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Sodium-glucose cotransporter-2 inhibitors have been shown to have significant metabolic, renal, and atherosclerotic cardiovascular disease benefits. Recent randomized controlled trials have extended these benefits to patients with heart failure. In fact, the robust findings from these studies in patients with any type of heart failure have led to the incorporation of this drug class in currently updated evidence-based guidelines for this condition. However, given the novelty in utilizing these agents in heart failure, there is uncertainty regarding place in therapy and sequencing in treatment. As such, this review aims to summarize existing literature to guide practitioners regarding the use of these agents in the management of heart failure. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) and atrial flutter (AFL) are associated with adverse outcomes in patients with heart failure and reduced ejection fraction (HFrEF). We investigated the effects of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on the incidence of AF and/or AFL in HFrEF patients. PubMed and ClinicalTrials.gov were systematically searched until March 2022 for randomized controlled trials (RCTs) that enrolled patients with HFrEF. A total of six RCTs with 9467 patients were included (N = 4731 in the SGLT2i arms; N = 4736 in the placebo arms). Compared to placebo, SGLT2i treatment was associated with a significant reduction in the risk of AF [relative risk (RR) 0.62, 95% confidence interval CI 0.44–0.86; P = 0.005] and AF/AFL (RR 0.64, 95% CI 0.47–0.87; P = 0.004). Subgroup analysis showed that empagliflozin use resulted in a significant reduction in the risk of AF (RR 0.55, 95% CI 0.34–0.89; P = 0.01) and AF/AFL (RR 0.50, 95% CI 0.32–0.77; P = 0.002). By contrast, dapagliflozin use was not associated with a significant reduction in the risk of AF (RR 0.69, 95% CI 0.43–1.11; P = 0.12) or AF/AFL (RR 0.82, 95% CI 0.53–1.27; P = 0.38). Additionally, a "shorter" duration (< 1.5 years) of treatment with SGLT2i remained associated with a reduction in the risk of AF (< 1.5 years; RR 0.58, 95% CI 0.36–0.91; P = 0.02) and AF/AFL (< 1.5 years; RR 0.52, 95% CI 0.34–0.80; P = 0.003). In conclusion, SGLT2i therapy was associated with a significant reduction in the risk of AF and AF/AFL in patients with HFrEF. These results reinforce the value of using SGLT2i in this setting. [ABSTRACT FROM AUTHOR]

SGLT2 inhibitors reduce cardiovascular death or hospitalization for heart failure, regardless of the presence or absence of diabetes in patients at high cardiovascular risk and in those with heart failure and reduced ejection fraction (HFrEF). In patients with HF and preserved EF, empagliflozin also showed favorable effects mainly related to the reduction of hospitalization for heart failure. These favorable effects are beyond the reduction of glycemic levels and mainly related to beneficial hemodynamic and anti-inflammatory effects of these drugs and improved cardiac energy metabolism. In this review, we aimed to evaluate the effects of SGLT2 inhibitor on cardiac remodeling and function, which is still incompletely clear. [ABSTRACT FROM AUTHOR]

This review summarizes and describes the current evidence addressing how sodium-glucose cotransporter 2 (SGLT2) inhibitors alter the function of sodium-hydrogen exchanger 1 (NHE-1), in association with their protective effects against adverse cardiovascular events. In the heart, SGLT2 inhibitors modulate the function of NHE-1 (either by direct inhibition or indirect attenuation of protein expression), which promotes cardiac contraction and an enhanced energy supply, in association with improved mitochondrial function, reduced inflammation/oxidative/endoplasmic reticulum stress, and attenuated fibrosis and apoptotic/autophagic cell death. The vasodilating effect of SGLT2 inhibitors has also been proposed due to NHE-1 inhibition. Moreover, platelet-expressed NHE-1 might serve as a target for SGLT2 inhibitors, since these drugs and selective NHE-1 inhibitors produce comparable activity against adenosine diphosphate-stimulated platelet activation. Overall, it is promising that the modulation of the functions of NHE-1 on the heart, blood vessels, and platelets may act as a contributing pathway for the cardiovascular benefits of SGLT2 inhibitors in diabetes and heart failure. [ABSTRACT FROM AUTHOR]

After initial strategies targeting inotropism and congestion, the neurohormonal interpretative model of heart failure (HF) pathophysiology has set the basis for current pharmacological management of HF, as most of guideline recommended drug classes, including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists, blunt the activation of detrimental neurohormonal axes, namely sympathetic and renin–angiotensin–aldosterone (RAAS) systems. More recently, sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor, combining inhibition of RAAS and potentiation of the counter-regulatory natriuretic peptide system, has been consistently demonstrated to reduce mortality and HF-related hospitalization. A number of novel pharmacological approaches have been tested during the latest years, leading to mixed results. Among them, drugs acting directly at a second messenger level, such as the soluble guanylate cyclase stimulator vericiguat, or other addressing myocardial energetics and mitochondrial function, such as elamipretide or omecamtiv-mecarbil, will likely change the therapeutic management of patients with HF. Sodium glucose cotransporter 2 inhibitors, initially designed for the management of type 2 diabetes mellitus, have been recently demonstrated to improve outcome in HF, although mechanisms of their action on cardiovascular system are yet to be elucidated. Most of these emerging approaches have shifted the therapeutic target from neurohormonal systems to the heart, by improving cardiac contractility, metabolism, fibrosis, inflammation, and remodeling. In the present paper, we review from a pathophysiological perspective current and novel therapeutic strategies in chronic HF. [ABSTRACT FROM AUTHOR]

New antidiabetic therapy that includes sodium-glucose co-transporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor (GLP-1R) agonists, and dipeptidyl peptidase 4 (DPP-4) inhibitors showed significant benefit on cardiovascular outcomes in patients with and without type 2 diabetes mellitus, and this was particularly confirmed for SGLT2 inhibitors in subjects with heart failure (HF) with reduced ejection fraction (HFrEF). Their role on patients with HF with preserved ejection fraction (HFpEF) is still not elucidated, but encouraging results coming from the clinical studies indicate their beneficial role. The role of GLP-1R agonists and particularly DPP-4 inhibitors is less clear and debatable. Findings from the meta-analyses are sending positive message about the use of GLP-1R agonists in HFrEF therapy and revealed the improvement of left ventricular (LV) diastolic function in HFpEF. Nevertheless, the relevant medical societies still consider their effect as neutral or insufficiently investigated in HF patients. The impact of DPP-4 inhibitors in HF is the most controversial due to conflicting data that range from negative impact and increased risk of hospitalization due to HF, throughout neutral effect, to beneficial influence on LV diastolic dysfunction. However, this is a very heterogeneous group of medications and some professional societies made clear discrepancy between saxagliptin that might increase risk of HF hospitalization and those DPP-4 inhibitors that have no effect on hospitalization. The aim of this review is to summarize current clinical evidence about the effect of new antidiabetic medications on LV diastolic function and their potential benefits in HFpEF patients. [ABSTRACT FROM AUTHOR]

Heart failure (HF) often coexists with insulin resistance (IR), and the incidence of HF in type 2 diabetes mellitus (T2DM) patients is significantly higher. The reciprocal relationship between HF and IR has long been recognized, and the integration complicates the therapy of both. A number of mechanisms ascribe to the progression of cardiac IR, in which the main factors are the shift of myocardial substrate metabolism. Studies have found that SGLT2 inhibitors, an anti-diabetic drug, can improve the cardiac prognosis of patients with T2DM, which may be at least partially due to the relief of cardiac IR. Basic and clinical studies have revealed the important role of cardiac IR in the pathogenesis and progression of HF, and studies suggest that energy metabolism plays an important role in the pathogenesis of cardiac IR and HF. SGLT2 inhibitors mediated cardiovascular benefits through various mechanisms such as improving substrate utilization and improving myocardial energy. The regulation of SGLT2 inhibitors on cardiac energy status including carbohydrates, fatty acids (FA), amino acids and ketones, ATP transfer to the cytoplasm, and mitochondrial functional status have received extensive attention in HF, but its specific mechanism of action is still unclear. Therefore, this article reviews the relationship between IR and HF from the perspective of energy metabolism; subsequently, targeting energy metabolism discusses the pivotal role of SGLT2 inhibitors in improving cardiac IR and HF based on basic and clinical research evidences, and sought to clarify the molecular mechanism involved. (Fig. 1). [ABSTRACT FROM AUTHOR]

This paper highlights the cardioprotective potential of sodium-glucose cotransporter 2 inhibitors (SLGT2i), as well as several most discussed mechanisms responsible for their cardioprotection. Cardiovascular diseases are considered a primary cause of death in nearly 80% of type 2 diabetes mellitus (T2DM) patients, with a 2–4-fold greater incidence of heart failure (HF) among diabetics. As novel hypoglycemics, SGLT2i showed exceptional cardiovascular benefits, reflected through robust reductions of cardiovascular mortality and hospitalization for HF in T2DM patients. Recently, those effects have been reported even in patients with HF and reduced ejection fraction irrespectively of diabetic status, suggesting that cardioprotective effects of SGLT2i are driven independently of their hypoglycemic actions. SGLT2i exerted hemodynamic and metabolic effects, partially driven by natriuresis and osmotic diuresis. However, those systemic effects are modest, and therefore cannot be completely related to the cardiac benefits of these agents in T2DM patients. Hence, increased circulating ketone levels during SGLT2i administration have brought out another hypothesis of a cardiac metabolic switch. Moreover, SGLT2i influence ion homeostasis and exert anti-inflammatory and antifibrotic effects. Their enviable influence on oxidative stress markers, as well as anti- and pro-apoptotic factors, have also been reported. However, since the main mechanistical contributor of their cardioprotection has not been elucidated yet, a joint action of systemic and molecular mechanisms has been suggested. In the light of ongoing trials evaluating the effects of SGLT2i in patients with HF and preserved ejection fraction, a new chapter of beneficial SGLT2i mechanisms is expected, which might resolve their main underlying action. [ABSTRACT FROM AUTHOR]

Modestly elevated circulating levels of the ketone β-hydroxybutyrate (βOHB) during treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors cause different beneficial effects on organs and cells, depending on the succinyl-CoA:3-ketoacid CoA transferase (SCOT) level. In the failing heart, SCOT is highly expressed/up-regulated, and thus, βOHB may be an energy source, in addition to fat and glucose oxidation. However, SCOT is not highly expressed/down-regulated in the kidney, and thus, βOHB may cause different beneficial effects, rather than acting as an alternative energy source in patients with chronic kidney disease (CKD). βOHB is an endogenous and specific inhibitor of class I histone deacetylases (HDACs) and the NLRP3 inflammasome, accumulates in the kidney because of its decreased utilization as an energy source due to the down-regulation of SCOT, and may induce beneficial effects such as inhibiting inflammation, oxidative stress, and fibrosis. In addition to restoring tubulo-glomerular feedback and improving renal proximal tubule oxygenation, SGLT2 inhibitors may play a renoprotective role by way of βOHB in patients with CKD. [ABSTRACT FROM AUTHOR]

Initially developed as glucose-lowering drugs, sodium-glucose co-transporter type 2 inhibitors (SGLT2i) have demonstrated to be effective agents for the risk reduction of cardiovascular (CV) events in patients with type 2 diabetes mellitus (T2DM). Subsequently, data has emerged showing a significant CV benefit in patients treated with SGLT2i regardless of diabetes status. Renal protection has been initially evaluated in CV randomized trials only as secondary endpoints; nonetheless, the positive results gained have rapidly led to the evaluation of nephroprotection as primary outcome in the CREDENCE trial. Different renal and vascular mechanisms can account for the CV and renal benefits enlightened in recent literature. As clinical guidelines rapidly evolve and the role of SGLT2i appears to become pivotal for CV, T2DM, and kidney disease management, in this review, we analyze the renal effects of SGLT2, the benefits derived from its inhibition, and how this may result in the multiple CV and renal benefits evidenced in recent clinical trials. [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a class of drugs that promote urinary glucose excretion in the treatment of diabetes, have provoked large interest of scientific and professional community due to their positive and, somehow, unexpected results in the three major cardiovascular outcome trials (EMPA-REG OUTCOME trial with empagliflozin, CANVAS Program with canagliflozin, and DECLARE-TIMI 58 with dapagliflozin). In fact, along with the reduction of major adverse cardiovascular events, SGLT2 inhibitors reduced significantly hospitalization for heart failure regardless of existing atherosclerotic cardiovascular disease or a history of heart failure. The latter have reminded us of the frequent but neglected entity of diabetic cardiomyopathy which is currently poorly understood despite its great clinical importance. Physiological mechanisms responsible for the benefits of SGLT2 inhibitors are complex and multifactorial and still not well defined. Interestingly, the time frame of their effect excludes a glucose- and antiatherosclerotic-mediated effect. It would be of great importance to better understand SGLT2 inhibitor mechanisms of action since they could have a potential to be used in early stages of diabetes as cardioprotective agents. There are widely available biomarkers as well as echocardiography that are used in everyday clinical practice and could elucidate physiological mechanisms in the heart protection with SGLT2 inhibitors treatment but studies are still lacking. The purpose of this minireview is to summarize the latest concepts about SGLT2 inhibitors and its benefits regarding diabetic cardiomyopathy especially on its early stage development and to discuss controversies and potential future developments in the field. [ABSTRACT FROM AUTHOR]

Patients with type 2 diabetes mellitus (DM) are at a substantially increased risk of heart failure (HF) and HF mortality. Despite the lack of evidence that tight glycemic control reduces the incidence of cardiovascular (CV) events, a growing body of evidence suggests that the choice of glucose-lowering agents may influence outcomes including HF. Thiazolidinediones are associated with a significant risk of HF. For metformin, sulphonylureas and insulin, little data is available to indicate the impact on HF. The glucagon-like peptide-1 (GLP-1) agonists, liraglutide and semaglutide, have been shown to reduce major CV events, but did not affect rates of hospitalization for HF. Clinical trials have demonstrated diverse effects of Dipeptidyl peptidase-4 (DPP-4) inhibitors on HF; saxagliptin showed an increased risk of HF admissions, alogliptin was associated with higher rates of new HF admissions, while sitagliptin had a neutral effect. The sodium-glucose cotransporter 2 (SGLT2) inhibitors, empagliflozin and canagliflozin, have been recently shown to reduce the incidence of HF and cardiovascular mortality in patients with and without a history of HF. This review will summarize key findings of the impact of glucose-lowering agents on CV safety and HF-associated outcomes, present available data on the underlying mechanisms for the benefits of the SGLT2 inhibitors on HF, and discuss strategies to improve outcomes in patients with DM and high CV risk. [ABSTRACT FROM AUTHOR]

The pathogenesis of diabetes mellitus (DM)-related cardiac dysfunction is thought to be multifactorial, and possibly a key factor for the development of heart failure with preserved ejection fraction (HFpEF) in patients with DM and preserved left ventricular (LV) ejection fraction. Currently, there is no effective treatment for HFpEF, which is presented as LV diastolic dysfunction. Furthermore, it is well known that, in addition to DM, hypertension and overweight/obesity are also important factors associated with HFpEF. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of diabetic medications indicated only for the treatment of type 2 DM, and a recent clinical trial showed that patients with this disease and at high risk for cardiovascular events attained cardiovascular benefits from SGLT2 inhibitor in comparison with placebo efficacy. In addition to reduction of glycated hemoglobin levels in patients with type 2 DM, SGLT2 inhibitors are associated with weight loss and reductions in blood pressure. However, despite such intriguing results, it remains uncertain whether SGLT2 inhibitors are beneficial for LV diastolic function in patients with DM. This review deals with the impact of SGLT2 inhibitors on LV diastolic function in patients with DM and their current potential for prevention of the future development of HFpEF in such patients. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a major risk factor for several cardiovascular (CV) conditions, including heart failure (HF). However, until recently, no therapy to treat patients with diabetes could also reduce CV risks related to HF. The EMPA-REG OUTCOME trial with empagliflozin was the first to demonstrate significant cardioprotective benefits in this population. Its impressive 35% reduction in hospitalizations for HF drew the attention of the scientific community to the possibility that pharmacologic sodium-glucose cotransporter 2 (SGLT2) inhibition could be part of the armamentarium for treating patients with HF, with and without diabetes. The recently published CANVAS Program (with canagliflozin) and real-life data from the CVD-Real Study (using dapagliflozin, empagliflozin, and canagliflozin) further strengthened this hypothesis, suggesting that the observed benefit is not restricted to a particular drug, but is rather a class effect. This review explores the effects of pharmacologic SGLT2 inhibitors' use in cardiac function and discusses the potential role of this class of medication as a treatment for HF. [ABSTRACT FROM AUTHOR]

Diabetes is a global epidemic and a leading cause of death with more than 422 million patients worldwide out of whom around 392 million alone suffer from type 2 diabetes (T2D). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are novel and effective drugs in managing glycemia of T2D patients. These inhibitors gained recent clinical and basic research attention due to their clinically observed cardiovascular protective effects. Although interest in the study of various SGLT isoforms and the effect of their inhibition on cardiovascular function extends over the past 20 years, an explanation of the effects observed clinically based on available experimental data is not forthcoming. The remarkable reduction in cardiovascular (CV) mortality (38%), major CV events (14%), hospitalization for heart failure (35%), and death from any cause (32%) observed over a period of 2.6 years in patients with T2D and high CV risk in the EMPA-REG OUTCOME trial involving the SGLT2 inhibitor empagliflozin (Empa) have raised the possibility that potential novel, more specific mechanisms of SGLT2 inhibition synergize with the known modest systemic improvements, such as glycemic, body weight, diuresis, and blood pressure control. Multiple studies investigated the direct impact of SGLT2i on the cardiovascular system with limited findings and the pathophysiological role of SGLTs in the heart. The direct impact of SGLT2i on cardiac homeostasis remains controversial, especially that SGLT1 isoform is the only form expressed in the capillaries and myocardium of human and rodent hearts. The direct impact of SGLT2i on the cardiovascular system along with potential lines of future research is summarized in this review. [ABSTRACT FROM AUTHOR]