Use Of Dapagliflozin Research Articles

Effect of short-term use of dapagliflozin on impaired awareness of hypoglycaemia in people with type 1 diabetes.

AimImpaired awareness of hypoglycaemia (IAH) affects about 25% of patients with type 1 diabetes (T1DM). IAH can be reversed by strict avoidance of hypoglycaemia for at least 3 weeks. Adjunctive treatment with sodium glucose cotransporter 2 inhibitors may reduce the risk of hypoglycaemia through reduction of glucose variability. We tested the hypothesis that short‐term use of dapagliflozin may improve awareness of hypoglycaemia in people with T1DM and IAH.Materials and MethodsFifteen patients with T1DM and IAH were included in this randomized double‐blind, placebo‐controlled cross‐over trial (age 49.7 ± 14.6 years, 40% men, disease duration 24.1 ± 14.2 years, glycated haemoglobin 7.5 ± 0.8% (58.6 ± 8.4 mmol/mol). They were treated with dapagliflozin 10 mg once daily or matching placebo, with a washout period of 2 weeks. At the end of each treatment period, participants underwent a modified hyperinsulinaemic normoglycaemic‐hypoglycaemic glucose clamp (glucose nadir 2.5 mmol/L). Blinded continuous glucose monitors were used in the final treatment weeks.ResultsTreatment with dapagliflozin significantly improved glycated haemoglobin [−0.32 ± 0.10 vs. 0.22 ± 0.13% (−4.1 ± 0.9 vs. 2.3 ± 1.4 mmol/mol), dapagliflozin vs. placebo, p = .007] and glucose variability (standard deviation, 2.6 ± 0.2 vs. 3.1 ± 0.3 mmol/L, p = .029), but did not affect the frequency of hypoglycaemia. During the hypoglycaemic clamp, dapagliflozin did not affect symptom responses (8.0 ± 3.4 vs. 5.2 ± 1.6, p = .31), but significantly reduced the need for exogenous glucose to maintain hypoglycaemia (3.2 ± 0.3 vs. 4.1 ± 0.4 mg/kg/min, p = .022).ConclusionsEight weeks of treatment with dapagliflozin did not restore hypoglycaemic awareness in people with T1DM and impaired awareness of hypoglycaemia, but ameliorated some clinical aspects.

The Role of Dapagliflozin in the Management of Heart Failure: An Update on the Emerging Evidence

The burden and cost of heart failure management, primarily in the form of hospitalization in the setting of decompensated heart failure, continue to be some of the biggest clinical challenges in cardiovascular medicine. In recently published randomized controlled trials, including DAPA-HF, sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin was shown to reduce hospitalization from heart failure or mortality associated with cardiovascular causes, when added to existing guideline-directed medical therapy. The American College of Cardiology (ACC) released a Clinical Pathway guideline that recommends the use of dapagliflozin in clinical management of heart failure, with or without diabetes. Furthermore, the results of the DAPA-CKD trial broaden the utility of dapagliflozin as a therapeutic option in patients with advanced kidney disease. In this article, the authors explore the existing evidence on dapagliflozin in heart failure with reduced ejection fraction and highlight the need for further research on uses of dapagliflozin in the world of heart failure.

Dapagliflozin for the treatment of type 2 diabetes mellitus – an update

ABSTRACT Introduction Diabetes is a global health concern with a prevalence of 463 million people. Importantly, despite the availability of numerous antidiabetic medications, type 2 diabetes mellitus (T2DM) is still associated with significant morbidity and mortality worldwide. One particular drug of interest is dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor that is commonly used in the treatment of Type 2 Diabetes Mellitus (T2DM). Areas covered This review outlines the current use and pharmacology of dapagliflozin, with a specific focus on recent evidence regarding benefits in patients with cardiovascular and chronic kidney disease. The article includes an overview of the efficacy and safety of this drug and provides the reader with the expert opinion and perspectives of the authors. Expert opinion Increasing evidence of the beneficial effects on morbidity and mortality in patients with Type 2 diabetes and concurrent heart failure, acute MI and renal failure are likely to see the usage of dapagliflozin in patients with these comorbidities increase over the next 5 years.

Highlights from Studies Presented at the Virtual American College of Cardiology Scientific Sessions 2021: Staying Updated with the Latest Advancements in Prevention.

Purpose of ReviewThis review highlights late-breaking science presented at the Virtual American College of Cardiology Scientific Sessions 2021 that demonstrated advancements in preventative cardiology and introduced novel therapeutic modalities for the management of chronic kidney disease, heart failure, and COVID-19.Recent FindingsThe studies reviewed include clinical trials that assessed the use of dapagliflozin in patients with respiratory failure due to COVID-19 (DARE-19 trial); evinacumab for patients with severe hypertriglyceridemia and pancreatitis; effect of genotype-guided oral P2y12 inhibitors vs conventional clopidogrel on long-term ischemic outcomes after percutaneous coronary intervention (TAILOR-PCI trial); anticoagulation in patients hospitalized with COVID-19 (ACTION trial); atorvastatin vs placebo in patients with COVID-19 admitted to the ICU (INSPIRATION-S trial); rehabilitation therapy in older acute heart failure patients (REHAB-HF trial); and aspirin dosing: a patient-centric trial assessing benefits and long-term effectiveness (ADAPTABLE trial). In addition, we review the results of the American College of Cardiology Global Heart Attack Initiative (GHATI). Finally, we discuss the secondary analysis of the STRENGTH trial assessing the association of achieved levels of omega-3 fatty acid levels and major cardiovascular outcomes.SummaryThe studies presented at the virtual American College of Cardiology Scientific Session 2021 represent remarkable contributions in the field of cardiovascular disease and prevention.

Clinician’s guide for dapagliflozin use in heart failure with reduced ejection fraction

Dapagliflozin belongs to a new class of drugs used for the treatment of heart failure — sodium-glucose cotransporter type 2 inhibitors (SGLT2i). Based on the DAPA-HF study results, dapagliflozin has become the first SGLT2i approved for the treatment of symptomatic chronic heart failure with reduced ejection fraction. The present review summarizes the most important clinical issues related to the treatment with this drug.

Pharmacokinetic characteristics and morphometric effects of sodium-glucose contransporter-2 inhibitors in men and women with type 2 diabetes mellitus (literature review and own results)

Background. According to the latest international clinical guidelines, gliflozins— sodium-glucose cotransporter-2 inhibitors— are indicated as oral antidiabetic drugs of second-third-line therapy in type 2 diabetes mellitus. Due to insulin-independent stimulation of glucosuria, gliflozins have extraglycemic effects such as weight loss, improved adipose tissue distribution, better plasma lipid profile, and decreased uricemia that in generally reduce the risk of cardiovascular complications. The purpose of this study was to evaluate the effectiveness of dapagliflozin in the treatment of men and women with type 2 diabetes mellitus with a metabolically unhealthy phenotype. Materials and methods. The study included 17 individuals with diabetes mellitus type 2 (11 men and 6women), aged 58.0±1.7 years (95% confidence interval 53–62), whose body composition was evaluated by bioelectric impedance using a Tanita analyzer BC-545N (Japan). Patients received therapy with dapagliflozin, antihypertensive and antihyperlipidemic drugs (statins). Results. A three-month use of dapagliflozin in a dose of 10 mg once daily caused a decrease in body mass index, waist circumference, improvement of body composition, in particular a reduction in total body fat (the significance of changes was determined using a paired t-test). No significant changes in muscle and bone mass, body composition, lipid profile, and uricemia level were observed. The group of women, in contrast to men, had a decreased level of visceral fat, which was accompanied by an improvement in the body’s water supply, and a reduction in the estimated metabolic age. Conclusions. Treatment of type 2 diabetes patients with sodium-glucose cotransporter-2 inhibitors for 3 months has reduced the degree of obesity and improved some indices of body composition. Confirmation of this trend can be obtained in further observations.

An investigation on the association between sodium glucose co-transporter 2 inhibitors use and acute pancreatitis: A VigiBase study.

To characterize acute pancreatitis (AP) related to sodium glucose co-transporter 2 inhibitors and to investigate this relationship through disproportionality analysis in an international pharmacovigilance database. We analyzed all AP reports for canagliflozin, dapagliflozin and/or empagliflozin from the WHOs Global adverse drug reactions database VigiBase® up to July 2019. We characterized the patients, reporters, and reactions, and we present the proportional reporting ratio (PRR) and information component (IC) for each of the gliflozins. AP cases were reports containing at least one of 11 previously selected preferred terms. Gliflozin exposure was considered for all reports with at least one gliflozin as suspected/ interacting drug. Of the 19 834 180 individual case safety reports in VigiBase, in 600 reports containing 618 AP group reactions, gliflozins were suspected/ interacting drugs. Men were affected in 52.3% of the cases and 59.6% of the patients were in the 45-64 years age group. The reporters were in 417 cases healthcare professionals. Most of the reactions were reported for canagliflozin (59.7%), followed by empagliflozin (21%) and dapagliflozin (19.2%) and were serious (98.6%). Most of the reactions' outcomes (84% of the patients) were favorable. Ketoacidosis was frequently associated with the AP (21.3%). Significant PRR and IC were found for pancreatitis and pancreatitis acute for all three gliflozins, pancreatitis necrotizing for canagliflozin and empagliflozin and pancreatitis relapsing for empagliflozin. Most of the AP cases were serious and with favorable outcome. We identified possible alternative causes for AP, like concomitant medication, hypertriglyceridemia, and cholelithiasis and a frequent association with ketoacidosis. We found a significant association between AP and the use of canagliflozin, dapagliflozin, and empagliflozin that would need further investigation.

Management of heart failure with reduced ejection fraction in 2021: an update for GPs.

In February 2021, the National Institute for Health and Care Excellence (NICE) approved the use of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor (SGLT2i) for patients with or without diabetes and with a left ventricular ejection fraction (LVEF) of <40%.1 This article provides some practical guidance for GPs on implementing the recommendation. Until recently, three groups of drugs were recommended by NICE as standard therapy to improve symptoms and prognosis in heart failure with reduced ejection fraction (HFrEF). The aspiration is for patients to receive them at the maximal tolerated doses (Table 1). The groups are: angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB) or angiotensin-neprilysin inhibitors (ARNI); beta-blockers (BB); and — for patients remaining symptomatic — mineralocorticoid receptor antagonists (MRA). View this table: Table 1. First- and second-line pharmacotherapy groups (’the four pillars’) known to reduce mortality in HFrEF and approved by NICEa In patients with persistent or worsening symptoms whose LVEF is <35%, any ACEI/ARB should be replaced with sacubitril–valsartan (Entresto®), the current sole licensed member of ARNI, as both symptoms and prognosis are improved.2 Chronic heart failure still carries a poor prognosis, worse than some cancers, with a mortality of 42% at 5 years after the diagnosis in the UK.3 In part this reflects incomplete optimisation of existing therapies. GPs have a major role to play in spotting the need for medicines optimisation (Table 1), considering non-pharmacological interventions, and liaising with the community heart failure nurse and cardiac rehabilitation teams. In the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial, addition of dapagliflozin reduced the composite cardiovascular endpoint (hospitalisation for heart failure, urgent outpatient diuretic, therapy, or cardiovascular death) by 26% with a Number …

134-LB: Efficacy and Safety of Dapagliflozin in Type 1 Diabetes: The RISING-STAR Study

Background and Objective: The safe method of instructing insulin dose reduction in combination with SGLT2 inhibitors, dapagliflozin for patients with type 1 diabetes mellitus has not been clarified. In this study, we conducted a stratified, two-arm, parallel comparative study with the primary endpoint of decreasing the frequency of hypoglycemia by instructing basal insulin dose reduction. Method: The basal insulin dose to total daily insulin dose (TDD) ratio was defined as less than 40% in group A and more than 40% in group B. Group B was instructed to reduce basal insulin dose, while group A was not. Results: Twenty-nine patients in group A and 28 patients in group B were included in the analysis due to withdrawal of consent before the start of the study. The frequency of hypoglycemia before and after the intervention was 0.23 times/day in group A to 0.26 times/day and 0.19 times/day in group B to 0.23 times/day, with no significant difference between the two groups (P=0.69). The frequency of ketosis, a secondary endpoint, also increased significantly after the intervention, from 0.013 times/day to 0.086 times/day in Group A (p=0.013) and from 0.013 times/day to 0.059 times/day in Group B (p=0.011). Time In Range on FGM improved from 63.6% to 69.7% in group A and from 59.0% to 69.1% in group B. MAGE improved from 121.7 mg/dL to 105.0 mg/dL in group A and from 123.4 mg/dL to 108.0 mg/dL in group B. DTSQ showed a significant improvement in question 2 regarding hyperglycemia in both groups after the intervention, from 3.6 to 2.5 (p=0.008) in group A and from 3.7 to 2.8 (p=0.017) in group B. Conclusion: In the patients who were able to self-adjust their insulin dose, there was no significant difference in the number of hypoglycemia occurrences after concomitant use of dapagliflozin with or without instruction to reduce basal insulin dose. Concomitant use of dapagliflozin resulted in less glycemic variability, prolonged TIR and improved patient satisfaction regarding with hyperglycemia. Disclosure M. Hamaguchi: Research Support; Spouse/Partner; AstraZeneca K. K. M. Yamazaki: None. T. Tanaka: None. M. Ishii: None. H. Okada: None. K. Mitsuhashi: None. N. Kitagawa: None. G. Hasegawa: None. M. Fukui: None. Funding AstraZeneca K.K.; Ono Pharmaceutical Co., Ltd.

793-P: Dapagliflozin Improves Renal Function in Obese Indian Diabetics with Microalbuminuria

SGLT2 inhibitors have gained appreciation following their acceptance as a treatment modality for people with type 2 diabetes. These agents promote glucosuia blocking the reabsorption of glucose from the proximal convoluted tubules in the kidneys. Due to the direct role on the nephrons, initially there were some concerns over their use among the renal compromised individuals. Urinary albumin to creatinine ratio (UACR) is considered as one of the indicators to access the renal function and to classify chronic kidney disease. RAAS blockers are the standard therapeutic options for reducing urinary albumin excretion among those with or without diabetes. This study aimed to find the renoprotective effect of dapagliflozin (DAPA) among obese Indian type 2 diabetics (T2D) with microalbuminuria and compared that with RAAS blockers. We considered 182 obese adults (BMI ≥30 kg/m2) with T2D and microalbuminuria for this study. Subjects were randomized into 2 groups. Those in DAPA group (n = 86, M/F: 51/35) were administered DAPA 10 mg once daily with breakfast, whereas subjects in the comparator (RAAS) arm (n = 96, M/F 54/42) were prescribed RAAS blockers (ARBs or ACE inhibitors). From comparable UACR and HbA1c at baseline, both groups witnessed a significant decline in the UACR at 12 weeks of intervention (p&amp;lt;0.02). The change in the UACR from baseline was higher in the DAPA arm, though it was not statistically different from RAAS arm (145.7± 32.8 to 89.5 ± 35.8 mg/g vs. 131.5 ± 44.6 to 94.3 ± 28.2 mg/g). Additionally, DAPA arm in contrast to RAAS arm, proved their glycemic benefits by demonstrating a significant reduction in the HbA1c (1.5 ± 1.2% vs. 0.3 ± 0.6%). There was a drop in blood pressure in the study and comparator arms, but RAAS agents were found to be more effective in lowering blood pressure (P &amp;lt;0.03). Dapagliflozin exhibited significant and numerically better reduction in UACR compared to RAAS blocking agents among obese microalbuminuric diabetics. Use of dapagliflozin also resulted in significant Hba1c reduction. Disclosure H. Mahapatra: None. L. Mahapatra: None. M. Khuntia: None. A. K. Sahoo: None.

14-OR: Risk of Acute Kidney Injury in Real-World Use of Dapagliflozin

A noninterventional postauthorization safety study in adult patients with type 2 diabetes compared the incidence of hospitalized diagnoses of acute kidney injury (hAKI) in new users of dapagliflozin and new users of comparator glucose-lowering drugs (GLDs), matched by index year, age, sex, and region. Comparators included GLDs other than SGLT2 inhibitors or monotherapy of insulin, metformin, or sulfonylureas. Data from US Medicare (2014-2017), US HealthCore Integrated Research Database (HIRD) (2014-2019), and UK Clinical Practice Research Datalink (CPRD) (2012-2018) were included. Incidence rates of hAKI were calculated by exposure group and compared with adjusted incidence rate ratios (aIRRs) with covariate adjustment by propensity score trimming and stratification. A pooled aIRR was estimated by the Mantel-Haenszel method. The number of included person-years of dapagliflozin and comparator exposure, respectively, was 12,389 and 30,737 in CPRD, 12,575 and 111,919 in HIRD, and 9,208 and 141,313 in Medicare. The mean age (years) was 57 in CPRD, 52 in HIRD, and 71 in Medicare. Approximately 41% in CPRD, 47% in HIRD, and 50% in Medicare were women. All aIRRs and upper 95% confidence limits (CI) were below the null (figure); the pooled aIRR was 0.70 (95% CI, 0.62-0.78). This real-world study shows a decreased risk of hAKI associated with dapagliflozin compared with other GLDs and aligns with results from dapagliflozin clinical trials. Disclosure C. Johannes: Other Relationship; Self; AstraZeneca. H. Chen: None. A. Gilsenan: Other Relationship; Self; AstraZeneca. J. Layton: Other Relationship; Self; AstraZeneca. D. C. Beachler: Employee; Self; Anthem Inc. (HealthCore). R. M. Ziemiecki: Research Support; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Pfizer Inc. L. Li: Other Relationship; Self; Pfizer Inc. H. E. Danysh: Other Relationship; Self; AstraZeneca. J. Dinh: None. P. R. Hunt: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. C. Karlsson: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca.

805-P: Risk of Severe Complications of Urinary Tract Infection in Real-World Use of Dapagliflozin

A noninterventional postauthorization safety study in patients with type 2 diabetes compared the sex-specific incidence of severe complications of urinary tract infections (sUTI) (pyelonephritis or urosepsis) in new users of dapagliflozin and new users of other comparator glucose-lowering drugs (GLDs), matched by index year, age, and region. Comparators included GLDs other than SGLT2 inhibitors, or monotherapy of insulin, metformin, or sulfonylureas. Data from US Medicare (2014-2017), US HealthCore Integrated Research Database (HIRD) (2014-2019), and UK Clinical Practice Research Datalink (CPRD) (2012-2018) were analyzed. Incidence rates of sUTI were compared by exposure group with adjusted incidence rate ratios (aIRRs) with covariate adjustment by propensity score trimming and stratification. Pooled aIRRs were estimated by the Mantel-Haenszel method. The total number of person-years of dapagliflozin and comparator exposure, respectively, was 17,265 and 161,176 for females and 22,594 and 194,388 for males. Mean age (years) in CPRD, HIRD, and Medicare was 58, 52, and 72 in females and 59, 52, and 71 in males, respectively. All aIRR estimates were below the null but imprecise (figure). The pooled aIRR was 0.76 (95% CI, 0.60-0.96) in females and 0.74 (95% CI, 0.56-1.00) in males. This real-world study did not find an increased risk of sUTI in females or males with dapagliflozin compared with other GLDs. Disclosure C. Johannes: Other Relationship; Self; AstraZeneca. H. Chen: None. A. Gilsenan: Other Relationship; Self; AstraZeneca. J. Layton: Other Relationship; Self; AstraZeneca. D. C. Beachler: Employee; Self; Anthem Inc. (HealthCore). R. M. Ziemiecki: Research Support; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Pfizer Inc. L. Li: Other Relationship; Self; Pfizer Inc. H. E. Danysh: Other Relationship; Self; AstraZeneca. J. Dinh: None. P. R. Hunt: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. C. Karlsson: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca.

The SGLT-2 inhibitor dapagliflozin reduces cell death and apoptosis in cardiomyocytes exposed to trastuzumab and doxorubicin through NLRP3-mediated pathways.

e15041 Background: The clinical trial “DECLARE-TIMI 58” (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), demonstrated that dapagliflozin, a sodium glucose cotransporter 2 inhibitor (SGLT2i), reduces the composite end point of cardiovascular death/hospitalization for heart failure in a broad population of patients with type 2 diabetes mellitus. We aimed to study if dapagliflozin could exerts cardioprotective and anti-inflammatory effects in doxorubicin and trastuzumab-induced cardiotoxicity through the analysis of multiple biochemical mechanisms. Methods: HL-1 adult cardiomyocytes were exposed to subclinical concentration of doxorubicin and trastuzumab (100 nM) alone or in combination with dapagliflozin at 50 nM. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity (MTS assay), study of lipid peroxidation (quantifying cellular malondialdehyde and 4-hydroxynonenal), and of intracellular Ca2+ homeostasis. Moreover, anti-inflammatory studies were also performed (protein expression of NLRP3 inflammasome; p65/NF-κB and cytokines involved in cardiotoxicity (interleukins 1β, 8 and 6). Results: Dapagliflozin increases significantly the cardiomyocytes viability during exposure to doxorubicin and trastuzumab. Its cardioprotective properties are explainable by the reduction of intracellular Ca2+ overload (-47,6% vs cells treated only to anticancer drugs; p&lt;0,001), of the lipid peroxidation phenomena (mean reduction of 35-43 % compared to cells exposed only to anticancer drugs; p&lt;0,001). Moreover, cardiomyocytes exposed to dapagliflozin during anticancer drugs have a reduced expression of pro-inflammatory cytokines involved in cardiotoxicity (- 37,3 % for interleukin-1β; -39,5 for Interleukin 8 ; -41,3 % for Interleukin 6 ; p&lt;0,001 for all). Notably, dapagliflozin reduces p65-NF-κB activation (- 36,5% vs cells treated only to anticancer drugs) and inhibits of 27,8 % the expression of NLRP3 inflammasome that consequently improves the mitochondrial homeostasis of cardiomyocytes. Conclusions: Dapagliflozin demonstrated cardioprotective properties during doxorubicin and trastuzumab exposure. Dapagliflozin improves the Ca2+ homeostasis and inhibits the pro-inflammatory “NLRP3- NF-κB –cytokines” pathways. The overall picture obtained provides the proof of concept for translational studies designed to investigate the cardioprotective use of dapagliflozin in HER2+ breast cancer patients.

Use and effectiveness of dapagliflozin in type 1 diabetes: Clinical experience data of six months

Use and effectiveness of dapagliflozin in type 1 diabetes: Clinical experience data of six months

Effect of taxifolin/dapagliflozin combination on colistin-induced nephrotoxicity in rats

Colistin is an antimicrobial agent that is used in resistant gram-negative infections. Its most common dose-limiting adverse effect is nephrotoxicity. The objective of our study was to explore the possible effects of each of taxifolin and dapagliflozin alone and in combination on colistin-induced nephrotoxicity in rats. Sixty male rats were randomized into six groups: Control; colistin; colistin + taxifolin; colistin + dapagliflozin; colistin + carboxymethyl cellulose (CMC) and colistin + taxifolin + dapagliflozin. Dapagliflozin, taxifolin, and CMC were given daily for 7 days, 4 hours before colistin injection. Kidney weight/body weight ratio and renal function tests were determined. Renal tissue nerve growth factor-β (NGF-β), transforming growth factor beta 1 (TGF-β1), proinflammatory cytokines, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB) p65, signal transducer and activator of transcription 3 (STAT3), oxidative stress parameters, beclin-1 and c-Jun NH2-terminal kinase (JNK) activities were measured. Kidneys were examined histopathologically and immunohistochemically. Taxifolin and/or dapagliflozin induced significant improvement in the renal functions and oxidative stress parameters with significant increase in tissue Nrf2, STAT3 and NGF-β accompanied with significant decrease in kidney weight/body weight ratio, tissue proinflammatory cytokines, TGF-β1, NF-κB (p65), TLR4, beclin-1 and JNK activities and improved the histopathological picture when compared to rats treated with colistin alone. This improvement was significant with taxifolin/dapagliflozin combination compared to rats treated with each of these agents alone. So, we concluded that the combined use of taxifolin and dapagliflozin may confer a therapeutic tool for attenuation of colistin-induced nephrotoxicity.

Safety of Dapagliflozin in Children with Heart Failure

PurposeDapagliflozin recently received FDA-approval for use in adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure (HF). This is the first report describing safety and use of dapagliflozin in children with HF.MethodsThis is a single-center, observational, retrospective analysis assessing safety of dapagliflozin when added to a background of guideline-directed medical therapy in 9 pediatric patients (age < 21 years) with HF. Only patients with dapagliflozin at steady-state and with follow-up data were included. Univariate comparisons were made using Wilcoxan signed rank test before and after addition of dapagliflozin.ResultsMedian age was 14.2 years (IQR 11.2-17.7; range 9-18). Of the 9 patients, 6 had dilated cardiomyopathy, 2 had single ventricle physiology, and 1 had diastolic HF. NYHA functional class was as follows: 6 were class II, 2 were class III, and 1 was class IV. Median baseline hemoglobin A1c was 5.5% (IQR 5.3-5.75). Most (78%) were started on dapagliflozin during a HF-related hospitalization. Median starting dose of dapagliflozin was 5 mg once daily (IQR 5-10). Mean follow-up was 30.6 days (SD 21.6). Median dose at follow-up was 10 mg once daily (IQR 7.5-10). Urine glucose was negative at baseline and 1+ to 3+ at follow-up confirming the pharmacodynamic effect of dapagliflozin. Total daily dose of loop diuretic was decreased 50% for 3 patients at follow-up. There were no significant differences in weight, blood pressure, heart rate, ejection fraction, B-type natriuretic peptide, estimated glomerular filtration rate or blood chemistries at follow-up. No adverse events such as urinary tract infections, hypoglycemia, fractures, hypovolemia or renal injury were observed. Dapagliflozin was discontinued in 1 patient due to receipt of a heart transplant.ConclusionDapagliflozin appears to be safe in the short term when added to guideline-directed medical therapy for children with heart failure. Dapagliflozin recently received FDA-approval for use in adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure (HF). This is the first report describing safety and use of dapagliflozin in children with HF. This is a single-center, observational, retrospective analysis assessing safety of dapagliflozin when added to a background of guideline-directed medical therapy in 9 pediatric patients (age < 21 years) with HF. Only patients with dapagliflozin at steady-state and with follow-up data were included. Univariate comparisons were made using Wilcoxan signed rank test before and after addition of dapagliflozin. Median age was 14.2 years (IQR 11.2-17.7; range 9-18). Of the 9 patients, 6 had dilated cardiomyopathy, 2 had single ventricle physiology, and 1 had diastolic HF. NYHA functional class was as follows: 6 were class II, 2 were class III, and 1 was class IV. Median baseline hemoglobin A1c was 5.5% (IQR 5.3-5.75). Most (78%) were started on dapagliflozin during a HF-related hospitalization. Median starting dose of dapagliflozin was 5 mg once daily (IQR 5-10). Mean follow-up was 30.6 days (SD 21.6). Median dose at follow-up was 10 mg once daily (IQR 7.5-10). Urine glucose was negative at baseline and 1+ to 3+ at follow-up confirming the pharmacodynamic effect of dapagliflozin. Total daily dose of loop diuretic was decreased 50% for 3 patients at follow-up. There were no significant differences in weight, blood pressure, heart rate, ejection fraction, B-type natriuretic peptide, estimated glomerular filtration rate or blood chemistries at follow-up. No adverse events such as urinary tract infections, hypoglycemia, fractures, hypovolemia or renal injury were observed. Dapagliflozin was discontinued in 1 patient due to receipt of a heart transplant. Dapagliflozin appears to be safe in the short term when added to guideline-directed medical therapy for children with heart failure.

Expert opinion of the Heart Failure Working Group of the Polish Cardiac Society on the use of dapagliflozin in the treatment of heart failure with reduced ejection fraction.

Heart failure (HF) is a global health problem inherent in an aging population with coexisting cardiovascular diseases. Based on data from the Polish National Health Fund (Polish, Narodowy Fundusz Zdrowia), approximately 1.2 million people in Poland currently suffer from HF, and 140 000 of them die annually. Recently, Poland was ranked fifth among the European Union countries regarding the number of patients with diagnosed HF and first in terms of the number of HF hospitalizations (547 per 100 000 population) among 34 countries associated in the Organization for Economic Cooperation and Development. In recent years, a significant progress has been made in the diagnosis and treatment of HF with reduced left ventricular ejection fraction (HFrEF), which has resulted in a reduction in cardiovascular and total mortality. Despite these advantages, 5-year survival in the course of HF is still worse than that observed in some types of cancer, both in the populations of men and women. Hence, the search for drugs improving the prognosis in this group of patients is still ongoing. Sodium-glucose cotransporter 2 inhibitors represent a new group of drugs that will undoubtedly be a milestone in the treatment of patients with HFrEF. This expert opinion covers the history of dapagliflozin, which, from a drug dedicated to the treatment of type 2 diabetes, has become one of the most effective drugs improving prognosis and quality of life as well as reducing the number of hospitalizations in patients with HF. This document presents the opinion from the experts of the Heart Failure Working Group of the Polish Cardiac Society on the most relevant studies on dapagliflozin and indications for its use.

Efficacy and safety of the SGLT2 inhibitor dapagliflozin in type 1 diabetes: A meta‑analysis of randomized controlled trials

Sodium glucose cotransporter-2 (SGLT2) is a sodium-dependent glucose transporter responsible for renal absorption of glucose. Dapagliflozin is an SGLT2 inhibitor used in patients with type 1 diabetes to promote urinary glucose excretion, but to date, randomized controlled trials (RCTs) to evaluate the effect of this drug in this disease have not been systematically evaluated. Therefore, the aim of the present study was to evaluate the efficacy and safety of dapagliflozin, as an adjuvant therapy to insulin, in the treatment of type 1 diabetes mellitus through a systematic review and meta-analysis. The Cochrane Library Database, Medline and Embase databases were used to search articles published between January 1st 2004 and February 5th 2020 with no language restrictions relating to RCTs. After extracting the data, the quality of the RCTs was evaluated and the data were statistically analyzed. A total of 4 RCTs with 1,691 participants were included. Dapagliflozin resulted in decreased glycosylated hemoglobin A1c (0.40-0.45%), body weight (2.52-3.85 kg), mean daily glucose (0.76-0.99 mmol/l) and mean amplitude of glucose excursion (0.54-1.07 mmol/l; all with P<0.00001) compared to placebo. Subgroup analysis by dose indicated no significant difference in all efficacy outcome indicators between dapagliflozin at 5 and at 10 mg (P>0.1). Compared with placebo, the use of dapagliflozin in patients with type 1 diabetes increased the risk of adverse events and serious adverse events (P<0.05), but did not increase the risks of infection, diabetic ketoacidosis (DKA) and discontinuation due to adverse events. Analysis by dose group suggested that no significant difference in all safety outcome indicators between dapagliflozin at 5 and at 10 mg (P>0.1). In conclusion, dapagliflozin had a significant effect on type 1 diabetes. However, the use of dapagliflozin significantly increased the incidence of adverse events and serious adverse events compared with placebo. Dapagliflozin-assisted short-term (24 weeks) insulin therapy for type 1 diabetes did not increase the risk of DKA but additional high-quality studies are required to determine its long-term efficacy and safety.

Protective effect of dapagliflozin on colistin-induced renal toxicity

Objectives: Multiple-drug resistance to Gram-negative bacteria has increased signifi-cantly in recent years. Colistin is increasingly used as a last line of defense against these bacteria. However, colistin has been associated with nephrotoxicity in experimental animals. This study explores the protective effect of dapagliflozin in a rodent model of nephrotoxicity. Material Method: The present study includes a total of 24 male rats, of which 16 were given a single 20 mg/kg dose of colistin (Colimycin 150 mg/mL) intravenously to induce renal toxicity. The remaining eight rats were given no drugs in order to serve as the control, Group A. The 16 rats treated with colistin were then divided into two groups. Rats in Group B received 0.9% NaCl saline solution at a dose of 30 mL/kg/day intraperitoneally (i.p.) and 10 mg/kg/day dapagliflozin (Forziga 10 mg) via oral gavage. Those in Group C received 0.9% NaCl saline solution at an i.p. dose of 30 mL/kg/day. Both saline and dapagliflozin were administered as described over the course of ten days. The animals were euthanized and blood samples were taken by cardiac puncture for further analysis. Their kidneys were removed for histopathological and biochemical examination. Results: Levels of creatinine, BUN, KIM-1, and MDA were significantly increased in the 16-rat (Groups B and C) treatment group, in comparison to the control group; however, these biomarkers were significantly normalized in Group B, which had received dapagliflozin in addition to saline. The GSH levels of Group C showed significant decline when compared to those of the control group, and were significantly normalized in Group B. Histologically, in Group 2, we observed severe tubular dilatation and tubular epithelial cell injury in comparison to the control group. These severe anatomical changes were decreased in Group B. Conclusion: Apart from its positive effect on glucose regulation, which is the usual purpose of dapagliflozin, we observed that in colistin-induced nephrotoxicity, it decreases oxidative stress by inhibiting SGLT-2, and has restorative effects in terms of histopathology and biochemistry. These findings offer hope that the use of dapagliflozin may be protective for contrast nephropathy, which causes renal tubule damage through oxidative mechanisms. Future studies will further clarify the mechanistic action of colistin and dapagliflozin, and may support the hypothesis that dapagliflozin can be used as an adjunctive therapy in all nephrotoxic conditions.

Effect of dapagliflozin in patients with heart failure on reducing cardiovascular mortality in federal project on the prevention of cardiovascular diseases

Aim.To assess the effect of dapagliflozin in patients with heart failure with reduced ejection fraction (HFrEF) on reducing cardiovascular mortality as the main goal of a federal project on the prevention of cardiovascular diseases.Material and methods.All adult Russian patients with a documented NYHA class II-IV HFrEF (EF £40%) were considered the target population. The characteristics of the patients corresponded to those of the Russian Hospital Heart Failure Registry (RUS-HFR). The study looked at an increase in the dapagliflozin use in addition to standard therapy by 10% of patients annually in 2021-2023 and calculated the number of deaths that could be prevented. Cardiovascular mortality curve was created by extrapolation of the DAPA-HF study results using the Kaplan-Meier method. Further, the contribution of prevented deaths with dapagliflozin to the achievement of regional and federal targets for reducing cardiovascular mortality was calculated for 1, 2, and 3 years.Results.In case of 10% annual increase in dapagliflozin use in patients with NYHA class II-IV HFrEF, this will allow:— to prevent an additional 1,736 cardiovascular deaths in the first year, achieving the target of federal project on the prevention of cardiovascular diseases in 2021 by 5,9%;— to prevent an additional 3,784 cardiovascular deaths in the second year, achieving the target of federal project on the prevention of cardiovascular diseases in 2022 by 12,9%;— to prevent an additional 5,485 cardiovascular deaths in the third year, achieving the target of federal project on the prevention of cardiovascular diseases in 2023 by 18,7%.Conclusion.The use of dapagliflozin in patients with HFrEF will reduce mortality from cardiovascular diseases.