Sodium-glucose co-transporter 2 (SGLT2) inhibitors are oral antidiabetic agents that have shown significant improvements in cardiovascular and renal outcomes among patients with heart failure (HF), regardless of diabetic status, establishing them as a cornerstone therapy. In addition to glycemic control and the osmotic diuretic effect, the inhibition of SGLT2 improves endothelial function and vasodilation, optimizing myocardial energy metabolism and preserving cardiac contractility. Moreover, SGLT2 inhibitors may exhibit anti-inflammatory properties and attenuate acute myocardial ischemia/reperfusion injury, thereby reducing cardiac infarct size, enhancing left ventricular function, and mitigating arrhythmias. These pleiotropic effects have demonstrated efficacy across various cardiovascular conditions, ranging from acute to chronic coronary syndromes and extending to arrhythmias, valvular heart disease, cardiomyopathies, cardio-oncology, and cerebrovascular disease. This review provides an overview of the current literature on the potential mechanisms underlying the effectiveness of SGLT2 inhibitors across a wide range of cardiovascular diseases beyond HF.

The effects of Sodium-glucose cotransporter-2 (SGLT-2) inhibitors on cardiac outcomes, cardiovascular mortality (CVM), and all-cause mortality (ACM) in type 2 diabetes mellitus (T2DM) patients have been reported heterogeneously in different studies.

PubMed, Scopus, Embase, Cochrane Library, and Scholar databases were searched with relevant MeSH terms from January 1, 2010, to November 14, 2023. The study used Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The primary outcomes in all trials included the risk of ACM, CVM, hospitalization for heart failure (HHF), myocardial infarction (MI), and cerebrovascular accidents (CVA) in T2DM patients who were treated with one of the SGLT-2 inhibitors. Heterogeneity between studies was evaluated using Cochran's Q and I2 tests. The Egger's test was used to check for publication bias.

Eighteen studies, including 70,830 participants, were included. A pooled estimate showed that SGLT-2 inhibitor treatment was significantly associated with reduced ACM (OR: 0.82, 95% CI: 0.75-0.90, p-value: 0.001, I2: 35.1%), CVM (OR: 0.88, 95% CI: 0.80-0.96, p-value: 0.001, I2: 0%), MI (OR: 0.88, 95% CI: 0.79-0.98, p-value: 0.001, I2: 0%), and HHF (OR: 0.67, 95% CI: 0.58-0.77, p-value: 0.001). SGL-2 inhibitor treatment had no significant relationship with CVA (stroke) (OR: 0.95, 95% CI: 0.8-1.10, p-value: 0.896). Subgroup analysis showed that the effect of SGLT-2 inhibitor treatment on outcomes varied based on the type of SGLT-2 inhibitor.

SGLT-2 inhibitor treatment significantly reduced CVM, ACM, MI, and HHF. Empagliflozin, Canagliflozin, and Dapagliflozin significantly reduced ACM. Canagliflozin was significantly associated with a reduction in CVM. All SGLT-2 inhibitor treatments were associated with a reduction in HHF.

Mitochondrial dysfunction with decreased ATP production and increased release of reactive oxygen species (ROS) is a hallmark of the failing heart. Although SGLT2 inhibitors have been shown to improve myocardial metabolism in the failing heart, independent of diabetes, the effect on mitochondria is not clear.

Our goal was to test the effect of the SGLT2 inhibitor ertugliflozin on mitochondrial gene expression and function in myocardium and isolated mitochondria from non-diabetic mice with dilated cardiomyopathy due to cardiac-specific over-expression of Gαq.

Gαq and wild type (WT) littermates 4 weeks of age were treated for 16 weeks with or without the SGLT2 inhibitor ertugliflozin (ERTU) formulated in the chow (0.5 mg/g chow).

From weeks 4 to 20, Gαq mice developed progressive cardiac hypertrophy, dilation, contractile dysfunction, myocyte apoptosis and interstitial fibrosis - all of which were prevented by ERTU treatment. Isolated cardiac mitochondria from Gαq mice had decreased maximal ATP production and increased ROS release - both of which were normalized by ERTU. In isolated beating hearts from Gαq mice, contractile reserve and high energy phosphates measured simultaneously by 31P NMR spectroscopy were decreased - and both were improved by ERTU. In Gαq mice, marked suppression of myocardial gene programs for oxidative phosphorylation and fatty acid metabolism was reversed by ERTU.

The SGLT2 inhibitor ERTU corrected the expression of myocardial gene programs for oxidative phosphorylation and fatty acid metabolism, and was associated with increased production of ATP, decreased release of mitochondrial ROS, and amelioration of the consequences of mitochondrial dysfunction on myocardial structure and function.

In addition to allogeneic factors, kidney transplant recipients (KTR) remain exposed to non-allogeneic conditions, such as hypertension, proteinuria, anemia, bone mineral disorder, metabolic acidosis and hyperuricemia. These conditions contribute to the progression of chronic kidney disease (CKD). This paper reviews the latest updates on therapeutic goals and strategies to address these non-allogeneic risk factors.

We undertook a literature review regarding the current recommendations and therapeutic targets for the treatment of non-allogeneic risk factors for CKD progression in KTR, as of 2024.

As evidence is limited, some factors' treatment is based on native CKD. Well supported by studies on KTR, the blood pressure target should be below 130/80 mmHg, and proteinuria ideally be kept under 500 mg/day, whenever possible due to its multifactorial nature, preferably through the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Revised optimal haemoglobin levels, and newly updated recommendations regarding treatment at earlier stages of bone mineral disorders, as well as other metabolic features and non-pharmacological interventions, are further addressed. A multidisciplinary approach with an individualized focus on treatment priorities for each patient leads to better therapeutic adherence and potentially improved outcomes.

We summarize the updated treatment goals for CKD in KTR, which are feasible to apply in daily practice and can contribute to better long-term patient and graft function survival.

The rising prevalence of Type 2 diabetes (T2D) has been closely associated with an increased incidence of cardiovascular diseases, particularly heart failure with preserved ejection fraction (HFpEF). Cardiometabolic disturbances in T2D, such as insulin resistance, hyperglycemia, and dyslipidemia, contribute to both microvascular and macrovascular complications, thereby intensifying the risk of heart failure. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), initially developed as glucose-lowering agents for T2D, have demonstrated promising cardiovascular benefits in patients with heart failure, including those with preserved ejection fraction (HFpEF), regardless of T2D status. These benefits include reduced heart failure hospitalization rates and improvements in various metabolic parameters. This review aims to critically examine the effects of SGLT2i on cardiac metabolism in HFpEF, evaluating whether the observed benefits can truly be attributed to their impact on myocardial energy regulation or whether they represent other, potentially confounding, mechanisms. We will focus on the key metabolic processes possibly modulated by SGLT2i, including myocardial glucose utilization, fatty acid oxidation, and mitochondrial function, and explore their effects on heart failure pathophysiology. Additionally, we will address the role of SGLT2i in other pathogenetic factors involved in HFpEF, such as sodium and fluid balance, inflammation, and fibrosis, and question the extent to which these mechanisms contribute to the observed clinical benefits. By synthesizing the current evidence, this review will provide an in-depth analysis of the mechanisms through which SGLT2i may influence cardiac metabolism in HFpEF, assessing whether their effects are supported by robust scientific data or remain speculative. We will also discuss the potential for personalized treatment strategies, based on individual patient characteristics, to optimize the therapeutic benefits of SGLT2i in managing both T2D and cardiovascular risk. This review seeks to clarify the true clinical utility of SGLT2i in the management of cardiometabolic diseases and HFpEF, offering insights into their role in improving long-term cardiovascular outcomes.

The production of ketones, referred to as ketogenesis, plays an essential role in maintaining energy homeostasis during prolonged fasting/starvation, which primarily stems from its ability to serve as a fuel source to support neuronal ATP production, thereby limiting muscle wasting. Over the years, the field has come to appreciate that ketones are much more than just a fuel source supporting neuronal metabolism, as many other oxidative organs, such as the heart and skeletal muscle, are capable of metabolizing ketones. Furthermore, ketones appear to be an important fuel source for exercising muscle. Beyond supporting ATP production, it is also becoming widely recognized that ketones are powerful signalling molecules, as they serve as ligands for G-protein coupled receptors and can even modify gene expression via regulating DNA post-translational modifications. As they play a key role in supporting whole-body physiology, it is not surprising that perturbations in ketone metabolism can contribute to various pathologies, particularly in relation to cardiometabolic diseases. Some of the strongest evidence supporting the aforementioned statement is seen for both heart failure and type 2 diabetes. Accordingly, we will review herein the multifaceted roles of ketones in supporting whole-body physiology, while interrogating the evidence to suggest whether modifying ketone metabolism may have a therapeutic role in the management of heart failure and type 2 diabetes.

Cellular senescence is the permanent cessation of cell proliferation and growth. Senescent cells accumulating in tissues and organs with aging contribute to many chronic diseases, mainly through the secretion of a pro-inflammatory senescence-associated secretory phenotype (SASP). Senotherapeutic (senolytic or senomorphic) strategies targeting senescent cells or/and their SASP are being developed to prolong healthy lifespan and treat age-related pathologies. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of anti-diabetic drugs that promote the renal excretion of glucose, resulting in lower blood glucose levels. Beyond their glucose-lowering effects, SGLT2 inhibitors have demonstrated protective effects against cardiovascular and renal events. Moreover, SGLT2 inhibitors have recently been associated with the inhibition of cell senescence, making them a promising therapeutic approach for targeting senescence and aging. This review examines the latest research on the senotherapeutic potential of SGLT2 inhibitors.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are currently recommended in patients with type 2 diabetes (T2D) to reduce serum glucose levels. Moreover, robust evidence has clearly demonstrated their beneficial cardiovascular and renal effects, making this class of drugs pivotal for the treatment of T2D, especially when complicated by diabetic kidney disease or heart failure. However, several other comorbidities are frequently encountered in T2D patients beyond these long-term diabetes complications, especially in the internal medicine setting. For some of these comorbidities, such as MAFLD and cognitive impairment, the association with diabetes is increasingly recognized, with the hypothesis of a common pathophysiologic background, whereas, for others, a coincident epidemiology linked to the ageing of populations, including that of T2D subjects, may be advocated. In the effort of personalizing T2D treatment, evidence on the potential effects of SGLT2i in these different clinical conditions is accumulating. The purpose of this narrative review is to update current literature on the effects of SGLT2i for the treatment of T2D in different clinical settings beyond glycaemic control, and to elucidate potential molecular mechanisms by which they exert these effects.

The role of sodium-glucose co-transporter inhibitors (SGLT2i) in heart failure is well-established. However, evidence supporting their use in acute myocardial infarction remains limited.

Two independent researchers conducted a comprehensive literature review on PubMed and Embase until April 2024. They identified 14 articles, consisting of randomized controlled trials and observational studies, investigating the use of SGLT2i in acute myocardial infarction. The analysis focused on cardiovascular outcomes, including all-cause mortality, cardiovascular mortality, major adverse cardiovascular events (MACE), heart failure exacerbation, strokes, and recurrence of acute coronary syndrome.

Our pooled analysis of 19,319 participants revealed a significant reduction in MACE [OR 0.50, 95 % CI [0.36; 0.70], p-value = 0.0001] and hospitalization due to heart failure [OR 0.59 (0.43-0.79), P < 0.0004] in the SGLT2i group compared to the control group. In contrast, there were no statistically significant differences between the SGLT2i and control groups regarding all-cause mortality, cardiovascular mortality, recurrence of acute coronary syndrome, or new-onset arrhythmia.

Our study highlights that among patients with acute myocardial infarction, the use of SGLT2i reduces MACE and hospitalizations due to heart failure. However, there was no significant reduction in mortality, recurrence of acute coronary syndrome, or arrhythmia in the SGLT2i group.

Diabetic cardiomyopathy is a unique cardiomyopathy that is common in diabetic patients, and it is also a diabetic complication for which no effective treatment is currently available. Moreover, relevant studies have revealed that a link exists between type 2 diabetes and heart failure and that abnormal thickening of EAT is inextricably linked to the development of diabetic heart failure. Numerous clinical studies have demonstrated that EAT is implicated in the pathophysiologic process of diabetic myocardial disease. In this overview, we will introduce the physiology, pathophysiology of the disease and potential therapeutic strategies, knowledge gaps, and future directions of the role of epicardial adipose tissue in type 2 diabetes mellitus and heart failure to promote the development of novel therapeutic approaches to improve the prognosis of patients with diabetic cardiomyopathy.

Insulin deficiency, often aggravated by insulin resistance, results in type 2 diabetes mellitus (T2DM). With the availability of glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, basal insulin (BI) therapy is no longer the first-line option after lifestyle modification plus oral agents is insufficient. In contrast to BI, the newer medications require minor titration, lower hyperglycemia in a glucose-dependent manner, and reduce body weight. Importantly, the newer agents reduce cardiorenal events in the short term. Nonetheless, insulin therapy continues to play a key role in control of hyperglycemia and therefore long-term prevention of vascular complications. Its use is essential in many circumstances, including metabolic emergencies, new diabetes onset, latent autoimmune diabetes (LADA), pregnancy, and when other agents are less desirable due to comorbidities. BI is needed in the frequent condition of failure of other therapies to keep HbA1c to target and/or intolerance of them. There are several advantages to the combination of BI with the newer medications given their different but complementary mechanisms of action, primarily, the lower dose of each, improving adherence and outcomes while decreasing the side effects. Multiple choices for single or combination use can better meet the variety of clinical phenotypes in the heterogeneous T2DM population, using the tenets of precision medicine.

Empagliflozin administered after acute myocardial infarction proofed to improve cardiometabolic parameters and biomarkers, but the impact on cardiac function is still largely unknown. The aim of this post-hoc echocardiographic sub-analysis of the EMMY trial was to provide in-depth echocardiographic analysis on the effects of empagliflozin versus placebo on standard and novel echocardiographic structural and functional parameters after acute myocardial infarction.

In this post-hoc analysis of the EMMY trial a subset of 313 patients (157 empagliflozin vs. 156 placebo) was enrolled for post-processing analysis of echocardiographic structural and functional parameters. On top of two-dimensional and Doppler parameters, myocardial deformation analyses were performed to assess ventricular and atrial strain values.

Left ventricular volumes showed significant differences in favor of empagliflozin over the course of the trial (change in left ventricular end-diastolic volume median [interquartile range] 8 [-3;19]% versus 13 [0;29]%, p = 0.048; left ventricular end-systolic volume -3 [-15;12]% versus 4 [-12;18]%, p = 0.044). This effect persisted after adjusting for baseline values, age, and sex. Left ventricular systolic and diastolic function overall improved over the course of the trial and parameters for diastolic function showed a distinct trend between groups but did not meet statistical significance in this cohort.

In this post-hoc analysis among patients with acute myocardial infarction, treatment with empagliflozin resulted in a significant beneficial effect on left ventricular end-diastolic and end-systolic volume, without significantly improving left ventricular or right ventricular functional parameters compared to placebo after 26 weeks.

NCT03087773.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as promising therapeutics for heart failure (HF). Nevertheless, evidence supporting the mechanism of SGLT2i efficacy in HF patients is currently limited. Genetic variation in SLC5A2 (encoding SGLT2) may influence HF progression and SGLT2i response, as well as inform potential SGLT2i mechanisms. Thus, this study investigated associations between SLC5A2 variation and clinical outcomes in SGLT2i-naïve and dapagliflozin-treated HF cohorts.

We analyzed two HF cohorts to identify variants associated with SGLT2i response pathways. Adjusted Cox proportional-hazard regression models were used to assess the effect of SLC5A2 variation on a primary composite outcome of cardiovascular (CV) hospitalization or all-cause mortality in SGLT2i-naïve patients, and HF hospitalization or CV death in dapagliflozin-treated patients. The initial cohort comprised 327 American HF patients naïve to SGLT2i throughout the study. Subsequently, a prospective cohort study of 190 Egyptian SGLT2i-naïve HF patients treated with dapagliflozin was analyzed. In this cohort, SNPs in UGT2B4 and SLC2A1 were also investigated. Changes in NT-proBNP levels, KCCQ-12 scores, echocardiographic parameters, and eGFR throughout 6-month follow-up were tested with linear regression models as secondary outcomes.

In SGLT2i-naïve patients, rs3813008 (SLC5A2) was significantly associated with reduced risk of the composite outcome of all-cause death or hospitalization (HR = 0.65, 95% CI: 0.47-0.89, P = 0.008). In the dapagliflozin-treated cohort, rs3813008 was also associated with death or hospitalization, but with increased risk in treated patients (HR = 3.38, 95% CI: 1.35-8.42, P = 0.008).

Our study suggests that SLC5A2 variation is associated with clinical outcomes in SGLT2i-naïve and treated HF patients, warranting further investigation of SLC5A2 and SGLT2i interactions.

Cardiovascular disease (CVD) and cancer represent significant global health challenges. An overlap between oncology and cardiology is compounded by cancer therapies, which are known to have cardiotoxic effects. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially developed for treating diabetes, have shown promising cardiovascular benefits in non-cancer populations, particularly in preventing heart failure (HF) and reducing HF-related hospitalization and mortality in large randomized controlled trials (RCTs) across the spectrum of left ventricular ejection fraction (LVEF). However, their potential cardioprotective role in cancer patients remains unclear.This systematic review and meta-analysis evaluated cardiovascular outcomes in cancer patients with type 2 diabetes undergoing chemotherapy with concomitant use of SGLT2i compared to those not using SGLT2i. Subgroup analyses were performed to explore patients without baseline HF and patients treated exclusively with anthracyclines.

A systematic review identified eleven observational retrospective studies (n=104,327 patients). Based on the National Institutes of Health Quality Assessment Tool (NIH-QAT) checklist, 2 studies were at moderate risk of bias, while all other included studies had a low risk of bias. Meta-analysis indicated that the use of SGLT2i was associated with a significant reduction in all-cause mortality (0.47, 95% CI 0.33-0.67, P<0.0001) and risk of HF hospitalization (0.44, 95% CI 0.27-0.72, P=0.001).

SGLT2i use may be associated with a significant reduction in all-cause mortality and risk of HF hospitalization in actively treated cancer patients with type 2 diabetes. Our study highlights the need for further investigation through prospective RCTs to confirm the efficacy and safety of SGLT2i in attenuating cardiotoxicity and supporting cardiovascular health in oncology settings.

Mounting evidence has established metabolic dysfunction-associated steatotic liver disease (MASLD) as an independent risk factor for heart failure (HF), particularly HFpEF. In this narrative review we explore the impact of MASLD on cardiovascular structure and function. We summarize findings from multiple cohort studies demonstrating that MASLD is associated with distinct patterns of adverse cardiac remodeling, including increased left ventricular concentricity and impaired diastolic function. These subclinical changes in cardiac structure and function often precede overt HF development and appear to occur in the context of multiple interconnected pathways involving metabolic dysfunction, systemic inflammation, adipose tissue dysregulation, vascular dysfunction, and altered hepatic hemodynamics. Early identification of cardiac structural and functional abnormalities through systematic screening may enable timely intervention in this high-risk population. Lifestyle modifications remain foundational, but achieving and maintaining significant weight loss is challenging. Recent clinical trials have shown promising results with cardiometabolic agents, particularly glucagon-like protein 1 receptor agonists, which demonstrate significant weight loss and hepatic and cardiovascular benefits. Despite these advances, key knowledge gaps remain regarding optimal screening strategies, mechanisms linking MASLD to HF, and targeted therapeutic approaches. Addressing these gaps will be essential for developing effective prevention and treatment strategies in this high-risk population.

Type 2 diabetes mellitus is associated with a 2-4 times increased risk of cardiovascular (CV) disease. Glucagon-like polypeptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) are two important classes of drugs with CV benefits independent of their antihyperglycemic efficacy. The CV outcome trials of both GLP1RA and SGLT2i have demonstrated CV superiority/neutrality concerning major adverse CV events (MACE). While GLP1RAs have exhibited a significant reduction in ischemic stroke and myocardial infarction (MI), SGLT2i have demonstrated a uniformly significant reduction in hospitalization for heart failure (HF) as a class effect. The unique clinical benefits and the distinct but complementary mechanisms of action make the combination of these drugs a mechanistically sound one. Recent meta-analyses suggest an independent and additive benefit of combination therapy of GLP1RA/SGLT2i vs monotherapy. Zhu et al, in a recent issue of the World Journal of Diabetes, demonstrates a numerically lower hazard ratio (HR) for CV outcomes with combination therapy vs monotherapy with either agent, with a reduction in MACE compared to GLP1RA alone [HR = 0.51, 95% confidence interval (CI): 0.16-1.65], or SGLT2i alone (HR = 0.48, 95%CI: 0.15-1.54). The CV death rate was also lower with combination therapy compared to GLP1RA alone (HR = 0.58, 95%CI: 0.08-3.39), or SGLT2i alone (HR = 0.55, 95%CI: 0.07-3.25). Fatal and non-fatal MI and fatal and non-fatal stroke were reduced with combination therapy compared to GLP1RA alone (HR = 0.45, 95%CI: 0.10-2.18 and HR = 0.86, 95%CI: 0.12-6.23, respectively), or SGLT2i alone (HR = 0.44, 95%CI: 0.09-2.10 and HR = 0.74, 95%CI: 0.10-5.47, respectively). Hospitalization for HF was prevented with combination therapy compared to GLP1RA alone (HR = 0.26, 95%CI: 0.03-1.88), or SGLT2i alone (HR = 0.33, 95%CI: 0.04-2.53). They also demonstrated that GLP1RA or SGLT2i monotherapy may not provide significant improvement in CV death and recurrent MI in patients with prior MI or HF, proposing a role for combination therapy in this subgroup. Appropriate patient selection is vital to optimize CV risk reduction as well as the cost-effectiveness of this combination therapy.

Dapagliflozin, an approved SGLT2 inhibitor, has been shown to have extra-glycemic effects like cardio-reno protection. However, the neuroprotective effects of SGLT2 inhibitors against diabetic neuropathy (DN) have not been explored. The current study aimed to determine the neuroprotective potential of Dapagliflozin against STZ-NAD-induced DN in Wistar rats via IGF-1 signaling. DN was induced by STZ-NAD in male Wistar rats. After 60 days of induction, behavioural tests were conducted to access DN, and treatment with Dapagliflozin (0.75 mg/kg & 1.50 mg/kg) was initiated for 30 days. At the end of the study, the brain and sciatic nerve were isolated and expression analysis of IGF-1R signaling molecules was carried out using western blotting, qRTPCR, and immunohistochemistry. Structural changes in the brain and sciatic nerve were ascertained by histopathology. The results showed that treatment with Dapagliflozin improved behavioural parameters in STZ-NAD-induced DN rats. The decreased expression levels of IGF1R signaling pathway molecules and increased expression of p-AKT were found to increase and decrease in the brain and sciatic nerve, respectively after the treatment. Histological studies demonstrated the restoration of normal architecture of the brain and sciatic nerve after treatment with dapagliflozin. The altered expression of IGF-1R signaling molecules established the neuroprotective potential of dapagliflozin against DN.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) preserve cardiac and renal function by mechanisms that are not completely elucidated. Among other things, SGLT2i promote nutrient-deprivation signalling, which might affect the immune function. As the fate of immune cells is controlled by their metabolism, we aimed to study the mitochondrial integrity of lymphocytes isolated from renal transplant recipients with type 2 diabetes (T2D) upon SGLT2i therapy instauration and six-month follow up. In this real-world pilot study, the mitochondrial respiration of isolated peripheral blood mononuclear cells was monitored in a Seahorse XFp extracellular-flux analyzer and cells were photographed with a confocal microscope. Mitochondrial mass, membrane potential, and superoxide content of lymphocyte subpopulations were measured by flow cytometry (MitoTrackerTM Green, TMRM, and MitoSOXTM Red probes). Leveraging in vivo conditions of immune cells, we evaluated their metabolic profiles associated with immune activation. Herein, we identified changes in redox homeostasis with sustained membrane polarization, and an increased mitochondrial biogenesis upon PHA stimulation that significantly correlated with changes in body weight and LDL-cholesterol levels, and a resultant compensatory mitochondrial function of lymphocytes. Our data suggest novel mechanisms induced by SGLT2i to modulate immune cells, which probably underlie the observed beneficial effects in kidney transplant recipients. Nonetheless, further mechanistic studies are required to extend these exploratory findings and encourage the use of this therapeutic strategy.

The relationship between initial changes in estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR), and their independent association with clinical outcomes in type 2 diabetes (T2D) patients receiving sodium-glucose cotransporter 2 inhibitors (SGLT2is), remains unclear.

This study aimed to investigate the association between initial changes in eGFR and UACR with consequent cardiovascular and kidney outcomes in an Asian population with T2D following SGLT2i treatment in a real-world setting.

Using a large multicenter medical database in Taiwan, we analyzed 8222 T2D patients with baseline and 3-month follow-up eGFR and UACR measurements, receiving SGLT2is between June 1, 2016, and December 31, 2021. We assessed risks of major adverse renal events (MARE), major adverse cardiovascular events (MACE), hospitalization for heart failure (HHF), and all-cause mortality using a Cox proportional hazards model.

After 3 months of SGLT2i treatment, patients were categorized based on early changes in eGFR (no decline, 0%-10% decline, > 10% decline) and UACR (no reduction, 0%-30% reduction, > 30% reduction). Among those with no initial eGFR decline (40.9%), 19.8% had no initial UACR reduction, 8.4% had 0% to 30% reduction, and 12.7% had greater than 30% reduction. For those with greater than 10% initial eGFR decline (21.5%), 6.5% had no UACR reduction, 4.3% had 0% to 30% reduction, and 10.7% had greater than 30% reduction. Patients with greater than 10% initial eGFR decline but no UACR reduction showed higher risks of MARE (adjusted HR [aHR]: 2.34; 95% CI, 1.32-4.15), MACE (aHR: 1.83; 95% CI, 1.01-3.29), and HHF/cardiovascular death (aHR: 1.93; 95% CI, 1.05-3.55) compared to those with modest early eGFR decline and UACR reduction.

T2D patients experiencing profound early eGFR decline without concordant UACR reduction while on SGLT2is represent a high-risk subgroup with worse clinical outcomes. These findings suggest the need for closer monitoring and potentially more aggressive therapeutic strategies for this patient population.

Patients with systemic lupus erythematosus (SLE) were excluded from sodium-glucose cotransporter 2 inhibitors (SGLT2i) clinical trials. It is unknown whether the cardiorenal benefits of SGLT2i extend to patients with SLE and comorbid type 2 diabetes (T2D).

We performed an emulated clinical trial in an insurance-based cohort in the United States, evaluating SGLT2i versus dipeptidyl peptidase-4 inhibitors (DPP4i) for primary prevention of cardiovascular, renal, and other clinical outcomes among patients with both SLE and comorbid T2D. SGLT2i initiators were matched to DPP4i initiators using propensity scores (PSs) based on clinical and demographic factors. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox models.

Outcomes among 2,165 patients starting SGLT2i and 2,165 PS-matched patients starting DPP4i were compared. Over 753.1 (±479.2) mean days, SGLT2i recipients had significantly lower risks of incident acute kidney injury (HR 0.49, 95% CI 0.39-0.63), chronic kidney disease (HR 0.61, 95% CI 0.50-0.76), end-stage renal disease (HR 0.40, 95% CI 0.20-0.80), heart failure (HR 0.72, 95% CI 0.56-0.92), emergency department visits (HR 0.90, 0.82-0.99), and severe sepsis (HR 0.61, 95% CI 0.39-0.94). Risks of all-cause mortality (HR 0.89, 95% CI 0.65-1.21), lupus nephritis (HR 0.67, 95% CI 0.38-1.15), myocardial infarction (HR 0.81, 95% CI 0.54-1.23), stroke (HR 1.03, 95% CI 0.74-1.44), and hospitalizations (HR 0.76, 95% CI 0.51-1.12) did not differ. Genital infection risk (HR 1.31, 95% CI 1.07-1.61) was increased, but urinary tract infection risk (HR 0.90, 95% CI 0.79-1.03) did not differ. No significant difference was observed for diabetic ketoacidosis risk (HR 1.07, 95% CI 0.53-2.14) and fractures (HR 0.95, 95% CI 0.66-1.36).

In this emulated clinical trial, treatment with SGLT2i, compared to DPP4i therapy, was associated with significantly reduced risks of several cardiorenal complications among patients with both SLE and T2D.

Sodium-glucose co-transporter inhibitors (SGLTis) have cardiovascular protective effects. We aimed to assess the effects of SGLTis on individual hard clinical endpoints and quality of life (QoL) in patients with cardiovascular risk factors.

Data was searched in PubMed, Embase, Cochrane Library and clinicaltrials.gov databases up to February 2024. Randomized controlled trials (RCTs) comparing SGLTis with placebo were included. The primary outcomes were individual hard clinical endpoints (Subset A) and QoL (Subset B). For Subset A, 13 RCTs including 90 413 patients were enrolled (age 66 ± 10.1 years, 35.7% female, follow-up 2.4 ± 0.3 years); as compared with placebo, SGLTis were associated with significantly lower risk of all-cause mortality [risk ratio (RR): 0.90, 95% confidence interval (CI): 0.86-0.94, P < 0.01], cardiovascular mortality (RR: 0.87, 95% CI: 0.82-0.92, P < 0.01), hospitalization for heart failure (HF) (RR: 0.72, 95% CI: 0.68-0.76, P < 0.01), HF events (RR: 0.72, 95% CI: 0.68-0.75, P < 0.01), hospitalization for any cause (RR: 0.91, 95% CI: 0.88-0.93, P < 0.01) and myocardial infarction (MI) (RR: 0.92, 95% CI: 0.85-0.99, P = 0.03). Notably, the favourable effect of SGLTis on all-cause mortality was more pronounced in younger (<65 years) patients (RR: 0.86, 95% CI: 0.81-0.92) and in studies with less female (RR: 0.84, 95% CI: 0.79-0.90). The favourable effect of SGLTis on MI was only observed in patients who received sotagliflozin (RR: 0.47, 95% CI: 0.31-0.73). For Subset B, nine RCTs including 2552 HF patients were enrolled (age 67.8 ± 12.4 years, 36.4% female, follow-up 3.4 ± 1.9 months); SGLTis were associated with significant improvement in QoL as compared with placebo.

In patients with a broad spectrum of cardiovascular risk factors, SGLTis substantially improve individual hard clinical outcomes and QoL.

Human-induced pluripotent stem cell (hiPSC) technology has been applied in pathogenesis studies, drug screening, tissue engineering, and stem cell therapy, and patient-specific hiPSC-derived cardiomyocytes (hiPSC-CMs) have shown promise in disease modeling, including diabetic cardiomyopathy. High glucose (HG) treatment induces lipotoxicity in hiPSC-CMs, as evidenced by changes in cell size, beating rate, calcium handling, and lipid accumulation. Empagliflozin, an SGLT2 inhibitor, effectively mitigates the hypertrophic changes, abnormal calcium handling, and contractility impairment induced by HG. Glucose concentration influences SGLT2 expression in cardiomyocytes, highlighting its potential role in diabetic cardiomyopathy. These findings support the potential utility of hiPSC-CMs in studying diabetic cardiomyopathy and the efficacy of empagliflozin in ameliorating HG-induced cardiomyocyte dysfunction. Such research may advance developments in precision medicine and therapeutic interventions for patients with diabetic cardiomyopathy.

Sodium-glucose co-transporters (SGLTs) mediate sodium and glucose transport across cell membranes. SGLT2 inhibitors have a recognized place within heart failure (HF) guidelines. We evaluated the effect of sotagliflozin on HF and cardiovascular outcomes in participants with type 2 diabetes. Scopus, Medline, Embase and Central were searched from inception until 2 June 2023. Randomized controlled trials evaluating sotagliflozin in type 2 diabetes participants and reporting HF events were selected. Major adverse cardiovascular events (MACE) and systolic blood pressure were evaluated. The Cochrane risk of bias tool (RoB 2.0) was used. Pooled mean difference (MD), relative risk (RR), 95% confidence intervals and the number needed to treat (NNT) were estimated (PROSPERO: CRD42023432732). We selected nine studies (n = 15 320 participants: n = 8040 intervention and n = 7280 control). The median follow-up was 13.4 months (Q1 = 13, Q3 = 21). One study recruited participants with HF at baseline. After a follow-up of >52 weeks, sotagliflozin significantly reduced the risk of HF [n = 8 studies; RR = 0.66 (0.64, 0.69)], stroke [n = 6 studies; RR = 0.75 (0.58, 0.97)] and MACE [n = 8 studies; RR = 0.73 (0.66, 0.81)]. The NNT was 20 and 26 for HF and MACE, respectively. Sotagliflozin lowered systolic blood pressure [n = 7; MD = -2.38 mmHg (-2.79, -1.97)]. No dose-dependent effect was identified for HF [200 mg: RR = 0.38 (0.16, 0.89), 400 mg: RR = 0.57 (0.39, 0.85), P-value = 0.22]. The high risk of bias was a limitation of this review. Sotagliflozin reduced HF and cardiovascular events in type 2 diabetes participants. Research exploring its effects in HF and comparisons with SGLT2 inhibitors is warranted to determine if dual SGLT inhibition surpasses selective inhibition.

The aim of our study was to evaluate the effects of dapagliflozin on the ventricular arrhythmia burden (VAb) in patients with heart failure with reduced ejection fraction (HFrEF) and an implantable cardioverter defibrillator (ICD), correlating the possible reduction in arrhythmic events and ICD therapies with the basal functional capacity, as well as the remodeling parameters induced by treatment.

A total of 117 outpatient ICD patients with a known diagnosis of HFrEF who underwent treatment with dapagliflozin were evaluated according to a prospective observational protocol. VAb (including sustained ventricular tachycardia, non-sustained ventricular tachycardia, ventricular fibrillation, and total ventricular events) and specific ICD therapies (anti-tachycardia pacing (ATP) and ICD shocks) were extrapolated from the devices' memory (events per patient per month) by comparing events in the observation period before and after the introduction of dapagliflozin.

The VAb was significantly reduced after dapagliflozin introduction (2.9 ± 1.8 vs. 4.5 ± 2.0, P = 0.01). The burden of appropriate ATPs was significantly reduced (0.57 ± 0.80 vs. 0.65 ± 0.91, P = 0.03), but not for ICD shocks. In patients with a more advanced functional class, a greater reduction in VAb was observed than in patients with a better initial functional capacity (2.2 ± 0.8 vs. 5.5 ± 1.8, P = 0.001 in the New York Heart Association (NYHA) III/IV group; 3.5 ± 2.1 vs. 4.5 ± 2.2, P = 0.02 in the NYHA I/II group). Considering two independent groups according to reverse remodeling (Δleft ventricular ejection fraction (LVEF) > 15%), a significant reduction in VAb was observed only in those patients who presented significant reverse remodeling (2.5 ± 1.1 vs. 5.1 ± 1.6, P = 0.01). A statistically significant interaction between the variation of total ventricular arrhythmias (VTA) and the basal NYHA class (F(1,115) = 142.25, P < 0.0001, partial η2 = 0.553), as well as between the variation of VTA and the ΔLVEF (F(1,115) = 107.678, P < 0.0001, partial η2 = 0.484) has been demonstrated using a two-way analysis of variance (ANOVA) test.

In ICD outpatients with HFrEF, dapagliflozin treatment produces a reduction in arrhythmic ventricular events. This improvement is more evident in patients who have a worse functional class and thus a more precarious hemodynamic state, and in patients who present with significant ventricular reverse remodeling. Therefore, we can hypothesize that the hemodynamic and structural improvements induced by treatment represent, at least in the short-medium term, some of the principal elements justifying the significant reduction in VAb.

Heart failure (HF) with preserved ejection fraction (HFpEF) affects more than 50% of HF patients worldwide, and more than 70% of HF patients aged over 65. This is a complex syndrome with a clinically heterogeneous presentation and a multifactorial pathophysiology, both of which make its diagnosis and treatment challenging. A Portuguese HF expert panel convened to address HFpEF pathophysiology and therapy, as well as appropriate management within the Portuguese context. This initiative resulted in two position papers that examine the most recently published literature in the field. The present Part I includes a review of the HFpEF literature covering pathophysiology, clinical presentation, diagnosis and treatment, including pharmacological and non-pharmacological strategies. Part II, the second paper, addresses the development of a holistic and integrated HFPEF clinical care system within the Portuguese context that is capable of reducing morbidity and mortality and improving patients' functional capacity and quality of life.

With the progress in diagnosis, treatment and imaging techniques, there is a growing recognition that impaired right ventricular (RV) function profoundly affects the prognosis of patients with heart failure (HF), irrespective of their left ventricular ejection fraction (LVEF). In addition, right HF (RHF) is a common complication associated with various diseases, including congenital heart disease, myocardial infarction (MI), pulmonary arterial hypertension (PAH) and dilated cardiomyopathy (DCM), and it can manifest at any time after left ventricular assist devices (LVADs). The sodium-glucose cotransporter 2 (SGLT2) inhibition by gliflozins has emerged as a cornerstone medicine for managing type 2 diabetes mellitus (T2DM) and HF, with an increasing focus on its potential to enhance RV function. In this review, we aim to present an updated perspective on the pleiotropic effects of gliflozins on the right ventricle and offer insights into the underlying mechanisms. We can ascertain their advantageous impact on the right ventricle by discussing the evidence obtained in animal models and monumental clinical trials. In light of the pathophysiological changes in RHF, we attempt to elucidate crucial mechanisms regarding their beneficial effects, including alleviation of RV overload, reduction of hyperinsulinaemia and inflammatory responses, regulation of nutrient signalling pathways and cellular energy metabolism, inhibition of oxidative stress and myocardial fibrosis, and maintenance of ion balance. Finally, this drug class's potential application and benefits in various clinical settings are described, along with a prospective outlook on future clinical practice and research directions.

Empagliflozin (EMPA), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, prevents endothelial dysfunction, but its effects on vascular tone in hypertension remain unclear. This study investigated whether EMPA modulates vasomotor tone via sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) pathways in spontaneously hypertensive rats (SHR) and controls (Wistar Kyoto rats, WKY). Functional (wire myography, organ bath) and biochemical (Western blot) studies were conducted on the third-order of the superior mesenteric arteries (sMAs) and/or aortas. EMPA induced concentration-dependent relaxation of preconstricted sMAs in both groups. In SHR, EMPA enhanced acetylcholine (Ach)-induced relaxation in sMAs and aortas and reduced constriction induced by phenylephrine (Phe) and U46619 in sMAs. The SIRT1 inhibitor (EX527) abolished EMPA's effects on Ach-mediated relaxation and U46619-induced vasoconstriction, while AMPK inhibition reduced Ach-mediated relaxation and Phe-induced vasoconstriction. SHR showed increased SGLT2 and SIRT1 expression and decreased pAMPK/AMPK levels in sMAs. In conclusion, EMPA might exert vasoprotective effects in hypertension by enhancing endothelium-dependent relaxation and reducing constriction via AMPK/SIRT1 pathways. These properties could improve vascular health in patients with hypertension and related conditions. Further studies are needed to explore new indications for SGLT2 inhibitors.

Heart failure (HF) is increasingly recognized as a heterogeneous cardiometabolic disorder, often in the context of overweight/obesity independently from diabetes. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce HF hospitalizations and cardiovascular mortality across ejection fraction (EF) categories, yet their early hemodynamic effects in cardiometabolic HF, and with preserved ejection fraction (HFpEF) in particular, remain underexplored.

A prospective, single-center study included 20 consecutive HF patients receiving SGLT2i alongside optimized therapy. Transthoracic echocardiography and non-invasive bioimpedance assessments (NICaS system) were performed at baseline and after 4 weeks.

The median patient age was 75 years [58-84], with 14 patients (70%) being overweight/obese, and only 4 patients with diabetes. The majority (65%) had HF with preserved EF (HFpEF), 25% with mildly reduced EF (HFmrEF), and 10% with reduced EF (HFrEF). At a median follow-up of 33 days [30-68], significant reductions were observed in body weight (67.65 kg [46-99.20] to 65.50 kg [46.30-97], p = 0.027) and systolic blood pressure (130 mmHg [100-150] to 116.50 mmHg [100-141], p = 0.015). Hemodynamic assessments revealed a significant decrease in total peripheral resistance index (TPRi, 3616.50 dynes·sec·cm3 [1600-5024] to 3098.50 dynes·sec·cm3 [1608-4684], p = 0.002). The left atrial volume index decreased significantly (42.84 ml/m² [27-69.40] to 41.15 ml/m² [26-62.60], p < 0.001); a significant decrease in peak tricuspid regurgitation velocity [2.52 m/Sect. (1.30-3.20]), vs. 2.21 m/Sect. (1.44-2.92), p = 0.023] and in pulmonary artery systolic pressure (PASP) [31.0 mmHg (15.0-40.0) vs. 25.50 mmHg (15.0-38.0-), p = 0.010] was observed. Patients with HFrEF or HFmrEF showed significant reduction in total body water (66.33 [51.45-74.45] vs. 58.68 [55.13-66.50]), while HFpEF patients (overweight/obese, n = 11, 79%) had a significant reduction in TPRi (3681 dynes·sec·cm3 [1600-5024] vs. 3085 dynes·sec·cm3 [1608-4684] p = 0.005).

Early hemodynamic responses to SGLT2i may differ across HF subtypes. In overweight patients with cardiometabolic HFpEF, our preliminary findings suggest an association with reduced vascular resistance, while in HFrEF/HFmrEF, the primary benefit appears to be volume unloading. However, the vascular effects of SGLT2i remain uncertain, and given the small sample size, these results should be interpreted as hypothesis-generating. Our findings also highlight the potential role of non-invasive hemodynamic monitoring in guiding therapy in 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.

Background and Objectives: Elevated blood sugar poses an increasingly significant challenge to healthcare systems worldwide. We aimed to assess the efficacy of the SGLT-2i class in achieving metabolic control in patients with T2DM within a real-world standard-of-care regimen. Material and Methods: A prospective analysis was conducted over 6 months including individuals receiving care in an outpatient department, with baseline assessments and follow-ups at 3 and 6 months. Results: A total of 280 patients were assessed, with a mean age of 63.69 ± 9.16, 53.9% of which were males, with a mean DM duration of 9.06 ± 5.64 years, and a DM duration varying from 6 months to 24 years. Discussion: Real-world evidence bridges the gap between guidelines and practice. It emphasizes the need to overcome clinical inertia in order to optimize patient outcomes and contributes to the body of evidence supporting the efficacy of fixed-dose SGLT-2i combinations in managing T2DM and associated comorbidities. Conclusions: We demonstrate the significant clinical and therapeutic impact of SGLT-2i in T2DM patients in a real-world setting. This class of medication not only positively influences glycemic and weight control but also reduces CV risk factors and visceral adiposity.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated potential neuroprotective and cardioprotective effects in preliminary studies. This study evaluates the efficacy of empagliflozin (EMPA) in reducing ischemia/reperfusion damage in both the brain and heart using rat models. Ischemic stroke and myocardial infarction (MI) were induced in male Sprague-Dawley rats, which were randomized into three groups: (1) Control (no EMPA), (2) Acute treatment (EMPA, 10 mg/kg IV, administered 10 min before ischemia and 1 min before reperfusion), and (3) Chronic treatment (EMPA, 20 mg/kg in food for 7 days before ischemia). Stroke was induced by middle cerebral artery occlusion (MCAO) for one hour, followed by 3 h of reperfusion, and MI was induced by left coronary artery occlusion for 30 min, followed by 3 h of reperfusion. Brain and heart tissues were analyzed for anatomic size of myocardial infarction and stroke. In the brain, cerebral infarction was significantly smaller in both EMPA treatment groups compared to controls (acute: 3.7 ± 1.2%, chronic: 6.9 ± 2.1% vs. control: 14.5 ± 2.5%, p < 0.05). Edema was also reduced in the EMPA groups (acute: 5.5 ± 0.9%, chronic: 5.9 ± 0.8% vs. control: 9.6 ± 1.2%, p < 0.05). In the heart, MI size was significantly reduced in both EMPA groups (acute: 46.9 ± 2.0%, chronic: 48.8 ± 5.8% vs. control: 70.0 ± 2.6%, p < 0.05), and no-reflow size was smaller in the EMPA groups (acute: 36.3 ± 3.3%, chronic: 33.9 ± 4.3% vs. control: 53.4 ± 3.3%, p < 0.05). EMPA treatment, both acute and chronic, significantly reduces cerebral infarct volume and edema, as well as myocardial infarct size and no-reflow in rat models of ischemic stroke and myocardial ischemia/reperfusion, indicating substantial neuroprotective and cardioprotective effects.