Impact of empagliflozin in patients with diabetes and heart failure

Pham, David; Rocha, Natalia de Albuquerque; McGuire, Darren K.; Neeland, Ian J.

doi:10.1016/j.tcm.2016.07.008

Cited by 22 publications

(17 citation statements)

References 43 publications

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“…SGLT-2 is a sodium–glucose cotransporter exclusively expressed in the kidney. They are mostly localized in the brush border membrane of the proximal tubule epithelial cells in the S1 segment of the proximal convoluted tubule [32, 33]. SGLT-2 expression is significantly increased in diabetic humans, rats, and db/db mice [34–36].…”

Section: Discussionmentioning

confidence: 99%

Empagliflozin, a sodium glucose co-transporter-2 inhibitor, alleviates atrial remodeling and improves mitochondrial function in high-fat diet/streptozotocin-induced diabetic rats

Shao

Meng

Lee³

et al. 2019

Cardiovasc Diabetol

208

153

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BackgroundDiabetes mellitus is an important risk factor for atrial fibrillation (AF) development. Sodium–glucose co-transporter-2 (SGLT-2) inhibitors are used for the treatment of type 2 diabetes mellitus (T2DM). Their cardioprotective effects have been reported but whether they prevent AF in T2DM patients are less well-explored. We tested the hypothesis that the SGLT-2 inhibitor, empagliflozin, can prevent atrial remodeling in a diabetic rat model.MethodsHigh-fat diet and low-dose streptozotocin (STZ) treatment were used to induce T2DM. A total of 96 rats were randomized into the following four groups: (i) control (ii) T2DM, (iii) low-dose empagliflozin (10 mg/kg/day)/T2DM; and (iv) high-dose empagliflozin (30 mg/kg/day)/T2DM by the intragastric route for 8 weeks.ResultsCompared with the control group, left atrial diameter, interstitial fibrosis and the incidence of AF inducibility were significantly increased in the DM group. Moreover, atrial mitochondrial respiratory function, mitochondrial membrane potential, and mitochondrial biogenesis were impaired. Empagliflozin treatment significantly prevented the development of these abnormalities in DM rats, likely via the peroxisome proliferator-activated receptor-c coactivator 1α (PGC-1α)/nuclear respiratory factor-1 (NRF-1)/mitochondrial transcription factor A (Tfam) signaling pathway.ConclusionsEmpagliflozin can ameliorate atrial structural and electrical remodeling as well as improve mitochondrial function and mitochondrial biogenesis in T2DM, hence may be potentially used in the prevention of T2DM-related atrial fibrillation.

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Section: Discussionmentioning

confidence: 99%

Empagliflozin, a sodium glucose co-transporter-2 inhibitor, alleviates atrial remodeling and improves mitochondrial function in high-fat diet/streptozotocin-induced diabetic rats

Shao

Meng

Lee³

et al. 2019

Cardiovasc Diabetol

208

153

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“…Glucose is actively transported from the gut lumen into the gastrointestinal epithelium primarily by SGLT1, highly expressed in the brush-border membrane of enterocytes. 121, 122 In hyperglycemia and insulin resistance, glucose and fructose absorption through the intestinal mucosa increases due to higher expression of SGLT1, GLUT2 and GLUT5 and increased brush border disaccharidases, sucrase, maltase and lactase activity. 121, 122 SGLT2 is exclusively expressed in the kidney and mostly localized in the brush border membrane of proximal tubule epithelial cells in the S1 segment of the proximal convoluted tubule.…”

Section: Molecular Protein Signature In Diabetic Cardiomyopathymentioning

confidence: 99%

Diabetic Cardiomyopathy

Jia

Hill

Sowers

2018

Circulation Research

1,190

709

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Heart failure and related morbidity and mortality are increasing at an alarming rate, in large part, because of increases in aging, obesity, and diabetes mellitus. The clinical outcomes associated with heart failure are considerably worse for patients with diabetes mellitus than for those without diabetes mellitus. In people with diabetes mellitus, the presence of myocardial dysfunction in the absence of overt clinical coronary artery disease, valvular disease, and other conventional cardiovascular risk factors, such as hypertension and dyslipidemia, has led to the descriptive terminology, diabetic cardiomyopathy. The prevalence of diabetic cardiomyopathy is increasing in parallel with the increase in diabetes mellitus. Diabetic cardiomyopathy is initially characterized by myocardial fibrosis, dysfunctional remodeling, and associated diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure. Impaired cardiac insulin metabolic signaling, mitochondrial dysfunction, increases in oxidative stress, reduced nitric oxide bioavailability, elevations in advanced glycation end products and collagen-based cardiomyocyte and extracellular matrix stiffness, impaired mitochondrial and cardiomyocyte calcium handling, inflammation, renin-angiotensin-aldosterone system activation, cardiac autonomic neuropathy, endoplasmic reticulum stress, microvascular dysfunction, and a myriad of cardiac metabolic abnormalities have all been implicated in the development and progression of diabetic cardiomyopathy. Molecular mechanisms linked to the underlying pathophysiological changes include abnormalities in AMP-activated protein kinase, peroxisome proliferator-activated receptors, O-linked N-acetylglucosamine, protein kinase C, microRNA, and exosome pathways. The aim of this review is to provide a contemporary view of these instigators of diabetic cardiomyopathy, as well as mechanistically based strategies for the prevention and treatment of diabetic cardiomyopathy.

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“…An emerging area has focused on non–GLUT-mediated glucose transport through the sodium-glucose cotransporters (SGLT), especially given that empagliflozin (an SGLT2 inhibitor) decreased HF incidence in diabetic patients (68) . The mechanism of this protection is likely multifaceted, including lowering of both glucose and sodium, as well as influences on glomerular filtration and the cardiorenal axis (69) . Interestingly, SGLT1 is induced in the heart during both diabetic and ischemic cardiomyopathy (70) , and phlorizin (another SGLT inhibitor) decreased cardiac glucose uptake and directly affected tolerance of the heart to ischemia (71) .…”

Section: Contributions Of Individual Substratesmentioning

confidence: 99%

Metabolic Origins of Heart Failure

Wende

Brahma

McGinnis

et al. 2017

JACC: Basic to Translational Science

159

149

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Summary For more than half a century, metabolic perturbations have been explored in the failing myocardium, highlighting a reversion to a more fetal-like metabolic profile (characterized by depressed fatty acid oxidation and concomitant increased reliance on glucose utilization). More recently, alterations in ketone body and amino acid/protein metabolism have been described during heart failure, as well as mitochondrial dysfunction and perturbed metabolic signaling (e.g., acetylation, O-GlcNAcylation). Although numerous mechanisms are likely involved, the current review provides recent advances regarding the metabolic origins of heart failure, and their potential contribution toward contractile dysfunction of the heart.

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Impact of empagliflozin in patients with diabetes and heart failure

Cited by 22 publications

References 43 publications

Empagliflozin, a sodium glucose co-transporter-2 inhibitor, alleviates atrial remodeling and improves mitochondrial function in high-fat diet/streptozotocin-induced diabetic rats

Empagliflozin, a sodium glucose co-transporter-2 inhibitor, alleviates atrial remodeling and improves mitochondrial function in high-fat diet/streptozotocin-induced diabetic rats

Diabetic Cardiomyopathy

Metabolic Origins of Heart Failure

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