect, due to reduced sodium reabsorption. Also, at this level, numerous studies have confirmed the beneficial effect of dapagliflozin in patients with chronic kidney disease, associated with a 44% reduced risk of progression in this pathology. SGLT2 inhibitors are associated with a reduction in blood pressure and weight loss, because of their diuretic effect, especially empagliflozin, which can explain the beneficial effects in patients with heart failure. In addition, mainly empagliflozin reduces stiffness and arterial resistance. Conclusions: Although the exact mechanism of action is unknown, SGLT2 inhibitors reduce the interstitial volume by blocking the tubular reabsorption of glucose. This leads to reduced blood pressure and enhanced endothelial function. Consequently, there have been improvements in hospitalization and fatality rates. Because of their beneficial effects, these medications have been guidelines for managing heart failure and chronic kidney disease.

The impact of sodium-glucose co-transporter 2 inhibitors (SGLT2-i) on reducing the risk of all-cause mortality and rehospitalization for heart failure (HF) in patients with acute myocardial infarction (AMI) remains unclear. This study aims to evaluate the effect of SGLT2-i on all-cause mortality and rehospitalization for HF in patients diagnosed with AMI. A comprehensive search was conducted in PubMed, Web of Science, the Cochrane Library, and Embase for relevant studies published up to May 2024, following the PICOS principle. Eligible studies included randomized clinical trials and cohort studies comparing SGLT2-i with placebo regarding all-cause mortality, rehospitalization for HF, cardiovascular mortality, and the incidence of nonfatal MI in AMI patients. Patient-level data from each trial were synthesized into a pooled dataset and analyzed using a mixed-effects or random-effects model based on the I2 statistic. Ten clinical trials enrolling 15,748 participants (6913 in the SGLT2-i group and 8835 in the placebo group) were included. The follow-up duration ranged from 12 weeks to 2.1 years. SGLT2-i significantly reduced rehospitalization for HF (RR: 0.69, 95% CI 0.60-0.81, P < 0.00001, I2 = 39%) compared to placebo. However, SGLT2-i did not significantly reduce the risk of all-cause death (RR: 0.85, 95% CI 0.72-1.00, P = 0.05, I2 = 46%), cardiovascular death (RR: 0.96, 95% CI 0.78-1.18, P = 0.67, I2 = 24%) or nonfatal MI (RR: 0.71, 95% CI 0.44-1.14, P = 0.16, I2 = 64%) during follow-up. Compared to placebo, SGLT2-i significantly reduced rehospitalization for HF in patients with AMI, but did not reduce the risk of all-cause death, cardiovascular death and nonfatal MI.