Sodium-glucose Cotransporter 2 Inhibitor Dapagliflozin Research Articles

The effects of complex therapy with the additional dapagliflozin intake on the copeptin level in the blood serum of patients with diabetic nephropathy

Objective — to determine the effects of drug therapy with inclusion of sodium‑glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on the blood levels of copeptin as a biomarker of renal and vascular lesions in patients with diabetic nephropathy (DN) at various disease stages.
 Materials and methods. Examinations involved 83 in‑hospital patients with DN, treated in the clinic of L. T. Mala National Institute of Therapy. Patients were divided into 2 groups depending on the therapy. 42 patients received a standard course of treatment, including antidiabetic drugs, renin‑angiotensin‑aldosterone system blockers and statins. In addition to standard therapy, the remaining 41 patients were administered SGLT2 inhibitor dapagliflozin in a dose of 10 mg per day. Patients were re‑examined after 6 months treatment. Determination of the copeptin level in blood serum was carried out by the enzyme immunoassay method using the set of reagents Human CPP Elisa Kit manufactured by FineTest, China.
 Results. The results of investigation of the effects of complex nephroprotective therapy on the lipid profile indicators in patients with type 2 diabetes mellitus (DM2) demonstrated significant decrease in the levels of total cholesterol by 11.78% (р <0.05), triglycerides by 19.75% (р <0.05) and non‑significant increase of high‑density lipoproteins by 5.10%. In patients with DM2 and with glomerular filtration rate (GFR) >90 mL/(min · 1.73 m2) (I stage chronic kidney disease (CKD)) the level of copeptin after treatment decreased by 19.3% (p <0.05); in patients with (DM2) and GFR of 60—89 mL/(min · 1.73 m2) (CKD II stage) — by 18.9% (p <0.05), and with GFR of 45—59 mL/(min · 1.73 m2) (CKD III stage) — by 24.8% (p <0.05). The significant decrease of copeptin levels was revealed in diabetic patients with both preserved and reduced GFR. In DM2 patients with normal GFR, the copeptin level after standard treatment decreased by 17.6% (p <0.05), and in case of dapagliflozin administration by 20.6% (p <0.05). In patients with reduced GFR, blood serum copeptin levels decreased by 18.9% (p <0.05) after standard therapy, and by 22.1% (p <0.05) under the influence of dapagliflozin.
 Conclusions. Complex therapy with the use of SGLT2 inhibitor dapagliflozin contributed to more significant reduction of copeptin levels in patients with DN compared to the standard treatment, regardless of the kidneys’ functional state. The decrease of copeptin levels against the background of the improved main clinical and laboratory parameters indicates not only an improvement in the kidneys’ functional state, but also reduction of cardiovascular risk in this group of patients.

#3015 EFFECT OF DAPAGLIFLOZIN ON ALBUMINURIA IN PATIENTS WITH TYPE 2 DIABETES AND CKD

Abstract Background and Aims Albuminuria in patients with diabetes presents a higher risk for adverse renal and cardiovascular (CV) outcomes. Sodium-glucose co-transporter 2 (SGLT2) inhibitors demonstrate improved albuminuria and reduces the risk of end-stage renal disease in patients with chronic kidney disease. The study aim was the impact of the SGLT2 inhibitor dapagliflozin on urine albumin-to-creatinine ratio (UACR) and GFR decline. Method In the single center trial, total 132 participants with CKD and type 2 diabetes (T2D) were randomly assigned to dapagliflozin (n = 78) 10 mg once daily or placebo (n = 54). Kidney inclusion criteria were eGFR 30-60ml/min/1.73 m2 and any UACR. The primary end point was a composite of sustained decline in eGFR ≥50%, end-stage renal disease, or kidney or cardiovascular death. Percentage treatment difference was estimated by geometric mean ratio for the overall cohort and by eGFR and UACR subgroups. Progression/regression of UACR were assessed. Hazard ratios, 95% confidence intervals (CI), and p-values were estimated by Cox proportional hazards model. Results Median baseline eGFR was 42.3ml/min/1.73 m2, with 5% at <30ml/min/1.73 m2. At baseline, median UACR was 103 mg/g, and 1/4 of patients had normoalbuminuria, 2/4 had micro, and 1/4 had macroalbuminuria. Median follow up was 18 months. The UACR difference for dapagliflozin vs placebo was -25.1% (95% CI -27.5, -23.2; p<0.001). Reductions were similar across eGFRs. In UACR 30-299mg/g and ≥300mg/g, reductions were significant in dapagliflozin (p<0.001). Progression risk was lower and regression risk higher in dapagliflozin vs placebo (p<0.001). Conclusion Dapagliflozin significantly slowed long-term eGFR decline in patients with CKD with T2D compared with placebo, and significantly reduced UACR and had favorable effects on UACR progression and regression.

Dapagliflozin Mitigates Hypotension in Lipopolysaccharide-Induced Acute Inflammation Independent of Glycemia Level.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been suggested to have anti-inflammatory properties in diabetes. The goal of this study was to evaluate the role of the SGLT2 inhibitor dapagliflozin (DAPA) in the attenuation of lipopolysaccharide (LPS)-induced hypotension. Male Wistar albino rats were divided into normal and diabetic groups and received DAPA (1 mg/kg/day) for two weeks followed by a single dose of 10 mg/kg LPS. Blood pressure was recorded throughout the study and the circulatory levels of cytokines were assessed using a multiplex array, while the aortas were harvested for analysis. DAPA attenuated the vasodilation and hypotension caused by LPS. Mean arterial pressure (MAP) was preserved in the normal and diabetic DAPA-treated septic groups (MAP = 83.17 ± 5.27, 98.43 ± 5.57 mmHg) compared to the vehicle-treated septic groups (MAP = 65.60 ± 3.31, 68.21 ± 5.88 mmHg). Most of the cytokines induced by LPS were decreased in the DAPA-treated septic groups. In the aorta, the inducible nitric oxide synthase-derived nitric oxide had lower expression in the DAPA-treated rats. In contrast, the expression of α-smooth muscle actin, a marker of the vessel's contractile state, was higher in the DAPA-treated rats in comparison with non-treated septic rats. These findings revealed that the protective role of DAPA against LPS-induced hypotension is likely to be glucose-lowering independent, as was observed in the non-diabetic septic group. Taken together, the results show that DAPA has a potential effect in the prevention of the hemodynamic disturbances of sepsis regardless of glycemia levels.

Dapagliflozin prevents abdominal visceral and subcutaneous adipose tissue dysfunction in the insulin-resistant canine model.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) promote urinary glucose excretion, induce weight loss, and reduce fat accumulation. The effects of the SGLT2i dapagliflozin (DAPA) on subcutaneous (SC) and visceral (VIS) adipose tissue function remain unclear. The objective of this study is to evaluate SC and VIS adipose tissue function in an insulin-resistant canine model. A total of 12 dogs were fed a high-fat diet (HFD) for 6 weeks and thenwere given a single low dose of streptozotocin (18.5 mg/kg) to induce insulin resistance. Animals were then randomized and exposed to DAPA (n = 6, 1.25 mg/kg) or placebo (n = 6) once per day for 6 weeks while remaining on the HFD. DAPA prevented further weight gain induced by the HFD and normalized fat mass. DAPA reduced fasting glucose and increased free fatty acids, adiponectin, and β-hydroxybutyrate. DAPA reduced adipocyte diameter and cell distribution. Furthermore, DAPA increased genes associated with beiging, lipolysis, and adiponectin secretion and the expression of the adiponectin receptor ADR2, in SC and VIS adipose tissue. DAPA increased AMP-activated protein kinase activity and maximal mitochondrial respiratory function, especially in the SC depot. Furthermore, DAPA reduced cytokines and ceramide synthesis enzymes in SC and VIS depots. For the first time, to our knowledge, we identify mechanisms by which DAPA enhances adipose tissue function in regulating energy homeostasis in an insulin-resistant canine model.

Dapagliflozin inhibits the activity of lateral habenula to alleviate diabetes mellitus-induced depressive-like behavior

The prevalence of depression in diabetes mellitus (DM) patients is very high, and it severely impacts the prognosis and quality of life of these patients. Sodium-glucose co-transporter 2 (SGLT2) inhibitors, a new type of oral hypoglycemic drugs, have been shown to alleviate depressive symptoms in DM patients; however, the mechanism underlying this effect is not well understood. The lateral habenula (LHb) plays an important role in the pathogenesis of depression expresses SGLT2, suggesting that the LHb may mediate antidepressant effects of SGLT2 inhibitors. The current study aimed to investigate the involvement of the LHb in the antidepressant effects of the SGLT2 inhibitor dapagliflozin. Chemogenetic methods were used to manipulate the activity of LHb neurons. Behavioral tests, Western blotting, immunohistochemistry, and neurotransmitter assays were used to determine the effects of dapagliflozin on the behavior of DM rats, AMP-activated protein kinase (AMPK) pathway and c-Fos expression in the LHb and 5-hydroxyindoleacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) ratio in the dorsal raphe nucleus (DRN). We found that DM rats demonstrated depressive-like behavior, increased c-Fos expression, and decreased AMPK pathway activity in the LHb. Inhibition of LHb neurons alleviated the depressive-like behavior of DM rats. Both systemic and local LHb administration of dapagliflozin alleviated the depressive-like behavior and reversed the changes of the AMPK pathway and c-Fos expression in the LHb of DM rats. Dapagliflozin, when microinjected into the LHb, also increased 5-HIAA /5-HT in the DRN. These results suggest that dapagliflozin directly acts on the LHb to alleviate DM-induced depressive-like behavior and that the underlying mechanism involves activating the AMPK signaling pathway, leading to the inhibition of LHb neuronal activity, which in turn increases serotonergic activity in the DRN. These results will help develop new strategies for the treatment of DM-induced depression.

The sodium glucose co-transporter 2 inhibitor dapagliflozin ameliorates the fluid-retaining effect of the endothelin A receptor antagonist zibotentan.

Endothelin A receptor antagonists (ETARA) slow chronic kidney disease (CKD) progression but their use is limited due to fluid retention and associated clinical risks. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) cause osmotic diuresis and improve clinical outcomes in CKD and heart failure. We hypothesized that co-administration of the SGLT2i dapagliflozin with the ETARA zibotentan would mitigate the fluid retention risk using hematocrit (Hct) and bodyweight as proxies for fluid retention. Experiments were performed in 4% salt fed WKY rats. First, we determined the effect of zibotentan (30, 100 or 300 mg/kg/day) on Hct and bodyweight. Second, we assessed the effect of zibotentan (30 or 100 mg/kg/day) alone or in combination with dapagliflozin (3 mg/kg/day) on Hct and bodyweight. Hct at Day 7 was lower in zibotentan versus vehicle groups [zibotentan 30 mg/kg/day, 43% (standard error 1); 100 mg/kg/day, 42% (1); and 300 mg/kg/day, 42% (1); vs vehicle, 46% (1); P<.05], while bodyweight was numerically higher in all zibotentan groups compared with vehicle. Combining zibotentan with dapagliflozin for 7 days prevented the change in Hct [zibotentan 100 mg/kg/day and dapagliflozin, 45% (1); vs vehicle 46% (1); P=.44] and prevented the zibotentan-driven increase in bodyweight (zibotentan 100 mg/kg/day+dapagliflozin 3 mg/kg/day = -3.65g baseline corrected bodyweight change; P=.15). Combining ETARA with SGLT2i prevents ETARA-induced fluid retention, supporting clinical studies to assess the efficacy and safety of combining zibotentan and dapagliflozin in individuals with CKD.

Dapagliflozin delays renal fibrosis in diabetic kidney disease by inhibiting YAP/TAZ activation

In diabetic kidney disease (DKD), the long-term hyperactivation of yes-associated protein (YAP)/transcriptional coactivator PDZ-binding motif (TAZ) in renal proximal tubule epithelial cells (RPTCs) plays an important role in progressive tubulointerstitial fibrosis. Sodium-glucose cotransporter 2 (SGLT2) is highly expressed in RPTCs, but its relationship with YAP/TAZ in tubulointerstitial fibrosis in DKD is still unknown. The purpose of this study was to clarify whether the SGLT2 inhibitor (SGLT2i) dapagliflozin could alleviate renal tubulointerstitial fibrosis in DKD by regulating YAP/TAZ. We examined 58 patients with DKD confirmed by renal biopsy and found that the expression and nuclear translocation of YAP/TAZ increased with the exacerbation of chronic kidney disease classification. In models of DKD, dapagliflozin showed similar effects to verteporfin, an inhibitor of YAP/TAZ, in reducing the activation of YAP/TAZ and downregulating the expression of their target genes, connective tissue growth factor (CTGF) and amphiregulin in vivo and in vitro. Silencing SGLT2 also confirmed this effect. Importantly, dapagliflozin showed a better effect than verteporfin in inhibiting inflammation, oxidative stress and fibrosis in the kidney in DKD rats. Taken together, this study proved for the first time that dapagliflozin delayed tubulointerstitial fibrosis at least partly by inhibiting YAP/TAZ activation, which further enriched the antifibrotic effect of SGLT2i.

Dapagliflozin protects against dilated cardiomyopathy progression by targeting NLRP3 inflammasome activation

Dilated cardiomyopathy (DCM) is the major cause of heart failure and has a poor prognosis. The accumulating evidence points to an essential role of the inflammatory component in the process of DCM. Inhibitors of sodium-glucose cotransporter 2 (SGLT2) are widely used to treat heart failure patients due to their cardiac benefits. However, their role in DCM remains unclear. We used the doxorubicin (Dox)-induced DCM model for our study. The SGLT2 inhibitor dapagliflozin (Dapa) improved cardiac function in mice treated with doxorubicin and attenuated the activation of the nucleotide-binding oligomerization domain-like receptor family protein 3 (NLRP3) inflammasome pathway and the expression of inflammatory factors. In addition, dapagliflozin suppresses NLRP3 activation by decreasing p38-dependent toll-like receptor 4 (TLR4) expression. In our study, dagliflozin improves cardiac function in DCM by inhibiting the activity of the NLRP3 inflammasome.Graphical

Sodium-glucose cotransporter 2 inhibition does not improve the acute pressure natriuresis response in rats with type 1 diabetes.

What is the central question of this study? Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular risk in patients with both diabetic and non-diabetic kidney disease: can SGLT2 inhibition improve renal pressure natriuresis (PN), an important mechanism for long-term blood pressure control, which is impaired in type 1 diabetes mellitus (T1DM)? What is the main finding and its importance? The SGLT2 inhibitor dapagliflozin did not enhance the acute in vivo PN response in either healthy or T1DM Sprague-Dawley rats. The data suggest that the mechanism underpinning the clinical benefits of SGLT2 inhibitors on health is unlikely to be due to an enhanced natriuretic response to increased blood pressure. Type 1 diabetes mellitus (T1DM) leads to serious complications including premature cardiovascular and kidney disease. Hypertension contributes importantly to these adverse outcomes. The renal pressure natriuresis (PN) response, a key regulator of blood pressure (BP), is impaired in rats with T1DM as tubular sodium reabsorption fails to down-regulate with increasing BP. We hypothesised that sodium-glucose cotransporter 2 (SGLT2) inhibitors, which reduce cardiovascular risk in kidney disease, would augment the PN response in T1DM rats. Non-diabetic or T1DM (35-50mg/kg streptozotocin i.p.) adult male Sprague-Dawley rats were anaesthetised (thiopental 50mg/kg i.p.) and randomised to receive either dapagliflozin (1mg/kg i.v.) or vehicle. Baseline sodium excretion was measured and then BP was increased by sequential arterial ligations to induce the PN response. In non-diabetic animals, the natriuretic and diuretic responses to increasing BP were not augmented by dapagliflozin. Dapagliflozin induced glycosuria, but this was not influenced by BP. In T1DM rats the PN response was impaired. Dapagliflozin again increased urinary glucose excretion but did not enhance PN. Inhibition of SGLT2 does not enhance the PN response in rats, either with or without T1DM. SGLT2 makes only a minor contribution to tubular sodium reabsorption and does not contribute to the impaired PN response in T1DM.

S-51-4: RENAL DENERVATION IMPROVES FLUID RETENTION BY MODULATING RENAL SGLT2 FUNCTION IN RATS WITH HEART FAILURE

Objective: Renal denervation (RDN) has been developed as a neuromodulation therapy for patients with treatment-resistant hypertension. RDN is expected to prevent not only hypertension but also heart failure (HF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to ameliorate HF and widely used for HF patients. The present study was conducted to assess the effect of RDN on HF and the interaction between renal sympathetic nerves and SGLT2 function in HF. Design and method: HF was induced by coronary artery ligation in rats. Four weeks after coronary artery ligation surgery, surgical bilateral RDN was performed. Western blot analysis was performed to assess the expression levels of SGLT2. One week after RDN surgery, as a functional test for SGLT2 activation, natriuretic response to intravenous injection of SGLT2 inhibitor dapagliflozin (0.5 mg/kg, i.v.) was investigated. Furthermore, the changes in expression and localization of SGLT2 were assessed in human embryonic kidney cells treated with norepinephrine directly, in vitro. Results: Western blot analysis indicated that renal SGLT2 expression is increased in rats with HF. RDN significantly reduced enhanced renal SGLT2 expression in HF. Natriuretic response to dapagliflozin were greater in HF than Sham (Cumulative sodium excretion at 120 min, 227 ± 35 vs. 133 ± 13 μEq/gkw, P &lt; 0.05, n = 6). RDN significantly attenuated natriuretic response to dapagliflozin in HF (Cumulative sodium excretion at 120 min, 138 ± 19 vs. 227 ± 35 μEq/gkw, P &lt; 0.05, n = 6). Direct application of norepinephrine on human embryonic kidney cells, in vitro, resulted in an increased expression of SGLT2 and specifically promoted the translocation of SGLT2 from the cytosol to the cell surface (Cytosolic SGLT2/GAPDH 0.51 ± 0.05 vs. 0.86 ± 0.08, Membranous SGLT2/Na-K-ATPase 1.06 ± 0.10 vs. 0.54 ± 0.03, P &lt; 0.01, n = 6). Moreover, RDN increased the cytosolic SGLT2 while decreasing membranous SGLT2 in the kidneys of rats with HF (Cytosolic SGLT2/GAPDH 1.30 ± 0.11 vs. 0.58 ± 0.09, Membranous SGLT2/Na-K-ATPase 0.51 ± 0.10 vs. 2.08 ± 0.08, P &lt; 0.01, n = 6). Conclusions: These findings suggest that the excessive activation of renal sympathetic nerves in HF increases the expression of SGLT2 protein trafficked by norepinephrine to cell membrane in proximal tubules resulting in greater sodium retention associated with HF condition. RDN mitigates the enhanced expression and activity of SGLT2 and ameliorates the subsequent sodium and water retention associated with HF, suggesting the potential therapeutic use of RDN for HF.

The effect of SGLT-2i administration on red blood cell distribution width in patients with heart failure and type 2 diabetes mellitus: A randomized study.

BackgroundRecent studies suggest that the pivotal mechanism of sodium glucose co-transporter-2 inhibitors (SGLT-2i) favorable action in patients with heart failure (HF) and type 2 diabetes mellitus (DM) is the stimulation of erythropoiesis via an early increase in erythropoietin (EPO) production which leads to hematocrit rise. Red blood cell distribution width (RDW) is a simple hematological parameter which reflects the heterogeneity of the red blood cell size (anisocytosis). Since, EPO has been also implicated in the pathophysiology of RDW increase, the current mechanistic study examined the effect of SGLT-2i administration on red blood cells size (RDW) in patients with HF and DM.MethodsThe present was a prospective single-center study. Patients (N=110) were randomly assigned to dapagliflozin (10 mg a day on top of antidiabetic treatment) or the control group. Inclusion criteria were: (a) age > 18 years, (b) history of type 2 DM and hospitalization for HF exacerbation within 6 months. The evaluation of patients (at baseline, 6 and 12 months) included clinical assessment, laboratory blood tests, and echocardiography. Data were modeled using mixed linear models with dependent variable the RDW index. In order to find factors independently associated with prognosis (1-year death or HF rehospitalization), multiple logistic regression was conducted with death or HF rehospitalization as dependent variable.ResultsAn RDW increase both after 6 and after 12 months was observed in the SGLT-2i (dapagliflozin) group (p < 0.001 for all time comparisons), whereas RDW didn't change significantly in the control group. The increase in RDW was positively correlated with EPO, while negatively correlated with ferritin and folic acid (p < 0.005 for all). Baseline RDW was significantly associated with 1-year death or rehospitalization, after adjusting for group (SGLT-2i vs. control), age, gender, smoking and BMI at baseline.ConclusionRDW increased with time in patients with HF and DM who received SGLT-2i (dapagliflozin). The increased RDW rates in these patients may stem from the induction of hemopoiesis from dapagliflozin. Baseline RDW was found to be independently associated with outcome in patients with HF and DM.

Dapagliflozin improves myocardial flow reserve in patients with type 2 diabetes: the DAPAHEART Trial: a preliminary report

ObjectiveCardiovascular (CV) outcome trials have shown that in patients with type 2 diabetes (T2D), treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) reduces CV mortality and hospital admission rates for heart failure (HF). However, the mechanisms behind these benefits are not fully understood. This study was performed to investigate the effects of the SGLT-2i dapagliflozin on myocardial perfusion and glucose metabolism in patients with T2D and stable coronary artery disease (coronary stenosis ≥ 30% and < 80%), with or without previous percutaneous coronary intervention (> 6 months) but no HF.MethodsThis was a single-center, prospective, randomized, double-blind, controlled clinical trial including 16 patients with T2D randomized to SGLT-2i dapagliflozin (10 mg daily) or placebo. The primary outcome was to detect changes in myocardial glucose uptake (MGU) from baseline to 4 weeks after treatment initiation by [(18)F]2-deoxy-2-fluoro-D-glucose (FDG) PET/CT during hyperinsulinemic euglycemic clamp. The main secondary outcome was to assess whether the hypothetical changes in MGU were associated with changes in myocardial blood flow (MBF) and myocardial flow reserve (MFR) measured by 13N-ammonia PET/CT. The study was registered at eudract.ema.europa.eu (EudraCT No. 2016-003614-27) and ClinicalTrials.gov (NCT 03313752).Results16 patients were randomized to dapagliflozin (n = 8) or placebo (n = 8). The groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, renal and heart function). There was no significant change in MGU during euglycemic hyperinsulinemic clamp in the dapagliflozin group (2.22 ± 0.59 vs 1.92 ± 0.42 μmol/100 g/min, p = 0.41) compared with the placebo group (2.00 ± 0.55 vs 1.60 ± 0.45 μmol/100 g/min, p = 0.5). Dapagliflozin significantly improved MFR (2.56 ± 0.26 vs 3.59 ± 0.35 p = 0.006 compared with the placebo group 2.34 ± 0.21 vs 2.38 ± 0.24 p = 0.81; pint = 0.001) associated with a reduction in resting MBF corrected for cardiac workload (p = 0.005; pint = 0.045). A trend toward an increase in stress MBF was also detected (p = 0.054).ConclusionsSGLT-2 inhibition increases MFR in T2D patients. We provide new insight into SGLT-2i CV benefits, as our data show that patients on SGLT-2i are more resistant to the detrimental effects of obstructive coronary atherosclerosis due to increased MFR, probably caused by an improvement in coronary microvascular dysfunction.Trial registration EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752

The Effect of SGLT2 Inhibitor Dapagliflozin on Serum Levels of Apelin in T2DM Patients with Heart Failure.

Apelin is a multifunctional peptide that plays a pivotal role in cardiac remodeling and HF manifestation because of counteracting angiotensin-II. We hypothesized that positive influence of sodium-glucose co-transporter-2 (SGLT2) inhibitor on cardiac function in T2DM patients with HF might be mediated by apelin and that its levels seem to be a target of management. A total of 153 type 2 diabetes mellitus (T2DM) patients with II/III HF NYHA class and average left ventricular (LV) ejection fraction (EF) of 46% have been enrolled and treated with dapagliflosin. The serum levels of apelin and N-terminal brain natriuretic pro-peptide (NT-proBNP) were measured at baseline and over a 6-month period of dapagliflosin administration. We noticed that administration of dapagliflozin was associated with a significant increase in apelin levels of up to 18.3% and a decrease in NT-proBNP of up to 41.0%. Multivariate logistic regression showed that relative changes of LVEF, LA volume index, and early diastolic blood filling to longitudinal strain ratio were strongly associated with the levels of apelin, whereas NT-proBNP exhibited a borderline significance in this matter. In conclusion, dapagiflosin exerted a positive impact on echocardiographic parameters in close association with an increase in serum apelin levels, which could be a surrogate target for HF management.

SGLT2 inhibitor dapagliflozin attenuates cardiac fibrosis and inflammation by reverting the HIF-2α signaling pathway in arrhythmogenic cardiomyopathy.

Excessive cardiac fibrosis and inflammation aberrantly contribute to the progressive pathogenesis of arrhythmogenic cardiomyopathy (ACM). Whether sodium-glucose cotransporter-2 inhibitor (SGLT2i), as a new hypoglycemic drug, benefits ACM remains unclear. Cardiomyocyte-specific Dsg2 exon-11 knockout and wild-type (WT) littermate mice were used as the animal model of ACM and controls, respectively. Mice were administered by gavage with either SGLT2i dapagliflozin (DAPA, 1mg/kg/day) or vehicle alone for 8 weeks. HL-1 cells were treated with DAPA to identify the molecular mechanism in vitro. All mice presented normal glucose homeostasis. DAPA not only significantly ameliorated cardiac dysfunction, adverse remodeling, and ventricular dilation in ACM but also attenuated ACM-associated cardiac fibrofatty replacement, as demonstrated by the echocardiography and histopathological examination. The protein expressions of HIF-2α and HIF-1α were decreased and increased respectively in cardiac tissue of ACM, which were compromised after DAPA treatment. Additionally, NF-κB P65 and IκB phosphorylation, as well as fibrosis indicators (including TGF-β, α-SMA, Collagen I, and Collagen III) were increased in ACM. However, these trends were markedly suppressed by DAPA treatment. Consistent with these results in vitro, DAPA alleviated the IκB phosphorylation and NF-κB p65 transcriptional activity in DSG2-knockdown HL-1 cells. Interestingly, the elective HIF-2α inhibitor PT2399 almost completely blunted the DAPA-mediated downregulation of indicators concerning cardiac fibrosis and inflammation. SGLT2i attenuated the ACM-associated cardiac dysfunction and adverse remodeling in a glucose-independent manner by suppressing cardiac fibrosis and inflammation via reverting the HIF-2α signaling pathway, suggesting that SGLT2i is a novel and available therapy for ACM.

Endothelin Receptor Antagonists for Kidney Protection: Lessons from the SONAR Trial.

Endothelin Receptor Antagonists for Kidney Protection: Lessons from the SONAR Trial.

Cardiovascular Outcomes in Patients Initiating First-Line Treatment of Type 2 Diabetes With Sodium-Glucose Cotransporter-2 Inhibitors Versus Metformin : A Cohort Study.

Evidence on the risk for cardiovascular events associated with use of first-line sodium-glucose cotransporter-2 inhibitors (SGLT-2i) compared with metformin is limited. To assess cardiovascular outcomes among adults with type 2 diabetes (T2D) who initiated first-line treatment with SGLT-2i versus metformin. Population-based cohort study. Claims data from 2 large U.S. commercial and Medicare databases (April 2013 to March 2020). Patients with T2D aged 18 years and older (>65 years in Medicare) initiating treatment with SGLT-2i or metformin during April 2013 to March 2020, without any use of antidiabetic medications before cohort entry, were identified. After 1:2 propensity score matching in each database, pooled hazard ratios (HRs) and 95% CIs were reported. First-line SGLT-2i (canagliflozin, empagliflozin, or dapagliflozin) or metformin. Primary outcomes were a composite of hospitalization for myocardial infarction (MI), hospitalization for ischemic or hemorrhagic stroke or all-cause mortality (MI/stroke/mortality), and a composite of hospitalization for heart failure (HHF) or all-cause mortality (HHF/mortality). Safety outcomes including genital infections were assessed. Among 8613 first-line SGLT-2i initiators matched to 17226 metformin initiators, SGLT-2i initiators had a similar risk for MI/stroke/mortality (HR, 0.96; 95% CI, 0.77 to 1.19) and a lower risk for HHF/mortality (HR, 0.80; CI, 0.66 to 0.97) during a mean follow-up of 12 months. Initiators receiving SGLT-2i showed a lower risk for HHF (HR, 0.78; CI, 0.63 to 0.97), a numerically lower risk for MI (HR, 0.70; CI, 0.48 to 1.00), and similar risk for stroke, mortality, and MI/stroke/HHF/mortality compared with metformin. Initiators receiving SGLT-2i had a higher risk for genital infections (HR, 2.19; CI, 1.91 to 2.51) and otherwise similar safety as those receiving metformin. Treatment selection was not randomized. As first-line T2D treatment, initiators receiving SGLT-2i showed a similar risk for MI/stroke/mortality, lower risk for HHF/mortality and HHF, and a similar safety profile except for an increased risk for genital infections compared with those receiving metformin. Brigham and Women's Hospital and Harvard Medical School.

Comparative Assessment of the Long-Term Effectiveness and Safety of Dapagliflozin and Empagliflozin as Add-on Therapy to Hypoglycemic Drugs in Patients with Type 2 Diabetes.

Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce blood glucose, blood pressure, and body weight in patients with type 2 diabetes (T2D). However, the comparative long-term effectiveness and safety of SGLT2i among similar drugs, administered at different doses, have not been assessed. In this study, we compared the long-term effectiveness and safety of SGLT2i (dapagliflozin versus empagliflozin) as add-on therapy to hypoglycemic agents in T2D patients. Methods This study was a single-center, 3-year, retrospective, observational study. For all patients in the study, drugs were evaluated for safety by documenting adverse drug reactions. The primary effectiveness was evaluated as the difference between hemoglobin A1c (HbA1c) values obtained at baseline and those obtained after 36 months of treatment. The proportion of participants with HbA1c levels <7.0% and <6.5% was also analyzed. Results In total, 680 patients were enrolled in this study. Using propensity score matching, 234 patients each from the dapagliflozin and empagliflozin groups were selected based on patient characteristics. After 36 months of treatment, clinical parameters (including HbA1c, fasting plasma glucose, alanine aminotransferase, triglyceride levels, body weight, and systolic blood pressure) decreased significantly in these groups. The changes from the baseline for the physiological values and clinical parameters did not vary among the different dose groups of SGLT2i. The incidence of adverse drug reactions was approximately 7–8%. All patients with observed serious adverse reactions were hospitalized for urinary tract infections. Conclusion Our study showed that the long-term continuous use of either dapagliflozin or empagliflozin as add-on therapy to hypoglycemic drugs for T2D patients is synergistically effective for lowering blood glucose, reducing body weight, and stabilizing blood pressure. Additionally, there was no significant difference in efficacy between dapagliflozin and empagliflozin, even with the administration of different doses of these agents.

Cardioprotection by selective SGLT-2 inhibitors in a non-diabetic mouse model of myocardial ischemia/reperfusion injury: a class or a drug effect?

Major clinical trials with sodium glucose co-transporter-2 inhibitors (SGLT-2i) exhibit protective effects against heart failure events, whereas inconsistencies regarding the cardiovascular death outcomes are observed. Therefore, we aimed to compare the selective SGLT-2i empagliflozin (EMPA), dapagliflozin (DAPA) and ertugliflozin (ERTU) in terms of infarct size (IS) reduction and to reveal the cardioprotective mechanism in healthy non-diabetic mice. C57BL/6 mice randomly received vehicle, EMPA (10mg/kg/day) and DAPA or ERTU orally at the stoichiometrically equivalent dose (SED) for 7days. 24h-glucose urinary excretion was determined to verify SGLT-2 inhibition. IS of the region at risk was measured after 30min ischemia (I), and 120min reperfusion (R). In a second series, the ischemic myocardium was collected (10th min of R) for shotgun proteomics and evaluation of the cardioprotective signaling. In a third series, we evaluated the oxidative phosphorylation capacity (OXPHOS) and the mitochondrial fatty acid oxidation capacity by measuring the respiratory rates. Finally, Stattic, the STAT-3 inhibitor and wortmannin were administered in both EMPA and DAPA groups to establish causal relationships in the mechanism of protection. EMPA, DAPA and ERTU at the SED led to similar SGLT-2 inhibition as inferred by the significant increase in glucose excretion. EMPA and DAPA but not ERTU reduced IS. EMPA preserved mitochondrial functionality in complex I&II linked oxidative phosphorylation. EMPA and DAPA treatment led to NF-kB, RISK, STAT-3 activation and the downstream apoptosis reduction coinciding with IS reduction. Stattic and wortmannin attenuated the cardioprotection afforded by EMPA and DAPA. Among several upstream mediators, fibroblast growth factor-2 (FGF-2) and caveolin-3 were increased by EMPA and DAPA treatment. ERTU reduced IS only when given at the double dose of the SED (20mg/kg/day). Short-term EMPA and DAPA, but not ERTU administration at the SED reduce IS in healthy non-diabetic mice. Cardioprotection is not correlated to SGLT-2 inhibition, is STAT-3 and PI3K dependent and associated with increased FGF-2 and Cav-3 expression.

Effects of the SGLT2 Inhibition on Cardiac Remodeling in Streptozotocin-Induced Diabetic Rats, a Model of Type 1 Diabetes Mellitus.

Clinical trials have shown that sodium glucose co-transporter 2 (SGLT2) inhibitors improve clinical outcomes in diabetes mellitus (DM) patients. As most studies were performed in Type 2 DM, the cardiovascular effects of SGLT2 inhibition still require clarification in Type 1 DM. We analyzed the effects of SGLT2 inhibitor dapagliflozin on cardiac remodeling in rats with streptozotocin-induced diabetes, an experimental model of Type 1 DM. Methods: Male Wistar rats were assigned into four groups: control (C, n = 14); control treated with dapagliflozin (C + DAPA, n = 14); diabetes (DM, n = 20); and diabetes treated with dapagliflozin (DM + DAPA, n = 20) for 8 weeks. Dapagliflozin dosage was 5 mg/kg/day. Statistical analyses: ANOVA and Tukey or Kruskal–Wallis and Dunn. Results: DM + DAPA presented decreased blood pressure and glycemia and increased body weight compared to DM (C 507 ± 52; C + DAPA 474 ± 50; DM 381 ± 52 *; DM + DAPA 430 ± 48 # g; * p < 0.05 vs. C; # p < 0.05 vs. C + DAPA and DM + DAPA). DM echocardiogram presented left ventricular and left atrium dilation with impaired systolic and diastolic function. Cardiac changes were attenuated by dapagliflozin. Myocardial hydroxyproline concentration and interstitial collagen fraction did not differ between groups. The expression of Type III collagen was lower in DM and DM + DAPA than their controls. Type I collagen expression and Type I-to-III collagen ratio were lower in DM + DAPA than C + DAPA. DM + DAPA had lower lipid hydroperoxide concentration (C 275 ± 42; C + DAPA 299 ± 50; DM 385 ± 54 *; DM + DAPA 304 ± 40 # nmol/g tissue; * p < 0.05 vs. C; # p < 0.05 vs. DM) and higher superoxide dismutase and glutathione peroxidase activity than DM. Advanced glycation end products did not differ between groups. Conclusion: Dapagliflozin is safe, increases body weight, decreases glycemia and oxidative stress, and attenuates cardiac remodeling in an experimental rat model of Type 1 diabetes mellitus.

Systemic proteomic and metabolomic signature of the SGLT2 inhibitor dapagliflozin

BackgroundDapagliflozin is a member of a new class of medication called gliflozins indicated for the treatment of diabetes. Gliflozins lower blood glucose levels by inhibition of the sodium glucose co‐transporter 2 (SGLT2), which is predominantly expressed in the S1 segment of renal proximal tubules and responsible for &gt;90% of renal glucose reabsorption. Gliflozins also protect the kidney and heart, which cannot be solely explained by blood glucose lowering. To gain further mechanistic insights, we determined the metabolomic and proteomic signature of dapagliflozin in a murine model of diabetes.MethodsMale C57BL/6 non‐diabetic wildtype and littermate Ins2 (Akita) diabetic mice, both fed a Western diet, were given dapagliflozin (10 mg/kg diet) or vehicle for one week (4 groups, N=8/group). Blood and urine glucose levels confirmed the expected treatment response. We analyzed metabolome, proteome and phosphoproteome for a range of tissues (kidney, liver, heart, smooth muscle, white adipose tissue) and body fluids (serum, urine, erythrocytes), and extended the analysis to the gut metaproteome. For untargeted metabolomics, analytes were measured by HILIC‐MS/MS and RP‐MS/MS. For proteomics and phosphoproteomics, TMT labelled (TMT16plex) peptides were separated by high pH reverse phase fractionation and measured by LC‐MS/MS including FAIMS (Thermo Scientific Orbitrap Exploris 480 mass spectrometer).ResultsMulti‐layered omics data were obtained comprising 11341 proteins, 14762 phosphorylation sites, and 217 metabolites. In general, dapagliflozin‐induced changes were more distinct in Western diet‐fed non‐diabetic than diabetic mice. Metabolomics revealed effects of dapagliflozin on amino acid, carbohydrate and lipid metabolism with most changes observed in urine, serum and liver. In comparison, dapagliflozin‐induced perturbations on proteome and phosphoproteome level were observed predominantly in kidney and affected ATP/lipid/carbohydrate/nitrogen metabolism, mitochondria, mitophagy, methyl transferases, methyl CpG‐binding, kinases, deacetylases, endosomes, cell junctions and gene expression. Interestingly, also the gut metaproteome was affected by dapagliflozin with significant changes in Bacteroides and Bifidobacterium species.ConclusionThe SGLT2 inhibitor dapagliflozin induces distinct effects on kidney proteomics, associated with robust metabolomic signatures in plasma, urine and liver, as well as effects on the gut metaproteome. These effects occurred independent of blood glucose levels and support a concept of pleiotropic effects of SGLT2 inhibition that may originate in the kidney but induce wide‐ranged extrarenal metabolic effects and consequences.