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A systematic literature review and meta-analysis was performed to evaluate the effects of dapagliflozin on low-density lipoprotein (LDL) cholesterol in type 2 diabetes mellitus. Data on changes in LDL cholesterol, adverse cardiac events (ACEs), glycated hemoglobin (HbA1c), and fasting blood glucose (FBG) were pooled in a meta-analysis. Data from dose comparison trials were separately pooled, and meta-analysis was conducted by using RevMan (5.4.1) and R (4.1.2). Dapagliflozin increased LDL cholesterol by 2.33 mg/dL (95% CI, 1.46 to 3.19; I2 = 0%; P < .00001), increased risk of ACEs by 1.56 (95% CI, 1.02 to 2.39; I2 = 0%; P < .04), decreased HbA1c by -0.41% (95% CI, -0.44 to -0.39; I2 = 85%; P < .00001), and decreased FBG by -13.51 mg/dL (95% CI, -14.43 to -12.59; I2 = 92%; P < .00001) versus any placebo or active comparator. Dapagliflozin 10 mg monotherapy increased LDL cholesterol by 1.71 mg/dL (95% CI, -1.20 to 4.62; I2 = 53%; P = .25) versus a 5 mg dose and by 1.04 mg/dL (95% CI, -1.17 to 3.26; I2 = 62%; P = .36) versus a 2.5 mg dose. Dapagliflozin 10 mg monotherapy increased LDL cholesterol by 3.13 mg/dL (95% CI, 1.31 to 4.95; I2 = 0%; P = .0008), increased the risk of ACEs by 1.26 (95% CI, 0.56 to 2.87; I2 = 0%; P = .58), decreased HbA1c by -0.4% (95% CI, -0.45 to -0.35; I2 = 89%; P < .00001), and decreased FBG by -8.39 mg/dL (95% CI, -10 to -6.77; I2 = 96%; P < .00001) versus a placebo or active comparator. Dapagliflozin monotherapy resulted in a minimal but statistically significantly (P = .0002) increase in LDL cholesterol. However, this minor change does not increase the risk of ACEs (P = .17) when compared with placebo or active comparator.
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BACKGROUND: Systemic arterial compliance and venous capacitance are typically impaired in patients with heart failure with preserved ejection fraction (HFpEF), contributing to hemodynamic congestion with stress. Sodium-glucose cotransporter-2 inhibitors reduce hemodynamic congestion and improve clinical outcomes in patients with HFpEF, but the mechanisms remain unclear. This study tested the hypothesis that Dapagliflozin would improve systemic arterial compliance and venous capacitance during exercise in patients with HFpEF. METHODS: In this secondary analysis from the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction Trial, 37 patients with HFpEF (mean age 68 ± 9 years, women 65%) underwent invasive hemodynamic exercise testing with simultaneous echocardiography at baseline and following treatment for 24 weeks with Dapagliflozin or placebo. Radial artery pressure (BP) was measured continuously using a fluid-filled catheter with transformation to aortic pressure, central hemodynamics were measured using high-fidelity micromanometers, and stressed blood volume was estimated from hemodynamic indices fit to a comprehensive cardiovascular model. RESULTS: There was no statistically significant effect of Dapagliflozin on resting BP, but Dapagliflozin reduced systolic BP during peak exercise (estimated treatment difference [ETD], -18.8 mm Hg [95% CI, -33.9 to -3.7] P=0.016). Reduction in BP was related to improved exertional total arterial compliance (ETD, 0.06 mL/mm Hg/m2 [95% CI, 0.003-0.11] P=0.039) and aortic root characteristic impedance (ETD, -2.6 mm Hg/mL*sec [95% CI: -5.1 to -0.03] P=0.048), with no significant effect on systemic vascular resistance. Dapagliflozin reduced estimated stressed blood volume at rest and during peak exercise (ETD, -292 mm Hg [95% CI, -530 to -53] P=0.018), and improved venous capacitance evidenced by a decline in ratio of estimated stressed blood volume to total blood volume (ETD, -7.3% [95% CI, -13.3 to -1.3] P=0.020). Each of these effects of Dapagliflozin at peak exercise were also observed during matched 20W exercise intensity. Improvements in total arterial compliance and estimated stressed blood volume were correlated with decreases in body weight, and reduction in systolic BP with treatment was correlated with the change in estimated stressed blood volume during exercise (r=0.40, P=0.019). Decreases in BP were correlated with reduction in pulmonary capillary wedge pressure during exercise (r=0.56, P<0.001). CONCLUSIONS: In patients with HFpEF, treatment with Dapagliflozin improved systemic arterial compliance and venous capacitance during exercise, while reducing aortic characteristic impedance, suggesting a reduction in arterial wall stiffness. These vascular effects may partially explain the clinical benefits with sodium-glucose cotransporter-2 inhibitors in HFpEF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04730947.
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BACKGROUND: The efficacy of dapagliflozin in patients with acute heart failure remains unclear. OBJECTIVE: To investigate the impact of dapagliflozin (DAPA) on loop diuretics use and 90-day readmission in patients with acute heart failure. METHODS: In a retrospective cohort study, patients diagnosed with acute heart failure or chronic heart failure with acute exacerbation admitted to Fuyang People's Hospital from January 2021 to April 2023, this study used DAPA (at a dose of 10 mg once daily) in combination with standard treatment. The patients were divided into DAPA group and DAPA-Free group based on whether they used DAPA in acute heart failure. To minimize the influence of confounding factors and ensure comparability between groups, we used propensity score matching (PSM). RESULTS: A total of 399 patients were included, with 206 patients (51.63%) in the DAPA group and 193 patients (48.37%) in the DAPA-Free group. PSM produced 160 pairs. After PSM, there were no statistically significant differences between the DAPA and DAPA-Free groups in terms of readmission of all causes (16.88% vs. 18.12%, OR 0.9141, 95% CI 0.5385-1.552, log rank P = 0.739) or readmission for heart failure (11.88% vs. 15.0%, OR 0.9077, 95% CI 0.4441-1.469, log rank P = 0.484) after 90-day follow-up. Patients in the DAPA group had a lower mean daily dose of intravenous loop diuretics compared to the DAPA-Free group (20 mg/d vs. 30.00 mg/d, P<0.001), lower total loop diuretic dose during hospitalization (106.06 ± 31.23 mg vs. 144.50 ± 45.39 mg, P = 0.038) and a decreased number of diuretic types used (11.88% vs. 23.12%, P = 0.008). CONCLUSIONS: DAPA reduced the dose of intravenous loop diuretics. However, it did not improve all-cause readmission for 90 days or readmission for heart failure after discharge.
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Compuestos de Bencidrilo , Glucósidos , Insuficiencia Cardíaca , Readmisión del Paciente , Puntaje de Propensión , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico , Humanos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/fisiopatología , Estudios Retrospectivos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Resultado del Tratamiento , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/uso terapéutico , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/efectos adversos , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/administración & dosificación , Enfermedad Aguda , Glucósidos/efectos adversos , Glucósidos/uso terapéutico , Glucósidos/administración & dosificación , Factores de Tiempo , Compuestos de Bencidrilo/uso terapéutico , Compuestos de Bencidrilo/efectos adversos , Compuestos de Bencidrilo/administración & dosificación , Factores de Riesgo , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Quimioterapia Combinada , China/epidemiología , Anciano de 80 o más Años , Medición de RiesgoRESUMEN
AIM: Sodium-glucose cotransporter 2 inhibitors (SGLT2is), used as a glucose-lowering therapy in people with type 2 diabetes (T2D), have significant cardiorenal benefits, reducing hospitalization for heart failure (HF) and cardiovascular mortality in patients with and without T2D. Recent clinical trial evidence suggests their potential utility in preventing incident T2D among the high-risk HF populations. Therefore, we aimed to assess whether this finding was reproducible in a real-world setting. METHODS: We performed a retrospective cohort analysis of 484 643 patients with HF, without baseline diabetes, prescribed either angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers with/without SGLT2is (treatment, n = 42 018; reference, n = 442 625) across 95 global health care organizations, using a large real-world ecosystem. Propensity score matching balanced arms 1:1 for confounders (n = 39 168 each arm). Subgroup analysis further evaluated the impact on patients with prediabetes and the efficacy of dapagliflozin/empagliflozin, specifically, on incident T2D and secondary outcomes, including all-cause mortality, acute pulmonary oedema and hospitalization. RESULTS: Treatment with SGLT2is significantly reduced incident T2D {hazard ratio (HR) 0.71 [95% confidence interval (CI) 0.63, 0.75]} in patients with HF. The analysis of patients with prediabetes found that SGLT2is further reduced incident T2D [HR 0.62 (95% CI 0.45, 0.80)]. The magnitude of reduction in incident T2D was higher in patients prescribed dapagliflozin [HR 0.47 (95% CI 0.39, 0.56)] versus empagliflozin [HR 0.81 (95% CI 0.70, 0.93)]. CONCLUSION: Treatment with SGLT2is in patients with HF was associated with a reduced risk of incident T2D, most strikingly in people with prediabetes.
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Background: The influence of genetic variants on the glucose-lowering effects of dapagliflozin remains unclear. This study aims to investigate the impact of polymorphisms in solute carrier family 5 member 2 (SLC5A2), uridine diphosphate glucuronosyltransferase 1A9 (UGT1A9), solute carrier family 2 member 2 (SLC2A2) and member 4 (SLC2A4) on the anti-hyperglycemic effect of dapagliflozin in patients with type-2 diabetes mellitus (T2DM). Methods: A total of 141 patients with T2DM were included in this prospective cohort study. Twenty-nine single nucleotide polymorphisms (SNPs) were selected and genotyped using the Sequenom MassArray platform or Sanger sequencing. Glycated hemoglobin (HbA1c) and fasting blood glucose (FBG) levels were compared before and after the treatment with dapagliflozin. Results: Among the 29 SNPs selected, 27 were successfully analyzed. After three months of dapagliflozin treatment, FBG levels were significantly reduced (8.00 mmol/L (5.45-10.71) mmol/L vs 6.40 mmol/L (5.45-9.20) mmol/L, p = 0.003) in patients with T2DM. However, there was no significant change in HbA1c levels (8.10% (6.88-10.00)% vs 8.10% (6.83-10.00)%, p = 0.452). Analysis of covariance showed that patients with the minor allele homozygote or heterozygote of rs12471030 (CT/TT), rs12988520 (AC/CC) or rs2602381 (TC/CC) had higher FBG levels compared to those with the major allele homozygote (p = 0.014, p = 0.024, and p = 0.044, respectively). After adjusting for baseline FBG level, age, gender, body mass index, use of insulin and use of metformin, three SNPs-rs12471030, rs12988520 and rs2602381-were associated with the anti-hyperglycemic effect of dapagliflozin. However, using a stringent significance threshold (p < 0.002 with Bonferroni correction), none of these selected SNPs were significantly associated with FBG and HbA1c levels after dapagliflozin treatment. Conclusion: After adjusting for confounding variables, polymorphisms in SLC5A2, UGT1A9, SLC2A2 and SLC2A4 genes were not associated with the anti-hyperglycemic effect of dapagliflozin in the Chinese population. Clinical Trial Registration Number: ChiCTR2200059645.
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BACKGROUND AND HYPOTHESIS: Clinical trials have demonstrated positive cardiovascular and kidney outcomes of sodium-glucose-co-transporter-2 (SGLT2) inhibitors in adult patients with diabetic and other chronic kidney diseases (CKD). Whether benefits extend to children, teenagers, and young adults with early-stage CKD is unknown. For this reason, the DOUBLE PRO-TECT Alport trial (NCT05944016) will study the progression of albuminuria in young patients with Alport syndrome (AS), the most common hereditary CKD, to assess the safety and efficacy of the SGLT2-inhibitor dapagliflozin. Patients living with AS and chronically elevated albuminuria have a high risk of kidney failure before the age of 50 years. METHODS AND RATIONALE: DOUBLE PRO-TECT Alport is a multicenter, randomized, double-blind, placebo-controlled trial (RCT). Participants (aged 10 to 39 years) must have a diagnosis of AS by genetic testing or kidney biopsy, be on a stable (> 3 months) maximum tolerated dose of a renin-angiotensin-system-inhibitor (RASi) and must have a Urinary Albumin to Creatinine Ratio (UACR) of >300 mg/g (pediatric) or >500 mg/g (adult).Eligible participants will be randomly assigned at a 2:1 ratio to 48 weeks of treatment with dapaglifozin 10 mg/day -to- matched placebo. Most participants are expected to be children with a normal glomerular filtration rate (eGFR). In addition to safety, the primary (change in UACR from baseline to Week 48) and key secondary (eGFR change from baseline to Week 52) efficacy outcomes will be analyzed with a mixed model repeated measures approach. Efficacy analyses will be performed primarily in the full analysis set according to the intention-to-treat principle. A sensitivity analysis will be performed using reference-based multiple imputation. CONCLUSION: DOUBLE PRO-TECT Alport will assess whether SGLT2-inhibitors can safely reduce change from baseline in UACR as a marker for progression of CKD in young patients living with AS.
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Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have a variety of cardiovascular and renoprotective effects and have been developed as novel agents for the treatment of heart failure. However, the beneficial mechanisms of SGLT2i on cardiac tissue need to be investigated further. In this study, we established a mouse model of acute myocardial infarction (AMI) using coronary artery constriction surgery and investigated the role of dapagliflozin (DAPA) in protecting cardiomyocytes from hypoxic injury induced by AMI. In vitro experiments were done using hypoxic cultured H9c2 ventricular cells to verify this potential mechanism. Expression of the SIRT family and related genes and proteins was verified by qPCR, Western blotting and immunofluorescence staining, and the intrinsic potential mechanism of cardiomyocyte death due to AMI and hypoxia was comprehensively investigated by RNA sequencing. The RNA sequencing results of cardiomyocytes from AMI mice showed that the SIRT family may be mainly involved in the mechanisms of hypoxia-induced cardiomyocyte death. In vitro hypoxia-induced ventricular cells showed the role of dapagliflozin in conferring resistance to hypoxic injury in cardiomyocytes. It showed that SIRT1/3/6 were downregulated in H9c2 cells in a hypoxic environment, and the addition of dapagliflozin significantly increased the gene and protein expression of SIRT1, 3 and 6. We then verified the underlying mechanisms induced by dapagliflozin in hypoxic cardiomyocytes using RNA-seq, and found that dapagliflozin upregulated the hypoxia-induced gene downregulation, which includes ESRRA, EPAS1, AGTRAP, etc., that associated with SIRTs-related and apoptosis-related signaling to prevent H9c2 cell death. This study provides laboratory data for SGLT2i dapagliflozin treatment of AMI and confirms that dapagliflozin can be used to treat hypoxia-induced cellular necrosis in cardiomyocytes, in which SIRT1 and SIRT3 may play an important role. This opens up further opportunities for SGLT2i in the treatment of heart disease.
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Compuestos de Bencidrilo , Glucósidos , Infarto del Miocardio , Miocitos Cardíacos , Transducción de Señal , Sirtuina 1 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Glucósidos/farmacología , Glucósidos/uso terapéutico , Animales , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Compuestos de Bencidrilo/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Ratones , Infarto del Miocardio/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Sirtuina 1/metabolismo , Sirtuina 1/genética , Transducción de Señal/efectos de los fármacos , Masculino , Sirtuina 3/metabolismo , Sirtuina 3/genética , Sirtuinas/metabolismo , Sirtuinas/genética , Línea Celular , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Hipoxia de la Célula/efectos de los fármacos , Ratas , Apoptosis/efectos de los fármacosRESUMEN
Introduction: The DAPA-CKD study showed a protective effect of dapagliflozin on kidney function in chronic kidney disease (CKD) patients with and without diabetes mellitus. Although dapagliflozin is expected to be effective also in CKD patients with autosomal dominant polycystic kidney disease (ADPKD), its efficacy and safety in this population remain unknown because ADPKD was an exclusion criterion in the DAPA-CKD study. Therefore, we evaluated the effects of dapagliflozin in CKD patients with ADPKD. Methods: We performed a retrospective observational study of seven patients with ADPKD treated with dapagliflozin at Toranomon Hospital, Tokyo, Japan. We analyzed changes in estimated glomerular filtration rate (eGFR) slope and annual height-corrected total kidney volume before and after starting dapagliflozin treatment. Results: The median observation period after starting dapagliflozin was 20 months. Four patients received concomitant tolvaptan. The eGFR slope before and after initiation of dapagliflozin could be calculated in six patients and improved in all of them except the one who did not receive a renin-angiotensin system (RAS) inhibitor. Annual height-corrected total kidney volume increased in all patients. Concurrent tolvaptan treatment had no effect. Conclusion: In CKD patients with ADPKD, dapagliflozin may increase kidney volume but may have a protective effect on kidney function when used concomitantly with RAS inhibitors.
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Objective: This study aimed to evaluate the efficacy and safety of polyethylene glycol loxenatide (PEG-Loxe) compared to those of dapagliflozin in patients with mild-to-moderate diabetic kidney disease (DKD), a prevalent microvascular complication of type 2 diabetes mellitus (T2DM). The study is set against the backdrop of increasing global diabetes incidence and the need for effective DKD management. Methods: This study constituted a single-center, randomized, open-label, clinical trial. The trial included patients with mild-to-moderate DKD and suboptimal glycemic control. Eligible participants were randomly allocated to one of the two groups for treatment with either PEG-Loxe or dapagliflozin. The primary endpoint was the change in UACR from baseline at 24 weeks. Results: Overall, 106 patients were randomized and 80 patients completed the study. Following 24 weeks of treatment, the PEG-Loxe group exhibited a mean percent change in baseline UACR of -29.3% (95% confidence interval [CI]: -34.8, -23.7), compared to that of -31.8% in the dapagliflozin group (95% CI: -34.8, -23.7). Both PEG-Loxe and dapagliflozin showed similar efficacy in reducing UACR, with no significant difference between the groups (p = 0.336). The HbA1c levels decreased by -1.30% (95% CI: -1.43, -1.18) in the PEG-Loxe group and by -1.29% (95% CI: -1.42, -1.17) in the dapagliflozin group (p = 0.905). The TG levels decreased by -0.56 mmol/L (95% CI: -0.71, -0.42) in the PEG-Loxe group and -0.33 mmol/L (95% CI: -0.48, -0.19) in the dapagliflozin group (p = 0.023). Differences in TC, HDL-C, LDL-C, SBP, and DBP levels between the groups were not statistically significant (all p > 0.05). Safety profiles were consistent with previous findings, with gastrointestinal adverse events being more common in the PEG-Loxe group. Conclusions: PEG-Loxe is as effective as dapagliflozin in improving urine protein levels in patients with mild-to-moderate DKD and offers superior benefits in improving lipid profiles. These findings support the use of PEG-Loxe in DKD management, contributing to evidence-based treatment options. Clinical Trial Registration: www.chictr.org.cn, identifier ChiCTR2300070919.
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Compuestos de Bencidrilo , Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Glucósidos , Polietilenglicoles , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Masculino , Femenino , Persona de Mediana Edad , Nefropatías Diabéticas/tratamiento farmacológico , Polietilenglicoles/uso terapéutico , Polietilenglicoles/efectos adversos , Polietilenglicoles/administración & dosificación , Glucósidos/uso terapéutico , Glucósidos/efectos adversos , Glucósidos/administración & dosificación , Compuestos de Bencidrilo/uso terapéutico , Compuestos de Bencidrilo/efectos adversos , Anciano , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/efectos adversos , Resultado del Tratamiento , Hemoglobina Glucada/análisis , Glucemia/efectos de los fármacos , Glucemia/análisis , AdultoRESUMEN
Chronic kidney disease (CKD) is a complication of diabetes that affects circulating drug concentrations and elimination of drugs from the body. Multiple drugs may be prescribed for treatment of diabetes and co-morbidities, and CKD complicates the pharmacotherapy selection and dosing regimen. Characterizing variations in renal drug clearance using models requires large clinical datasets that are costly and time-consuming to collect. We propose a flexible approach to incorporate impaired renal clearance in pharmacokinetic (PK) models using descriptive statistics and secondary data with mechanistic models and PK first principles. Probability density functions were generated for various drug clearance mechanisms based on the degree of renal impairment and used to estimate the total clearance starting from glomerular filtration for metformin (MET) and dapagliflozin (DAPA). These estimates were integrated with PK models of MET and DAPA for simulations. MET renal clearance decreased proportionally with a reduction in estimated glomerular filtration rate (eGFR) and estimated net tubular transport rates. DAPA total clearance varied little with renal impairment and decreased proportionally to reported non-renal clearance rates. Net tubular transport rates were negative to partially account for low renal clearance compared with eGFR. The estimated clearance values and trends were consistent with MET and DAPA PK characteristics in the literature. Dose adjustment based on reduced clearance levels estimated correspondingly lower doses for MET and DAPA while maintaining desired dose exposure. Estimation of drug clearance rates using descriptive statistics and secondary data with mechanistic models and PK first principles improves modeling of CKD in diabetes and can guide treatment selection.
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Compuestos de Bencidrilo , Tasa de Filtración Glomerular , Glucósidos , Hipoglucemiantes , Metformina , Modelos Biológicos , Insuficiencia Renal Crónica , Compuestos de Bencidrilo/farmacocinética , Compuestos de Bencidrilo/administración & dosificación , Metformina/farmacocinética , Metformina/administración & dosificación , Glucósidos/farmacocinética , Glucósidos/administración & dosificación , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/administración & dosificación , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacocinética , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Simulación por Computador , MasculinoRESUMEN
BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular (CV) outcomes in patients with or without Type 2 diabetes and heart failure (HF). However, studies have shown conflicting evidence regarding their efficacy in patients following acute myocardial infarction (MI). We conducted a pilot systematic review and meta-analysis to synthesise the available evidence regarding the effectiveness of SGLT2 inhibitors in MI. METHODS: A systematic literature search was conducted using PubMed/MEDLINE, the Cochrane Library and Embase databases to identify randomised controlled trials (RCTs) that compared clinical outcomes of SGLT2 inhibitors with placebo following MI. We conducted the statistical analysis using RevMan, version 5.4 and pooled risk ratios (RRs) along the corresponding 95% confidence interval (CI) for all outcomes. RESULTS: Five RCTs reporting data for 11,211 patients were included in our study. The mean follow-up duration was 43.8 weeks. Our pooled analysis showed that SGLT2 inhibitors significantly reduced the risk of hospitalisations for heart failure (HHF) (RR = 0.76, 95% CI: 0.61-0.88, p = 0.001) in patients with MI. However, the risk of all-cause mortality (RR = 1.05, 95% CI: 0.78-1.41, p = 0.76), CV mortality (RR = 1.04, 95% CI = 0.84-1.29, p = 0.73) and all-cause hospitalisations (RR = 1.06, 95% CI: 0.96-1.17, p = 0.25) remained comparable across the two groups. CONCLUSION: SGLT2 inhibitors reduce HHF without affecting all-cause mortality, CV mortality and all-cause hospitalisations. However, further evidence is required to reach a definitive conclusion.
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Infarto del Miocardio , Ensayos Clínicos Controlados Aleatorios como Asunto , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Resultado del Tratamiento , Insuficiencia Cardíaca/tratamiento farmacológicoRESUMEN
Chronic kidney disease (CKD) affects approximately 13% of people globally, including 20%-48% with type 2 diabetes (T2D), resulting in significant morbidity, mortality, and healthcare costs. There is an urgent need to increase early screening and intervention for CKD. We are experts in diabetology and nephrology in Central Europe and Israel. Herein, we review evidence supporting the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for kidney protection and discuss barriers to early CKD diagnosis and treatment, including in our respective countries. SGLT2 inhibitors exert cardiorenal protective effects, demonstrated in the renal outcomes trials (EMPA-KIDNEY, DAPA-CKD, CREDENCE) of empagliflozin, dapagliflozin, and canagliflozin in patients with CKD. EMPA-KIDNEY demonstrated cardiorenal efficacy across the broadest renal range, regardless of T2D status. Renoprotective evidence also comes from large real-world studies. International guidelines recommend first-line SGLT2 inhibitors for patients with T2D and estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m2, and that glucagon-like peptide-1 receptor agonists may also be administered if required for additional glucose control. Although these guidelines recommend at least annual eGFR and urine albumin-to-creatinine ratio screening for patients with T2D, observational studies suggest that only half are screened. Diagnosis is hampered by asymptomatic early CKD and under-recognition among patients with T2D and clinicians, including limited knowledge/use of guidelines and resources. Based on our experience and on the literature, we recommend robust screening programmes, potentially with albuminuria self-testing, and SGLT2 inhibitor reimbursement at general practitioner (GP) and specialist levels. High-tech tools (artificial intelligence, smartphone apps, etc.) are providing exciting opportunities to identify high-risk individuals, self-screen, detect abnormalities in images, and assist with prescribing and treatment adherence. Better education is also needed, alongside provision of concise guidelines, enabling GPs to identify who would benefit from early initiation of renoprotective therapy; although, regardless of current renal function, cardiorenal protection is provided by SGLT2 inhibitor therapy.
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BACKGROUND: Right ventricular (RV) fibrosis is an important pathological change that occurs during the development of right heart failure (RHF) induced by pulmonary hypertension (PH). Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been shown to play a major role in left heart failure, but it is unclear whether it has a positive effect on RHF. This study aimed to clarify the effect of DAPA on PH-induced RHF and investigate the underlying mechanisms. METHODS: We conducted experiments on two rat models with PH-induced RHF and cardiac fibroblasts (CFs) exposed to pathological mechanical stretch or transforming growth factor-beta (TGF-ß) to investigate the effect of DAPA. RESULTS: In vivo, DAPA could improve pulmonary hemodynamics and RV function. It also attenuated right heart hypertrophy and RV fibrosis. In vitro, DAPA reduced collagen expression by increasing the production of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9). Additionally, DAPA was found to reduce reactive oxygen species (ROS) levels in CFs and the right heart in rats. Similar to DAPA, the ROS scavenger N-acetylcysteine (NAC) exerted antifibrotic effects on CFs. Therefore, we further investigated the mechanism by which DAPA promoted collagen degradation by reducing ROS levels. CONCLUSIONS: In summary, we concluded that DAPA ameliorated PH-induced structural and functional changes in the right heart by increasing collagen degradation. Our study provides new ideas for the possibility of using DAPA to treat RHF.
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Diabetes mellitus is a metabolic disorder caused by a dysfunction in insulin action or secretion, leading to an elevation in blood glucose levels. It is a highly prevalent condition and as a result, the NHS spends 10 % of its entire budget on diabetes mellitus care, that is equivalent to £10 billion a year. Diabetes mellitus has been linked with vascular and neurological complications which may be associated with the progression of neurodegeneration and Alzheimer's disease. Chronic hyperglycaemia increases the production of the reactive oxidant species (ROS) such as methylglyoxal (MGO). MGO has been linked with vascular complications, neuropathy and cytotoxicity. The main aim of this study was to investigate the potential beneficial effect of antidiabetic agents such as metformin and dapagliflozin on human brain neuronal cells (SH-SY5Y) treated with MGO. SH-SY5Y cells were cultured in DMEM/F12 media and subjected overnight incubation with one of the following treatment conditions: Control (untreated); MGO (1 µM); MGO (100 µM); metformin (100 µM) + MGO (100 µM); and dapagliflozin (10 µM) + MGO (100 µM). Several assays were conducted to explore the effect of the treatment groups on the SH-SY5Y cells. These included: MTT assay; LDH assay, peroxynitrite fluorescence assay, and laser scanning confocal microscopy. MGO (100 µM) led to significant cell injury and damage and significantly reduced the survival of the cells by approximately 50-75 %, associated with significant increase in peroxynitrite. The addition of metformin (100 µM) or dapagliflozin (10 µM) represented significant protective effects on the cells and prevented the cell damage caused by the high MGO concentration. As a result, the findings of this research reveal that MGO-induced cell damage may partly be mediated by the generation of peroxynitrite, while the antidiabetic agents such as metformin and dapagliflozin prevent brain cell death, which potentially may play prophylactic roles against the risk of dementia in diabetic patients.
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Compuestos de Bencidrilo , Glucósidos , Hipoglucemiantes , Metformina , Neuronas , Piruvaldehído , Humanos , Compuestos de Bencidrilo/farmacología , Piruvaldehído/toxicidad , Metformina/farmacología , Glucósidos/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Hipoglucemiantes/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/citología , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neuroblastoma/patología , Neuroblastoma/metabolismoRESUMEN
PURPOSE: We evaluated the pharmacokinetics, safety, and tolerability of a fixed-dose combination (FDC) of dapagliflozin/sitagliptin versus individual component (IC) tablets in healthy Western and Korean participants. The combination of these antihyperglycemic drugs provides efficient glucose control, and the use of FDC has generally been shown to improve medication adherence in individuals with type 2 diabetes mellitus (T2DM). METHODS: Two randomized, open-label, two-period, two-treatment, single-dose, single-center, crossover bioequivalence studies conducted on healthy fasted German participants (aged 18-55 years; Western study) and South Korean participants (aged 19-55 years; Korean study) were included. In both studies, pharmacokinetic parameters (maximum [peak] plasma concentration [Cmax], area under the plasma concentration-time curve from zero to the last quantifiable concentration [AUClast], and area under the plasma concentration-time curve from zero to infinity [AUCinf]) were used to assess the bioequivalence of 10 mg dapagliflozin/100 mg sitagliptin FDC (Treatment A) with their ICs (Treatment B) under fasted conditions. Safety and tolerability were assessed throughout the study. FINDINGS: Forty-six healthy participants (male, 60.9%; mean age, 39.5 years; mean body mass index [BMI], 23.9 kg/m2) were randomized in the Western study, and 51 healthy participants (male, 100.0%; mean age, 24.6 years; mean BMI, 23.9 kg/m2) were randomized in the Korean study. In both studies, the participants were randomized 1:1 into treatment sequence AB and treatment sequence BA. Dapagliflozin/sitagliptin FDC was bioequivalent to IC tablets in both Western and Korean studies, as the 90% confidence interval of the FDC to IC ratios of the geometric least-squares means of the pharmacokinetic parameters for both dapagliflozin and sitagliptin was within the 0.8000-1.2500 bioequivalence criterion limit. The observed differences in pharmacokinetic parameters, such as Cmax, AUClast, and AUCinf, between the Western and Korean studies were not clinically meaningful. Dapagliflozin/sitagliptin FDC and their ICs were well tolerated, with no serious adverse events reported in any of the study populations. IMPLICATIONS: The 10 mg dapagliflozin/100 mg sitagliptin FDC and IC formulations were bioequivalent in fasted healthy Western and Korean participants, with no new safety concerns identified, thus offering a useful alternative for patients currently receiving individual medications as part of their treatment regimen. CLINICAL TRIAL REGISTRATION: Western study (clinicaltrials.gov: NCT05266404) and Korean study (clinicaltrials.gov: NCT05453786).
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Background: We compared kidney and cardiorenal protection in patients without type 2 diabetes across urine albumin-creatinine ratio (UACR) levels after initiation on dapagliflozin for the treatment of chronic kidney disease (CKD). Methods: OPTIMISE-CKD is an observational study describing dapagliflozin treatment for CKD. Adult patients with CKD without type 2 diabetes were included in the primary analysis. Baseline UACR was grouped as normal/mildly elevated (0-29 mg/g), low (30-200 mg/g) and high (>200 mg/g). Outcomes were estimated glomerular filtration rate (eGFR) trajectories/slopes, cardiorenal complications and all-cause mortality. Results: In total, 1480 patients had low (n = 796) and high (n = 684) UACR. The two groups were similar at baseline, aged 75 and 74 years, and 42% and 39% female, respectively. After dapagliflozin initiation, an acute eGFR dip of 3 mL/min/1.73 m2 was observed, followed by a flat development in both groups. The eGFR slope [95% confidence interval (CI)] for patients with low UACR was 0.79 mL/min/1.73 m2 per year (-0.59, 2.56), and similar to patients with high UACR [0.40 mL/min/1.73 m2 per year (-0.46, 1.38)]. Risks of cardiorenal complications and all-cause mortality were similar, with adjusted hazard ratios of 0.89 (95% CI 0.66, 1.19) and 1.10 (95% CI 0.63, 1.92), respectively. Analogous results were found in those with normal/mildly elevated UACR. Conclusions: Dapagliflozin in patients without type 2 diabetes for the treatment of CKD demonstrated similar kidney protection, cardiorenal and all-cause mortality risk across UACR levels. This suggests that the efficacy of dapagliflozin found in clinical trials expands to real-world patients with CKD, regardless of albuminuria levels.
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BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have recently been linked to be associated with acute pancreatitis (AP), but the clinical characteristics are unclear. This study investigated the clinical characteristics of SGLT-2i and AP and provided reference for the prevention and treatment of AP. RESEARCH DESIGN AND METHODS: Case reports, case series, and clinical studies of SGLT2i induced AP were collected by retrieving Chinese and English data from the database until December 31, 2023. RESULTS: Twenty-one patients were included, with a median age of 50.5 years (range 26,73). SGLT-2i were mainly involved in empagliflozin (13 cases, 61.9%), canagliflozin (4 cases, 19%) and dapagliflozin (4 cases, 19%). The median time from initial administration to the onset of AP was 21 days (range 1, 120). Abdominal pain (21 cases, 100%) was the most commonly complained symptom. The median lipase value was 388 U/L (range 36, 10000), and the median amylase value was 535 U/L (range 26, 3765). Twenty-one patients recovered completely after stopping the drug and receiving conservative treatment. CONCLUSIONS: SGLT-2i are associated with AP. Given the rising prescription of SGLT-2i, physicians should consider these agents as a potential cause of pancreatitis after excluding other etiologies.
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Hyperuricemic nephropathy (HN) is a global metabolic disorder characterized by uric acid (UA) metabolism dysfunction, resulting in hyperuricemia (HUA) and tubulointerstitial fibrosis (TIF). Sodium-dependent glucose transporter 2 inhibitor, dapagliflozin, has shown potential in reducing serum UA levels in patients with chronic kidney disease (CKD), though its protective effects against HN remain uncertain. This study investigates the functional, pathological, and molecular changes in HN through histological, biochemical, and transcriptomic analyses in patients, HN mice, and UA-stimulated HK-2 cells. Findings indicate UA-induced tubular dysfunction and fibrotic activation, which dapagliflozin significantly mitigates. Transcriptomic analysis identifies estrogen-related receptor α (ERRα), a downregulated transcription factor in HN. ERRα knockin mice and ERRα-overexpressed HK-2 cells demonstrate UA resistance, while ERRα inhibition exacerbates UA effects. Dapagliflozin targets ERRα, activating the ERRα-organic anion transporter 1 (OAT1) axis to enhance UA excretion and reduce TIF. Furthermore, dapagliflozin ameliorates renal fibrosis in non-HN CKD models, underscoring the therapeutic significance of the ERRα-OAT1 axis in HN and CKD.
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Compuestos de Bencidrilo , Fibrosis , Glucósidos , Hiperuricemia , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Glucósidos/farmacología , Glucósidos/uso terapéutico , Compuestos de Bencidrilo/farmacología , Fibrosis/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/complicaciones , Humanos , Ratones , Masculino , Receptor Relacionado con Estrógeno ERRalfa , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/patología , Enfermedades Renales/metabolismo , Riñón/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Ratones Endogámicos C57BL , Ácido Úrico/sangre , Receptores de Estrógenos/metabolismo , Proteína 1 de Transporte de Anión Orgánico/metabolismo , Proteína 1 de Transporte de Anión Orgánico/genética , Línea Celular , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/patología , Modelos Animales de Enfermedad , FemeninoRESUMEN
Introduction: Despite the provision of renin-angiotensin-aldosterone-system inhibitors and immunosuppressive therapies, membranous nephropathy often progresses to end-stage kidney disease (ESKD). The objective of this prespecified analysis was to assess the safety and efficacy of dapagliflozin in patients with membranous nephropathy enrolled in the DAPA-CKD trial. Methods: Patients with an estimated glomerular filtration rate (eGFR) of 25-75 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) 200-5,000 mg/g were randomized to dapagliflozin 10 mg once daily or placebo, along with standard-of-care and followed for median 2.4 years. The primary endpoint was a composite of ≥50% sustained decline in eGFR, ESKD, or kidney or cardiovascular death. Exploratory efficacy endpoints included eGFR slope and UACR. Results: Among DAPA-CKD participants with membranous nephropathy, 19 were randomized to dapagliflozin and 24 to placebo. The mean (SD) age was 59.9 ± 12.1 years, the mean eGFR was 45.7 ± 12.1 mL/min/1.73 m2, and the median UACR was 1,694.5 (25%, 75% range 891-2,582.5) mg/g. Two of 19 (11%) patients randomized to dapagliflozin and five of 24 (21%) randomized to placebo experienced the primary composite endpoint. Total and chronic mean eGFR slopes for dapagliflozin and placebo were -3.87 and -4.29 and -2.66 and -4.22 mL/min/1.73 m2/year, respectively; corresponding between-group mean differences were 0.42 and 1.57 mL/min/1.73 m2/year. Dapagliflozin reduced geometric mean (SEM) UACR relative to placebo (-29.3% ± 1.2% vs. -3.6% ± 1.1%; between-group mean difference [95% CI] -26.7 [-50.4, 8.3]). Four (21%) patients randomized to dapagliflozin and seven (29%) randomized to placebo experienced a serious adverse event. Conclusion: In membranous nephropathy, the effects of dapagliflozin on kidney disease progression and albuminuria were generally favorable; there was insufficient power to justify formal inference testing.