Empagliflozin confers cardioprotective benefits among patients with heart failure, across the range of ejection fraction (EF), regardless of type 2 diabetes status. The long-term cost-effectiveness of empagliflozin for the treatment of heart failure (HF) in the Philippines remains unclear. This study aims to determine the economic benefit of adding empagliflozin to the standard of care (SoC) vs the SoC alone for HF in the Philippines.

Using a Markov model, we predicted lifetime costs and clinical outcomes associated with treating HF in the Philippine setting. We used estimates of treatment efficacy, event probabilities, and derivations of utilities from the EMPEROR trials. Costs were derived from hospital tariffs and expert consensus. Separate analyses were performed for patients with left ventricular EF > 40%, categorized under mid-range ejection fraction or preserved ejection fraction (HFmrEF/HFpEF), and patients with left EF ≤ 40%, categorized under HF with reduced ejection fraction (HFrEF).

Our model predicted an average of 0.09 quality-adjusted life year (QALY) gains among HFmrEF/HFpEF patients and HFrEF patients when empagliflozin was compared to SoC. The addition of empagliflozin in the treatment results in a discounted incremental lifetime cost of PHP 62,692 (USD 1,129.99) and PHP 17,215 (USD 308.67) for HFmrEF/HFpEF and HFrEF, respectively. The incremental cost-effectiveness ratio (ICER) of empagliflozin is PHP 198,270 (USD 3,570.72)/QALY and PHP 742,604 (USD 13,385.08)/QALY for HFrEF and HFmrEF/HFpEF, respectively.

This study employed parameters derived from short-term clinical trial data, alongside metrics representative of Asian populations, which are not specific to the Philippine cohort.

Adding empagliflozin to the SoC in comparison to the SoC is associated with improved clinical outcomes and quality-of-life, at additional costs for both HFrEF and HFmrEF/HFpEF.

The use of guideline-directed medical therapy (GDMT) in heart failure (HF) has been shown to decrease hospitalization and mortality risks. However, the implementation of GDMT remains suboptimal. This study aimed to evaluate the challenges of GDMT intolerance in a real-world setting.

The study initially screened 263 patients diagnosed with acute HF. All patients attempted to initiate quadruple GDMT before discharge; patients who failed to initiate quadruple GDMT were classified in the GDMT Intolerant Group, while those who successfully initiated GDMT were classified in the GDMT Group. The primary endpoint was the time to first worsening HF events or death due to HF within 180 days.

Nearly half of the study patients cannot tolerate quadruple therapy at discharge and the main intolerance reasons of GDMT were renal insufficiency and hypotension. Patients who tolerated quadruple GDMT at discharge were more likely to use quadruple at the endpoint GDMT (92.4 % vs 27.8 %). Only 13.4 % of overall patients ultimately used the maximum dose of all four GDMTs at endpoint, patients with de novo HF had better prognosis than ADCHF (Acute Decompensated Chronic HF) patients, and GDMT Initiation at discharge was associated with a reduced risk of worsening HF in both HF patients, and the more types of medication initiated at discharge, the better the prognosis of the patients.

Real-world implementation of GDMT and dose up-titration remains challenging, with a high proportion of patients unable to tolerate quadruple GDMT, with renal insufficiency and hypotension being the most challenging factors.

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.

Guideline-directed medical therapy (GDMT) is recommended for all patients with heart failure with reduced ejection fraction (HFrEF). Despite this, little data exist describing GDMT use in diverse, real-world populations including the use of vasodilators, prescribed primarily to Black populations. We sought, among a diverse population of HFrEF patients, to determine (1) GDMT use rates and target dosing by medication class and (2) predictors of GDMT use and target dosing by medication class.

We utilized electronic health records (EHRs) from Kaiser Permanente (KP) Mid-Atlantic States, a large integrated health system. Included patients had heart failure and left ventricular ejection fraction (EF) of ≤40% between 2015 and 2021. GDMT was defined by five medication classes-angiotensin-converting enzyme (ACE) inhibitors (ACEis)/angiotensin receptor blockers (ARBs)/angiotensin receptor-neprilysin inhibitors (ARNis), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), sodium-glucose cotransporter 2 inhibitors (SGLT2is) and vasodilators (Black patients only). Proportions of patients on GDMT and target dose rates were examined. Logistic regression determined, within each class, predictors of medication use and being at ≥80% of the target dose.

A total of 3154 patients were included. Among the 93.8% on some form of GDMT, 82.8%, 81.4%, 23.5%, 3.6% and 13.4% were on ACEis/ARBs/ARNis, BBs, MRAs, SGLT2is and vasodilators (Black patients only), respectively. Among treated patients, 45.8%, 21.4%, 77.6%, 100% and 14.7% were treated at ≥80% of the target dose for ACEis/ARBs/ARNis, BBs, MRAs, SGLT2is and vasodilators, respectively. Overall, increasing age, higher EF, atrial fibrillation/flutter, chronic obstructive pulmonary disease (COPD), prior stroke and dementia were associated with decreased odds of GDMT use. Conversely, higher body mass index (BMI), Black race, higher glomerular filtration rate (GFR), recent echo and cardiac defibrillator were associated with increased odds of GDMT use. Among treated, higher BMI, higher systolic blood pressure, haemoglobin A1C ≥ 6.5% and cardiac defibrillator were associated with higher odds of being at ≥80% of the target dose.

Our study using real-world data from a diverse health system demonstrated gaps in GDMT use among patients with HFrEF, specifically older patients with more comorbidities.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have shown promise in reducing cardiovascular mortality and hospitalization due to heart failure (HF), a significant global health issue. This study aims to evaluate the incremental net benefit (INB) of SGLT-2i in HF patients through a systematic review and meta-analysis of cost-utility studies.

We searched five databases from their inception until Aug 30, 2024, economic evolution studies reporting cost-effectiveness and cost-utility analyses comparing SGLT-2i combined with standard triple-therapy versus standard triple-therapy alone in HF patients were selected. INB as the primary outcome was calculated in monetary units adjusted for purchasing power parity in 2022 US dollars.

This review included 46 studies, with 41 studies (55 comparisons) pooled into meta-analysis. Adding SGLT2is was cost-effective compared to standard triple-therapy alone, from both healthcare system perspective (INB, $4042.08; 95 % CI, $1758.70-$6325.46) and payer perspective (INB, $12,972.84; 95 % CI, $4711.5-$21,234.22). However, subgroup analyses showed non-significant economic benefit in HF patients with preserved ejection fraction (HFpEF) both from the healthcare system perspective (INB, -$639.32; 95 % CI, -$1850.09-$571.44) and the payer perspective (INB, $3611.07; 95 % CI, -$208.49-$7430.64). Additionally, HF patients from low- and middle-income countries did not show significant economic benefit from the payer perspective (INB, $55,645.70; 95 % CI, -$51,000.00-$160,000.00).

The findings suggest that adding SGLT-2i is cost-effective compared to conventional standard triple-therapy alone, from both healthcare system and payer perspectives. Nevertheless, the economic benefits are limited in HFpEF and those from low- and middle-income countries. Further research is needed to explore the cost-effectiveness from a broader societal perspective.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors improve health status and outcomes in the setting of heart failure (HF) across the range of ejection fraction (EF). Baseline kidney disease is common in HF, complicates HF management and is strongly linked to worse health status. This study aimed to assess whether the treatment effects of dapagliflozin on health status vary based on estimated glomerular filtration rate (eGFR).

We conducted a pooled participant-level analysis of two double-blind, randomized trials, DEFINE-HF (n = 236) and PRESERVED-HF (n = 324), which evaluated dapagliflozin versus placebo. Both multicentre studies enrolled adults with HF, New York Heart Association Class II or higher, elevated natriuretic peptides, and an EF < 40% in DEFINE-HF or >45% in PRESERVED-HF. The primary exposure was eGFR. The main outcome was the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at 12 weeks. Across both trials, there were 583 (99.3%) participants with a baseline eGFR. The median (25th, 75th) eGFR was 59 (46, 77) mL/min/1.73 m2. Dapagliflozin improved KCCQ-CSS at 12 weeks [placebo-adjusted difference, +5.0 points, 95% confidence interval (CI) 2.6-7.5; P < 0.001], and this was consistent in participants with an eGFR ≥ 60 (+6.0 points, 95% CI 2.4-9.7; P = 0.001) and eGFR < 60 (+4.1 points, 95% CI 0.5-7.7; P = 0.025) (P interaction = 0.46). The benefits of dapagliflozin on KCCQ-CSS remained robust across eGFR when modelled as a continuous variable (P interaction = 0.48).

Dapagliflozin led to early and clinically meaningful improvements in health status in HF patients, regardless of EF or baseline eGFR.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce major cardiovascular events among individuals with heart failure regardless the ejection fraction. The effect of SGLT2 inhibitors on health-related quality of life (HRQoL) and physical capacity are still unclear.

To investigate the effects of SGLT2 inhibitors on HRQoL and physical capacity in patients with heart failure.

We systematically searched PubMed, Embase, and Cochrane Central databases for randomized controlled trials (RCTs) comparing SGLT2 inhibitors to placebo in this population. The outcomes analyzed were mean changes in Kansas City Cardiomyopathy Questionnaire (KCCQ) score and its domains: total symptoms score (TSS), physical limitations score (PLS), clinical summary score (CSS) and overall summary score (OSS), as well as the six-minute walk test (6MWT) and peak oxygen uptake (peak VO2).

Eighteen RCTs with 23,848 participants were included. There was a statistical significant improvement in KCCQ TSS (MD: 3.33; 95% CI 1.84 to 4.81; p < 0.001) in HFrEF, HFpEF and non-diabetic subgroups. Consistent findings were found in KCCQ PLS, KCCQ CSS, and KCCQ OSS. The distance covered in the 6MWT was significant higher (MD: 12.8; 95% CI 1.06 to 24.54; p = 0.03) and peak VO2 was increased (MD: 1.06; 95% CI 0.57 to 1.55; p < 0.001).

SGLT2 inhibitors improve HRQoL and functional capacity in patients with HF regardless the ejection fraction and co-diagnosis of diabetes.

The last released European guidelines on the management of heart failure (HF) recommend in patients with chronic HF with reduced ejection fraction (HFrEF) a pharmacological approach based on four fundamental drugs to be rapidly implemented and then uptitrated to modify disease progression. The aim of the Optimization of Therapy in the Italian Management of Heart Failure (OPTIMA-HF) registry is to collect data on chronic HF outpatients in different settings of care. In the present analysis, we report the first analysis of the OPTIMA-HF registry, focusing on the real-life use of guideline-directed medical therapy in patients affected by HFrEF.

OPTIMA-HF is an observational, cross-sectional, multicentre, real-life Italian registry conducted in two different clinical settings: HF outpatients' clinics of Italian hospitals and community HF outpatients' services. The study comprises a T0 phase-retrospective data collection, in which data of consecutive HF outpatients seen between January and October 2022 were collected; an educational activity phase; and a T1 phase-prospective data collection, in which data of consecutive HF outpatients seen between September 2023 and November 2023 were collected. In the present analysis, we describe the T0 phase focusing on HFrEF drug prescription rates, types, doses, combination therapy, the presence of contraindications and reasons of non-optimized treatment.

Twenty-nine centres enrolled 2110 HF patients, of which 1390 (65.9%) had HFrEF [69.5 ± 11.9 years, 76.2% males, 4.1 years since HF diagnosis, median ejection fraction (EF) 33%]. Among HFrEF patients, 89.1% were on treatment with renin-angiotensin-aldosterone system inhibitor (RAASi)/angiotensin receptor neprilysin inhibitor (ARNI) (72% ARNI and 17.1% RAASi), 95.1% with beta-blockers, 75.8% with mineralocorticoid receptor antagonists (MRA) and 63.2% with sodium/glucose cotransporter 2 inhibitors (SGLT2i). Despite high prescription rates, a non-negligible number of patients with no contraindications were not treated with each specific drug. Patients taking all four drug classes, as recommended by guidelines, were mere 46.9%. Regarding doses, a still low number of patients on RAASi/ARNI and beta-blockers were treated with a dose ≥50% of the target doses recommended by the European guidelines.

The OPTIMA-HF registry reported that HFrEF fundamental drugs are prescribed in most Italian patients; however, <50% of patients receive optimal combination therapy, and still not a satisfying number of patients receive target doses. Strategies to improve implementation of guideline-directed medical therapy are needed to improve HF prognosis.

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.

Understanding heart failure (HF) characteristics is essential to improve patient outcomes. Categorizing HF beyond left ventricular ejection fraction (LVEF) is challenging due to heterogeneous clinical presentation and aetiologies. Despite global studies on HF, the role of LVEF on mortality remains controversial. We explored the association of LVEF with mortality, considering sex differences and comorbidities in a cohort from the largest tertiary cardiovascular centre in Switzerland.

HF patients admitted to the University Hospital of Bern from January 2015 to December 2019 were evaluated. LVEF was used to classify patients into HF with preserved ejection fraction (HFpEF), HF with mid-range ejection fraction (HFmrEF) and HF with reduced preserved ejection fraction (HFrEF) categories. Cox proportional hazard models and time-stratified analyses adjusted for potential confounders were employed.

A total of 5824 HF patients were included, and 2912 died over a median follow-up time of 3.39 years. Mortality rates across LVEF categories showed no significant differences, while overall, women showed significantly higher mortality; 30 day mortality was lower in the HFpEF category [hazard ratio (HR) 0.67, 95% confidence interval (CI): 0.52-0.88, P = 0.003], with persistent effects upon stratification in males (HR 0.59, 95% CI: 0.42-0.81, P < 0.001) and non-diabetics (HR 0.62, 95% CI: 0.44-0.87, P = 0.005). An isolated reduction in HFpEF mortality was observed in females after 1 year (HR 0.72, 95% CI: 0.53-0.98, P = 0.035).

The prognostic role of LVEF on all-cause mortality remains unclear, while differences in mortality rate distribution between women and men mirror established HF pathophysiological sex differences. Future HF studies should focus on HF aetiology and include measures beyond LVEF for comprehensive characterization.

Real-world evidence involving healthcare database studies is well established for making causal inferences in post-market drug safety studies and methods, data, and research infrastructure for evaluating effectiveness have advanced in recent years. The rapidly expanding field of etiologic research using insurance claims and electronic health records databases is being evaluated for supporting effectiveness claims. One such use case to support regulatory decision-making on effectiveness is for expanding indications beyond existing effectiveness claims. Confidence in the validity of findings from cohort studies conducted using databases (hereafter "database study") to support indication expansions could be increased through a structured benchmarking process of an initial database study against RCT evidence followed by calibration of a subsequent database study based on differences in results observed in the initial RCT-database pair. This paper proposes a benchmark, expand, and calibration (BenchExCal) approach to trial emulation and describes the design and process for evaluating the performance of the approach through both simulation studies; five planned empirical examples are also described. The project will provide insights regarding how a first-stage benchmarking emulation of a completed trial for an existing indication can be used to calibrate, increase confidence, and improve interpretation of the results for a second-stage emulation of a hypothetical trial that could potentially provide evidence for an expanded indication. Although the examples have been selected to provide a variety of learnings, five use cases do not address all clinical and data scenarios that may be encountered when seeking a supplemental indication for a marketed drug.

We conducted a systematic review with pairwise (PMA) and network meta-analyses (NMA) to evaluate sodium-glucose transport protein 2 inhibitor (SGLT2i) effects in patients with both heart failure (HF) and type 2 diabetes mellitus (T2DM). Five databases were searched up to April 15, 2025. Primary outcomes were all-cause mortality (ACM), cardiovascular death (CVD), all-cause hospitalization (ACH), and hospitalization for heart failure (HHF). SGLT2i class effects versus control were assessed via PMA and individual SGLT2i comparative efficacy via NMA plus ranking using p-scores. Seventeen randomized controlled trials (n = 17,809) were included. Arms included canagliflozin (n = 2), dapagliflozin (n = 6), empagliflozin (n = 6), ertugliflozin (n = 1), ipragliflozin (n = 1), sotagliflozin (n = 1), placebo (n = 13), and standard of care (n = 4). Compared to control, SGLT2i significantly reduced ACM (HR 0.87, 95 %CI 0.78 to 0.98, low quality of evidence [QoE]), ACH (HR 0.74, 95 %CI 0.62 to 0.88, high QoE), and HHF (HR 0.70, 95 %CI 0.63 to 0.77, low QoE); but not CVD (HR 0.87, 95 %CI 0.76 to 1.00, very low QoE). Canagliflozin ranked highest in decreasing ACM (p-score = 0.86), CVD (p-score = 0.82), and HHF (p-score = 0.88). In patients with HF and T2DM, SGLT2i class effects include ACM, ACH, and HHF reduction. Among SGLT2i, canagliflozin showed greatest ACM, CVD, and HHF benefit.

Glycogen Storage Disease Ib (GSD Ib) is a disease that associates both neutropenia and neutrophil dysfunction, thereby causing recurrent infections and inflammatory bowel disease (IBD). As of now, the standard treatment of these complications has been the administration of granulocyte-stimulating factor (GCSF). However, recent studies have found that the use of empagliflozin, an antidiabetic drug, may have benefits by reducing the levels of 1,5 anhydroglucitol-6-phosphate (1,5-AG6P), a metabolite that accumulates in the cytosol of neutrophils and blocks the use of glucose.

We therefore report our experience with three patients, one of them being a liver and kidney transplant recipient, with promising results. Morbidity has been greatly reduced in all cases consisting in weight gain, better neutrophil count and management of respiratory, osteoarticular and gastrointestinal comorbidities. Overall, an improvement in quality of life has been observed.

SGLT2 inhibitors, and specifically empagliflozin offer promising results in improving morbidity and quality of life in patients with GSD Ib. In the cases presented, including a patient with double liver-kidney transplant, a good profile of tolerance, safety and effectiveness has been observed.

Empagliflozin offers promising results in improving morbidity and quality of life in patients with GSD Ib, including the first double organ transplant patient treated with this drug.

Patients with non-ischaemic cardiomyopathy (NICMP) have a class IIa primary prevention indication for an implantable cardioverter-defibrillator (ICD). Recent studies have shown that the evidence for a survival benefit following ICD implantation in this patient group is not particularly robust. In 2023, the Dutch Society of Cardiology published an update of the ESC guideline to better select patients with NICMP for ICD implantation. The objective of this study was to analyse the impact of this guideline on the number of indications in a retrospective cohort of patients who had received an ICD and whether the patients without an indication were also without appropriate ICD therapy.

A single-centre, retrospective observational study was performed in 134 patients with NICMP who underwent ICD implantation for primary prevention between 2015 and 2020.

After applying the new Dutch guideline, 74 out of 134 patients with NICMP without a high-risk phenotype (35 patients) had no ICD indication (group 2). The remaining 25 patients were considered to have an ICD indication (group 1). During a median follow-up of 66 months (interquartile range 52-81) the incidence of appropriate ICD therapy (antitachycardia pacing and shock) was comparable in both groups: 4 patients in group 1 (16%) and 9 in group 2 (12%), p = 0.623.

The new 2023 guideline for ICD implantation in NICMP patients does indeed rule out a significant group of patients from ICD implantation. Nevertheless, our data show that patients without an indication still had comparable rates of appropriate ICD therapy.

Outcomes of stopping sodium-glucose cotransporter 2 inhibitors (SGLT2i) 5 days before open heart surgery (euglycemic diabetic ketoacidosis [eDKA] rate, mortality, infection, hospital, and cardiovascular intensive care unit [CVICU] length of stay [LOS]).

Retrospective study.

Academic university hospital.

Adult open heart surgery patients.

Patients on SGLT2i who stopped medications 5 days before open heart surgery versus non-SGLT2i-using patients.

We evaluated patients who were told to stop SGLT2i 5 days before receiving open heart surgery for eDKA development within 24 hours of hospital admission (12/14/2022 to 10/25/2023). Non-eDKA outcomes were compared between SGLT2i users and non-users using Wilcoxon rank sum and Chi-square testing as appropriate. Of 540 open heart surgery patients, 48 (8.9%) were prescribed SGLT2i's before surgery; of these, 0 (0%) developed eDKA within 24 hours of hospital admission. Hospital LOS was statistically longer for patients with SGLT2i use (median [interquartile range]: 4 [4-5] v 4 [3-6] days, p = 0.003; mean [standard deviation]: 4 [3] v 5 [2], p = 0.03). We found no significant difference between patients with and without SGLT2i use in CVICU LOS (median [interquartile range]: 1.67 [0.95-2.09] v 1.17 [0.96-1.88] days, p = 0.14), in-hospital mortality (2.1% [1] v 0.6% [3], p = 0.3), or sternal infections (0 [0.0%] v 2 [0.4%], p > 0.9).

Postoperative eDKA was absent in SGLT2i patients told to stop medications 5 days before open heart surgery. LOS and infection and mortality rates appeared similar between the two cohorts. Stopping SGLT2i medications 5 days before open heart surgery appears safe.

Despite availability of an array of antihypertensive drugs, malignant hypertension remains a life-threatening condition, and new therapeutic strategies for the treatment of malignant hypertension and malignant hypertension-associated organ damage are needed. The aim of the present study was to assess the effects of nitric oxide (NO)-independent soluble guanylyl cyclase (sGC) stimulator on the course of malignant hypertension. The second aim was to investigate if the treatment with sodium-glucose cotransporter type 2 (SGLT2) inhibitor would augment the expected beneficial actions of the sGC stimulation on the course of malignant hypertension.

As a model of malignant hypertension, Ren-2 transgenic rats (TGR) treated with nonspecific NO synthase inhibitor (Nω-nitro- l -arginine methyl ester, l -NAME) was used. Blood pressure (BP) was monitored by radiotelemetry, and the treatment was started 3 days before administration of l -NAME.

The treatment with sGC stimulator BAY 41-8543, alone or combined with SGLT2 inhibitor empagliflozin, abolished malignant hypertension-related mortality in TGR receiving l -NAME. These two treatment regimens also prevented BP increases after l -NAME administration in TGR, and even decreased BP below values observed in control TGR, and prevented cardiac dysfunction and malignant hypertension-related morbidity. The treatment with the SGLT2 inhibitor empagliflozin did not further augment the beneficial actions of sGC stimulator on the course of malignant hypertension-related mortality.

The treatment with NO-independent sGC stimulator displayed marked protective actions on the course of malignant hypertension-related mortality and malignant hypertension-related cardiac damage. This suggests that application of sGC stimulator could be a promising therapeutic means for the treatment of malignant hypertension.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as transformative therapies in the management of chronic heart failure (HF), offering substantial reductions in mortality and hospitalizations. Beyond their initial classification as diuretics, SGLT2i exert a spectrum of cardioprotective effects that extend far beyond renal modulation. By activating autophagic pathways and mimicking a starvation-like state, SGLT2i enhance cellular bioenergetics and mitigate acute injury, potentially underpinning both their immediate and sustained cardiometabolic benefits when administered early in acute care settings. In acute decompensated HF, early initiation of SGLT2i enhances clinical decongestion by increasing diuresis, improving diuretic efficiency, and mitigating diuretic resistance, translating to shorter hospitalizations and reduced readmissions and mortality. In acute myocardial infarction, SGLT2i reduce the incidence of first and total HF hospitalizations, arrhythmic events, adverse cardiac remodelling, and contrast-induced acute kidney injury, while mitigating stent failure and atherosclerotic progression. Furthermore, they demonstrated efficacy in preventing new-onset and recurrent supraventricular and ventricular arrhythmias. However, the evidence remains inconclusive regarding their impact on sudden cardiac death or outcomes following cardiac arrest. In critically ill patients, SGLT2i use is associated with reduced rates of acute kidney injury and the need for renal replacement therapy, with promising implications for the management of sepsis and multi-organ dysfunction. Importantly, adverse effects such as renal impairment, electrolyte disturbances, acid-base imbalances, urinary tract infections, and dysglycemia appear infrequently in this population. This narrative review synthesizes the underlying pathophysiological mechanisms, current clinical evidence, and potential future applications of early SGLT2i therapy in acute care settings, providing insights into their expanding role in contemporary cardiovascular medicine.

The gap between maximally tolerated medical therapy and consideration for permanent mechanical circulatory support and/or cardiac transplant or palliative treatment of moderate to severe heart failure represents an underserved patient population. New therapies are evolving which may not only improve quality of life for these patients but also improve hemodynamics and potentially reverse the progression of the disease. This review is focused on one such therapy, synchronized diaphragmatic stimulation. Current clinical results suggest that patients experience improved exercise tolerance, quality of life, and hemodynamic function over 6-12 months of therapy which can be safely implemented through a minimally invasive laparoscopic procedure, often as an outpatient. This technology has been granted breakthrough device designation and is being evaluated for a double-blinded, randomized controlled trial by the US FDA.

The effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on reducing cardiovascular events in different subgroups of diabetic patients are under investigation. The current systematic review and meta-analysis investigated the effects of SGLT2 inhibitors on preventing cardiovascular events and mortality and their adverse events in patients with active cancer and diabetes undergoing cardiotoxic cancer treatment.

We searched PubMed, Embase, Web of Science, and Scopus to find studies investigating the effects of SGLT2 inhibitors on patients with diabetes and confirmed cancer until 19 August 2024. Meta-analyses were conducted using the random-effects model to compare all-cause mortality, cancer-associated mortality, heart failure (HF) hospitalization, arrhythmia, and adverse event rates such as ketoacidosis, hypoglycemia, urinary tract infection, and sepsis between patients with or without SGLT2 inhibitors use. Risk ratios (RRs) with 95% confidence intervals (CI) were used to compare outcomes between SGLT2 inhibitors and non-SGLT2 inhibitors groups.

Eleven studies were included with 88,096 patients with confirmed cancer (49% male). Among the total population, 20,538 received SGLT2 inhibitors (age 61.68 ± 10.71), while 67,558 did not receive SGLT2 inhibitors (age 68.24 ± 9.48). The meta-analysis found that the patients who received SGLT2 inhibitors had a significantly lower mortality rate than those who did not receive SGLT2 inhibitors (RR 0.46, 95% CI 0.34 to 0.63, p-value < 0.0001). Similarly, the cancer-associated mortality rate was also lower (RR 0.29, 95% CI 0.27 to 0.30, p-value < 0.0001). Further analysis found that the SGLT2 inhibitor group had a lower rate of HF hospitalization, compared to controls (RR 0.44, 95% CI 0.27 to 0.70, p-value = 0.0007). Moreover, patients receiving SGLT2 inhibitors had a statistically lower rate of arrhythmia (RR 0.38, 95% CI 0.26 to 0.56, p-value < 0.0001). Finally, patients in the SGLT2 inhibitors group had a lower rate of adverse events (RR 0.51, 95% CI 0.42 to 0.62, p-value < 0.0001).

SGLT2 inhibitors are effective in reducing mortality (all-cause and cancer-associated), HF hospitalization, arrhythmia, and drug adverse events in patients with cancer. If confirmed in future studies, these agents could be a potentially ideal candidate to prevent cardiotoxicity of cancer therapies.

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

Chronic left ventricular heart failure (CLHF) represents a significant public health challenge globally, marked by high morbidity and mortality. CLHF is a leading cause of hospitalization, placing considerable strain on healthcare systems. This study aims to analyze in-hospital outcomes for CLHF patients in Germany over nine years (2014-2022), examining trends in morbidity, mortality, healthcare costs, and complications.

Data were sourced from the Federal Statistical Office (DESTATIS), covering 2,616,462 inpatient CLHF cases (ICD-10-GM I50.11-I50.14) in Germany from 2014 to 2022. CLHF hospitalizations increased from 288,019 in 2014 to 311,782 in 2019, then declined in 2020 but started again to rise from 2021 to 2022. The proportion of patients with advanced CLHF (NYHA stage IV) decreased slightly from 54.09% in 2014 to 50.36% in 2020 (p < 0.0001). Notable comorbidity trends included rising rates of atrial fibrillation and chronic kidney disease. Complications such as cardiogenic shock and acute kidney injury increased over time (both p < 0.0001). Despite a decrease in mortality rates from 2014 to 2019 (p < 0.0001), in-hospital mortality rose to 8.84% in 2022 (p < 0.0001). Median revenue volume and hospitalization duration showed a pre-pandemic increase but declined in 2020.

The study highlights a complex interplay of factors affecting CLHF management in Germany, as a representative example for a high-income country. While advancements in treatment have improved some outcomes, the COVID-19 pandemic significantly impacted hospitalization trends and in-hospital mortality. The findings underscore the need for ongoing improvements in CLHF management and resilient healthcare strategies to address future challenges.

Sodium-glucose transport protein-2 (SGLT2) inhibitors, initially developed for glycemic control in type 2 diabetes mellitus (T2DM), have emerged as potential cardioprotective agents, reducing cardiovascular mortality and improving heart failure outcomes. Recent evidence suggests that SGLT2 inhibitors exert anti-inflammatory effects, particularly through modulating the inflammasome pathway. This review explores the role of the inflammasome in acute myocardial infarction (AMI) in T2DM and discusses the mechanisms by which SGLT2 inhibitors influence this pathway. We evaluate current studies on the impact of SGLT2 inhibitors on key inflammatory mediators, particularly the NLRP3 inflammasome, and discuss their potential therapeutic implications for reducing inflammation and myocardial injury in patients with T2DM experiencing AMI. In summary, the key novelties in this review lie in its focused mechanistic approach on the inflammasome pathway, its integration of diabetes and cardiovascular research, and its potential to influence future therapeutic strategies for AMI in T2DM patients. It offers a novel angle by tying together molecular mechanisms of inflammation with clinical implications in a specific patient population that faces high cardiovascular risk.

Diabetes is a well-established risk factor for stroke. Understanding the pathophysiology of this connection is crucial to implementing appropriate prevention strategies. Lately, there has been a paradigm shift in the care of individuals with diabetes toward the use of glucose-lowering medications with potential cardiovascular, cerebrovascular or cardiorenal benefits. The aim of this article is to provide a critical analysis of the role of diabetes in cerebrovascular disease and current evidence and recommendations for the use of glucose-lowering medication with particular focus on the sodium glucose cotransporter-2 inhibitor (SGLT2i) class.

Intensive glycemic control in individuals with diabetes reduces the risk of microvascular complications, but there is less clear evidence for decreasing risk of macrovascular events (e.g., stroke). A multifaceted management of diabetes addressing healthy lifestyle practices, glycemic control, and optimization of other cardiovascular risk factors is highly recommended. SGLT2i are the latest class of antihyperglycemic agents available for diabetes management. Canagliflozin and empagliflozin are associated with reduction in major adverse cardiovascular events (MACE). Dapagliflozin did not reduce the rate of MACE but is associated with reduction in heart-failure related death and hospitalization and has the potential to decrease dementia risk. Ertugliflozin decreases rates of hospitalization related to heart failure however it was non-inferior to placebo in reducing MACE. There is increasing evidence that the use of SGLT2i may reduce the risk of stroke, particularly hemorrhagic stroke, in individuals with type 2 diabetes and a high risk of cardiovascular events, and that SGLT2i may also be beneficial for brain health by decreasing risk of cognitive decline and dementia. Antihyperglycemic therapy should be tailored to patients' circumstances. SGLT2i treatment should be considered in patients with type 2 diabetes and established or high-risk cardiovascular disease, heart failure, or chronic kidney disease, to reduce the overall cerebro-cardiovascular and renal risks.

Over the past few decades, the rising burden of metabolic disease, including type 2 diabetes, prediabetes, obesity, and metabolic dysfunction-associated steatotic liver disease, has corresponded with fundamental shifts in the landscape of heart failure (HF) epidemiology, including the rising prevalence of HF with preserved ejection fraction. It has become increasingly important to understand the role of extracardiac contributors and interorgan communication in the pathophysiology and phenotypic heterogeneity of HF. Whereas traditional epidemiological strategies have separately examined individual contributions of specific comorbidities to HF risk, these approaches may not capture the shared mechanisms and more complex, bidirectional relationships between cardiac and noncardiac comorbidities. In this review, we highlight the cardiac, kidney, liver, and metabolism multiorgan interactions and pathways that complicate HF development and progression and propose research strategies to further understand HF in the context of multiple organ disease. This includes evolving epidemiological approaches such as multiomics and machine learning which may better capture common underlying mechanisms and interorgan crosstalk. We review existing preclinical models of HF and how they have enhanced our understanding of the role of multiorgan disease in the development of HF subtypes. We suggest recommendations as to how clinical practice across multiple specialties should screen for and manage multiorgan involvement in HF. Finally, recognizing the advent of novel combinatorial therapeutic agents that may have multiple indications across the cardiac-kidney-liver metabolism continuum, we review the current clinical trials landscape. We specifically highlight a pressing need for the design of more inclusive trials that examine the contributions of multimorbidity and incorporate multiorgan end points, which we propose may lead to outcomes that are evermore clinically relevant today.

Accumulation of senescent cells is an increasingly recognized factor in the development and progression of cardiovascular (CV) disease (CVD). Senescent cells of different types display a pro-inflammatory and matrix remodelling molecular programme, known as the 'senescence-associated secretory phenotype' (SASP), which has roots in (epi)genetic changes. Multiple therapeutic options (senolytics, anti-SASP senomorphics, and epigenetic reprogramming) that delete or ameliorate cellular senescence have recently emerged. Some drugs routinely used in the clinics also have anti-senescence effects. However, multiple challenges hinder the application of novel anti-senescence therapeutics in the clinical setting. Understanding the biology of cellular senescence, advantages and pitfalls of anti-senescence treatments, and patients who can profit from these interventions is necessary to introduce this novel therapeutic modality into the clinics. We provide a guide through the molecular machinery of senescent cells, systematize anti-senescence treatments, and propose a pathway towards senescence-adapted clinical trial design to aid future efforts.

There has been increasing research into non-insulin therapies to assist people living with type 1 diabetes (T1D) improve their glucose control and to help prevent the development and progression of vascular and kidney complications. In particular, the sodium-glucose co-transporter (SGLT) inhibitor class of medication has received attention as an adjunctive therapy in T1D. These medications have an established and important role in the management of type 2 diabetes, heart failure and chronic kidney disease. Unfortunately, SGLT inhibitors, especially when taken during periods of fasting or intercurrent illness, can precipitate diabetic ketoacidosis. Considering the above, SGLT inhibitors have failed to obtain an indication for use in the setting of T1D. Here we review the potential glycaemic, cardiovascular and kidney benefits of SGLT inhibitors for people with T1D.

Microvascular endothelial cells dysfunction can significantly worsen ischaemic stroke outcomes by disrupting tight junctions and increasing the acquisition of adhesion molecules, accelerating blood-brain barrier (BBB) disruption and pro-inflammatory response. The identification of drugs that improve endothelial cell function may be crucial for ischaemic stroke. It has been validated that empagliflozin (EMPA), a novel antidiabetic drug, protects endothelial cells regardless of the diabetic status of the patient. However, the impact of EMPA on stroke outcomes is unclear. We hypothesized that EMPA would exert a beneficial effect on ischaemic stroke outcome by protecting microvascular endothelial cells against tight junction disruption and the increase of adhesion molecules.

Young adult male mice were administered with EMPA or vehicle (dimethyl sulfoxide) daily for 7 days before being subjected to transient middle cerebral artery occlusion (tMCAO). Neurological deficits were evaluated for up to 28 days post-tMCAO. Infarct volume, BBB disruption, and inflammatory status were assessed 1 day after tMCAO.bEnd.3 cells and primary brain microvascular endothelial cells were treated with EMPA or vehicle under oxygen and glucose deprivation/reperfusion (OGD/R), and the lactate dehydrogenase release, transendothelial electrical resistance, leakage of fluorescein isothiocyanate-dextran, and tight junction and adhesion molecules proteins were examined. Mechanistic studies probing the effect of EMPA on endothelial cells were conducted by RNA-seq. EMPA treatment before ischaemia markedly improved infarct volume, BBB disruption, and inflammation 1-day post-tMCAO, and further enhanced neurobehavioral function up to 28 days. Pre-treatment of EMPA attenuated endothelial cell dysfunction under OGD/R conditions. In mechanistic terms, RNA-seq data from isolated cerebral microvessels revealed that the Wnt/β-catenin signalling pathway was preserved in the EMPA group, in contrast to the vehicle group. Pre-treatment with EMPA inhibited β-catenin ubiquitination and promoted β-catenin translocation from the cytoplasm to the nucleus to improve endothelial cell function. Importantly, the β-catenin inhibitor XAV-939 eliminated this protective function of EMPA.

EMPA administration before tMCAO attenuated ischaemia/reperfusion-induced BBB disruption and inflammation via β-catenin-mediated protection of cerebral microvascular endothelial cells. Therefore, EMPA shows potential for improving stroke outcomes as an adjunctive preventive strategy.

The purpose of the current study is to evaluate the role of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in the treatment of patients with diabetes with newly diagnosed acute myocardial infarction (AMI).

This multicenter, prospective, cohort study included 1161 patients with diabetes with newly diagnosed AMI. The primary endpoint events included rehospitalization for heart failure (HF) and major adverse cardiovascular events (MACEs). The secondary endpoint events were recurrent MI and cardiac death.

Patients were categorized into the SGLT2i group and the non-SGLT2i group. During a median follow-up of 1.8 (1.5-2.3) years, the risk of hospitalization for HF (HR 0.58; 95% CI 0.36-0.94; P = 0.026) and MACEs (HR 0.59; 95% CI 0.40-0.86; P = 0.006) were lower in the SGLT2i group, with a similar trend observed for cardiac death (HR 0.51; 95% CI 0.27-0.99; P = 0.046). SGLT2i appears to be a better choice for all such patients. However, our research further found the above trends were observed mainly in the LVEF < 50% subgroup. In addition, our study also revealed novel findings that the protective effect of SGLT2i was not altered by baseline levels of HbA1c in these patients, nor by different SGLT2i medications.

The outcomes of the current investigation suggest that SGLT2i is preferred as a hypoglycemic and cardiovascular protective drug for patients with diabetes with newly diagnosed AMI. It could improve cardiovascular outcomes, reducing the risk of rehospitalization for HF and MACEs, particularly in patients with reduced LVEF.

Role of SGLT2I in Patients with Myocardial Infarction, NCT06245980. https://clinicaltrials.gov/ct2/show/NCT06245980 . Retrospectively registered.

Overweight and obesity are major risk factors for heart failure (HF), contributing to its development through metabolic, neurohormonal, haemodynamic, and inflammatory alterations. While overweight/obesity increases the risk of developing HF, its impact on patient outcomes remains complex. The "obesity paradox" suggests that a higher BMI may be associated with improved survival in patients with established HF. However, recent GLP-1 receptor agonist (GLP-1 RA) trials suggest that intentional weight loss positively influences outcomes in overweight/obese patients with HF. This seemingly contradictory evidence highlights the need for a deeper understanding of the mechanisms linking adiposity to HF outcomes. A more precise characterization of adiposity phenotypes using alternative and accurate measures of pathological fat accumulation is crucial in identifying individuals who may benefit most from anti-obesity treatments. In this context, recent research underscores the role of epicardial adipose tissue (EAT) in HF pathophysiology, as it directly influences cardiac function and structure through inflammatory, metabolic, and mechanical effects. This narrative review summarises current evidence on the impact of weight loss on HF outcomes, focusing on recent GLP-1 RA trial results. Additionally, it highlights epidemiological and molecular data supporting EAT as a novel adiposity measure that might allow refining patient selection for pharmacological weight-loss treatments. Finally, it emphasizes the need for future research to identify causal pathways linking alternative measures of visceral fat accumulation to HF outcomes. These efforts will be essential in optimizing the benefits of novel weight-loss treatments, ensuring effective and individualized therapeutic strategies for overweight or obese patients with HF.

To compare long-term complications for people with type 2 diabetes mellitus (T2DM) following second-line treatment in routine practice with sulphonylureas (SU), dipeptidyl peptidase-4 inhibitors (DPP4i), or sodium-glucose co-transporter-2 inhibitors (SGLT2i) added to metformin.

We used the RAPIDS microsimulation model to predict diabetes complications over 5 years after second-line treatment initiation. We combined information on 'real-world' treatment duration in England from the Clinical Practice Research Datalink with evidence on treatment effectiveness from Randomised Controlled Trials (RCTs). We estimated between-treatment differences in the probabilities of end-stage kidney disease (ESKD), heart failure hospitalisation (HF), diabetic eye disease, myocardial infarction (MI), and lower-extremity amputation (LEA).

The predicted probabilities of complications within 5 years were lower following second-line treatment with SGLT2i compared to SU and DPP4i. The mean (95% CI) difference (reduction) in the predicted probability of ESKD following SGLT2i versus SU was -0.81% (-0.89, -0.73), and for SGLT2i versus DPP4i the corresponding difference was -0.87% (-0.95, -0.79). The reduction in the probability of HF following SGLT2i versus SU was -0.90% (-1.01, -0.80), and for SGLT2i versus DPP4i it was -0.95% (-1.06, -0.84). The corresponding differences in the probabilities of diabetic eye disease following SGLT2i versus SU were -1.41% (-1.57, -1.26), and for SGLT2i versus DPP4i was -0.44% (-0.59, -0.29). The predicted probabilities of LEA were similar across treatments. Pre-existing CVD did not modify the predicted probabilities of complications.

For a general T2DM population, second-line treatment with SGLT2i rather than SU or DPP4i can reduce the probability of complications within 5 years.

Background: The 2023 ESC Heart Failure (HF) Guidelines recommend the rapid up-titration of guideline-directed medical therapy (GDMT) for all patients after HF hospitalisation. Real-world data on the implementation of a rapid up-titration programme (RTP) are scarce. Methods: We aimed to summarise the primary experiences of a six-week RTP in a multicentre observational study of five cardiology centres, evaluating the GDMT applied and the target doses (TDs) achieved during the RTP. The safety of RTP in relation to exceeding the "safety indicators" used in the STRONG-HF trial and any serious adverse events were observed. Changes in the left ventricular ejection fraction (LVEF) after RTP were evaluated. Results: Among the 90 consecutive patients (age: 56 [49-63] years, HFrEF: 96%, NT-proBNP at discharge: 1390 [735-2835] pg/mL; continuous variables are presented as median and interquartile ranges, while categorical variables are shown as absolute numbers and percentages, respectively), a remarkable proportion of patients received GDMT at hospital discharge; however, target doses were rarely achieved (RASi: 100%, TD RASi: 11%; βB: 97%, TD βB: 6%; MRA: 99%, TD MRA: 82%; SGLT2i: 98%, TD SGLT2i: 98%; triple therapy [TT: RASi + βB + MRA]: 96%, TD TT: 2%, quadruple therapy [QT: RASi + βB + MRA]: 94%, TD QT: 2%). After the six-week RTP, 100% of the total cohort (TC) were receiving RASi; 99-99-99% were receiving βB, MRA, and SGLT2i medications; and altogether, 98-98% were on TT and QT. In total, 78-78% of the patients received ≥50% of the TDs of TT and QT, while 51-51% of the TC were on TDs of TT and QT. During the RTP, no serious adverse events were observed. Between two and four months after the RTP, 51% of HFrEF patients evolved to the HFimpEF category. Conclusions: The present multicentre, observational study confirms that RTP is feasible and safe in real-world clinical practice, leading to a remarkably large proportion of patients receiving GDMT by the end of the six-week RTP, resulting in a significant increase in LVEF.

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are increasingly used in patients with type 2 diabetes, chronic kidney disease, and heart failure. However, their safety and efficacy in patients with congenital or surgically altered urogenital anatomy remains underexplored. Methods: We conducted a narrative review of current evidence regarding the use of SGLT2i in patients with urinary tract malformations, urinary diversions, and functional voiding disorders. Key risks, clinical considerations, and management strategies were synthesized from the existing literature and case reports. Results: Patients with benign prostatic hyperplasia, vesicoureteral reflux, neurogenic bladder, nephrostomies, and ileal conduits may face increased risks of urinary tract infections, fungal colonization, and therapy-related complications due to persistent glycosuria and altered urinary flow. Nevertheless, these patients may still benefit from SGLT2i's systemic renal and cardiovascular effects. Individualized risk assessment, close monitoring, and multidisciplinary management are essential. Conclusions: Patients with urological abnormalities represent a high-risk but potentially high-reward population for SGLT2i therapy. A cautious, tailored approach is necessary, and future dedicated research is urgently needed to better guide clinical practice.