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SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 62837

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Special Issue Editor

Dr. Anastasios Lymperopoulos

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Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
Interests: cardiovascular G protein-coupled receptors (GPCRs); heart failure; autonomic control of the circulation; adrenal physiology and pharmacology; adrenergic receptors; angiotensin receptors; signal transduction; gene therapy; aldosterone pharmacology; GPCR-Kinases; arrestins; G protein signaling
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Special Issue Information

Dear Colleagues,

Originally developed for restoring euglycemia in diabetes mellitus, SGLT2 inhibitors (SGLT2i’s) are increasingly being demonstrated to exert beneficial effects in patients, extending beyond blood glucose regulation. For instance, they reduce cardiovascular disease mortality, ameliorate kidney disease progression, lower blood pressure, and confer weight loss, even in non-diabetics or in people with end-stage chronic kidney disease. Therefore, a lot of information regarding the physiological effects and pharmacological mechanisms of SGLT2i’s remains to be obtained, necessitating more research to fully grasp their therapeutic potential.

On these grounds, this Special Issue of the International Journal of Molecular Sciences is focused on studies that explore the biological and pharmacological effects of SGLT2i`s in human physiology and disease. Investigations with a solid basic/molecular research foundation and/or translational potential are of particular interest, including papers exploring novel molecular and cellular mechanisms underlying the effects of these drugs, as well as pre-clinical investigations testing novel hypotheses that advance the molecular and clinical pharmacology of SGLT2 inhibitors. Original investigations, review articles, and short communications will all be considered. Purely clinical investigations are not suitable but clinical submissions with at least some component of molecular studies are quite welcome.

Suggested disease areas/topics to be covered include (but are by no means limited to) the following:

cell biology;
signal transduction;
autonomic nervous system;
atherosclerosis/lipid disorders;
cancer;
hypertension;
cognitive dysfunction/neurodegeneration and other central nervous system (CNS) disorders;
heart failure and cardiac arrhythmias;
metabolic syndrome/diabetes mellitus;
stem cell biology/physiology;
inflammatory and/or autoimmune diseases and pain;
cardiovascular endocrinology (e.g., adrenal gland and neuronal control of the circulation);
end-organ damage and sepsis;
respiratory diseases;
kidney disorders;
vascular pathologies;
aging;
obesity/adipose tissue biology;
drug–drug interactions with other drug classes;
adverse effects and toxicology;
pharmacogenetics/pharmacogenomics;
metabolism and pharmacokinetics in humans;
effects in special populations (pediatric, geriatric, pregnancy, etc.);
sex differences in drug action/response;
cellular energetics/mitochondria;
nuclear biology/DNA damage;
oxidative stress.

Dr. Anastasios Lymperopoulos
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

diabetes
glucose reduction
metabolic disorders
heart failure
cardiovascular disease
signal transduction
kidney disease
hypertension
obesity
adverse effects
neurodegeneration
inflammation

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Published Papers (14 papers)

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Editorial

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4 pages, 663 KiB

Open AccessEditorial

Editorial to the IJMS Special Issue on Sglt2 Inhibitors Vol. 1

by Anastasios Lymperopoulos

Int. J. Mol. Sci. 2023, 24(8), 6873; https://doi.org/10.3390/ijms24086873 - 7 Apr 2023

Viewed by 1372

Abstract

The goal of this Special Issue is to highlight the ever-increasing progress in pharmacological research on sodium-glucose co-transporter (SGLT) type 2 (SGLT2) inhibitors or gliflozins [...] Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control)

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Research

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15 pages, 46634 KiB

Open AccessArticle

Empagliflozin Ameliorates Free Fatty Acid Induced-Lipotoxicity in Renal Proximal Tubular Cells via the PPARγ/CD36 Pathway in Obese Mice

by Chiang-Chi Huang, Chia-An Chou, Wei-Yu Chen, Jenq-Lin Yang, Wen-Chin Lee, Jin-Bor Chen, Chien-Te Lee and Lung-Chih Li

Int. J. Mol. Sci. 2021, 22(22), 12408; https://doi.org/10.3390/ijms222212408 - 17 Nov 2021

Cited by 31 | Viewed by 4698

Abstract

High serum levels of free fatty acids (FFAs) could contribute to obesity-induced nephropathy. CD36, a class B scavenger receptor, is a major receptor mediating FFA uptake in renal proximal tubular cells. Empagliflozin, a new anti-diabetic agent, is a specific inhibitor of sodium-glucose co-transporter 2 channels presented on renal proximal tubular cells and inhibits glucose reabsorption. In addition, empagliflozin has shown renoprotective effects. However, the mechanism through which empagliflozin regulates CD36 expression and attenuates FFA-induced lipotoxicity remains unclear. Herein, we aimed to elucidate the crosstalk between empagliflozin and CD36 in FFA-induced renal injury. C57BL/6 mice fed a high-fat diet (HFD) and palmitic acid-treated HK-2 renal tubular cells were used for in vivo and in vitro assessments. Empagliflozin attenuated HFD-induced body weight gain, insulin resistance, and inflammation in mice. In HFD-fed mice, CD36 was upregulated in the tubular area of the kidney, whereas empagliflozin attenuated CD36 expression. Furthermore, empagliflozin downregulated the expression of peroxisome proliferator-activated receptor (PPAR)-γ. Treatment with a PPARγ inhibitor (GW9662) did not further decrease PPARγ expression, whereas a PPARγ antagonist reversed this effect; this suggested that empagliflozin may, at least partly, decrease CD36 by modulating PPARγ. In conclusion, empagliflozin can ameliorate FFA-induced renal tubular injury via the PPARγ/CD36 pathway. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control)

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11 pages, 4267 KiB

Open AccessArticle

Luseogliflozin, a SGLT2 Inhibitor, Does Not Affect Glucose Uptake Kinetics in Renal Proximal Tubules of Live Mice

by Anqi Zhang, Daisuke Nakano, Wararat Kittikulsuth, Yuka Yamashita and Akira Nishiyama

Int. J. Mol. Sci. 2021, 22(15), 8169; https://doi.org/10.3390/ijms22158169 - 29 Jul 2021

Cited by 3 | Viewed by 2828

Abstract

Proximal tubules (PTs) take up most of the glucose in the glomerular filtrate and return it to peritubular capillary blood. Sodium-glucose cotransporter 2 (SGLT2) at the apical membrane takes up glucose into the cell. Glucose then flows across the cells and is transported to the interstitium via glucose transporter 2 (GLUT2) at the basolateral membrane. However, glucose transport under SGLT2 inhibition remains poorly understood. In this study, we evaluated the dynamics of a fluorescent glucose analog, 2-NBDG, in the PTs of live mice treated with or without the SGLT2 inhibitor, luseogliflozin. We employed real-time multiphoton microscopy, in which insulin enhanced 2-NBDG uptake in skeletal muscle. Influx and efflux of 2-NBDG in PT cells were compared under hypo-, normo-, and hyperglycemic conditions. Luseogliflozin did not exert significant effects on glucose influx parameters under any level of blood glucose. Our results suggest that blood glucose level per se does not alter glucose influx or efflux kinetics in PTs. In conclusion, neither SGLT2 inhibition nor blood glucose level affect glucose uptake kinetics in PTs. The former was because of glucose influx through basolateral GLUT2, which is an established bidirectional transporter. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control)

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21 pages, 4883 KiB

Open AccessArticle

The Sodium-Glucose Cotransporter-2 Inhibitor Canagliflozin Alleviates Endothelial Dysfunction Following In Vitro Vascular Ischemia/Reperfusion Injury in Rats

by Sevil Korkmaz-Icöz, Cenk Kocer, Alex A. Sayour, Patricia Kraft, Mona I. Benker, Sophia Abulizi, Adrian-Iustin Georgevici, Paige Brlecic, Tamás Radovits, Sivakkanan Loganathan, Matthias Karck and Gábor Szabó

Int. J. Mol. Sci. 2021, 22(15), 7774; https://doi.org/10.3390/ijms22157774 - 21 Jul 2021

Cited by 19 | Viewed by 3194

Abstract

Vascular ischemia/reperfusion injury (IRI) contributes to graft failure and adverse clinical outcomes following coronary artery bypass grafting. Sodium-glucose-cotransporter (SGLT)-2-inhibitors have been shown to protect against myocardial IRI, irrespective of diabetes. We hypothesized that adding canagliflozin (CANA) (an SGLT-2-inhibitor) to saline protects vascular grafts from IRI. Aortic rings from non-diabetic rats were isolated and immediately mounted in organ bath chambers (control, n = 9–10 rats) or underwent cold ischemic preservation in saline, supplemented either with a DMSO vehicle (IR, n = 8–10 rats) or 50µM CANA (IR + CANA, n = 9–11 rats). Vascular function was measured, the expression of 88 genes using PCR-array was analyzed, and feature selection using machine learning was applied. Impaired maximal vasorelaxation to acetylcholine in the IR-group compared to controls was significantly ameliorated by CANA (IR 31.7 ± 3.2% vs. IR + CANA 51.9 ± 2.5%, p < 0.05). IR altered the expression of 17 genes. Ccl2, Ccl3, Ccl4, CxCr4, Fos, Icam1, Il10, Il1a and Il1b have been found to have the highest interaction. Compared to controls, IR significantly upregulated the mRNA expressions of Il1a and Il6, which were reduced by 1.5- and 1.75-fold with CANA, respectively. CANA significantly prevented the upregulation of Cd40, downregulated NoxO1 gene expression, decreased ICAM-1 and nitrotyrosine, and increased PECAM-1 immunoreactivity. CANA alleviates endothelial dysfunction following IRI. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control)

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15 pages, 4567 KiB

Open AccessArticle

Characteristics of Ventricular Electrophysiological Substrates in Metabolic Mice Treated with Empagliflozin

by Shih-Jie Jhuo, I-Hsin Liu, Wei-Chung Tasi, Te-Wu Chou, Yi-Hsiung Lin, Bin-Nan Wu, Kun-Tai Lee and Wen-Ter Lai

Int. J. Mol. Sci. 2021, 22(11), 6105; https://doi.org/10.3390/ijms22116105 - 5 Jun 2021

Cited by 17 | Viewed by 3319

Abstract

Empagliflozin (EMPA) is a sodium–glucose transporter 2 (SGLT2) inhibitor that functions as a new-generation glucose-lowering agent and has been proven to be beneficial for patients with cardiovascular diseases. However, the possible benefits and mechanisms of its antiarrhythmic effects in cardiac tissue have not yet been reported. In this study, we elucidated the possible antiarrhythmic effects and mechanisms of EMPA treatment in cardiac tissues of metabolic syndrome (MS) mice. A total of 20 C57BL/6J mice (age: 8 weeks) were divided into four groups: (1) control group, mice fed a standard chow for 16 weeks; (2) MS group, mice fed a high-fat diet for 16 weeks; (3) EMPA group, mice fed a high-fat diet for 12 weeks and administered EMPA at 10 mg/kg daily for the following 4 weeks; and (4) glibenclamide (GLI) group, mice fed a high-fat diet for 12 weeks and administered GLI at 0.6 mg/kg daily for the following 4 weeks. All mice were sacrificed after 16 weeks of feeding. The parameters of electrocardiography (ECG), echocardiography, and the effective refractory period (ERP) of the left ventricle were recorded. The histological characteristics of cardiac tissue, including connexin (Cx) expression and fibrotic areas, were also evaluated. Compared with the MS group, the ECG QT interval in the EMPA group was significantly shorter (57.06 ± 3.43 ms vs. 50.00 ± 2.62 ms, p = 0.011). The ERP of the left ventricle was also significantly shorter in the EMPA group than that in the GLI group (20.00 ± 10.00 ms vs. 60.00 ± 10.00 ms, p = 0.001). The expression of Cx40 and Cx43 in ventricular tissue was significantly lower in the MS group than in the control group. However, the downregulation of Cx40 and Cx43 was significantly attenuated in the EMPA group compared with the MS and GLI groups. The fibrotic areas of ventricular tissue were also fewer in the EMPA group than that in the MS group. In this study, the ECG QT interval in the EMPA group was shorter than that in the MS group. Compared with the MS group, the EMPA group exhibited significant attenuation of downregulated connexin expression and significantly fewer fibrotic areas in ventricles. These results may provide evidence of possible antiarrhythmic effects of EMPA. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control)

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15 pages, 1742 KiB

Open AccessArticle

Sodium Glucose Co-Transporter 2 Inhibitors Ameliorate Endothelium Barrier Dysfunction Induced by Cyclic Stretch through Inhibition of Reactive Oxygen Species

by Xiaoling Li, Gregor Römer, Raphaela P. Kerindongo, Jeroen Hermanides, Martin Albrecht, Markus W. Hollmann, Coert J. Zuurbier, Benedikt Preckel and Nina C. Weber

Int. J. Mol. Sci. 2021, 22(11), 6044; https://doi.org/10.3390/ijms22116044 - 3 Jun 2021

Cited by 42 | Viewed by 3410

Abstract

SGLT-2i’s exert direct anti-inflammatory and anti-oxidative effects on resting endothelial cells. However, endothelial cells are constantly exposed to mechanical forces such as cyclic stretch. Enhanced stretch increases the production of reactive oxygen species (ROS) and thereby impairs endothelial barrier function. We hypothesized that the SGLT-2i’s empagliflozin (EMPA), dapagliflozin (DAPA) and canagliflozin (CANA) exert an anti-oxidative effect and alleviate cyclic stretch-induced endothelial permeability in human coronary artery endothelial cells (HCAECs). HCAECs were pre-incubated with one of the SGLT-2i’s (1 µM EMPA, 1 µM DAPA and 3 µM CANA) for 2 h, followed by 10% stretch for 24 h. HCAECs exposed to 5% stretch were considered as control. Involvement of ROS was measured using N-acetyl-l-cysteine (NAC). The sodium-hydrogen exchanger 1 (NHE1) and NADPH oxidases (NOXs) were inhibited by cariporide, or GKT136901, respectively. Cell permeability and ROS were investigated by fluorescence intensity imaging. Cell permeability and ROS production were increased by 10% stretch; EMPA, DAPA and CANA decreased this effect significantly. Cariporide and GKT136901 inhibited stretch-induced ROS production but neither of them further reduced ROS production when combined with EMPA. SGLT-2i’s improve the barrier dysfunction of HCAECs under enhanced stretch and this effect might be mediated through scavenging of ROS. Anti-oxidative effect of SGLT-2i’s might be partially mediated by inhibition of NHE1 and NOXs. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control)

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12 pages, 259 KiB

Open AccessCommunication

Empagliflozin Inhibits IL-1β-Mediated Inflammatory Response in Human Proximal Tubular Cells

by Markus Pirklbauer, Sebastian Sallaberger, Petra Staudinger, Ulrike Corazza, Johannes Leierer, Gert Mayer and Herbert Schramek

Int. J. Mol. Sci. 2021, 22(10), 5089; https://doi.org/10.3390/ijms22105089 - 11 May 2021

Cited by 20 | Viewed by 3269

Abstract

SGLT2 inhibitor-related nephroprotection is—at least partially—mediated by anti-inflammatory drug effects, as previously demonstrated in diabetic animal and human studies, as well as hyperglycemic cell culture models. We recently presented first evidence for anti-inflammatory potential of empagliflozin (Empa) under normoglycemic conditions in human proximal tubular cells (HPTC) by demonstrating Empa-mediated inhibition of IL-1β-induced MCP-1/CCL2 and ET-1 expression on the mRNA and protein level. We now add corroborating evidence on a genome-wide level by demonstrating that Empa attenuates the expression of several inflammatory response genes in IL-1β-induced (10 ng/mL) normoglycemic HPTCs. Using microarray-hybridization analysis, 19 inflammatory response genes out of >30.000 human genes presented a consistent expression pattern, that is, inhibition of IL-1β (10 ng/mL)-stimulated gene expression by Empa (500 nM), in both HK-2 and RPTEC/TERT1 cells. Pathway enrichment analysis demonstrated statistically significant clustering of annotated pathways (enrichment score 3.64). Our transcriptomic approach reveals novel genes such as CXCL8/IL8, LOX, NOV, PTX3, and SGK1 that might be causally involved in glycemia-independent nephroprotection by SGLT2i. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control)

13 pages, 4776 KiB

Open AccessArticle

Sodium-Glucose Co-Transporter 2 Inhibitors Correct Metabolic Maladaptation of Proximal Tubular Epithelial Cells in High-Glucose Conditions

by Kohsuke Shirakawa and Motoaki Sano

Int. J. Mol. Sci. 2020, 21(20), 7676; https://doi.org/10.3390/ijms21207676 - 16 Oct 2020

Cited by 22 | Viewed by 3540

Abstract

Glucose filtered in the glomerulus is actively reabsorbed by sodium-glucose co-transporter 2 (SGLT2) in proximal tubular epithelial cells (PTEC) and passively returned to the blood via glucose transporter 2 (GLUT2). Healthy PTEC rely primarily on fatty acid beta-oxidation (FAO) for energy. In phase III trials, SGLT2 inhibitors improved outcomes in diabetic kidney disease (DKD). Tubulointerstitial renal fibrosis due to altered metabolic reprogramming of PTEC might be at the root of the pathogenesis of DKD. Here, we investigated the molecular mechanism of SGLT2 inhibitors’ renoprotective effect by examining transcriptional activity of Spp1, which encodes osteopontin, a key mediator of tubulointerstitial renal fibrosis. With primary cultured PTEC from Spp1-enhanced green fluorescent protein knock-in mice, we proved that in high-glucose conditions, increased SGLT2- and GLUT-mediated glucose uptake is causatively involved in aberrant activation of the glycolytic pathway in PTEC, thereby increasing mitochondrial reactive oxygen species (ROS) formation and transcriptional activation of Spp1. FAO activation did not play a direct role in these processes, but elevated expression of a tubular-specific enzyme, myo-inositol oxygenase, was at least partly involved. Notably, canagliflozin blocked overexpression of myo-inositol oxygenase. In conclusion, SGLT2 inhibitors exerted renoprotective effects by inhibiting aberrant glycolytic metabolism and mitochondrial ROS formation in PTEC in high-glucose conditions. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control)

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Review

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14 pages, 1179 KiB

Open AccessReview

Effects of SGLT2 Inhibitors beyond Glycemic Control—Focus on Myocardial SGLT1

by Alex Ali Sayour, Mihály Ruppert, Attila Oláh, Kálmán Benke, Bálint András Barta, Eszter Zsáry, Béla Merkely and Tamás Radovits

Int. J. Mol. Sci. 2021, 22(18), 9852; https://doi.org/10.3390/ijms22189852 - 12 Sep 2021

Cited by 14 | Viewed by 4963

Abstract

Selective sodium–glucose cotransporter 2 (SGLT2) inhibitors reduced the risk of hospitalization for heart failure in patients with or without type 2 diabetes (T2DM) in large-scale clinical trials. The exact mechanism of action is currently unclear. The dual SGLT1/2 inhibitor sotagliflozin not only reduced hospitalization for HF in patients with T2DM, but also lowered the risk of myocardial infarction and stroke, suggesting a possible additional benefit related to SGLT1 inhibition. In fact, several preclinical studies suggest that SGLT1 plays an important role in cardiac pathophysiological processes. In this review, our aim is to establish the clinical significance of myocardial SGLT1 inhibition through reviewing basic research studies in the context of SGLT2 inhibitor trials. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control)

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13 pages, 533 KiB

Open AccessReview

Treatment Response to SGLT2 Inhibitors: From Clinical Characteristics to Genetic Variations

by Jasna Klen and Vita Dolžan

Int. J. Mol. Sci. 2021, 22(18), 9800; https://doi.org/10.3390/ijms22189800 - 10 Sep 2021

Cited by 15 | Viewed by 3600

Abstract

SGLT2 (sodium-glucose cotransporter 2) inhibitors are a new class of antihyperglycaemic drugs that act on the proximal tubules of the kidney. They have shown efficacy in the management of diabetes mellitus type 2 and their cardiovascular and renal safety have been extensively investigated and confirmed in clinical trials. However, inter-individual differences in response to treatment with SGLT2 inhibitors may present in everyday clinical practice, and good predictors of glycemic response and the risk for adverse events in an individual patient are lacking. As genetic variability of SGLT2 may influence the treatment response, pharmacogenetic information could support the choice of the most beneficial treatment strategy in an individual patient. This review focuses on the clinical and genetic factors that may influence the treatment response to SGLT2 inhibitors in type 2 diabetes patients with comorbid conditions. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control)

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19 pages, 694 KiB

Open AccessReview

Effects of Sodium-Glucose Co-Transporter 2 Inhibitors on Vascular Cell Function and Arterial Remodeling

by William Durante, Ghazaleh Behnammanesh and Kelly J. Peyton

Int. J. Mol. Sci. 2021, 22(16), 8786; https://doi.org/10.3390/ijms22168786 - 16 Aug 2021

Cited by 57 | Viewed by 5549

Abstract

Cardiovascular disease is the leading cause of morbidity and mortality in diabetes. Recent clinical studies indicate that sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in patients with diabetes. The mechanism underlying the beneficial effect of SGLT2 inhibitors is not completely clear but may involve direct actions on vascular cells. SGLT2 inhibitors increase the bioavailability of endothelium-derived nitric oxide and thereby restore endothelium-dependent vasodilation in diabetes. In addition, SGLT2 inhibitors favorably regulate the proliferation, migration, differentiation, survival, and senescence of endothelial cells (ECs). Moreover, they exert potent antioxidant and anti-inflammatory effects in ECs. SGLT2 inhibitors also inhibit the contraction of vascular smooth muscle cells and block the proliferation and migration of these cells. Furthermore, studies demonstrate that SGLT2 inhibitors prevent postangioplasty restenosis, maladaptive remodeling of the vasculature in pulmonary arterial hypertension, the formation of abdominal aortic aneurysms, and the acceleration of arterial stiffness in diabetes. However, the role of SGLT2 in mediating the vascular actions of these drugs remains to be established as important off-target effects of SGLT2 inhibitors have been identified. Future studies distinguishing drug- versus class-specific effects may optimize the selection of specific SGLT2 inhibitors in patients with distinct cardiovascular pathologies. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control)

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19 pages, 2313 KiB

Open AccessReview

Cardioprotection by SGLT2 Inhibitors—Does It All Come Down to Na⁺?

by Maximilian Trum, Johannes Riechel and Stefan Wagner

Int. J. Mol. Sci. 2021, 22(15), 7976; https://doi.org/10.3390/ijms22157976 - 26 Jul 2021

Cited by 49 | Viewed by 7955

Abstract

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are emerging as a new treatment strategy for heart failure with reduced ejection fraction (HFrEF) and—depending on the wistfully awaited results of two clinical trials (DELIVER and EMPEROR-Preserved)—may be the first drug class to improve cardiovascular outcomes in patients suffering from heart failure with preserved ejection fraction (HFpEF). Proposed mechanisms of action of this class of drugs are diverse and include metabolic and hemodynamic effects as well as effects on inflammation, neurohumoral activation, and intracellular ion homeostasis. In this review we focus on the growing body of evidence for SGLT2i-mediated effects on cardiac intracellular Na⁺ as an upstream mechanism. Therefore, we will first give a short overview of physiological cardiomyocyte Na⁺ handling and its deterioration in heart failure. On this basis we discuss the salutary effects of SGLT2i on Na⁺ homeostasis by influencing NHE1 activity, late I_Na as well as CaMKII activity. Finally, we highlight the potential relevance of these effects for systolic and diastolic dysfunction as well as arrhythmogenesis. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control)

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11 pages, 1227 KiB

Open AccessReview

Pleiotropic Effects of Sodium-Glucose Cotransporter-2 Inhibitors: Renoprotective Mechanisms beyond Glycemic Control

by Tomoaki Takata and Hajime Isomoto

Int. J. Mol. Sci. 2021, 22(9), 4374; https://doi.org/10.3390/ijms22094374 - 22 Apr 2021

Cited by 21 | Viewed by 7489

Abstract

Diabetes mellitus is a major cause of chronic kidney disease and end-stage renal disease. However, the management of chronic kidney disease, particularly diabetes, requires vast improvements. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for the treatment of diabetes, have been shown to protect against kidney injury via glycemic control, as well as various other mechanisms, including blood pressure and hemodynamic regulation, protection from lipotoxicity, and uric acid control. As such, regulation of these mechanisms is recommended as an effective multidisciplinary approach for the treatment of diabetic patients with kidney disease. Thus, SGLT2 inhibitors are expected to become key drugs for treating diabetic kidney disease. This review summarizes the recent clinical evidence pertaining to SGLT2 inhibitors as well as the mechanisms underlying their renoprotective effects. Hence, the information contained herein will advance the current understanding regarding the pleiotropic effects of SGLT2 inhibitors, while promoting future research in the field. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control)

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10 pages, 751 KiB

Open AccessHypothesis

Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland

by Anastasios Lymperopoulos, Jordana I. Borges, Natalie Cora and Anastasiya Sizova

Int. J. Mol. Sci. 2021, 22(14), 7684; https://doi.org/10.3390/ijms22147684 - 19 Jul 2021

Cited by 32 | Viewed by 4468

Abstract

Heart failure (HF) remains the leading cause of morbidity and death in the western world, and new therapeutic modalities are urgently needed to improve the lifespan and quality of life of HF patients. The sodium-glucose co-transporter-2 (SGLT2) inhibitors, originally developed and mainly indicated for diabetes mellitus treatment, have been increasingly shown to ameliorate heart disease, and specifically HF, in humans, regardless of diabetes co-existence. Indeed, dapagliflozin has been reported to reduce cardiovascular mortality and hospitalizations in patients with HF and reduced ejection fraction (HFrEF). This SGLT2 inhibitor demonstrates these benefits also in non-diabetic subjects, indicating that dapagliflozin’s efficacy in HF is independent of blood glucose control. Evidence for the effectiveness of various SGLT2 inhibitors in providing cardiovascular benefits irrespective of their effects on blood glucose regulation have spurred the use of these agents in HFrEF treatment and resulted in FDA approvals for cardiovascular indications. The obvious question arising from all these studies is, of course, which molecular/pharmacological mechanisms underlie these cardiovascular benefits of the drugs in diabetics and non-diabetics alike. The fact that SGLT2 is not significantly expressed in cardiac myocytes (SGLT1 appears to be the dominant isoform) adds even greater perplexity to this answer. A variety of mechanisms have been proposed over the past few years and tested in cell and animal models and prominent among those is the potential for sympatholysis, i.e., reduction in sympathetic nervous system activity. The latter is known to be high in HF patients, contributing significantly to the morbidity and mortality of the disease. The present minireview first summarizes the current evidence in the literature supporting the notion that SGLT2 inhibitors, such as dapagliflozin and empagliflozin, exert sympatholysis, and also outlines the main putative underlying mechanisms for these sympatholytic effects. Then, we propose a novel hypothesis, centered on the adrenal medulla, for the sympatholytic effects specifically of dapagliflozin. Adrenal medulla is responsible for the production and secretion of almost the entire amount of circulating epinephrine and of a significant percentage of circulating norepinephrine in the human body. If proven true experimentally, this hypothesis, along with other emerging experimental evidence for sympatholytic effects in neurons, will shed new light on the pharmacological effects that mediate the cardiovascular benefits of SGLT2 inhibitor drugs, independently of their blood glucose-lowering effects. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control)

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