Non-diabetic Heart Failure Patients Research Articles

Impact of Diabetes Mellitus on Heart Failure Patients: Insights from a Comprehensive Analysis and Machine Learning Model Using the Jordanian Heart Failure Registry.

Heart failure (HF) is a common final pathway of various insults to the heart, primarily from risk factors including diabetes mellitus (DM) type 2. This study analyzed the clinical characteristics of HF in a Jordanian population with a particular emphasis on the relationship between DM and HF. This prospective study used the Jordanian Heart Failure Registry (JoHFR) data. Patients with HF were characterized by DM status and HF type: HF with preserved ejection fraction (HFpEF) or HF with reduced ejection fraction (HFrEF). Demographics, clinical presentations, and treatment outcomes were collected. Statistical analyses and machine learning techniques were carried out for the prediction of mortality among HF patients: Recursive Feature Elimination with Cross-Validation (RFECV) and Synthetic Minority Over-sampling Technique with Edited Nearest Neighbors (SMOTEENN) were employed. A total of 2007 patients with HF were included. Notable differences between diabetic and non-diabetic patients are apparent. Diabetic patients were predominantly male, older, and obese (p < 0.001 for all). A higher incidence of HFpEF was observed in the diabetes cohort (p = 0.006). Also, diabetic patients had significantly higher levels of cholesterol (p = 0.008) and LDL (p = 0.003), reduced hemoglobin levels (p < 0.001), and more severe renal impairment (eGFR; p = 0.006). Machine learning models, particularly the Random Forest Classifier, highlighted its superiority in mortality prediction, with an accuracy of 90.02% and AUC of 80.51%. Predictors of mortality included creatinine levels >115 µmol/L, length of hospital stay, and need for mechanical ventilation. This study underscores notable differences in clinical characteristics and outcomes between diabetic and non-diabetic heart failure patients in Jordan. Diabetic patients had higher prevalence of HFpEF and poorer health indicators such as elevated cholesterol, LDL, and impaired kidney function. High creatinine levels, longer hospital stays, and the need for mechanical ventilation were key predictors of mortality.

Effect of Metformin on Oxidative Stress and Left Ventricular Geometry in Nondiabetic Heart Failure Patients: A Randomized Controlled Trial.

Introduction: There is an increasing interest in using metformin in cardiovascular diseases and its potential new roles. Only two randomized controlled trials investigated the effect of metformin in nondiabetic heart failure (HF) patients. However, none of these studies assess the role of metformin in reducing oxidative stress. We hypothesized that metformin might improve oxidative stress and left ventricular remodeling in nondiabetic HF patients with reduced ejection fraction (HFrEF). Methods and Methods: Seventy HFrEF patients (EF 37% ± 8%; median age 66 years) were randomized to metformin (n = 35) or standard of care (SOC) for HF (n = 35) for 6 months in addition to standard therapy. Outcomes included the difference in the change (Δ) in total antioxidant capacity (TAC) and malondialdehyde (MDA), both assessed colorimetrically and left ventricular mass index (LVMI) assessed through transthoracic echocardiography. Results: Compared with the SOC, metformin treatment increased TAC [Δ = 0.12 mmol/L, confidence intervals (95% CIs): 0.03-0.21; P = 0.007]. TAC increased significantly only in the metformin group (0.90 ± 0.08 mmol/L at baseline vs. 1.04 ± 0.99 mmol/L at 6 months, P < 0.05). Metformin therapy preserved LVMI (Δ = -23 g/m2, 95% CI: -42.91 to -4.92; P = 0.014) and reduced fasting plasma glucose (Δ = -6.16, 95% CI: -12.31 to -0.02, P = 0.047) compared with the SOC. Results did not change after adjusting for baseline values. Changes in MDA left ventricular ejection fraction (LVEF) and blood pressure were not significantly different between groups. Conclusion: Metformin treatment in HF patients with reduced LVEF improved TAC and prevented the increase in LVMI compared with the SOC. These effects of metformin warrant further research in HF patients without diabetes to explore the potential benefits of metformin. Trial Registration Number: This protocol was registered in ClinicalTrials.gov under the number NCT05177588.

Effect of Aerobic Exercise training on Insulin Resistance among Non-Diabetic Heart Failure Patients

Effect of Aerobic Exercise training on Insulin Resistance among Non-Diabetic Heart Failure Patients

Effect of Aerobic Exercise training on Insulin Resistance among Non-Diabetic Heart Failure Patients

Effect of Aerobic Exercise training on Insulin Resistance among Non-Diabetic Heart Failure Patients

Lower low density lipoprotein cholesterol associates to higher mortality in non-diabetic heart failure patients

BackgroundIn patients with established heart failure (HF) low total cholesterol levels associate with worse prognosis. Evidence concerning the impact of Low-density lipoprotein cholesterol (LDL-c) in HF is scarce. We aimed to evaluate the prognostic impact of LDL-c in patients with HF, both with and without diabetes mellitus (DM). MethodsWe retrospectively analyzed outpatients with chronic HF with systolic dysfunction followed in our HF clinic from January/2012 to May/2018. LDL-c was calculated using the Friedewald's formula. Patients without a complete lipid profile were excluded. The endpoint under analysis was all-cause mortality. Patients were followed until January/2021. A Cox-regression analysis was used to study the prognostic impact of LDL-c. The LDL-c cut-off used was 100 mg/dL (mean value). Analysis was stratified according to the coexistence of DM. Multivariate models were built adjusting for age, sex, coronary artery disease, atherosclerotic non-coronary artery disease, arterial hypertension, smoking status, statin use, severity of systolic dysfunction, creatinine clearance and evidence-based therapy. ResultsWe studied 522 chronic HF patients, mean age was 70 years, 66.5% males. Severe systolic dysfunction was present in 42.7%, 30.5% had coronary heart disease, 60.5% had arterial hypertension, 41.6% had DM. A total of 92.0% were treated with beta blocker, 87.5% with an ACEi/ARB and 29.1% with a MRA. During a median follow-up of 53 (interquartile range 33–73) months, 235 (45%) patients died. Patients with LDL-c ≤100 mg/dL presented increased multivariate-adjusted risk of all-cause mortality: HR = 1.58 (95% CI: 1.08–2.30), p = 0.02. When patients were stratified according to DM, LDL-c ≤100 mg/dL was independently associated with increased death risk – HR = 1.55 (95% CI:1.05–2.30), p = 0.03 in patients without DM; in patients with DM no association was detected – multivariate-adjusted HR = 1.18 (95% CI: 0.77–1.80), p = 0.44. ConclusionNon-DM HF patients with LDL-c>100 mg/dL have a 35% reduction in the mortality risk when compared with those with lower values. The “cholesterol paradox” in HF also applies to LDL-c in non-DM patients.

Safety and efficacy of SGLT2 inhibitors in diabetic and non-diabetic heart failure patients, a meta-analysis of randomized controlled trials

Abstract Background Heart failure (HF) is the most common cardiovascular causes of hospitalization in people over 60 years affecting about 64.3 million people worldwide. Few studies have investigated sodium glucose like transporter-2 inhibitors (SGLT-2I) role in diabetic and non-diabetic patients with HF. Objective We conducted our meta-analysis to further investigate SGLT-2I role in diabetic and non-diabetic HF patients. Methods PubMed, Scopus, web of science, and Embase were searched. All clinical trials that compared the effect of SGLT2 inhibitors versus placebo on heart failure patients were included. Dichotomous data were extracted, pooled as risk ratio (RR) with 95% confidence interval, and analyzed via RevMan version 5.3 for windows using Mantel Haenszel (M-H) method. Results Twelve randomized clinical trials were included for analysis with a total number of 69024 patients. SGLT2I significantly lowered the risk of hospitalization for heart failure (HHF) in diabetic (RR=0.68, 95% CI 0.63–0.74) and non-diabetic patients (RR=0.75, 95% CI 0.62–0.89). Also, it significantly lowered mortality risk in both diabetic (RR=0.87, 95% CI 0.77–0.99) and non-diabetic patients (RR=0.93, 95% CI 0.70–1.23). Further analyses for serious adverse events were conducted, and SGLT-2I showed a significant lower risk in diabetic (RR=0.94, 95% CI 0.90–0.98) and non-diabetic patients (RR=0.72, 95% CI 0.38–1.39), yet with no observed difference over placebo in the risk of stroke. Conclusion SGLT2 inhibitors showed a favorable effect in lowering cardiovascular mortality, HHF, and stroke in diabetic patients with heart failure. In non-diabetic patients, they significantly reduce HHF, yet with no difference on cardiovascular mortality and stroke. Therefore, more trials are needed to establish their effect in non-diabetic patients. Funding Acknowledgement Type of funding sources: None.

In-hospital glycemic variability and all-cause mortality in patients hospitalized with acute heart failure: analysis of the KorAHF registry

Abstract Introduction Glycemic variability (GV) is known to be a poor prognostic marker in various diseases including cardiovascular disease. Purpose We investigated the association of GV with all-cause mortality in patients with acute heart failure (HF). Methods The Korean Acute Heart Failure registry enrolled patients hospitalized for acute HF from 2011 to 2014. Among survivors of the index hospitalization, we analyzed those who had ≥3 blood glucose measurements before discharge. Patients were divided into two groups based on their coefficient of variation (%CV) as an indicator of GV. We investigated all-cause mortality at 6 month and 1 year after discharge. Results The study analyzed 2,617 patients (median age 72 years, 53% male). During the median follow-up period of 11 months, 583 (22%) patients died. Compared to alive patients, patients who died had a significantly higher diabetes prevalence (46% vs. 41%, P=0.035) and higher %CV (31.0% vs. 27.5%, P&amp;lt;0.001). Kaplan-Meier curve analysis revealed that a high GV (%CV &amp;gt;21%) was associated with lower cumulative survival to all-cause death compared with a low GV (%CV ≤21%) (log-rank P&amp;lt;0.001). Multivariate Cox proportional analysis showed that a high GV was associated with an increased risk of 6-month mortality (hazard ratio [HR] 2.02, 95% CI 1.58–2.59, P&amp;lt;0.001) and one-year mortality (HR 1.57, 95% CI 1.29–1.91, P&amp;lt;0.001). The risk of high GV for one-year mortality was significant in non-diabetic patients (HR 1.98, 95% CI 1.55–2.53, P&amp;lt;0.001), but not in diabetic patients (HR 1.24, 95% CI 0.91–1.69, P=0.176; P-for-interaction=0.030). Conclusion A high GV (%CV &amp;gt;21%) before discharge was associated with all-cause mortality within 1 year, especially in non-diabetic acute HF patients. Funding Acknowledgement Type of funding sources: None.

Diabetic Cardiomyopathy: A Case Report

Diabetes has become in a few years a veritable epidemic affecting several million people in the world. The cardiovascular complications are the leading cause of death in diabetics. More particularly, cardiac involvement is essentially summarized in ischemic heart disease, cardiac autonomic neuropathy and more recently described diabetic cardiomyopathy, a specific entity responsible for – or contributing to – the onset of heart failure which is related to a diastolic dysfunction preceding an alteration of the systolic function and whose prognosis makes all the seriousness of this pathology. Indeed, large epidemiological studies have demonstrated that diabetes is an independent risk factor for heart failure. These data are supported by numerous preclinical studies, highlighting metabolic abnormalities, calcium homeostasis, or even neuro-hormonal, in models of diabetes. Optimal glycemic control appears to limit the incidence and severity of heart failure in diabetics. The treatment of diabetic cardiomyopathy is no different from that of non-diabetic heart failure patients. A better understanding of this entity therefore necessitates close collaboration between cardiologists and diabetologists.

Can glucose-lowering medications improve outcomes in non-diabetic heart failure patients? A Bayesian network meta-analysis.

AimsThe cardioprotective effects of glucose‐lowering medications in diabetic patients with heart failure (HF) are well known. Several large randomized controlled trials (RCTs) have recently suggested that the cardioprotective effects of glucose‐lowering medications extend to HF patients regardless of diabetic status. The aim of this study was to conduct a Bayesian network meta‐analysis to evaluate the impact of various glucose‐lowering medications on the outcomes of non‐diabetic HF patients.Methods and resultsMedline and Embase were searched for RCTs investigating the use of glucose‐lowering medications in non‐diabetic HF patients in August 2021. Studies were included in accordance with the inclusion and exclusion criteria, and data were extracted with a pre‐defined datasheet. Primary outcomes include serum N‐terminal prohormone of brain natriuretic peptide (NT‐proBNP) levels, left ventricular ejection fraction (LVEF), and maximal oxygen consumption (PVO2). A Bayesian network meta‐analysis was performed to compare the effectiveness of different classes of glucose‐lowering medications in improving HF outcomes. Risk‐of‐bias was assessed using Cochrane Risk‐of‐Bias tool 2.0 for randomized trials (ROB2). Seven RCTs involving 2897 patients were included. Sodium‐glucose transporter 2 inhibitor (SGLT2i) was the most favourable in lowering NT‐proBNP, with the significant reduction in NT‐proBNP when compared with glucagon‐like peptide‐1 receptor agonists (GLP1‐RA) [mean differences (MD): −229.59 pg/mL, 95%‐credible intervals (95%‐CrI): −238.31 to −220.91], metformin (MD: −237.15 pg/mL, 95%‐CrI: −256.19 to −218.14), and placebo (MD: −228.00 pg/mL, 95%‐CrI: −233.99 to −221.99). SGLT2i was more effective in improving LVEF for HF with reduced ejection fraction patients relative to GLP1‐RA (MD: 8.09%, 95%‐CrI: 6.30 to 9.88) and placebo (MD: 6.10%, 95%‐CrI: 4.37 to 7.84). SGLT2i and GLP1‐RA were more favourable to placebo in improving PVO2, with significant increase of PVO2 at a MD of 1.60 mL/kg/min (95%‐CrI: 0.63 to 2.57) and 0.86 mL/kg/min (95%‐CrI: 0.66 to 1.06), respectively. All three drugs had comparable safety profiles when compared with placebo.ConclusionsThis Bayesian network meta‐analysis demonstrated that SGLT2i, when compared with GLP1‐RA and metformin, was superior in improving LVEF in HF with reduced ejection fraction patients, as well as improving PVO2 and NT‐proBNP in non‐diabetic HF patients. Further large‐scale prospective studies are needed to confirm these preliminary findings.

Prognostic value of sST2 in heart failure patients with diabetes

Abstract Background Soluble suppression of tumorigenesis-2 (sST2) is released in response to inflammation and vascular injury, and holds prognostic value in heart failure (HF). Type 2 diabetes (T2D) is characterized by a pro-inflammatory status and is highly prevalent among HF patients, with adverse impact on outcomes. The clinical value of sST2 in HF patients with T2D has never been characterized. Purpose We aimed to assess sST2 clinical correlates and prognostic value in HF patients with T2D. Methods Individual data of 3476 patients with stable chronic HF from 5 cohorts from the BIOS (Biomarkers In Heart Failure Outpatient Study) dataset were analysed, with available N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), and sST2 levels. Results Mean age was 65±12 years (75% males). T2D was present in 1386 patients (40%), who had higher body mass index (BMI, 27 [24–30] vs. 26 [23–29] kg/m2, p&amp;lt;0.001), lower estimated glomerular filtration rate (eGFR, 56±22 vs. 60±19 mL/min/1,73 m2, p&amp;lt;0.001), higher sST2 (33 [24–47] vs. 27 [20–40] ng/mL, p&amp;lt;0.001), NT-proBNP (1735 [742–3963] vs. 1450 [514–3299] ng/L, p&amp;lt;0.001), hs-TnT (28 [16.2–51.5] vs. 17 [9–31] ng/L, p&amp;lt;0.001) and high-sensitivity C-reactive protein (hs-CRP, 6 [2–11] vs. 4. [2–9] mg/L, p=0.003) (Figure). Differences between sST2 levels in patients with or without T2D were influenced by hs-CRP (p for interaction=0.010) and hs-TnT (p=0.031), but not by NT-proBNP and eGFR. At multivariate linear regression analysis, NT-proBNP, hs-TnT and hs-CRP were independently associated with sST2 levels in both T2D and non-T2D patients. Compared with patients without T2D, those with T2D showed higher 1-year all-cause mortality (12% vs. 10%, p=0.034), cardiovascular mortality (9% vs. 7%, p=0.011), and HF hospitalization rate (22% vs. 12%, p&amp;lt;0.001). In a prognostic model including age, sex, eGFR, ischemic vs- non-ischemic aetiology, left ventricular ejection fraction class, New York Heart Association class, NT-proBNP, hs-TnT, and hs-CRP, sST2 retained independent prognostic value in both patients with or without T2D for 1-year all-cause and cardiovascular mortality, and 1-year HF hospitalization, with higher optimal cut-offs for mortality prediction in T2D vs. non-T2D (39 and 45 vs. 29 and 29 ng/mL respectively for 1-year all-cause and cardiovascular mortality). Conclusions sST2 is higher in HF patients with T2D and likely linked to a pro-inflammatory status. sST2 maintains its prognostic value both in diabetic and non-diabetic HF patients, independently of NT-proBNP, hs-TnT and hs-CRP. Funding Acknowledgement Type of funding sources: None. Figure 1

Sodium-Glucose Cotransporter-2 Inhibitor–Associated Euglycemic Diabetic Ketoacidosis After Orthotopic Heart Transplant in a Prediabetic Patient: A Case Report

Postoperative euglycemic diabetic ketoacidosis (euDKA) associated with sodium-glucose cotransporter-2 (SGLT2) inhibitor use has been well-documented and carries a Food and Drug Administration recommendation to hold SGLT2 inhibitors 3 to 4 days before a planned surgical procedure. Unfortunately, many surgical procedures, such as orthotopic heart transplant (OHT), are unplanned and unpredictable. With the increasing use of SGLT2 inhibitors in diabetic and non-diabetic heart failure patients, new challenges in patient management and perioperative risk have arisen. We report a case in which SGLT2 inhibitor-associated euDKA complicated the postoperative course of a prediabetic patient who had undergone OHT.

Overview of Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors for the Treatment of Non-diabetic Heart Failure Patients.

Heart failure (HF) is a clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood, and results in low life quality and expectancy, creating a significant burden on the healthcare system. The pharmacological HF management has remained unchanged for a decade, however, several randomized clinical trials have demonstrated the potential clinical benefits of sodium-glucose cotransporter-2 inhibitors, an antidiabetic agent, by reducing the rate of hospitalizations for HF, cardiovascular death, and all-cause death. The cardioprotective effects are characterized by reduction of inflammatory, metabolic and ionic dyshomeostasis despite the diabetic status. Since the United States Food and Drug Administration (FDA) approval in May 2020, SGLT2 inhibitors have been used mostly in heart failure with reduced ejection fraction (HFrEF). In this review article, we provide a comprehensive overview of the potential benefits, effectiveness, and safety profile of SGLT2 inhibitors used in HF patients with no history of diabetes mellitus.

The prognostic impact of uric acid in acute heart failure according to coexistence of diabetes mellitus

Background and aimsIncreased uric acid levels predict higher mortality in heart failure (HF) patients. Patients with diabetes mellitus (DM) appear to have increased xanthine oxidase activity. We aimed to study if the association between uric acid and mortality in acute HF was different according to the coexistence of DM. Methods and resultsWe studied a cohort of patients hospitalized due to acute HF in 2009–2010. Patients with no uric acid measurement upon admission were excluded from the analysis. Follow-up: 2 years; endpoint: all-cause mortality. Patients with elevated uric acid (>80.0 mg/L) were compared with those with lower values. We used a multivariate Cox-regression analysis to assess the prognostic impact of uric acid (both continuous and categorical variable: cut-off 80.0 mg/L). The analysis was stratified according to coexistence of DM. We studied 569 acute HF patients, 44.6%male, mean age 76 years, 290 were diabetic. Median admission uric acid: 81.2 mg/L and 52.2%had uric acid >80.0 mg/L. Elevated uric acid predicted all-cause mortality in acute HF only in patients with DM. The multivariate-adjusted HR of 2-year mortality was 1.68 (95 % CI: 1.15–2.46) for diabetic HF patients with uric acid>80.0 mg/L compared to those with lower levels (p = 0.008) and 1.10 (95 % CI: 1.03–1.18) per each 10 mg/L increase in uric acid (p = 0.007). In non-diabetic HF patients, uric acid was not associated with mortality. ConclusionsIncreased uric acid predicts ominous outcome in acute HF patients with diabetes, however, it is not prognostic associated in non-diabetics. Uric acid may play a different role in acute HF depending on DM status.

Sodium-Glucose Cotransporter Inhibitors in Non- Diabetic Heart Failure: A Narrative Review.

Heart failure (HF) is one of the leading public health problems with a substantial burden in the global healthcare system. Although significant efforts are based on prevention, early recognition, and proper management of HF, the worldwide surge of risk factors like hypertension, diabetes, and obesity has further complicated the existing problem. This study aims to define the role of the sodium-glucose cotransporter 2 (SGLT2) inhibitors in non-diabetic HF. We performed a comprehensive literature review to examine the available evidence in the clinical implications of SGLT2 inhibitors in non-diabetic HF using the online databases (PubMed and Embase). We identified two RCTs-DAPA-HF and DEFINE-HF, which were conducted to analyze the net clinical benefit of dapagliflozin in non-diabetic HF patients. Although we could not study the composite effects of these studies due to the difference in outcome measures, the individual outcomes look promising. The number needed to treat (NNT) to prevent one primary event was 21 (95% CI: 15 to 38) in the DAPA study. In DEFINE HF study, responder analysis showed a significant proportion of patients in the treatment arm experienced improvements in the functional status with clinically meaningful improvement in KCCQ-OS by 3.7 points and KCCQ-CS by 4.6 points with NNT of 10 and 7, respectively, at 12 weeks. Both studies also showed low safety concerns in patients without T2D. The outcomes of the two RCTs, DAPA-HF and DEFINE-HF, that studied the effects of SGLT2 inhibitors in non-diabetic HF showed promising clinical outcomes. Although we are waiting for other prospective RCTs to reflect similar results and safety profiles, it seems the SGLT2 inhibitors can have broader clinical implications in managing non-diabetic HF with improved cardiovascular outcomes.

Abstract 14981: Altered Gene Expression in Diabetic Heart Failure Patients

Introduction: Diabetes and heart failure are very closely associated. Diabetes patients have an increased risk of developing heart failure and heart failure patients are at higher risk of developing diabetes. Changes occur in myocardial glucose metabolism in end stage heart failure patients and newer therapies for diabetes such as SGLTi improve heart failure outcomes. Our objective was to identify transcriptional changes associated with diabetes in heart failure patients. Methods: Transcriptional profiles were compared in heart tissues obtained at the time of LVAD implant among diabetic heart failure (HF) (n=16), non-diabetic (n=10) HF patients and control (n=3) non failing hearts. RNASeq analysis utilized a custom-targeted panel for 140 genes on the Ion Torrent Personal Genome Machine. Coverage analysis as well as mapping the reads and alignment was done using the Ion Torrent Browser SuiteTM. The Bejamini-Hochberg method was used to control the false discovery rate to be no more than 0.05. Ingenuity Pathway Analysis (IPA) was also performed to understand the biological pathways involved. Results: Our sample population was 82% male with an average age of 51 and 84% Caucasian, 14% African American and 2% Asian. Average ejection fraction was quite low &lt;25% and average NYHA was 3.5 in the HF populations. Expressions of contractile muscle and ion channels proteins decreased significantly between HF patients and control. Increased expression of chemokine ligand 4 (CCL4), chemokine ligand 2 (CCL2) and collagen type 1 alpha1 (COL1A1) were observed in diabetic HF compared to non-diabetic HF patients. IPA analysis with log fold change between HF and control revealed activation of both methylation genes DNMT3A and B, necrosis of cardiac muscle and death of cardiomyocytes with 2.0 Z score. Conclusions: Diabetic heart failure patients have increased expression of chemokines and extracellular matrix genes, which may contribute to disease progression. Up regulation of CCL4 and CCL2 in diabetic HF patients may cause additional risk of heart diseases through inflammatory pathways and increased expression of collagen may contribute to myocardial fibrosis. Down regulation of contractile proteins, and ion channels were similar in diabetic and non-diabetic HF patients.

An evaluation of empagliflozin and it’s applicability to hypertension as a therapeutic option

ABSTRACT Introduction Sodium-glucose cotransporter 2 (SGLT2) inhibitors such as Empagliflozin are novel antihyperglycemic drugs approved for the treatment of type 2 diabetes (T2D). In addition to its glucose-lowering effects, Empagliflozin promotes weight loss, blood pressure reduction, and other beneficial metabolic benefits. Areas covered This review outlines the pharmacokinetics, pharmacodynamics, safety, and tolerability of Empagliflozin and discusses its role in diabetes-associated hypertension. Expert opinion Empagliflozin was the first in class to not only demonstrate safety of SGLT2 inhibition but also cardio- and reno-protective effects in an adequately powered cardiovascular outcome trial. The EMPA-REG study showed significant reductions in mortality from cardiovascular causes, hospitalization for heart failure, and progression of diabetic kidney disease. These benefits cannot be attributed to glycemic control alone, suggesting the involvement of other SGLT2 inhibition-mediated mechanisms. Recent data suggests the potential utility of SGLT2 inhibition in other conditions including type 1 diabetes (T1D) and non-diabetic heart failure patients with clinical trials currently being conducted. In concert with ongoing pre-clinical investigations to unravel the mechanisms contributing to cardiorenal protection, the full therapeutic potential of SGLT2 inhibition will become apparent over the next few years and promises to be one of the major success stories in clinical medicine. Abbreviations T1D: type 1 diabetes; T2D: type 2 diabetes; SGLT2: sodium-glucose cotransporter 2; CVD: cardiovascular disease; SBP: systolic blood pressure; DBP: diastolic blood pressure; SNS: sympathetic nervous system; BP: blood pressure; CV: cardiovascular; ZDF: Zucker diabetic fatty; CKD: chronic kidney disease; FDA: Food and Drug Administration

Impact of diabetes on heart failure outcomes: Results from NATURE-HF

Several studies have reported the impact of diabetes on mortality and hospitalization in patients with heart failure (HF). However, the extent of this risk remains imperfectly known in community-based cohorts. We examined the independent prognostic impact of diabetes on the one-year risk of mortality and hospitalization in patients with HF. We conducted a prospective observational study NATURE-HF (National Tunisian Registry of Heart Failure) between October 2017 and January 2019. Demographics, clinical and etiological characteristics as well as one-year outcome were recorded. Among 2040 patients with HF (mean age 63.6 ± 12.6 years, 70.9% male), 731 (44.5%) had prior diabetes. Diabetic patients were older and had greater body mass index than non-diabetics. Left ejection fraction was similar in the two groups. There was no significant difference in all-cause death (odds ratio [OR] [95% CI 1.29] [0.953, 1.615]) and cardiovascular death (0.956 [0.568, 1.609]) between diabetic and non-diabetic HF patients, however,diabetes was associated with a higher risk for hospitalization (2.208 [1.579, 3.089]), and the combined end point of all-cause death or hospitalization (1.654, [1.319, 2.072]). There was an increased risk for a composite of death or HF admissions in diabetic patients with ischemic cardiomyopathy (23.9 vs. 14.1% respectively, P < 0.001). The co-existence of heart failure and diabetes has significant impact on outcomes and confers a worse prognosis than heart failure alone, especially in patients with ischemic cardiomyopathy.

Sodium glucose cotransporter (SGLT)-2 inhibitors alleviate the renal stress responsible for sympathetic activation.

This review focuses on the pathogenic role of sodium glucose cotransporter (SGLT)-2 in the development of renal dysfunction and heart failure in patients with diabetes, by emphasizing the concept of reno-cardiac syndrome (kidney injury worsens cardiac condition) and by substantiating the deleterious effect of sympathetic overdrive in this context. Furthermore, the review proposes a mechanistic hypothesis to explain the benefits of SGLT2 inhibitors, specifically that SGLT-2 inhibitors reduce sympathetic activation at the renal level. To illustrate this point, several examples from both animal experiments and clinical observations are introduced. The bidirectional interaction of the heart and kidney were deeply implicated as an exacerbator of heart failure and renal failure without diabetes. Renal cortical ischemia and abnormal glucose metabolism of tubular epithelial cells are likely to exist as common pathologies in nondiabetic heart failure patients. It is no wonder why SGLT-2 inhibitors are specifically being studied even in the absence of diabetes, both for heart failure and also for renal failure.

Red blood cell distribution width as a prognostic marker in patients with heart failure and diabetes mellitus

BackgroundRed blood cell distribution width (RDW) is an established prognostic marker in acute and chronic heart failure (HF). Recent studies have pointed out a link among RDW, diabetes mellitus (DM) and inflammation. We sought to investigate the prognostic value and longitudinal pattern of RDW in patients with concomitant HF and DM, which remains unknown.MethodsA total of 218 patients (71 diabetics) who presented with acute HF had RDW measured at admission, discharge and 4, 8 and 12 months post-discharge. The study endpoint was all-cause mortality or rehospitalization for HF during 1-year follow-up.ResultsThe study endpoint was met in 33 patients (46.5%) with DM and in 54 patients (36.7%) without DM. RDW at admission was associated with higher event rate both in HF patients with and without DM (adjusted HR: 1.349, p = 0.002, 95% CI 1.120–1.624 and adjusted HR: 1.142, p = 0.033, 95% CI 1.011–1.291 respectively). In addition, a significant interaction was found between diabetes and RDW longitudinal changes (βinteraction = −0.002; SE = 0.001; p = 0.042).ConclusionsDespite the similar prognostic significance of RDW in diabetic and non-diabetic HF patients regarding the study endpoint, longitudinal changes were found to be significantly different between these two groups of HF patients. This might be due to the higher inflammatory burden that diabetic HF patients carry and may provide new insights to the pathophysiological mechanism of RDW increase in HF, which remains unknown.

Identification of nondiabetic heart failure-associated genes by bioinformatics approaches in patients with dilated ischemic cardiomyopathy.

Heart failure (HF) is a common pathological condition affecting 4% of the worldwide population. However, approaches for predicting or treating nondiabetic HF (ND-HF) progression are insufficient. In the current study, the gene expression profile GSE26887 was analyzed, which contained samples from 5 healthy controls, 7 diabetes mellitus-HF patients and 12 ND-HF patients with dilated ischemic cardiomyopathy. The dataset of 5 healthy controls and 12 ND-HF patients was normalized with robust multichip average analysis and the differentially expressed genes (DEGs) were screened by unequal variance t-test and multiple-testing correction. In addition, the protein-protein interaction (PPI) network of the upregulated and downregulated genes was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins database and the Cytoscape software platform. Subsequently, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. A total of 122 upregulated and 133 downregulated genes were detected. The most significantly up- and downregulated genes were EIF1AY and SERPINE1, respectively. In addition, 38 and 77 nodes were obtained in the up- and downregulated PPI network. DEGs that owned the highest connectivity degree were USP9Y and UTY in the upregulated network, and CD44 in the downregulated networks, respectively. NPPA and SERPINE1 were also found to be hub genes in the PPI network. Several GO terms and pathways that were enriched by DEGs were identified, and the most significantly enriched KEGG pathways were drug metabolism and extracellular matrix-receptor interaction. In conclusion, the two DEGs, NPPA and SERPINE1, may be important in the pathogenesis of HF and may be used for the diagnosis and treatment of HF.