ABSTRACT
Aim: To provide a pooled effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on cardiovascular outcomes in patients with heart failure with preserved ejection fraction (HFpEF: _x0001_50%) or/and mildly reduced EF (HFmrEF: 41e49%) regardless of baseline diabetes. Methods: We systemically searched PubMed/MEDLINE, Embase, Web of Science databases and clinical trial registries using appropriate keywords till August 28, 2022, to identify randomized controlled trials (RCTs) or post-hoc analysis of RCTs, reporting cardiovascular death (CVD) and/or urgent visits/hospitalization for heart failure(HHF) in patients with HFmrEF/HFpEF receiving SGLTi vs. placebo. Hazard ratios (HR) with 95% confidence intervals (CI) for outcomes were pooled together using generic inverse variance method with fixed-effects model. Results: We identified six RCTs, pooling data retrieved from 15,769 patients with HFmrEF/HFpEF. Pooled analysis showed that compared to placebo, SGLT2i use was significantly associated with improved CVD/ HHF outcomes in HFmrEF/HFpEF (pooled HR 0.80, 95% CI: 0.74, 0.86, p < 0.001, I 2 ¼ 0%). When separately analyzed, benefits of SGLT2i remained significant across HFpEF (N ¼ 8891, HR 0.79, 95% CI: 0.71, 0.87, p < 0.001, I 2 ¼ 0%) and HFmrEF (N ¼ 4555, HR 0.77, 95% CI: 0.67, 0.89, p < 0.001, I 2 ¼ 40%). Consistent benefits were observed also in HFmrEF/HFpEF subgroup without baseline diabetes (N ¼ 6507, HR 0.80, 95% CI: 0.70, 0.91, p < 0.001, I 2 ¼ 0%). Sensitivity analysis including the DELIVER and EMPEROR-Preserved trials found a trend towards significant beneficial effects on CV deaths with no heterogeneity (HR 0.90, 95% CI: 0.79, 1.02, p ¼ 0.08, I 2 ¼ 0%). Conclusions: This meta-analysis established the place of SGLT2i as a foundational therapy among patients with HF with preserved and mildly reduced EF regardless of diabetes.
ABSTRACT
Objective:To analyze the efficacy and safety of dapagliflozin combined with metformin in the treatment of type 2 diabetes.Methods:A prospective research method was adopted. A total of 60 patients with type 2 diabetes who were treated in Huainan Chaoyang Hospital from January 2019 to December 2021 were collected as research objects, and the above patients were divided into the observation group (30 cases) and the control group (30 cases) according to the random number table method. After admission, they were treated with oral metformin sustained-release tablets combined with exercise and diet control. On this basis, the observation group was treated with dapagliflozin, while the control group was treated with glimepiride. The blood glucose-related indexes after 3 months of treatment, blood lipid indexes after 1 month of treatment, and adverse reactions were compared between the two groups of patients.Results:After 3 months of treatment, the fasting blood glucose (FBG), 2 h postprandial blood glucose (2 h PBG) and glycosylated hemoglobin (HbA 1c) of the two groups were significantly lower than those before treatment, observation group: (6.60 ± 1.01) mmol/L vs. (7.76 ± 1.82) mmol/L, (10.43 ± 2.74) mmol/L vs. (14.05 ± 3.84) mmol/L, (5.90 ± 1.56)% vs. (8.46 ± 2.07)%; control group: (6.77 ± 0.95) mmol/L vs. (7.82 ± 1.38) mmol/L, (10.17 ± 2.23) mmol/L vs. (14.01 ± 2.63) mmol/L, (6.14 ± 1.51)% vs. (8.73 ± 1.58)% ( P<0.05), but there was no difference in FBG, 2 h PBG and HbA 1c between the two groups ( P>0.05). The total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in the observation group were significantly lower than those in the control group: (5.02 ± 0.98) mmol/L vs. (5.71 ± 0.77) mmol/L, (2.81 ± 0.69) mmol/L vs. (3.39 ± 0.87) mmol/L ( P<0.05). There was no difference in adverse reactions ( P>0.05). Conclusions:For patients with type 2 diabetes mellitus, on the basis of metformin sustained-release therapy, whether combined with dapagliflozin or glimepiride therapy has good hypoglycemic effect, but dapagliflozin has more advantages in improving blood lipids.
ABSTRACT
Male diabetic individuals present a marked impairment in fertility; however, knowledge regarding the pathogenic mechanisms and therapeutic strategies is unsatisfactory. The new hypoglycemic drug dapagliflozin has shown certain benefits, such as decreasing the risk of cardiovascular and renal events in patients with diabetes. Even so, until now, the effects and underlying mechanisms of dapagliflozin on diabetic male infertility have awaited clarification. Here, we found that dapagliflozin lowered blood glucose levels, alleviated seminiferous tubule destruction, and increased sperm concentrations and motility in leptin receptor-deficient diabetic db/db mice. Moreover, the glucagon-like peptide-1 receptor (GLP-1R) antagonist exendin (9-39) had no effect on glucose levels but reversed the protective effects of dapagliflozin on testicular structure and sperm quality in db/db mice. We also found that dapagliflozin inhibited the testicular apoptotic process by upregulating the expression of the antiapoptotic protein B-cell lymphoma 2 (BCL2) and X-linked inhibitor of apoptosis protein (XIAP) and inhibiting oxidative stress by enhancing the antioxidant status, including total antioxidant capacity, total superoxide dismutase (SOD) activity, and glutathione peroxidase (GPx) activity, as well as decreasing the level of 4-hydroxynonenal (4-HNE). Exendin (9-39) administration partially reversed these effects. Furthermore, dapagliflozin upregulated the glucagon-like peptide-1 (GLP-1) level in plasma and GLP-1R expression by promoting AKT8 virus oncogene cellular homolog (Akt) phosphorylation in testicular tissue. Exendin (9-39) partially inhibited Akt phosphorylation. These results suggest that dapagliflozin protects against diabetes-induced spermatogenic dysfunction via activation of the GLP-1R/phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Our results indicate the potential effects of dapagliflozin against diabetes-induced spermatogenic dysfunction.
Subject(s)
Mice , Animals , Male , Proto-Oncogene Proteins c-akt/metabolism , Antioxidants , Phosphatidylinositol 3-Kinases/metabolism , Semen/metabolism , Diabetes MellitusABSTRACT
【Objective】 To observe the clinical effect of combination therapy of sacubitril valsartan and dapagliflozin in heart failure with reduced ejection fraction (HFrEF) and non-diabetes patients. 【Methods】 This study involved 96 patients with HFrEF and non-diabetes. The patients were randomly divided into control group (50 cases) and observation group (46 cases). On the basis of routine treatment, the control group was treated with sacubitril valsartan, while the observation group was treated with sacubitril valsartan and dapagliflozin. After 1-month and 6-month treatment, we monitored blood pressure, N-terminal pro brain natriuretic peptide (NT-proBNP), high sensitivity troponin T (cTnT), fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), left ventricular ejection fraction (LVEF), left ventricular end diastolic diameter (LVEDd), left atrial diameter (LAD), left ventricular posterior wall thickness (LVPW), Minnesota soda heart failure life quality score (MLHFQ), the incidence of rehospitalization and death, and major adverse cardiovascular events (MACE) in the two groups. 【Results】 After 6 months, systolic blood pressure, cTnT, NT-proBNP, LVEDd, LVPW, and LAD of the observation group were significantly decreased compared with the control group (P0.05). 【Conclusion】 The combination treatment of sacubitril valsartan and dapagliflozin on HFrEF and non-diabetes patients can significantly improve cardiac function, inhibit myocardial remodeling, reduce the incidence of MACE, and improve the prognosis.
ABSTRACT
【Objective】 To investigate the role and mechanism of dapagliflozin (Dapa), a sodium glucose co-transporter 2 inhibitor, in acute liver injury. 【Methods】 Eight-week-old C57BL6/J mice were given a single intraperitoneal injection of CCl4 to induce acute liver injury. The mice were preventively given 5 mg/kg Dapa by gavage 24 h and 2 h before CCl4 injection, while those in the control group were given an equal volume of solvent gavage. After 24 h, the mice were anesthetized and sacrificed. H&E staining, plasma biochemistry, RT-qPCR, and Western blotting were used to detect the severity of liver injury and the expressions of macrophage-related genes. 【Results】 In the CCl4 group, hepatic infiltration of inflammatory cells increased, and liver and renal functions significantly deteriorated, which was further aggravated by Dapa. CCl4 could promote the expressions of M1 macrophages and fibrosis-related genes in the liver, but reduce those of M2 and antioxidant-related genes, and the latter was further inhibited by Dapa. In addition, the protein expression of arginase 1 decreased and that of SGLT2 increased after Dapa intervention, while NF-κB pathway did not change significantly, suggesting that Dapa might directly affect the energy metabolism homeostasis in the liver and aggravate acute liver injury induced by CCl4. 【Conclusion】 Dapa can exacerbate hepatic and renal damage in acute stage of liver injury, inhibit macrophages M2 polarization, and aggravate oxidative stress and inflammatory injury induced by CCl4.
ABSTRACT
Objective:To investigate the clinical effect of dapagliflozin combined with metformin on type 2 diabetes mellitus (T2DM).Methods:A total of 100 patients with T2DM who received treatment in The Second People's Hospital of Hefei from June 2019 to May 2021 were included in this study. They were randomly divided into a control group ( n = 50) and an experimental group ( n = 50). The control group was treated with metformin, and the experimental group was treated with dagglitazin combined with metformin. All patients were treated for 3 months. Blood glucose index, blood lipid level, and the incidence of adverse reactions were compared between the two groups. Results:After treatment, fasting blood glucose, 2-hour post-prandial blood glucose, and glycosylated hemoglobin in the experimental group were (5.56 ± 0.37) mmol/L, (8.32 ± 0.23) mmol/L, and (6.17 ± 0.26)% respectively, which were significantly lower than (6.96 ± 0.48) mmol/L, (9.58 ± 0.39) mmol/L, and (7.27 ± 0.26)% respectively in the control group ( t = 3.59, 6.92, 5.03, all P < 0.05). The total cholesterol and triglyceride in the experimental group were (3.58 ± 0.53) mmol/L and (1.25±0.26) mmol/L, respectively, which were significantly lower than (4.94 ± 0.58) mmol/L and (1.93 ± 0.18) mmol/L in the control group ( t = 3.16, 4.25, both P < 0.05). There was no significant difference in the incidence of adverse reactions between the two groups ( P > 0.05). Conclusion:Dapagliflozin combined with metformin can effectively control blood glucose and blood lipid in T2DM patients without increasing adverse reactions.
ABSTRACT
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have varied metabolic effects beyond increasing glycosuria. This consensus review examines the role of dapagliflozin in health promotion, particularly its benefits in patients with and without type 2 diabetes mellitus (T2DM) and in cardiorenal rehabilitation post-coronavirus disease 2019 (COVID-19). Consensus recommendations were developed by subject experts in Endocrinology and Diabetology based on the online meeting held on 27 June 2020 to review the available evidence related to the role of SGLT2 inhibitors, with a focus on cardiovascular and renal metabolic therapy. Evidence suggests that dapagliflozin has a direct role in improving clinical outcomes in patients with chronic kidney disease (CKD) or heart failure (HF). These benefits of dapagliflozin were independent of reduction in blood pressure, glycemic control and weight, and also extend to patients without diabetes. The use of dapagliflozin in metabolic syndrome was endorsed by the majority of the experts; however, this would be off-label. It was opined that the role of dapagliflozin would currently be limited to treating T2DM with a focus on preventing HF or kidney disease progression. The need for conducting multidisciplinary academic meetings to have a balanced approach regarding the use of dapagliflozin among nondiabetic patients and the need for detailed evaluation of the role of SGLT2 inhibitors in vasculometabolic and cardiorenal rehabilitation post-COVID was also suggested.
ABSTRACT
As per current statistics, India accounts for more than 74 million individuals living with diabetes. Many of these individuals have associated cardiovascular disease (CVD) and chronic kidney disease (CKD) comorbidities. Optimal glycemic management is important because uncontrolled glycemia may accelerate the macrovascular and microvascular complications, further aggravating the comorbid conditions. Metformin is used as the first-line therapy in most persons. However, there are some who do not tolerate metformin, are unable to achieve required glycemic targets or require greater efforts for cardiovascular (CV) risk reduction. These patients require an alternative hypoglycemic agent to be used as either monotherapy or as combination treatment with metformin, respectively. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are one such novel class of drugs that can be used as either monotherapy or as part of two drug (dual) or three drug (triple) combinations with other oral hypoglycemic agents or insulin. Dapagliflozin is a promising option for managing type 2 diabetes with CV and renal benefits, weight and blood pressure reducing properties. A low risk of hypoglycemia and drug-drug interactions are the added advantages. In this article, the authors have reviewed the existing clinical evidences on dapagliflozin and highlighted its place in the diabetes management landscape
ABSTRACT
Objective:To explore if protective effects of dapagliflozin (Dapa) administration on attenuating DOX-induced myocardial injury in rats.Methods:A total of 30 specific pathogens free grade 8 week old male Sprague Dawley rats. Rats were randomly divided into three groups. Control group (Con group, n = 5), rats received intraperitoneal saline (1.25 ml/kg) injection once per week plus saline (8 mg/kg) daily via gavage for 6 weeks. Dox group ( n = 15) rats received intraperitoneal Dox (2.5 mg/kg) injection once per week plus saline (8 mg/kg) daily via gavage for 6 weeks. Dox + Dapa group ( n = 10), rats received intraperitoneal Dox (2.5 mg/kg) injection once per week plus Dapagliflozin (4 mg/kg) daily via gavage for 6 weeks, observed to week 10. Survival status, echocardiography, pathology, and expression of Bcl-2, Bax gene and protein were observed. Results:The survival rate of ats in Con, Dox, and Dapa+Dox groups was 100.0%, 66.7% and 90.0% respectively. The echocardiography were performed in Con, Dox, and Dapa+Dox groups left ventricular ejection fraction was (95.40 ± 2.51)%, (83.09 ± 4.92)% and (91.71 ± 3.45)%, respectively; left ventricular fraction shortening was (66.80 ± 7.43)%, (47.27 ± 5.10)% and (59.43 ± 6.92)%, respectively; Both indexes in Dapa+Dox group was higher than that in Dox group, but lower than that in Con group, all P<0.05; Left ventricular end-diastolic diameter was (4.80 ± 0.83) mm, (5.90 ± 0.83) mm and (4.85 ± 0.69) mm respectively; left ventricular end-systolic diameterwas (1.80 ± 0.44) mm, (2.90 ± 0.53) mm and (2.00 ± 0.57) mm in Con, Dox, and Dapa + Dox groups, respectively; Both indexes in Dapa + Dox group was decreased than that in Dox group, but Dapa + Dox group was increased than that in Con group, all P<0.05. Pathologic changes have been shown that myocardial fibers arranged neatly in the Con group under HE staining, while those broken myocardial fibers disordered arranged in the Dox group, and those changes in the Dapa + Dox group were slightly relieved than that in Dox group. The collagen volume fraction of rats in Con, Dox and Dapa+Dox groups were (2.64 ± 1.04)%, (16.85 ± 1.70)% and (6.75 ± 1.89)% under sirius red staining, Dapa+Dox group was lower than that in Dox group but higher than that in Con group, all P<0.05. Pathologic changes under transmission electron microscope have been shown that a few of normal structure mitochondria in the Con group. A large number of swollen mitochondria with disappeared mitochondrial crest in the Dox group; but neatly arranged with mitochondrial crest blurred in the Dapa+Dox group. The quantitative real-time PCR was used to detected Bcl-2 and Bax, there were 0.93 ± 0.09, 0.35 ± 0.30 and 0.89 ± 0.25 in Bcl-2, 0.99 ± 0.10, 3.10 ± 0.10 and 0.86 ± 0.04) in Bax, while Bcl-2/Bax 0.94 ± 0.17, 0.11 ± 0.06 and 1.03 ± 0.27, respectively. The westernblot was used to detected Bcl-2 and Bax, there were 1.00 ± 0.18, 0.32 ± 0.20 and 1.30 ± 0.41 in Bcl-2, 0.66 ± 0.11, 2.44 ± 0.66 and 0.90 ± 0.61 in Bax, while Bcl-2/Bax: 1.50 ± 0.18, 0.12 ± 0.05 and 1.80 ± 0.82, respectively; the above results shown that both myocardial Bax mRNA and protein expression in Dox group were higher than that in Dapa + Dox group and Con group, both P<0.05, and there was no difference in the two later groups, P>0.05; both the myocardial Bcl-2 mRNA and protein expression in Dox group were lower than that in Dapa+Dox group and Con group, both P<0.05, and there was no difference between two later groups, P>0.05; Bcl-2/Bax in Dox group was significantly lower thanthat in Dapa+Dox groupand Con group, both P<0.05, and there was no difference between Dapa+Dox group and Con group, P>0.05. Conclusions:Simultaneous dapagliflozin treatment significantly attenuated DOX-induced cardiotoxicity, which might be related to prevent myocardial apoptosis.
ABSTRACT
Objective:To investigate the clinical efficacy and prognosis of sacubatrovalsartan combined with dapagliflozin in patients with heart failure with reduced ejection fraction (HFrEF).Methods:Totally 206 consecutive patients with HFrEF in our hospital from March 2021 to September 2021 were enrolled and randomly(random number) divided into the control group ( n = 51), the sacubatrovalsartan group ( n = 52), the dapagliflozin group ( n=51) and the combined treatment group ( n= 52). The baseline clinical data of patients and laboratory examination results were collected. The changes of related results before and after treatment in each group were analyzed and compared. After discharge, the enrolled patients were followed up by outpatient or telephone for an average of 6 months to determine whether the patients had heart failure rehospitalization, ventricular arrhythmia, major adverse cardiovascular events (MACE), etc. Results:After anti-heart failure treatment, there were significant differences in NT-proBNP, left ventricular ejection fraction (LVEF) and soluble growth stimulating gene 2 protein (ST2) among the four groups. NT-proBNP and ST2 in the combined treatment group were significantly lower than those in the other groups, and LVEF was significantly higher. Compared with the control group, the rehospitalization due to heart failure and MACE events in the other three groups were significantly lower ( P < 0.05), and the combined treatment group had the lowest ( P < 0.05). The Kaplan-Meier survival curve showed that the survival probability of the other groups was significantly higher than that of the control group, and was the highest in the combined treatment group. Conclusions:The clinical efficacy and prognosis of HFrEF patients could be significantly improved after the treatment of sacubatrovalsartan combined with dapagliflozin.
ABSTRACT
Objective:To investigate the efficacy and safety of dapagliflozin combined with liraglutide in the treatment of type 2 diabetes mellitus complicated by chronic heart failure.Methods:Ninety patients with type 2 diabetes mellitus complicated by chronic heart failure, who received treatment in the Siming Branch of the First Affiliated Hospital of Xiamen University from August 2018 to August 2020, were included in this study. They were randomly assigned to receive either routine treatment + liraglutide (control group, n = 45) or routine treatment + liraglutide + dapagliflozin (observation group, n = 45) for 16 weeks. Blood glucose control, glycosylated hemoglobin level, cardiac function grade, serum N-terminal B-type natriuretic peptide precursor level, left ventricular ejection fraction, total effective rate, and adverse reactions were compared between the control and observation groups before and after treatment. Results:There were no significant differences in blood glucose level, glycosylated hemoglobin, and cardiac function grade between the two groups (all P > 0.05) before treatment. After treatment, fasting blood glucose level, 2-hour postprandial glucose level, glycosylated hemoglobin level, cardiac function grade, N-terminal B-type natriuretic peptide precursor , and left ventricular ejection fraction were (7.21 ± 1.23) mmol/L, (9.14 ± 2.24) mmol/L, (7.03 ± 2.59)%, (1.25 ± 0.21), (548.9 ± 116.3) ng/L, and (46.7 ± 7.5)%, respectively, in the observation group and they were (9.45 ± 2.21) mmol/L, (11.24 ± 5.29) mmol/L, (8.23 ± 1.91)%, (2.23 ± 0.46), (510.3 ± 110.7) ng/L, and (48.1 ± 6.8)%, respectively in the control group. There were significant differences in these indexes between the two groups ( t = 24.03, 20.47, 51.09, 32.42, 10.19, 13.23, all P < 0.05). Total effective rate was significantly higher in the observation group than in the control group [97.78% (44/45) vs. 80.00% (36/45), χ2 = 7.20, P < 0.05). There was no significant difference in the incidence of adverse reactions between the two groups ( P > 0.05). Conclusion:Dapagliflozin combined with liraglutide is highly effective in the treatment of type 2 diabetes mellitus complicated by chronic heart failure. The combined therapy has good effects on blood glucose level and cardiac function and is certainly safe.
ABSTRACT
ObjectiveTo study the clinical efficacy of dapagliflozin combined with Shexiang Baoxinwan （SXBXW） in the treatment of acute heart failure with reduced ejection fraction （HFrEF） and syndrome of Qi deficiency and blood stasis. MethodA total of 176 patients hospitalized due to acute HFrEF （syndrome of Qi deficiency and blood stasis） were selected and randomized into control group， SXBXW group， dapagliflozin group， and SXBXW + dapagliflozin group （the latter three groups were called the intervention groups）. The New York Heart Association （NYHA） class， 6-minute walk test （6MWT） score， Kansas City Cardiomyopathy Questionnaire （KCCQ） score， traditional Chinese medicine （TCM） syndrome score， N-terminal pro-brain natriuretic peptide （NT-proBNP）， soluble suppression of tumorigenicity 2 （sST2）， interleukin-6 （IL-6）， and hypersensitive C-reactive protein （hs-CRP） of the patients were evaluated and measured at the time of admission， 1 week after treatment， and 2 weeks of treatment. Furthermore， the hospital stay， in-hospital mortality， and 30-day re-admission rate were recorded. Statistical analysis was performed to evaluate the efficacy of each group. ResultAfter 1 week of treatment， the SXBXW group exhibited superior NYHA class， KCCQ score， TCM syndrome score and curative effect， IL-6， and hs-CRP to the control group （P<0.05， P<0.01）. After 2 weeks of treatment， the SXBXW group showed superior TCM syndrome score， TCM curative effect， and hs-CRP （P<0.05， P<0.01） to the control group. The dapagliflozin group was superior to the control group in terms of TCM syndrome score， NT-proBNP， and sST2 （P<0.05， P<0.01） after 1 week of treatment and in terms of NYHA class， KCCQ score， NT-proBNP， sST2， and hospital stay （P<0.05， P<0.01） after 2 weeks of treatment. The SXBXW + dapagliflozin group exhibited better efficacy than the control group in terms of NYHA class， 6MWT score， KCCQ score， TCM syndrome score and curative effect， NT-proBNP， sST2， IL-6， and hs-CRP （P=0.014） after 1 week of treatment and in terms of NYHA class， KCCQ score， TCM syndrome score and curative effect， NT-proBNP， sST2， IL-6， hs-CRP， and hospital stay （P<0.01） after 2 weeks of treatment. ConclusionSXBXW and dapagliflozin have good therapeutic effect on acute HFrEF and syndrome of Qi deficiency and blood stasis， and their combination demonstrated better therapeutic effect， with good safety and tolerability.
ABSTRACT
@#AIM: To explore the effect of dapagliflozin on the apoptosis and oxidative stress of high glucose-induced human retinal vascular endothelial cells and its regulatory effect on forkhead FOXO4. <p>METHODS: High glucose-induced human retinal vascular endothelial cells(HRVECs)were used to establish a cell injury model(high glucose group). Experimental groups include high glucose+dapagliflozin low-dose group(1ng/L dapagliflozin), high glucose+dapagliflozin medium-dose group(5ng/L dapagliflozin), high glucose+dapagliflozin high-dose group(10ng/L dapagliflozin), high glucose+dapagliflozin high-dose+pcDNA group, high glucose+dapagliflozin high-dose+pcDNA-FOXO4 group, and normal sugar group(5.5mmol/L D-glucose). Flow cytometry was used to detect the apoptosis rate. The levels of superoxide dismutase(SOD)and malondialdehyde(MDA)were tested with corresponding kits. Western blot assay was used to detect the protein level of FOXO4. <p>RESULTS: Compared with the normal sugar group, the apoptosis rate(<i>P</i><0.05), the level of MDA(<i>P</i><0.05)and FOXO4(<i>P</i><0.05)were increased, but the level of SOD was decreased(<i>P</i><0.05)in high-glucose group. Compared with the high glucose group, cell apoptosis rate(<i>P</i><0.05), the level of MDA(<i>P</i><0.05)and the protein level of FOXO4 were decreased(<i>P</i><0.05), but the level of SOD was increased(<i>P</i><0.05)in high glucose+medium-dose dapagliflozin group and high glucose+high-dose dapagliflozin group. Compared with high glucose+dapagliflozin high-dose+pcDNA group, the apoptosis rate(<i>P</i><0.05)and the level of MDA(<i>P</i><0.05)were increased, but the level of SOD was decreased(<i>P</i><0.05)in high glucose+dapagliflozin high-dose+pcDNA-FOXO4 group(<i>P</i><0.05). <p>CONCLUSION: Dapagliflozin could inhibit oxidative stress and cell apoptosis in high glucose-induced HRVECs by down-regulating FOXO4, thereby reducing cell damage.
ABSTRACT
Objective:To investigate the protective effect of dapagliflozin on cell damage and in HK-2 cells induced by high concentration of glucose.Methods:HK-2 cells were divided into four groups: control group (NC) , high glucose model group (HG) , dapagliflozin group (CS-179) and metformin group (PC) . After treatment with different drugs for 24 h, CCK-8 assay was applied to determine HK-2 cells viability; ROS, SOD, CAT and MDA levels were measured by a multi-detection reader; The protein expression of Nrf2 was determined by Western blot.Results:The results of CCK8 showed that the cell survival rate of the high glucose model group was 58.0%±0.8%, and that of the dapagliflozin group was 87.0%±0.4%. Dapagliflozin significantly increased the survival rate of HK-2 cells, and the results were statistically significant ( P<0.01) . The microplate reader test found that compared with the high glucose model group (ROS: 3.46 ± 0.05, MDA: 25.37 ± 0.61, SOD: 55.89 ± 4.09, CAT: 10.22 ± 1.67) , dapagliflozin reduced the accumulation of ROS (1.97±0.04) and MDA (9.5±0.4) caused by high glucose in HK-2 cells (both P<0.01) , increasing the vigor of SOD (114.95±4.19) and CAT (32.83±2.01) (both P<0.01) . Compared with the expression of Nrf2 protein in the high glucose model group (0.26±0.03) , the expression of Nrf2 protein (0.48±0.03) in dapagliflozin group was significantly increased ( P<0.01) . Conclusion:Dapagliflozin can alleviate the HK-2 cells damage induced by high concentration of glucose via reducing oxidative damage, and acti-vating Nrf2 antioxidant transcription factor.
ABSTRACT
@#Diabetes Mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both. DM is a significant health care concern. Worldwide, the prevalence is increasing at an alarming rate despite using different classes of anti-hyperglycemic agents. Although several treatment options reduce hyperglycemia, only half the patients achieve desirable glycemic targets. Newer treatments that significantly reduce hyperglycemia with novel mechanism of action and acceptable safety profiles are warranted to reduce complications associated with type 2 DM. Sodium-glucose cotransporter-2 inhibitors are anti-hyperglycemic agents with unique mechanism of action that lower blood glucose level independent of insulin. Recent findings on efficacy and safety establish their role in the treatment of DM. Sodium-glucose cotransporter-2 inhibitors may be an option in type 2 DM patients not willing or not ready to start insulin, those requiring additional glucose lowering and in those with acceptable risk factor profiles. Dapagliflozin (Farxiga) can be used at any stage of type 2 DM as a mono-therapy or in combination with other oral hypoglycemic agents and insulin. This review highlights the efficacy and safety of dapagliflozin as an anti-hyperglycemic agent and its use in co-morbid conditions like chronic kidney disease and cardiovascular diseases
ABSTRACT
OBJECTIVE：To excavate and evaluate ADR signals of SGLT 2 inhibitors as canagliflozin ，dapagliflozin and empagliflozin，and to provide reference for rational drug use in the clinic. METHODS ：The proportional reporting ratio （PRR）and reporting odds ratio （ROR）were used to find the adverse drug reactions （ADR）signal of SGLT 2 inhibitors as canagliflozin ， dapagliflozin and empagliflozin from the second quarter of 2013 to the third quarter of 2020 in the US FDA Adverse Event Reporting System （FAERS）. The basic information （including gender ，age，reporting year ，reporting country ，severe ADR ）and safety warning signals of corresponding patients in ADR report were analyzed. RESULTS ：Among 6 029 375 ADR reports ，SGLT2 inhibitors of 43 807 ADR reports were concomitant and suspected drugs ；there were 19 301 ADR reports of canagliflozin ，10 960 ADR reports of dapagliflozin ，13 546 ADR reports of empagliflozin. Except for the ADR patients with unknown gender and missing age ，the gender distribution of the included reports was balanced ，mainly in the range of 50-75 years old. The reporting year was mainly in 2018，and the main reporting country was the United States ，with“hospitalization or prolonged hospitalization ” as the main serious ADR. A total of 573 ADR signals were obtained ，involving 26 systems，mainly focusing on metabolic and nutritional diseases ，endocrine disorders ，kidney and urinary system disease ，infection and invasion diseases ，etc. The results showed that there were 14 main ADR signals in the top 10 ADR of canagliflozin ，dapagliflozin and empagliflozin. The strongest ADR signals of dapagliflozin and empagliflozin were ketoacidosis （PRR＝119.64/140.11，95％CI lower limit of ROR ＝148.28/ 178.78）and fungal infection （PRR＝47.76/34.77，95％ CI lower limit of ROR ＝50.69/36.28）；except above signals in addition ， toe amputation （PRR＝489.79，95％CI lower limit of ROR ＝520.15）and osteomyelitis （PRR＝61.42，95％CI lower limit of ROR＝65.38）were strong in the ADR signals of canagliflozin. CONCLUSIONS ：SGLT2 inhibitors have a higher security risk in metabolic and nutritional diseases ，endocrine disorders ，kidney and urinary system ，and infection and intrusion diseases. Dapagliflozin，canagliflozin and empag liflozin are prone to cause ADR such as ketoacidosis and fungal infection ，while canagliflozin is easy to cause ADRs such as toe amputation and osteomyelitis.
ABSTRACT
Introduction: In patients with type 2 diabetes mellitus,dapagliflozin, the sodium–glucose cotransporter 2 inhibitorhas been shown to improve diabetic control and reduceblood pressure. The main objective of the study is to evaluateefficacy of SGLT2 inhibitor dapagliflozin on markers of macroand micro vascular complications as add on treatment in type2 diabetes patients in real world set up.Material and methods: This was an observational studydone in real world set up. 87 patients were initially selectedamong whom 5 patients were lost in follow up and 2 patientswere excluded as they discontinued the study medicine. 80patients who received dapagliflozin 10 mg once daily for 24weeks in addition to metformin 1000 mg and glimepiride2 mg combination. Changes in both systolic and diastolicblood pressure, HbA1c (Glycated haemoglobin), fasting andpostprandial plasma glucose, lipid profile (including Totalcholesterol, Triglycerides, LDL and HDL cholesterol), serumcreatinine, serum microalbuminuria, eGFR and HOMA IRwere noted. All pathological test was executed at NABLaccredited lab.Results: After 24 weeks from baseline there was almost1.4% reduction in HbA1c. Fasting and post prandial bloodglucose was significantly reduced within 24 weeks. HOMAIR was significantly changed. No marked changes were seenin serum creatinine, microalbuminuria and eGFR. There wasa favorable reduction in lipid profile.Conclusion: Dapagliflozin has a very potent glycemic effectand has a significant impact on markers of macro and microvascular complications as add on treatment in type 2 diabetespatients. In conclusion it can be stated that early addition ofdapagliflozin therapy not only helps T2DM patients to achievetheir glycemic control but also prevents further macro andmicro vascular complications by reducing markers and riskfactors.
ABSTRACT
Diabetes mellitus and its complications are major international health problems in which there are many limitations to the orthodox approaches in the treatment. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of diabetic medications, with a different mechanism of action that may reduce risk of cardiovascular complications. To evaluate the effect of SGLT2 inhibitor monotherapy on cardiovascular complications in patients with type-2 diabetes and to compare its effect with the first-line therapy, metformin. Eighty rats divided into four groups were used: nondiabetic, diabetic nontreated, diabetic ? met and diabetic ? dapa. At the end, the arterial blood pressure and cardiac performance were assessed. Glycemic index, lipid profile, total antioxidant capacity, malondialdehyde, tumour necrosis factor a were measured. DNA changes were assessed from the hearts and aortae. Aortic tissue changes recorded using haematoxylin and eosin, Masson trichrome and iNOS immune stain. Glycemic index, lipid profile, oxidative stress and inflammatory parameters were significantly improved in both metformin and dapagliflozin treated groups with significant improvement in blood pressure and cardiac performance. Also, there were noticeable significant reduction in DNA fragmentation in aortic and cardiac tissues and reduction in collagen deposition and iNOS expression in aortic tissue. Dapagliflozin treatment results’ significantly surpassed improvement of metformin treatment nearly in all parameters. Total genomic DNA extraction proved that SGL2 inhibitor (dapagliflozin) has superior glycemic control and cardiovascular protective effect over metformin especially in type-2 diabetes with high fat intake.
ABSTRACT
Objective: To investigate the effect of dapagliflozin on the liver function of the patients with type 2 diabetes mellitus (T2DM) complicated with non-alcoholic fatty liver disease (NAFLD), and to analyze its improvement effect on liver injury of the T2DM patients. Methods: The clinical data of 68 T2DM patients complicated with NAFLDS who did not receive any treatment were retrospectively analyzed, including 30 patients in acarbose group and 38 patients in dapagliflozin group, and the patients in two groups received acarbose 150 mg · d-1 + metformin 2 000 mg · d-1 and dapagliflozin 10 mg · d-1 + metformin 2 000 mg · d-1 treatment for 24 weeks, respectively. The general data of the patients before and after treatment were collected. The fasting venous blood of the patients in two groups was collected and the serum biochemical indexes and liver function indexes were detected. The serum biochemical indexes included fasting blood glucose (FBG) and glycosylated hemoglobin (HbAlc), and the homeostasis model assessment 2-insulin resistance index (HMOA2-IR) was calculated. The liver function indexes included aspartic transaminase (AST), alanine aminotransferase (ALT), glutamyltranspeptidase (GGT), alkaline phosphatase (ALP), total bilirubin (TBIL), and direct bilirubin (DBIL); the non-alcoholic fatty liver disease fibrosis score (NAFLDFS) was calculated. The each detection index of the patients in two groups was compared and analyzed. Results: Compared with before treatment, the levels of FBG, HbAlc, AST, GGT, and ALP and HOMA2-IR in acarbose group after treatment were significantly decreased (P<0.01) and the levels of TBIL was significantly increased (P<0.01). Compared with before treatment, the levels of FBG, HbAlc, AST, ALT, GGT, and ALP and HOMA2-IR, NAFLDFS in dapagliflozin group were significantly decreased after treatment (P<0.01) and the levels of TBIL and DBIL were significantly increased (P<0.01). The levels of FBG, AST, ALT, GGT, and ALP and NAFLDF in dapagliflozin group after treatment were significantly decreased compared with acarbose group (P<0.01). Conclusion: Dagliflozin can improve the liver function of the patients with T2DM complicated with NAFLD, and its mechanism may be related to the effect of dapagliflozin decreasing the blood glucose and body weight.
ABSTRACT
OBJECTIVE：To evaluate the economic value of dapagliflozin combined with metformin in the treatment of type 2 diabetes mellitus （T2DM）. METHODS ：Based on related literatures and phase 3 randomized controlled clinical trial （RCT）of metformin alone or combined with dapagliflozin for T2DM，Markov model was built to simulate the dynamic changes of 3 schemes such as 5 mg dapagliflozin combined with metformin ，10 mg dapagliflozin combined with metformin or metformin alone （the dose of metformin were all 1 500 mg）in the treatment of T 2DM patients without or with complications and death . Quality adjusted life years（QALYs）was used as a health output indicator and the threshold of willingness-to-pay was 3 times of GDP in 2019. Cohort simulation in Markov model was applied to obtain long-term effect and cost of 3 schemes in the treatment of T 2DM. The incremental cost-effectiveness ratio （ICER）was analyzed ；the sensitivity of cost ，utility and discount was analyzed to check the stability of the analysis result. RESULTS ：According to the results of Markov model cohort simulation ，after 10 years of disease progression，compared with metformin alone ，ICER of 5 mg dapagliflozin combined with metformin was 41 259.17 yuan/QALYs， and that of 10 mg dapagliflozin combined with metformin was 92 824.85 yuan/QALYs. Compared with 5 mg dapagliflozin combined with metformin ，ICER of 10 mg dapagliflozin combined with metformin was 1 209 525.95 yuan/QALYs. Extension of termination time to 20 or 30 years had no effect on results. According to the sensitivity analysis ，the change of key parameters in the set range did not affect the model results ，indicating the result was stable. CONCLUSIONS ：For T 2DM，5 mg dapagliflozin combined with metformin is more cost-effective .