Selective Sodium-glucose Cotransporter 2 Research Articles

Evaluation of the effects of empagliflozin on acute lung injury in rat intestinal ischemia-reperfusion model.

Empagliflozin is a selective sodium-glucose co-transporter (SGLT2) inhibitor that is approved for the treatment of type 2 diabetes. The beneficial effects of empagliflozin on other organ systems including the heart and kidneys have been proven. The aim of this study is to evaluate the role of empagliflozin on acute lung injury induced by intestinal ischemia-reperfusion (I/R). A total of 27 male Wistar albino rats were divided into three groups: sham, I/R, and I/R + empagliflozin; each group containing nine animals. Sham group rats underwent laparotomy without I/R injury. Rats in the I/R group underwent laparotomy, 1h of after ischemia-reperfusion injury (superior mesenteric artery ligation was followed by 2h of reperfusion). Rats in I/R were given empagliflozin (30mg/kg) by gastric gavage for 7days before the ischemia-reperfusion injury. All animals were killed at the end of reperfusion and lung tissue samples were obtained for immunohistochemical staining and histopathological investigation in all groups. Serum glucose, AST, ALT, creatinine, native thiol, total thiol, and disulfide levels and disulfide-native thiol, disulfide-total thiol, and native thiol-total thiol ratios as well as the IMA levels were analyzed and compared among the groups. While intestinal I/R significantly increases serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatinine levels; did not cause any change in homeostasis parameters and IMA level. Empagliflozin treatment had no significant effect on biochemical parameters. Empagliflozin treatment induced a significant decrease in positive immunostaining for IL-1, IL-6, TNF-alpha, caspase 3, caspase 8, and caspase 9 compared to the I/R group in lung tissue samples. Intestinal I/R caused severe histopathological injury including edema, hemorrhage, increased thickness of the alveolar wall, and infiltration of inflammatory cells into alveolar spaces. Empagliflozin treatment significantly attenuated the severity of intestinal I/R injury. It was concluded that empagliflozin treatment may have beneficial effects in acute lung injury, and, therefore, has the potential for clinical use.

Comparative study on the cardioprotective effect of selective sodium glucose co-transporter 2 inhibitors in a non-diabetic mouse model of myocardial ischemia/reperfusion injury

Comparative study on the cardioprotective effect of selective sodium glucose co-transporter 2 inhibitors in a non-diabetic mouse model of myocardial ischemia/reperfusion injury

Clinical Evaluation of Dapagliflozin in the Management of CKD: Focus on Patient Selection and Clinical Perspectives.

Dapagliflozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor that was recently approved in the USA and the EU for the treatment of adults with chronic kidney disease (CKD) with or without diabetes mellitus (DM). The DAPA-CKD trial showed a 39% decline in the risk of worsening kidney function, onset of end-stage kidney disease, or kidney failure-related death. Patients with lower levels of eGFR and higher levels of albuminuria are among those who stand to gain the greatest absolute benefits. These benefits were similar in both patients with or without diabetes, thus undermining the hypothesis that these drugs mitigate glycemia-related nephrotoxicity. Suggested mechanisms for renal protection include hemodynamic effects; BP reduction and improving salt sensitivities and metabolic effects; and glucose, uric acid and triglycerides (TG)-lowering effects. There have been already many excellent reviews on dapagliflozin and CKD management. Most of them cover both efficacy and safety. This review will focus on clinical perspectives and patient selection for the practicing clinician.

Cardioprotection by selective SGLT2 inhibitors in a non-diabetic mouse model of myocardial ischemia/reperfusion injury: a class or a drug effect?

Abstract Background Empagliflozin (EMPA), Dapagliflozin (DAPA) and Ertugliflozin (ERTU) are selective sodium glucose co-transporter 2 inhibitors (SGLT2i) acting against type 2 diabetes mellitus. Purpose Due to differences in clinical trial outcomes, we aimed to 1) compare the cardioprotective effects of selective SGLT2i in terms of infarct size (IS) reduction and 2) reveal the mechanism of cardioprotection in non-diabetic mice. Methods C57BL/6 mice were randomized and orally received EMPA (10mg/kg/day), DAPA (9.0mg/kg/day), ERTU (9.7mg/kg/day) or vehicle for 7 days. IS was measured after 30' ischemia (I), and 120' reperfusion (R). EMPA, DAPA and ERTU were given at equivalent stoichiometrically doses (ESD). Body weight and fasting blood glucose (FBG) levels were determined at baseline and at the end of the treatment. On the 7th day, mice were housed in metabolic cages for 24 hours. Urine volume (UV), food and water uptake and 24h-glucose levels were determined to examine the extend of SGLT-2 inhibition by the drugs. In a second series, the ischemic myocardium was taken (10'R), shotgun proteomics were performed and several cardioprotective pathways were evaluated. In a third series, the dominant pathways were evaluated through molecular analyses and mitochondrial functionality. The causal relationships in the mechanism of protection, was established by inhibiting the concomitant cardioprotective pathways. Static, the specific STAT-3 inhibitor and wortmannin (a PI3K inhibitor) were administered and IS was measured upon 30'I/120' R. Results EMPA and DAPA but not ERTU reduced IS at this dose. Body weight and FBG levels were not affected by the treatments. EMPA, DAPA and ERTU lead to significant increase in UV and urinary glucose levels compared to the control group independently of the water and food intake. There was no significant difference in the parameters among the different SGLT-2i indicating that the chosen doses are sufficient to produce the same pharmacological SGLT-2 inhibition in mice. Proteomics revealed mitochondrial metabolism and NF-kB signaling as significant. Only EMPA preserved mitochondrial functionality in complex I & II linked oxidative phosphorylation. NF-kB, RISK and STAT-3 activation and the downstream reduction in apoptosis were evident in EMPA and DAPA groups coinciding with IS reduction. Static and wortmannin significantly attenuated IS reduction both in EMPA and DAPA groups indicating that STAT-3 and PI3K activation are the leading mechanisms of cardioprotection. Among several upstream mediators, fibroblast growth factor 2 (FGF-2) and caveolin-3 were increased in EMPA and DAPA groups. Conclusions Short term EMPA, DAPA and ERTU at the chosen ESD inhibit SGLT-2i in a similar extent but only EMPA and DAPA reduce IS. Our study reveals drug specific effects on cardioprotection against I/R injury. Cardioprotection afforded by EMPA and DAPA are STAT-3 and PI3K dependent and associated with increased FGF-2 and Cav-3 expression. Funding Acknowledgement Type of funding sources: None.

Empagliflozin rescues primary murine cardiac fibroblasts, but not cardiomyocytes, from hypoxia-reoxygenation injury through STAT3-mediated cascades

Abstract Introduction Empagliflozin (EMPA) is a selective sodium glucose co-transporter 2 inhibitor (SGLT2i) and an established drug against type 2 diabetes mellitus. Cardiovascular clinical outcome trials on EMPA have shown a reduced mortality rate related to major cardiovascular events, but the precise mechanism of action remains elusive. We have previously proved that chronic EMPA administration reduces infarct size in an in vivo murine model of ischemia / reperfusion injury, irrespective of the diabetic status. The cardioprotective effect of EMPA was attributed to the increase of Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation. Purpose In this study we aimed to decipher the cell specific effects of EMPA on primary adult ventricular murine cardiomyocytes (pAVMCs) and primary murine cardiac fibroblasts (pMCFs), subjected to hypoxia/reoxygenation (HYP/REO) and to 1) investigate the effect of EMPA on cell death, and 2) reveal the mechanism of cardioprotection. Methods PAVMCs and pMCFs were isolated from adult C57BL/6 murine hearts (n=4–6) and were incubated with EMPA (500nM–100nM) for 24 hours. Cells were then subjected to 3 hours of HYP (99% N2), followed by 1 hour of REO. STATTIC, a selective STAT3 inhibitor was used (500nM–1μM) to determine the contribution of STAT3 on the observed effect. MTT assay was performed at the end of REO to determine cell viability. To unravel the mechanism of cardioprotection, the experimental protocol was repeated, and the cells were either stained with dihydroethidium (DHE) dye to determine relative oxidative stress changes or were harvested for isolation of total protein content. We focused on STAT3 and Akt kinase as key mediators of the cardioprotective survivor activating factor enhancement (SAFE) and the reperfusion injury salvage kinase (RISK) pathways. We also investigated the expression of Cardiotrophin-1 (CT-1), as a potential upstream mediator of STAT3 phosphorylation. Results The evaluation of cell death revealed that pMCFs viability was significantly increased upon EMPA treatment. Added to this, STATTIC co-treatment with EMPA blunted the protective effect on pMCFs, which indicates that EMPA's protection is STAT3-mediated. Oxidative stress remained unaltered by the treatments. Investigation of the molecular pathways that are responsible for the increased viability of pMCFs revealed that EMPA treatment induces an increased phosphorylation of STAT3 and an increase in CT-1 expression, which are both reversed by STATTIC. Akt phosphorylation and expression remained unchanged by EMPA treatment. Notably, the effect of EMPA on pAVMCs' viability was negligible. Conclusion(s) EMPA does not protect pAVMCs, from HYP/REO injury. EMPA rescues the pMCFs in a STAT-3 dependent manner which indicates that EMPA's cardioprotective effect is cell specific and implicates the SAFE pathway. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Boehringer Ingelheim International GmbHGrant title: “Investigation of the distinct effects of Empagliflozin on different cell populations of the healthy myocardium”

SGLT-2 inhibition by empagliflozin exerts neutral effects on experimental arterial thrombosis in a murine model of low-grade inflammation

Abstract Introduction Low-grade inflammation couples dysmetabolic states to insulin resistance and atherosclerotic cardiovascular disease (ASCVD). Selective sodium-glucose co-transporter 2 (SGLT-2) inhibition by empagliflozin improves clinical outcomes in patients with ASCVD independently of glucose-lowering. Yet, its mechanism of action remains largely undetermined. Purpose We aimed to test whether empagliflozin affects arterial thrombus formation in baseline conditions or low-grade inflammation, a systemic milieu shared among patients with ASCVD. Methods Sixteen-week-old C57BL/6 mice were randomly assigned to acute administration of empagliflozin (25 mg/kg BW) or vehicle, of which a subgroup was pre-treated biweekly over 4 weeks with super-low-dose lipopolysaccharide (LPS; 5 ng/kg BW), before carotid thrombosis was induced by photochemical injury. The translational value of these findings was investigated in primary human aortic endothelial cells (HAECs) and plasma samples of patients randomized to empagliflozin therapy. Results The between-group difference in doppler-flow probe detected time-to-occlusion (TTO) remained within the predefined equivalence margin (Δ=|10.50|), irrespective of low-grade inflammation (95% confidence interval [CI], −9.82 to 8.85 and −9.20 to 9.69), while glucose dropped by 1.64 and 4.84 mmol/l, respectively (Fig. 1). Ex vivo platelet aggregometry suggests similar platelet activation status, corroborated by unchanged circulating platelet-factor 4 (PF4) plasma levels. In concert, carotid PAI-1 expression and TF activity remained unaltered upon SGLT-2 inhibition, and no difference in plasma D-dimer levels was detected, suggesting comparable coagulation cascade activation and fibrinolytic activity (Fig. 1). In HAECs pre-treated with LPS, empagliflozin neither changed TF activity nor PAI-1 expression (Fig. 2). Accordingly, among patients with established ASCVD or at high cardiovascular (CV) risk randomized to 10 mg empagliflozin daily signatures of thrombotic (i.e., TF) and fibrinolytic activity (i.e., PAI-1) remained unchanged, while plasma glucose declined significantly during 3 months of follow-up (Fig. 2). Conclusion SGLT-2 inhibition by empagliflozin does not impact experimental arterial thrombus formation, neither under baseline conditions nor during sustained low-grade inflammation, and has no impact on proxies of thrombotic/fibrinolytic activity in patients with ASCVD. The beneficial pleiotropic effects of empagliflozin are likely independent of pathways mediating thrombosis. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swiss National Science FoundationSwiss Heart FoundationFoundation for Cardiovascular Research–Zurich Heart House

Empagliflozin attenuates arrhythmogenesis via inhibition of O-GlcNAcylation in diastolic phase of diabetic cardiomyopathy

Abstract Background Diabetic cardiomyopathy is an important complication of diabetes mellitus (DM) and reported to increase the risk of fatal ventricular arrhythmias. Recent clinical trials showed that empagliflozin (EMPA), a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, improved cardiovascular outcomes regardless of the presence of diabetes and the traditional cardiovascular risk factors. Despite the promising benefit of EMPA on heart failure treatment, its beneficial effect in the context of anti-arrhythmic therapy has not been fully examined. We therefore aimed to examine anti-arrhythmic effect of acute EMPA treatment especially onto calcium (Ca2+) handling in diabetic cardiomyocytes. Methods We assessed echocardiography, hemodynamic study, electrophysiology, Ca2+ handling and protein expression in C57BLKS/J-leprdb/db mice (db/db mice), a leptin receptor-deficient model of obesity and Type 2 diabetes, and their non-diabetic lean heterozygous Leprdb/+ littermates (db/+ mice). Results The 16-week-old db/db mice had preserved systolic function but exhibited diastolic dysfunction. In arrhythmia induction using ex-vivo Langendorff-perfused hearts, db/db mice showed a significantly increased premature ventricular complex (PVC) by 2x Ca2+ and 1μM isoproterenol load than control, which was attenuated by EMPA perfusion (1 μM). Diabetic cardiomyocytes showed an increased frequency of spontaneous Ca2+ sparks and waves, and decreased Ca2+ transient amplitude and sarcoplasmic reticulum (SR) Ca2+ content. Ca2+ transient decay tau and time to 50% decay were significantly prolonged in diabetic cardiomyocytes. These data indicating the impaired Ca2+ handling in diabetic cardiomyocytes were normalized by acute administration of EMPA (1 μM), while the administration of NHE inhibitor (Cariporide 10 μM) did not show significant differences. In the protein expression analysis, CaMKII Thr287 autophosphorylation and CaMKII-dependent RyR2 S2814 phosphorylation were significantly increased in diabetic hearts, which were inhibited by short-term (30 min) perfusion of EMPA (1 μM). The expressions of SERCA2a and phospholamban were not significantly different among three groups. Lastly, whole hearts O-GlcNAcylation, one of the important post translational modifications, was significantly reduced by EMPA treatment. Conclusion EMPA improved intracellular Ca2+ handling and attenuated arrhythmogenesis in mice with diabetic cardiomyopathy at the diastolic dysfunction phase, suggesting that EMPA may exhibit this anti-arrhythmic effect by normalization of intracellular calcium handling via inhibiting O-GlcNAcylation. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Boehringer Ingelheim

Dapagliflozin Protects H9c2 Cells Against Injury Induced by Lipopolysaccharide via Suppression of CX3CL1/CX3CR1 Axis and NF-κB Activity.

Dapagliflozin, a selective Sodium-glucose cotransporter-2 (SGLT2) inhibitor, has been shown to play a key role in the control and management of metabolic and cardiac diseases. The current study aims to address the effects of dapagliflozin on the expression of fractalkine (FKN), known as CX3CL1, and its receptors CX3CR1, Nuclear factor-kappa B(NF-κB) p65 activity, Reactive oxygen species (ROS), and inflammation in LPS-treated H9c2 cell line. H9c2 cells were cultured with lipopolysaccharide (LPS) to establish a model of LPS-induced damage, and then, subsequently were treated with dapagliflozin for 72 h. Our work included measurement of cell viability (MTT), Malondialdehyde (MDA), intracellular ROS, tumor necrosis factor-α (TNF-α), NF-κB activity, and expression of CX3CL1/CX3CR1. The results showed that LPS-induced reduction of cell viability was successfully rescued by dapagliflozin treatment. The cellular levels of MDA, ROS, and TNF-α, as an indication of cellular oxidative stress and inflammation, were significantly elevated in H9c2 cells compared to the control group. Furthermore, dapagliflozin ameliorated inflammation and oxidative stress through the modulation of the levels of MDA, TNF-α, and ROS. Correspondingly, dapagliflozin reduced the expression of CX3CL1/CX3CR1, NF-κB p65 DNA binding activity, and it also attenuated nuclear acetylated NF-κB p65 in LPS-induced injury in H9c2 cells compared to untreated cells. These findings shed light on the novel pharmacological potential of dapagliflozin in the alleviation of LPS-induced CX3CL1/CX3CR1-mediated injury in inflammatory conditions such as sepsis-induced cardiomyopathy.

Empagliflozin mitigates type 2 diabetes-associated peripheral neuropathy: a glucose-independent effect through AMPK signaling

Diabetic peripheral neuropathy (DPN) represents a severe microvascular condition that dramatically affects diabetic patients despite adequate glycemic control, resulting in high morbidity. Thus, recently, anti-diabetic drugs that possess glucose-independent mechanisms attracted attention. This work aims to explore the potentiality of the selective sodium-glucose cotransporter-2 inhibitor, empagliflozin (EMPA), to ameliorate streptozotocin-induced DPN in rats with insight into its precise signaling mechanism. Rats were allocated into four groups, where control animals received vehicle daily for 2 weeks. In the remaining groups, DPN was elicited by single intraperitoneal injections of freshly prepared streptozotocin and nicotinamide (52.5 and 50 mg/kg, respectively). Then EMPA (3 mg/kg/p.o.) was given to two groups either alone or accompanied with the AMPK inhibitor dorsomorphin (0.2 mg/kg/i.p.). Despite the non-significant anti-hyperglycemic effect, EMPA improved sciatic nerve histopathological alterations, scoring, myelination, nerve fibers’ count, and nerve conduction velocity. Moreover, EMPA alleviated responses to different nociceptive stimuli along with improved motor coordination. EMPA modulated ATP/AMP ratio, upregulated p-AMPK while reducing p-p38 MAPK expression, p-ERK1/2 and consequently p-NF-κB p65 as well as its downstream mediators (TNF-α and IL-1β), besides enhancing SOD activity and lowering MDA content. Moreover, EMPA downregulated mTOR and stimulated ULK1 as well as beclin-1. Likewise, EMPA reduced miR-21 that enhanced RECK, reducing MMP-2 and -9 contents. EMPA’s beneficial effects were almost abolished by dorsomorphin administration. In conclusion, EMPA displayed a protective effect against DPN independently from its anti-hyperglycemic effect, probably via modulating the AMPK pathway to modulate oxidative and inflammatory burden, extracellular matrix remodeling, and autophagy.

Beyond the Glycaemic Control of Dapagliflozin: Impact on Arterial Stiffness and Macroangiopathy.

Dapagliflozin is a selective sodium–glucose cotransporter 2 inhibitor (SGLT2i) indicated for the treatment of type 2 diabetes mellitus (T2DM), heart failure with reduced ejection fraction and chronic kidney disease. In all indications, treatment can be initiated in adults with estimated glomerular filtration rate of at least 25 mL/min/1.73 m2. As monotherapy or as an additive therapy, dapagliflozin has been shown to promote better glycaemic control, associated with a reduction in body weight and blood pressure in a wide range of patients. In addition, dapagliflozin has a positive impact on arterial stiffness, helps to control the lipid profile and contributes to a reduced risk of cardiovascular complications. This article reviews the current scientific evidence on the role of dapagliflozin in cardiovascular risk factors including arterial stiffness, cardiovascular disease and heart failure in patients with T2DM, with the aim of helping to translate this evidence into clinical practice. The underuse of SGLT2i in actual clinical practice is also discussed.

Dapagliflozin, Liraglutide, and Their Combination Attenuate Diabetes Mellitus-Associated Hepato-Renal Injury-Insight into Oxidative Injury/Inflammation/Apoptosis Modulation.

In this study, we aim to explore the beneficial therapeutic impacts of dapagliflozin (Dapa), a highly potent, reversible, and selective sodium–glucose cotransporter-2 inhibitor, and liraglutide (Lira), a glucagon-like peptide-1 (GLP-1) receptor agonist, as hypoglycaemic agents for the management of diabetes mellitus (DM), as well as their combination against DM-induced complications, including hepato-renal injury. Indeed, the progression of DM was found to be associated with significant hepatic and renal injury, as confirmed by the elevated biochemical indices of hepatic and renal functions, as well as histopathological examination. Dapa, Lira, and their combination effectively attenuated DM-induced hepatic and renal injury, as confirmed by the recovery of hepatic and renal functional biomarkers. The administration of both drugs significantly reduced the tissue contents of MDA and restored the contents of GSH and catalase activity. Moreover, NF-κB and TNF-α expression at the protein and gene levels was significantly reduced in the liver and the kidney. This was in parallel with the significant reduction in the caspase-3 content in the liver and the kidney, as well as suppressed cleaved caspase-3 expression in the hepatic and renal specimens, as confirmed by immune–histochemical analysis. Notably, the combined Dapa/Lira treatment demonstrated an additive superior hepato-renal protective impact compared with the use of either drug alone. Thus, it appears that Dapa and Lira, through the coordinated modulation of oxidative, inflammatory, and apoptotic signalling, confer a significant hepato-renal protective impact against DM-induced complications and tissue injury.

Dose-dependent glucosuria of DWP16001, a novel selective sodium-glucose cotransporter-2 inhibitor, in healthy subjects.

DWP16001 is a novel sodium-glucose cotransporter-2 inhibitor under development for the treatment of type 2 diabetes mellitus. This study was conducted to evaluate the pharmacokinetics, pharmacodynamics and safety of DWP16001 after single and multiple doses in healthy subjects. A randomized, double-blind, placebo- and active-controlled, single- and multiple-dose study was conducted. Twelve subjects in each dose group received a single dose (0.2, 0.5, 1.0, 2.0 or 5.0mg) or multiple doses (0.1, 0.3, 0.5, 1.0 or 2.0mg once daily for 15 consecutive days) of DWP16001, dapagliflozin 10mg or placebo at a ratio of 8:2:2. Serial blood and interval urine samples were collected for the pharmacokinetic and pharmacodynamic analyses. The safety and tolerability of DWP16001 were also assessed. A dose-dependent increase in the urinary glucose excretion was observed after a single dose, and the steady state urinary glucose excretion was 50-60 g/d after multiple doses in the dose range of 0.3-2.0mg. DWP16001 was rapidly absorbed with the time to peak plasma concentration of 1.0-3.0hours, and it exhibited a mean elimination half-life of 13-29hours. The systemic exposure to DWP16001 increased proportionally with multiple dose administrations in the range of 0.1-2.0mg. DWP16001 was well tolerated in all dose groups. DWP16001 induced glucosuria in a dose-dependent manner, and systemic exposure was observed after multiple doses. DWP16001 was well tolerated in single oral doses of up to 5.0mg and in multiple oral doses of up to 2.0mg.

No apparent pharmacokinetic interactions were found between henagliflozin: A novel sodium‐glucose co‐transporter 2 inhibitor and glimepiride in healthy Chinese male subjects

Henagliflozin is a novel selective sodium-glucose co-transporter 2 (SGLT2) inhibitor with similar inhibitory effect to ertugliflozin. Glimepiride is widely used to treat type 2 diabetes mellitus (T2DM) with few cardiovascular side effects. In the present study, we aimed at evaluating the pharmacokinetic (PK) interactions between henagliflozin and glimepiride. An open-label, single-centre, single-arm, 3-period, 3-treatment, self-control study was conducted in twelve healthy Chinese male subjects. During each study period, subjects received a single oral dose of glimepiride 2mg, multiple oral doses of henagliflozin 10mg or a combination of the two drugs. Serial blood samples were collected 24h post-dosing for PK analyses. Finger-tip blood glucose was also tested for safety evaluation. Co-administration of henagliflozin with glimepiride did not affect their plasma PK profiles. For henagliflozin, the 90% confidence intervals for the geometric mean ratio (GMR) for the maximum plasma concentrations at steady-state (Cmax ss ) and the area under the plasma concentration-time curve during a dosing interval at steady-state (AUCτ, ss ) of combination therapy to henagliflozin alone were 1.00 (0.93-1.08) and 1.00 (0.98-1.02), respectively. For glimepiride, the corresponding values of combination therapy to glimepiride alone were 1.00 (0.88-1.13) for maximum plasma concentrations (Cmax ), 0.91 (0.84-0.99) for the area under the plasma concentration-time curve from 0-24h (AUC0-24h ) and 0.91 (0.83-1.00) for the plasma concentration-time curve from 0h to infinite (AUC0-inf ), respectively. All values fell within the equivalence range of 0.8-1.25. All monotherapies and combination therapy led to no serious adverse events and were well tolerated. Multiple doses of henagliflozin did not exert a significant change on glimepiride PK profiles and a single dose of glimepiride had little effect on henagliflozin blood concentration. Thus, henagliflozin can be co-administered with glimepiride without dose adjustment of either drug.

Beyond the Glycaemic Control of Dapagliflozin: Microangiopathy and Non-classical Complications.

Dapagliflozin is a selective sodium-glucose cotransporter 2 inhibitor (SGLT2i) indicated for the treatment of type 2 diabetes mellitus (T2DM), heart failure (HF) with reduced ejection fraction (EF) and chronic kidney disease (CKD). In monotherapy or as an additive therapy, dapagliflozin aids glycaemic control, is associated with reductions in blood pressure and weight, and promotes a favourable lipid profile. In this review, we address the impact of dapagliflozin on cardiovascular risk factors and common microangiopathic complications such as kidney disease and retinopathy in patients with T2DM. Furthermore, we evaluate its potential beneficial effects on other less frequent complications of diabetes, such as macular oedema, cognitive impairment, non-alcoholic fatty liver disease and respiratory disorders during sleep. Moreover, the underuse of SGLT2i in clinical practice is discussed. Our goal is to help translate this evidence into clinical practice.

Adiponectin accumulation in the retinal vascular endothelium and its possible role in preventing early diabetic microvascular damage

Adiponectin (APN), a protein abundantly secreted from adipocytes, has been reported to possess beneficial effects on cardiovascular diseases in association with its accumulation on target organs and cells by binding to T-cadherin. However, little is known about the role of APN in the development of diabetic microvascular complications, such as diabetic retinopathy (DR). Here we investigated the impact of APN on the progression of early retinal vascular damage using a streptozotocin (STZ)-induced diabetic mouse model. Our immunofluorescence results clearly showed T-cadherin-dependent localization of APN in the vascular endothelium of retinal arterioles, which was progressively decreased during the course of diabetes. Such reduction of retinal APN accompanied the early features of DR, represented by increased vascular permeability, and was prevented by glucose-lowering therapy with dapagliflozin, a selective sodium-glucose co-transporter 2 inhibitor. In addition, APN deficiency resulted in severe vascular permeability under relatively short-term hyperglycemia, together with a significant increase in vascular cellular adhesion molecule-1 (VCAM-1) and a reduction in claudin-5 in the retinal endothelium. The present study demonstrated a possible protective role of APN against the development of DR.

Beyond The Glycaemic Control of Dapagliflozin: Impact on Arterial Stiffness and Macroangiopathy

Dapagliflozin is a selective sodium-glucose cotransporter 2 nhibitor (SGLT2i) indicated for the treatment of type 2 diabetes mellitus (T2DM), heart failure with reduced ejection fraction and chronic kidney disease. In all indications, treatment can be initiated in adults with estimated glomerular filtration rate ≥25 ml/min/1,73 m². As monotherapy or as an additive therapy, dapagliflozin has been shown to promote better glycaemic control, associated with a reduction in body weight and blood pressure in a wide range of patients. In addition, dapagliflozin has a positive impact on arterial stiffness, helps to control the lipid profile and contributes to a reduced risk of cardiovascular complications. This article reviews the current scientific evidence on the role of dapagliflozin in cardiovascular risk factors including arterial stiffness, cardiovascular disease and heart failure in patients with T2DM, with the aim to help translating this evidence into clinical practice. The underuse of SGLT2i in actual clinical practice is also discussed. Key words: Dapagliflozin; Sodium-Glucose Transporter 2 Inhibitors; Type 2 Diabetes Mellitus; Cardiovascular Diseases; Heart Failure; Therapeutic Inertia.

WEIGHT LOSS EFFECT OF SODIUM-GLUCOSE COTRANSPORTER-2 (SGLT2) INHIBITORS IN PATIENTS WITH OBESITY WITHOUT DIABETES: A SYSTEMATIC REVIEW.

Obesity is a chronic disorder with excessive accumulation and hypertrophy of adipose cells. Selective sodium-glucose cotransporter-2 (SGLT2) Inhibitor has shown an effect of weight loss in several studies. However, weight loss in patients with obesity without diabetes remains unclear. This systematic review aims to address the weight loss effects of SGLT 2 inhibitors in obese subjects without diabetes. We incorporated search engines from Pubmed, EBSCO host, and Proquest. The inclusion criteria for this research were full-text, written in English, written in Bahasa Indonesia, reported the effect of SGLT 2 inhibitors for weight loss in obese patients, the design of the studies, outcomes, and the results of the study. We created a data extraction table to gather the required data for the review. The exclusion criteria for this study were incomplete outcomes, not full-text studies, case reports, literature review, and irrelevant studies. A total of 451 studies were identified from research database. There are 7 studies eligible to be included in this review. Weight loss effects of SGLT2 Inhibitors were observed in all the studies included in this review. SGLT2 inhibitor is an effective weight loss therapy in patients with obesity without diabetes.

Discovery of GCC5694A: A potent and selective sodium glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes

Sodium-dependent glucose co-transporter 2 (SGLT2) has emerged as a promising drug target for the treatment of type 2 diabetes, and recently, several SGLT2 inhibitors have been approved for clinical use. A series of molecules with a C-aryl glucoside scaffold was designed and synthesized for biological evaluation. Among the molecules tested, a dihydrobenzofuran-containing analog, 14g (GCC5694A), exhibited excellentin vitro activity against SGLT2 (IC50 = 0.460 nM), good selectivity for SGLT1, and good metabolic stability. Data from further evaluation of the compound in animal models showed that this molecule is a promising candidate for development as an anti-diabetic agent.

Left ventricular SGLT1 expression correlates with the extent of myocardial nitro-oxidative stress in rat models of heart failure

Abstract Introduction Recently, selective sodium glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce hospitalization for heart failure (HF) in patients with HF, irrespective of type 2 diabetes mellitus (T2DM). The mechanism of action is currently unclear as SGLT2 is not expressed in the heart. Unlike selective SGLT2 inhibitors, the dual SGLT1/2 inhibitor sotagliflozin not only reduced hospitalization for HF, but also decreased the risk of myocardial infarction, suggesting cytoprotective action. Even though SGLT1 it highly expressed in the sarcolemma of cardiomyocytes, its pathophysiological role is unclear. Previous studies have postulated that SGLT1 propagates nitro-oxidative stress in cardiomyocytes through NADPH oxidases. Purpose We aimed to assess myocardial left ventricular (LV) SGLT1 protein expression in two rat models of chronic heart failure and assess possible downstream effectors. Methods We evoked chronic HF in male rats by pressure overload using transverse aortic constriction (TAC, n=7) or by volume overload using aorto-caval fistula (ACF, n=7). Respective sham operated animals (Sham-T or Sham-A, both n=7) served as controls. At the end of the protocol, LV function was assessed using echocardiography and invasive pressure-volume analysis. Myocardial protein expression analysis was performed by western blotting, whereas nitro-oxidative stress was quantified by immunohistochemical staining for 3-nitrotyrosine (3-NT). Results In both TAC and ACF, systolic and diastolic dysfunction was evident, whereas LV mass was significantly increased compared with respective controls. The LV protein expression of SGLT1 was significantly upregulated in both HF models (∼1.5-fold increase, both P<0.01). Whereas the phosphorylation of ERK1/2 was decreased only in ACF, AMPKα activity was significantly reduced in both types of HF. The protein expression of the Nox4 NADPH isoform was substantially upregulated in both TAC and ACF (both P<0.01). The expression of SGLT1 and Nox4 showed a strong positive correlation in the Sham-T plus TAC (r=0.855, P<0.001) and Sham-A plus ACF (r=0.798, P=0.001) cohorts, respectively. Furthermore, SGLT1 expression positively correlated with the extent of myocardial nitro-oxidative stress as assessed by 3-NT staining (Sham-T plus TAC: r=0.833, P=0.015; Sham-A plus ACF: r=0.762, P=0.037). Conclusions LV SGLT1 protein expression was upregulated in both pressure and volume overload-induced HF, irrespective of aetiology, and correlated significantly with Nox4 expression and with the extent of myocardial nitro-oxidative stress. These suggest that SGLT1 might play an important role in the pathophysiology of HF. Future studies should elucidate the possible link between the upregulation of SGLT1 in HF and the increase of myocardial nitro-oxidative stress, so that the salutary effects of the dual SGLT1/2 inhibitor sotagliflozin could be partially explained. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Research, Development and Innovation Fund of Hungary (NVKP_16-1-2016-0017)Ministry for Innovation and Technology in Hungary (2020-4.1.1.-TKP2020)National Research, Development and Innovation Office (NKFIH) of Hungary (K134939 to TR)

Empagliflozin protects the heart against ischemia/reperfusion-induced sudden cardiac death

BackgroundEmpagliflozin is a selective sodium–glucose cotransporter 2 (SGLT2) inhibitor used to lower blood sugar in adults with type 2 diabetes. Empagliflozin also exerts cardioprotective effects independent from glucose control, but its benefits on arrhythmogenesis and sudden cardiac death are not known. The purpose of this study was to examine the effect of empagliflozin on myocardial ischemia/reperfusion-provoked cardiac arrhythmia and sudden cardiac death in vivo.MethodsMale Sprague Dawley rats were randomly assigned to sham-operated, control or empagliflozin groups. All except for the sham-operated rats were subjected to 5-min left main coronary artery ligation followed by 20-min reperfusion. A standard limb lead II electrocardiogram was continuously measured throughout the experiment. Coronary artery reperfusion-induced ventricular arrhythmogenesis and empagliflozin therapy were evaluated. The hearts were used for protein phosphorylation analysis and immunohistological assessment.ResultsEmpagliflozin did not alter baseline cardiac normal conduction activity. However, empagliflozin eliminated myocardial vulnerability to sudden cardiac death (from 69.2% mortality rate in the control group to 0% in the empagliflozin group) and reduced the susceptibility to reperfusion-induced arrhythmias post I/R injury. Empagliflozin increased phosphorylation of cardiac ERK1/2 after reperfusion injury. Furthermore, inhibition of ERK1/2 using U0126 abolished the anti-arrhythmic action of empagliflozin and ERK1/2 phosphorylation.ConclusionsPretreatment with empagliflozin protects the heart from subsequent severe lethal ventricular arrhythmia induced by myocardial ischemia and reperfusion injury. These protective benefits may occur as a consequence of activation of the ERK1/2-dependent cell-survival signaling pathway in a glucose-independent manner.