Effects of dapagliflozin on human epicardial adipose tissue: modulation of insulin resistance, inflammatory chemokine production, and differentiation ability

Díaz‐Rodriguez, Esther; Agra, Rosa M.; Teijeira-Fernández, Elvis; Adrio, Belén; García‐Caballero, Tomás; González-Juanatey, José Ramón; Eiras, Sonia

doi:10.1093/cvr/cvx186

Cited by 138 publications

(93 citation statements)

References 48 publications

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“…Treatment with SGLT2 inhibitors is poised to ameliorate many of the pathophysiological abnormalities seen in HFpEF. 14 In clinical trials, the use of SGLT2 inhibitors has been shown to reduce the quantity of epicardial adipose tissue (independently of effect on body weight), [35][36][37] and these drugs ameliorate the inflammation of adipose tissue surrounding the heart and great vessels 38,39 and the associated abnormalities of cardiac filling and aortic distensibility in both experimental and clinical HFpEF. 18,[40][41][42] Furthermore, SGLT2 inhibitors act to inhibit sodium reabsorption in the proximal renal tubules, in which the majority of renal sodium retention occurs [43][44][45] ; this action explains the marked reduction in plasma and/or interstitial volume and haemoconcentration seen in randomized controlled trials in type 2 diabetes.…”

Section: Sample Size Calculations and Study Conductmentioning

confidence: 99%

Evaluation of the effects of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR‐Preserved Trial

Anker

Butler

Filippatos

et al. 2019

European J of Heart Fail

200

169

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Background The principal biological processes that characterize heart failure with a preserved ejection fraction (HFpEF) are systemic inflammation, epicardial adipose tissue accumulation, coronary microcirculatory rarefaction, myocardial fibrosis and vascular stiffness; the resulting impairment of left ventricular and aortic distensibility (especially when accompanied by impaired glomerular function and sodium retention) causes increases in cardiac filling pressures and exertional dyspnoea despite the relative preservation of left ventricular ejection fraction. Independently of their actions on blood glucose, sodium–glucose co‐transporter 2 (SGLT2) inhibitors exert a broad range of biological effects (including actions to inhibit cardiac inflammation and fibrosis, antagonize sodium retention and improve glomerular function) that can ameliorate the pathophysiological derangements in HFpEF. Such SGLT2 inhibitors exert favourable effects in experimental models of HFpEF and have been found in large‐scale trials to reduce the risk for serious heart failure events in patients with type 2 diabetes, many of whom were retrospectively identified as having HFpEF. Study design The EMPEROR‐Preserved Trial is enrolling ≈5750 patients with HFpEF (ejection fraction >40%), with and without type 2 diabetes, who are randomized to receive placebo or empagliflozin 10 mg/day, which is added to all appropriate treatments for HFpEF and co‐morbidities. Study aims The primary endpoint is the time‐to‐first‐event analysis of the combined risk for cardiovascular death or hospitalization for heart failure. The trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all‐cause mortality and recurrent hospitalization events, and will assess a wide range of biomarkers that reflect important pathophysiological mechanisms that may drive the evolution of HFpEF. The EMPEROR‐Preserved Trial is well positioned to determine if empagliflozin can have a meaningful impact on the course of HFpEF, a disorder for which there are currently few therapeutic options.

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Section: Sample Size Calculations and Study Conductmentioning

confidence: 99%

Evaluation of the effects of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR‐Preserved Trial

Anker

Butler

Filippatos

et al. 2019

European J of Heart Fail

200

169

View full text Add to dashboard Cite

show abstract

“…[161][162][163][164] Newer glucose-lowering drugs have been evaluated in large-scale trials, but, in most cases, these investigations did not systematically identify AF events and hence the number of captured AF events was too small to allow for meaningful analysis. 165 Nevertheless, it is noteworthy that the risk for AF appears to be numerically reduced by sodium-glucose cotransporter 2 inhibitors, 166 which are known to reduce the mass and inflammation of epicardial adipose tissue [167][168][169][170] and which have been shown to decrease the incidence of HF events, including those caused by HFpEF. 4…”

Section: Metformin and Sodium-glucose Cotransporter 2 Inhibitorsmentioning

confidence: 99%

Do most patients with obesity or type 2 diabetes, and atrial fibrillation, also have undiagnosed heart failure? A critical conceptual framework for understanding mechanisms and improving diagnosis and treatment

Packer

2019

European J of Heart Fail

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Obesity and diabetes can lead to heart failure with preserved ejection fraction (HFpEF), potentially because they both cause expansion and inflammation of epicardial adipose tissue and thus lead to microvascular dysfunction and fibrosis of the underlying left ventricle. The same process also causes an atrial myopathy, which is clinically evident as atrial fibrillation (AF); thus, AF may be the first manifestation of HFpEF. Many patients with apparently isolated AF have latent HFpEF or subsequently develop HFpEF. Most patients with obesity or diabetes who have AF and exercise intolerance have increased left atrial pressures at rest or during exercise, even in the absence of diagnosed HFpEF. Among patients with AF, those who also have latent HFpEF have increased risk for systemic thromboembolism and death. The identification of HFpEF in patients with obesity or diabetes alters the risk‐to‐benefit relationship of commonly prescribed treatments. Bariatric surgery and statins can ameliorate AF and reduce the risk for HFpEF. Conversely, antihyperglycaemic drugs that promote adipogenesis or cause sodium retention (insulin and thiazolidinediones) may increase the risk for heart failure in patients with an underlying ventricular myopathy. Patients with obesity and diabetes who undergo catheter ablation for AF are at increased risk for AF recurrence and for post‐ablation increases in pulmonary venous pressures and worsening heart failure, especially if HFpEF coexists. Therefore, AF may be the earliest indicator of HFpEF in patients with obesity or type 2 diabetes, and recognition of HFpEF alters the management of these patients.

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“…The decreased toxicity of glucose to endothelial cells may be a potential mechanism in preventing diabetic ApoE-/-mice atherosclerosis [27]. And dapagli ozin could improve the differentiation of epicardial adipose tissue and perivascular adipose tissue [28]. In addition, SGLT2 inhibitor could enhance lipoprotein clearance through heparan sulfate proteoglycans (HSPG) and bile acid pathways [14], which could protect from atherosclerosis progression.…”

Section: Discussionmentioning

confidence: 99%

Empagliflozin Protects Atherosclerosis Progression by Modulating Lipid Profiles and Sympathetic Activity

Liu

et al. 2020

Preprint

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Background: Several large clinical trials have confirmed the cardioprotective role of Sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes. Here we investigated that empagliflozin, as an SGLT2 inhibitor, could alleviate atherosclerosis progression.Methods: ApoE-/- mice were fed on a western diet for 12 weeks to induce atherosclerosis. On the 7th week, a group of mice were treated with drinking water containing empagliflozin (10mg/kg/day) while another group was still fed on normal water. On 12th week, the whole aortas of each group were harvested. The Oil red O, HE and movat staining were performed for atherosclerotic lesion area and size. Mouse serum lipid profiles (TC, TG, LDL-C, and HDL-C), systemic inflammation level (IL-1β, IL-6 and IL-10), renin-angiotensin-aldosterone system (RAAS) and sympathetic activity (norepinephrine, and neuropeptide Y) were measured by ELISA.Results: Empagliflozin reduced the atherosclerotic lesion burden in ApoE-/- mice. Besides, empagliflozin decreased the body weight, lipid profiles, RAAS and sympathetic activity. However, the anti-inflammation effect of empagliflozin was not significantly evident. Conclusions: Empagliflozin can partly prevent atherosclerosis in ApoE-/- mice, which could be attributed to its inhibition on lipid profiles, and sympathetic activity.

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Effects of dapagliflozin on human epicardial adipose tissue: modulation of insulin resistance, inflammatory chemokine production, and differentiation ability

Cited by 138 publications

References 48 publications

Evaluation of the effects of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR‐Preserved Trial

Evaluation of the effects of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR‐Preserved Trial

Do most patients with obesity or type 2 diabetes, and atrial fibrillation, also have undiagnosed heart failure? A critical conceptual framework for understanding mechanisms and improving diagnosis and treatment

Empagliflozin Protects Atherosclerosis Progression by Modulating Lipid Profiles and Sympathetic Activity

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