Potential Therapeutic Benefits of Sodium-Glucose Cotransporter 2 Inhibitors in the Context of Ischemic Heart Failure: A State-Of-The-Art Review

2021 ◽  
Vol 19 ◽  
Author(s):  
Mauro Gitto ◽  
Dimitrios A. Vrachatis ◽  
Gianluigi Condorelli ◽  
Konstantinos Papathanasiou ◽  
Bernhard Reimers ◽  
...  
Keyword(s):  
Heart Failure ◽  
Systolic Function ◽  
Coronary Revascularization ◽  
Deep Understanding ◽  
Active Role ◽  
Left Ventricular ◽  
Sglt2 Inhibitors ◽  
Reduced Ejection Fraction ◽  
Therapeutic Benefits ◽  
Sodium Glucose Cotransporter

: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of anti-diabetic agents that block the reabsorption of glucose in the proximal convoluted tubule of the nephron, thereby contributing to glycosuria and lowering blood glucose levels. SGLT2 inhibitors have been associated with improved cardiovascular outcomes in patients with diabetes, including a reduced risk of cardiovascular death and hospitalizations for heart failure. Recently, DAPA-HF and EMPEROR REDUCED trials showed the beneficial cardiovascular effect of SGLT2 inhibitors in patients with heart failure with consistently reduced ejection fraction (HFrEF) regardless of the presence of diabetes. Moreover, some exploratory studies suggested that these drugs improve Left Ventricular (LV) systolic function and oppose LV adverse remodeling in patients with HFrEF. However, the exact mechanisms that mediated for this benefit are not fully understood. Beyond glycemic control, enhanced natriuresis, increased erythropoiesis, improved endothelial function, changes in myocardial metabolism, anti-inflammatory and anti-oxidative properties may all play an active role in SGLT2 inhibitors’ cardiovascular benefits. A deep understanding of the pathophysiological interplay is key to define which HF phenotype could benefit more from SGLT2 inhibitors. Current clinical evidence on the comparison of different HF etiologies is limited to posthoc subgroup analysis of DAPA-HF and EMPEROR-REDUCED, which showed similar outcomes in patients with or without ischemic HF. On the other hand, in earlier studies of patients suffering from diabetes, rates of classic ischemic endpoints, such as myocardial infarction, stroke or coronary revascularization, did not differ between patients treated with SGLT2 inhibitors or placebo. The aim of this review is to discuss whether SGLT2 inhibitors may improve prognosis in patients with ischemic HF, not only in terms of reducing re-hospitalizations and improving left ventricular function but also by limiting coronary artery disease progression and ischemic burden.

scholarly journals Retrospective evaluation of echocardiographic variables for prediction of heart failure hospitalization in heart failure with preserved versus reduced ejection fraction: A single center experience

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0244379
Author(s):  
Michael M. Hammond ◽  
Changyu Shen ◽  
Stephanie Li ◽  
Dhruv S. Kazi ◽  
Marwa A. Sabe ◽  
...  
Keyword(s):  
Heart Failure ◽  
Wall Thickness ◽  
Systolic Function ◽  
Medical Center ◽  
Left Ventricular ◽  
Single Center ◽  
Reduced Ejection Fraction ◽  
Medicare Claims ◽  
Structural Variables ◽  
Eccentric Hypertrophy

Background Limited data exist on the differential ability of variables on transthoracic echocardiogram (TTE) to predict heart failure (HF) readmission across the spectrum of left ventricular (LV) systolic function. Methods We linked 15 years of TTE report data (1/6/2003-5/3/2018) at Beth Israel Deaconess Medical Center to complete Medicare claims. In those with recent HF, we evaluated the relationship between variables on baseline TTE and HF readmission, stratified by LVEF. Results After excluding TTEs with uninterpretable diastology, 5,900 individuals (mean age: 76.9 years; 49.1% female) were included, of which 2545 individuals (41.6%) were admitted for HF. Diastolic variables augmented prediction compared to demographics, comorbidities, and echocardiographic structural variables (p < 0.001), though discrimination was modest (c-statistic = 0.63). LV dimensions and eccentric hypertrophy predicted HF in HF with reduced (HFrEF) but not preserved (HFpEF) systolic function, whereas LV wall thickness, NT-proBNP, pulmonary vein D- and Ar-wave velocities, and atrial dimensions predicted HF in HFpEF but not HFrEF (all interaction p < 0.10). Prediction of HF readmission was not different in HFpEF and HFrEF (p = 0.93). Conclusions In this single-center echocardiographic study linked to Medicare claims, left ventricular dimensions and eccentric hypertrophy predicted HF readmission in HFrEF but not HFpEF and left ventricular wall thickness predicted HF readmission in HFpEF but not HFrEF. Regardless of LVEF, diastolic variables augmented prediction of HF readmission compared to echocardiographic structural variables, demographics, and comorbidities alone. The additional role of medication adherence, readmission history, and functional status in differential prediction of HF readmission by LVEF category should be considered for future study.

Cardio-protective effects of sodium-glucose co-transporter 2 inhibitors: focus on heart failure

2020 ◽  
Vol 26 ◽  
Author(s):  
Dimos Karangelis ◽  
C. David Mazer ◽  
Dimitrios Stakos ◽  
Aphrodite Tzifa ◽  
Spiros Loggos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Large Scale ◽  
Mechanisms Of Action ◽  
Sglt2 Inhibitors ◽  
Protective Effects ◽  
Reduced Ejection Fraction ◽  
Risk Of Death ◽  
Sodium Glucose Cotransporter ◽  
Myocardial Energetics

Background: Type 2 diabetes mellitus (DM) is associated with a considerable risk of cardiovascular and renal disease, including heart failure. Sodium–glucose cotransporter 2 (SGLT2) inhibitors have demonstrated unprecedented cardiorenal protective effects in large scale clinical trials of patients with or without diabetes and either established cardiovascular disease (CV) or multiple CV risk factors. Objective: Herein we aim to focus on the role of SGLT2 inhibitors regarding the improvement in heart failure outcomes and the proposed mechanisms of action by which these drugs confer their beneficial effect. Methods: PubMed, Embase and Google Scholar databases were searched to identify eligible articles which are comprehensively summarized and discussed. Results: The most commonly discussed mechanisms of action are diuresis and natriuresis, reduction in preload, afterload, and ventricular mass, as well as stimulation of erythropoietin production and improved myocardial energetics. SGLT2 inhibitors improve outcomes in patients with established heart failure (HF) and reduce the risk of death and HF admissions in patients with established chronic HF with reduced ejection fraction (HFrEF), either with or without diabetes. Conclusion: Potential key mechanisms that may explain the notable cardioprotective benefits of SGLT2 inhibitors have been outlined. These agents have recently received class Ia recommendation in specific groups of people with DM to lower the risk of hospitalization for HF and risk of death, while these benefits may also extend to people without diabetes. It remains to be seen whether they will also emerge as treatment approaches in the acute phase of CV episodes.

scholarly journals Effects of Apelin on Left Ventricular-Arterial Coupling and Mechanical Efficiency in Rats with Ischemic Heart Failure

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Qiufang Ouyang ◽  
Tao You ◽  
Jinjian Guo ◽  
Rong Xu ◽  
Quehui Guo ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Diastolic Pressure ◽  
Systolic Function ◽  
Mechanical Efficiency ◽  
Left Ventricular ◽  
Mesenteric Arteries ◽  
Stroke Work ◽  
Reduced Ejection Fraction ◽  
Left Ventricular Arterial Coupling

Apelin plays important roles in cardiovascular homeostasis. However, its effects on the mechanoenergetics of heart failure (HF) are unavailable. We attempted to investigate the effects of apelin on the left ventricular-arterial coupling (VAC) and mechanical efficiency in rats with HF. HF was induced in rats by the ligation of the left coronary artery. The ischemic HF rats were treated with apelin or saline for 12 weeks. The sham-operated animals served as the control. The left ventricular (LV) afterload and the systolic and diastolic functions, as well as the mechanoenergetic indices were estimated from the pressure-volume loops. Myocardial fibrosis by Masson’s trichrome staining, myocardial apoptosis by TUNEL, and collagen content in the aorta as well as media area in the aorta and the mesenteric arteries were determined. Our data indicated that HF rats manifested an increased arterial load (Ea), a declined systolic function (reduced ejection fraction, +dP/dtmax, end-systolic elastance, and stroke work), an abnormal diastolic function (elevated end-diastolic pressure, τ, and declined −dP/dtmax), and decreased mechanical efficiency. Apelin treatment improved those indices. Concomitantly, increased fibrosis in the LV myocardium and the aorta and enhanced apoptosis in the LV were partially restored by apelin treatment. A declined wall-to-lumen ratio in the mesenteric arteries of the untreated HF rats was further reduced in the apelin-treated group. We concluded that the rats with ischemic HF were characterized by deteriorated LV mechanoenergetics. Apelin improved mechanical efficiency, at least in part, due to the inhibiting cardiac fibrosis and apoptosis in the LV myocardium, reducing collagen deposition in the aorta and dilating the resistant artery.

scholarly journals Lessons learned from the DAPA-HF trial concerning the mechanisms of benefit of SGLT2 inhibitors on heart failure events in the context of other large-scale trials nearing completion

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Milton Packer
Keyword(s):  
Heart Failure ◽  
Large Scale ◽  
Cardiovascular Death ◽  
Sglt2 Inhibitors ◽  
Adverse Outcomes ◽  
Lessons Learned ◽  
Reduced Ejection Fraction ◽  
Sodium Glucose Cotransporter ◽  
Patients With Diabetes ◽  
Artery Disease

Abstract Four large-scale trials in type 2 diabetes have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors prevent the occurrence of serious heart failure events. Additionally, the DAPA-HF trial demonstrated a benefit of dapagliflozin to reduce major adverse outcomes in patients with established heart failure with a reduced ejection fraction. The trial sheds light on potential mechanisms. In DAPA-HF, the benefits of dapagliflozin on heart failure were seen to a similar extent in both patients with or without diabetes, thus undermining the hypothesis that these drugs mitigate glycemia-related cardiotoxicity. The action of SGLT2 inhibitors to promote ketogenesis is also primarily a feature of the action of these drugs in patients with diabetes, raising doubts that enhanced ketogenesis contributes to the benefit on heart failure. Also, dapagliflozin does not have a meaningful effect to decrease circulating natriuretic peptides, and it did not potentiate the actions of diuretics in DAPA-HF; moreover, intensification of diuretics therapy does not reduce cardiovascular death, questioning a benefit of SGLT2 inhibitors that is mediated by an action on renal sodium excretion. Finally, although hematocrit increases with SGLT2 inhibitors might favorably affect patients with coronary artery disease, in DAPA-HF, the benefit of dapagliflozin was similar in patients with or without an ischemic cardiomyopathy; furthermore, increases in hematocrit do not favorably affect the clinical course of patients with heart failure. Therefore, the results of DAPA-HF do not support many currently-held hypotheses about the mechanism of action of SGLT2 inhibitors in heart failure. Ongoing trials are likely to provide further insights.

Dapagliflozin in a Real-World Chronic Heart Failure Population: How Many Are Actually Eligible?

Cardiology ◽  
2021 ◽  
pp. 1-6
Author(s):  
Sérgio Maltês ◽  
Gonçalo J.L. Cunha ◽  
Bruno M.L. Rocha ◽  
João Presume ◽  
Renato Guerreiro ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Real World ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Disease Modifying Drugs ◽  
Reduced Ejection Fraction ◽  
Sodium Glucose Cotransporter ◽  
Patients With Heart Failure

<b><i>Background:</i></b> In patients with heart failure (HF) and reduced ejection fraction (HFrEF) with or without type 2 diabetes mellitus, the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin was recently shown to reduce the risk of worsening HF or death from cardiovascular causes in the dapagliflozin in patients with heart failure and reduced ejection fraction (DAPA-HF) trial. Our goal was to investigate how many patients in a real-world setting would be eligible for dapagliflozin according to the DAPA-HF enrolment criteria. <b><i>Methods:</i></b> This is a single-center retrospective study enrolling consecutive, unselected patients followed up in an HF clinic from 2013 to 2019. Key DAPA-HF inclusion criteria (i.e., left ventricular ejection fraction [LVEF] ≤40% and NT-proBNP ≥600 pg/mL [or ≥900 pg/mL if atrial fibrillation]) and exclusion criteria (estimated glomerular filtration rate [eGFR] &#x3c;30 mL/kg/1.73 m<sup>2</sup> and systolic blood pressure [SBP] &#x3c;95 mm Hg) were considered. <b><i>Results:</i></b> Overall, 479 patients (age 76 ± 13 years; 50.5% male; 78.9% hypertensive; 45.1% with an eGFR &#x3c;60 mL/min/1.73 m<sup>2</sup>; 36.5% with TD2M; and 33.5% with ischaemic HF) were assessed. The median SBP was 128.5 (112.0–146.0) mm Hg, mean eGFR was 50.8 ± 23.7 mL/min/1.73 m<sup>2</sup>, and median NT-proBNP was 2,183 (IQR 1,010–5,310) pg/mL. Overall, 155 (32.4%) patients had LVEF ≤40%. According to the DAPA-HF trial key criteria, 90 patients (18.8%) would be eligible for dapagliflozin. The remainder would be excluded due to LVEF &#x3e;40% (67.6%), eGFR &#x3c;30 mL/min/1.73 m<sup>2</sup> (19.4%), NT-proBNP below the cutoff (16.7%), and/or SBP &#x3c;95 mm Hg (6.5%). If we center the analysis to those with LVEF ≤40%, 58.1% would be eligible for dapagliflozin. The remainder would be excluded due to an eGFR &#x3c;30 mL/min/1.73 m<sup>2</sup> (20%), NT-proBNP below the cutoff (16.1%), and/or SBP &#x3c;95 mm Hg (8.4%). <b><i>Conclusion:</i></b> Roughly half of our real-world HFrEF cohort would be eligible for dapagliflozin according to the key criteria of the DAPA-HF trial. The main reason for non-eligibility was an eGFR &#x3c;30 mL/min/1.73 m<sup>2</sup>. However, two-thirds of patients had LVEF &#x3e;40%. These findings show that dapagliflozin is a promising complementary new drug in the therapeutic armamentarium of most patients with HFrEF, while highlighting the urgent need for disease-modifying drugs in mid-range and preserved LVEF and the need to assess the efficacy and safety of SLGT2i in advanced kidney disease patients. The results of ongoing SGLT2i trials in these LVEF subgroups are eagerly awaited.

scholarly journals Treatment of Heart Failure with Mid-Range Ejection Fraction: What Is the Evidence

2021 ◽  
Vol 10 (2) ◽  
pp. 203
Author(s):  
Eleni-Evangelia Koufou ◽  
Angelos Arfaras-Melainis ◽  
Sahil Rawal ◽  
Andreas P. Kalogeropoulos
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Current Knowledge ◽  
Systolic Function ◽  
Angiotensin Receptor Blockers ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Current Evidence ◽  
Converting Enzyme Inhibitors ◽  
Reduced Ejection Fraction

In this review, we briefly outline our current knowledge on the epidemiology, outcomes, and pathophysiology of heart failure (HF) with mid-range ejection fraction (HFmrEF), and discuss in more depth the evidence on current treatment options for this group of patients. In most studies, the clinical background of patients with HFmrEF is intermediate between that of patients with HF and reduced ejection fraction (HFrEF) and patients with HF and preserved ejection fraction (HFpEF) in terms of demographics and comorbid conditions. However, the current evidence, stemming from observational studies and post hoc analyses of randomized controlled trials, suggests that patients with HFmrEF benefit from medications that target the neurohormonal axes, a pathophysiological behavior that resembles that of HFrEF. Use of β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and sacubitril/valsartan is reasonable in patients with HFmrEF, whereas evidence is currently scarce for other therapies. In clinical practice, patients with HFmrEF are treated more like HFrEF patients, potentially because of history of systolic dysfunction that has partially recovered. Assessment of left ventricular systolic function with contemporary noninvasive modalities, e.g., echocardiographic strain imaging, is promising for the selection of patients with HFmrEF who will benefit from neurohormonal antagonists and other HFrEF-targeted therapies.

scholarly journals Nine contemporary therapeutic directions in heart failure

Heart Asia ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. e011150 ◽  
Author(s):  
Zaid Almarzooq ◽  
Manan Pareek ◽  
Lauren Sinnenberg ◽  
Muthiah Vaduganathan ◽  
Mandeep R. Mehra
Keyword(s):  
Heart Failure ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Scientific Progress ◽  
Left Ventricular ◽  
Ventricular Assist Devices ◽  
Left Ventricular Assist Devices ◽  
Ventricular Assist ◽  
Reduced Ejection Fraction ◽  
Sodium Glucose Cotransporter

The global burden of heart failure has continued to increase dramatically with 26 million people affected and an estimated health expenditure of $31 billion worldwide. Several practice-influencing studies were reported recently, bringing advances along many frontiers in heart failure, particularly heart failure with reduced ejection fraction. In this article, we discuss nine distinct therapeutic areas that were significantly influenced by this scientific progress. These distinct areas include the emergence of sodium-glucose cotransporter-2 inhibitors, broadening the application of angiotensin-neprilysin inhibition, clinical considerations in therapy withdrawal in those patients with heart failure that ‘recover’ myocardial function, benefits of low-dose direct oral anticoagulants in sinus rhythm, targeted therapy for treating cardiac amyloidosis, usefulness of mitral valve repair in heart failure, the advent of newer left ventricular assist devices for advanced heart failure, the role of ablation in atrial fibrillation in heart failure, and finally the use of wearable defibrillators to address sudden death.

scholarly journals P791 Left atrial stiffness as a predictor of cardiac events in patients with heart failure and reduced ejection fraction: the impact of diabetes

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
I Bytyci ◽  
N R Pugliese ◽  
A Bajraktari ◽  
M Mazzola ◽  
G Bajraktari ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Left Atrial ◽  
Ventricular Remodeling ◽  
Systolic Function ◽  
Left Ventricular ◽  
Diabetic Patients ◽  
Reduced Ejection Fraction ◽  
Patients With Heart Failure ◽  
The Impact

Abstract Background and Aim Diabetes mellitus (DM) affects left ventricular remodeling in patients with heart failure (HF), but its effect on left atrial (LA) remodeling and their combined effect on survival and other clinical events (CE) remain to be elucidated. We evaluated in this study the relationship between DM and left atrial (LA) remodeling in a group of HF patients with reduced ejection fraction (HFrEF), Methods This studied 136 consecutive HFrEF patients (65 ± 11 years), 36 diabetics, using conventional and tissue Doppler echocardiography. LA dimension and function were measured and cavity stiffness was calculated with the formula: LA stiffness = E/e’ratio/LA strain. Results The age, gender, LV end-systolic dimension, LV end-diastolic dimension, LV EF and BNP level did not differ between diabetic and non-diabetic patients. Diabetic patients with HFrEF had higher NYHA functional class (p = 0.02), reduced right ventricle (RV) systolic function (p = 0.01) and increased LA stiffness (p = 0.02) . At follow up of 55 ± 37 months, survival free from CE was 69% in non-diabetics compared with 44.4% in diabetics (X2 12.7; p&lt; 0.0001). The CE free survival was lower in patients with increased LA stiffnes, irrespective of the presence of DM: 1) Patients with HFrEF without DM and normal LA stiffness (85%); 2) Patients with HFrEF without DM and with increased LA stiffness (50%); 3) Patients with HFrEF with DM and with normal LA stiffness (71%) and patients with HFrEF with DM and with increased LA stiffness (27%) (X2 29.6; p&lt; 0.0001, Figure 1). Conclusion Compromised LA stiffness as surrogate of LA remodeling is associated with poor outcome in patients with heart failure and reduced EF. The presence of diabetes in patients with HFrEF and increased LA stiffness has incremental prognostic value. Abstract P791 Figure.

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