Inhibitor Dapagliflozin Research Articles

Safety and efficacy of dapagliflozin versus empagliflozin as add-on therapy in type 2 diabetes mellitus management

Objectives: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are drugs used as the oral hypoglycaemic that have a significant effect in lowering blood glucose, glycated haemoglobin (HbA1c), weight and blood pressure in patients of type 2 diabetes mellitus (T2DM). SGLT-2 inhibitors, such as empagliflozin and dapagliflozin, are used in addition to diet and exercise to help persons with T2DM improve their glucose control. The drugs are combined with other antidiabetic medications or used as monotherapy. Materials and Methods: The aim of this study was to evaluate the efficacy and the safety of the drug dapagliflozin against empagliflozin in individuals with T2DM as an add-on treatment. The study is carried out in a Tertiary Care Hospital in Coimbatore using a prospective observational research design. T2DM patients with a HbA1c level of >7% are included in the study. Patient information was collected by patient interviews and from the patient file. Participants in the study are categorised into two groups: one group consists of patients taking oral dapagliflozin in doses of 5 mg or 10 mg alongside other oral hypoglycemic agents (OHAs), while the other group comprises patients taking oral empagliflozin in doses of 10 mg or 20 mg alongside other OHAs. The endpoints were to assess the safety and effectiveness of each SGLT-2 inhibitor by monitoring changes in the diabetic profile, body weight, body mass index (BMI), blood pressure and cardiovascular risk. Results: The study included 100 patients, with 56 males and 44 females. Most participants were aged 51–60 years. In both treatment groups, A and B, significant reductions in body weight Group A: 3.14 kg and Group B: 2.29 kg and BMI Group A: 0.65 kg/m2 and Group B: 0.84 kg/m2 were observed after 6 months of treatment follow-up. Both groups experienced decreases in HbA1c levels from baseline to 6 months of treatment. The mean differences in HbA1c were 0.36% in Group A and 0.55% in Group B; empagliflozin led to a more significant reduction in HbA1c (0.19%) compared to dapagliflozin. Significant reductions were noted in fasting blood sugar (FBS) and postprandial blood sugar (PPBS) levels in both groups. Both dapagliflozin and empagliflozin were associated with reductions in systolic blood pressure (SBP) after 6 months of therapy. Dapagliflozin showed a greater reduction in SBP of 10.26 mmHg compared to 4.2 mmHg with empagliflozin. In addition, dapagliflozin increases diastolic blood pressure (DBP) by 2.25 mmHg, while empagliflozin reduces DBP by 3.61 mmHg. While both groups experienced reductions in SBP, only the group using empagliflozin showed a significant reduction in DBP. The Framingham risk score showed significant reductions in mean differences observed in both groups after 6 months of treatment, with a mean difference of 1.08% in Group A and 2.17% in Group B. However, the score is not statistically different between the groups. Both drugs exhibited equal effects on the prevention of cardiovascular risk. Both drugs exhibited a similar safety profile, with mild-to-moderate adverse events reported, including urinary tract infections (Group A: 18% and Group B: 12%) and hypoglycaemia (Group A: 24% and Group B: 20%) during the study period. Conclusion: SGLT-2 inhibitors dapagliflozin and empagliflozin have favourable efficacy and safety in the management of T2DM; both drugs show equal effects on HbA1c, FBS, PPBS, body weight and BMI. Empagliflozin led to a more significant reduction in HbA1c compared to dapagliflozin. In both hypertensive and non-hypertensive patients, dapagliflozin exhibited greater systolic blood pressure reduction compared to empagliflozin, whereas empagliflozin exhibited greater reduction in diastolic blood pressure compared to dapagliflozin; in contrast, dapagliflozin has shown to increase DBP. Further investigation is required to explore the blood pressure effects of SGLT-2 inhibitors in a large population. In addition, these drugs decreased cardiovascular risk. Both medications exhibited fewer instances of hypoglycaemic episodes and urinary tract infections.

Radiomics features of CMR LGE images may detect early myocardial effects of SGLT2 Inhibitor Dapagliflozin in diabetic patients without heart disease

Radiomics features of CMR LGE images may detect early myocardial effects of SGLT2 Inhibitor Dapagliflozin in diabetic patients without heart disease

Dynamics of uric acid concentration against the background of early dapagliflozin use in patients with acute decompensation of heart failure

Background. Acute decompensation of heart failure (ADHF) is an urgent problem of modern cardiology due to unfavourable prognosis and high frequency of repeated hospitalizations. The risk of acute kidney injury in patients with ADHF, which significantly worsens clinical outcomes, is high, including due to elevated uric acid levels. Aim. To evaluate the effect of sodium-glucose cotransporter type 2 inhibitor dapagliflozin in patients with ADHF with reduced left ventricular ejection fraction (LVEF) on uric acid levels. Materials and methods. The study included 122 patients with ADHF and reduced LVEF (28±6%), III FC 97 (79.5%) patients and II FC 25 (20.5%). All patients received therapy for ADHF according to available guidelines. Patients were divided into two groups: the first group standard therapy, patients in the second group were added dapagliflozin at a dose of 10 mg to standard therapy. Dapagliflozin was administered on average on the 2nd day (1–3) from admission to the hospital on condition of stable haemodynamics. The duration of follow-up was 6 months. The level of uric acid, creatinine, glomerular filtration rate, NT-proBNP, CRP and ST2 at the time of inclusion in the study and 6 months after hospital discharge were analysed. Results. In patients with ADHF and reduced LVEF, a uric acid level equal to or greater than 667.9 μmol/L during hospitalisation predicted a high risk of death during the 6-month follow-up period. Decrease of uric acid level was observed only on the background of dapagliflozin therapy 472 (366–594) μmol/L initially, 326 (275–419) μmol/L when ADHF compensation was achieved (p0.001), after 6 months the significant changes remained – 359 (263–410) μmol/L (p0.001). Against the background of dapagliflozin therapy there was a significant decrease in NT-proBNP level after 6 months from 2059 pg/ml (1456–4204.5) to 1101 pg/ml (415.8–3371.5); p0.006; decrease in ST2 concentration after 6 months from 24. 4 ng/ml (15.1–35) to 19.4 ng/ml (13.3–30.1); p0.041; decrease in SRP after six months from 2.9 mg/L (1.2–7.1) to 2.1 mg/L (0.9–2.8); p0.015; no worsening of renal function was noted. Conclusion. It can be concluded that dapagliflozin has a favourable safety and efficacy profile when used in patients with ADHF and hyperuricemia.

A STUDY ON THE PREVALENCE OF ADVERSE EFFECTS ASSOCIATED WITH SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITOR DAPAGLIFLOZIN IN A TERTIARY CARE CENTRE

Objectives: The objective of this study was to assess the prevalence of adverse effects associated with sodium-glucose cotransporter 2 inhibitors (SGLT2i) dapagliflozin in a real-world setting. Methods: This observational study was conducted prospectively over 3 months in a tertiary care center in India. It focused on in-patients aged over 18 who were diagnosed with heart failure, Type 2 diabetes mellitus, or chronic kidney disease, and undergoing treatment with SGLT2i, specifically dapagliflozin, at doses of 5 or 10 mg. Patients with a glomerular filtration rate of <25 mL/min/1.73 m², pregnant or lactating women, and individuals with end-stage renal disease or undergoing dialysis were excluded from this study. Patient demographics, clinical history, and medication usage were collected using a structured pro forma. Results: Among 60 patients, 15 (25%) experienced adverse effects. Women and those over 50 years had a significantly higher prevalence of adverse effects. The common adverse effects were urinary tract infection 5 (8.3%), urinary-like symptoms 4 (6.6%), gastrointestinal upset 3 (5%), weakness 2 (3%), and hyponatremia 1 (1.6%). The dosage (5 mg and 10 mg) was significantly associated with side effects (p<0.002). Management strategies varied, including discontinuation, temporary halting, or no change in treatment. Conclusion: The observed higher prevalence of adverse effects in older individuals, particularly women, and with higher drug doses further emphasizes the necessity for close clinical monitoring during the initial phases of treatment.

The Incidence of Contrast-induced Acute Kidney Injury in Patients on Dapagliflozin Undergoing Percutaneous Coronary Interventions

Background: Sodium glucose cotransporter 2 receptor inhibitor (SGLT2i) dapagliflozin protects the renal function of individuals with coronary artery disease (CAD) and reduces incidence of contrast-induced acute kidney injury (CI-AKI) among individuals having percutaneous coronary interventions (PCI). The purpose of this work was to assess the CI-AKI incidence across individuals on dapagliflozin underwent PCI. Methods: This single-center, prospective observational work had been conducted on 200 diabetic individuals ranging in age between 25 and 80 years old, both genders, with CAD were going to have elective coronary angiogram and PCI. We identified CI-AKI by the ESUR and KDIGO definition. Patients were divided into two equal groups: Group I: Type 2 diabetes mellitus (T2DM) were on dapagliflozin (SGLT2i) and group II: T2DM were on non SGLT2i glucose-lowering drugs. Results: CI AKI according to European society of urogenital radiology (ESUR) and kidney disease improving global outcome score were significantly higher among group II contrasted to group I (P<0.05). no significant correlations existed between contrast volume and creatinine post-PCI, estimated glomerular filtration rate (eGFR) post-PCI, high-density lipoprotein, total cholesterol, and hemoglobin A1c in both groups. Dapagliflozin use was significantly correlated with 76.2% risk reduction of AKI. Dapagliflozin usage had been correlated with a 72.6% risk reduction of AKI but with borderline significance (P = 0.064). eGFR post-PCI was significantly greater among group I cootrasted to group II (P <0.05). Conclusions: Regarding the predictors of AKI according to ESUR criteria, multivariate logistic regression analysis and demonstrated that using dapagliflozin was substantially correlated with 76.2% risk reduction of AKI controlling for age, sex, hypertension, smoking, and dyslipidemia.

Dapagliflozin targets SGLT2/SIRT1 signaling to attenuate the osteogenic transdifferentiation of vascular smooth muscle cells

Vascular calcification is a complication that is frequently encountered in patients affected by atherosclerosis, diabetes, and chronic kidney disease (CKD), and that is characterized by the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). At present, there remains a pressing lack of any effective therapies that can treat this condition. The sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin (DAPA) has shown beneficial effects in cardiovascular disease. The role of this inhibitor in the context of vascular calcification, however, remains largely uncharacterized. Our findings revealed that DAPA treatment was sufficient to alleviate in vitro and in vivo osteogenic transdifferentiation and vascular calcification. Interestingly, our study demonstrated that DAPA exerts its anti-calcification effects on VSMCs by directly targeting SGLT2, with the overexpression of SGLT2 being sufficient to attenuate these beneficial effects. DAPA was also able to limit the glucose levels and NAD+/NADH ratio in calcified VSMCs, upregulating sirtuin 1 (SIRT1) in a caloric restriction (CR)-dependent manner. The SIRT1-specific siRNA and the SIRT1 inhibitor EX527 attenuated the anti-calcification effects of DAPA treatment. DAPA was also to drive SIRT1-mediated deacetylation and consequent degradation of hypoxia-inducible factor-1α (HIF-1α). The use of cobalt chloride and proteasome inhibitor MG132 to preserve HIF-1α stability mitigated the anti-calcification activity of DAPA. These analyses revealed that the DAPA/SGLT2/SIRT1 axis may therefore represent a viable novel approach to treating vascular calcification, offering new insights into how SGLT2 inhibitors may help prevent and treat vascular calcification.Graphical abstractDapagliflozin attenuated vascular smooth muscle cells osteogenic transdifferentiation and vascular calcification through the SIRT1-mediated deacetylation and degradation of HIF-1α in a manner dependent on caloric restriction.

Effect of dapagliflozin on pulmonary vascular remodeling in rats with chronic hypoxic pulmonary arterial hypertension

Objective To investigate the effects of sodium-glucose co-transporter 2 inhibitor dapagliflozin on pulmonary vascular remodeling in a rat model of chronic hypoxic pulmonary arterial hypertension. Methods Eighteen female Sprague–Dawley rats were divided into three groups: control (CON), chronic hypoxia (HYP), and chronic hypoxia + dapagliflozin. The HYP and dapagliflozin groups were subjected to hypoxia and received saline or dapagliflozin. The CON group was normoxic and received saline. Body weight and fasting blood glucose were measured, and after 21 days, lung and heart tissues were analyzed for pulmonary artery reconstruction and right ventricular hypertrophy. Western blotting assessed Bax and Bcl-2 protein levels. Results Chronic hypoxia increased pulmonary artery wall thickness and lung fibrosis and caused right ventricular hypertrophy. Dapagliflozin reduced these changes, decreasing artery wall thickness, fibrosis, and hypertrophy while increasing the Bax/Bcl-2 ratio. Conclusion Dapagliflozin alleviates chronic hypoxia-induced pulmonary artery wall thickening and lung tissue fibrosis in rats, potentially through proapoptotic effects.

Efficacy and safety of dapagliflozin in non-diabetic patients with primary anterior ST-elevation myocardial infarction initiated in early hospital period

Abstract Background The effectiveness of SGLT2 inhibitors has been proven in all types of chronic heart failure (HFpEF, HFmrEF, and HFrEF), regardless of the presence of diabetes mellitus. There are still no clear recommendations regarding the timing of SGLT2 inhibitor administration after myocardial infarction (MI) and its influence on prognosis. It can be assumed that it is appropriate to consider the possibility that, if started quickly after the presentation of acute MI, SGLT inhibition might enhance outcomes in patients. Objective This study aims to investigate the efficacy and safety of the SGLT2 inhibitor Dapagliflozin in primary anterior ST-segment elevation myocardial infarction (STEMI) initiated in early hospital period, irrespective of heart failure manifestation. Methods The study includes 124 non-diabetic patients with primary anterior STEMI who underwent primary PCI and had left ventricular ejection fraction (LV EF) ≤45% and NT-proBNP > 900 pg/ml at symptom onset within 24 hours, regardless of heart failure symptom manifestation. Patients with cardiogenic shock were excluded. 62 patients received standard medical treatment including beta-blockers, ACE inhibitors (Control group), while the other 62 patients were administered the SGLT2 inhibitor Dapagliflozin 10 mg once a day during the first 48 hours of inpatient treatment, in addition to standard therapy (Dapa group). All patients were followed up for one year. Echocardiography was performed during the first 24 hours. Echocardiography and NT-proBNP were repeated at the end of the year. The primary endpoint was the one-year heart failure hospitalizations and secondary endpoints included one year cardiovascular mortality and changes in NT-proBNP, plasma creatinine and glycosylated hemoglobin levels. Results The study shows a significant difference in heart failure hospitalization between the groups. In the Control group, it was 25.8%, and in the Dapa group, it was 8.1% (p = 0.008). Initially, there were no significant changes in NT-proBNP levels; 1152.2 ± 222.4 pg/ml in the Control group and 1197.3 ± 279.8 pg/ml in the Dapa group (p= 0.33). At the end of a year, NT-proBNP increased in the Control group (1827.4 ± 317.8 pg/ml), whereas in the Dapa group, it significantly decreased (613.5 ± 215.6 pg/ml) (p < 0.01). One-year cardiovascular mortality in the Control and Dapa groups was 9.7% and 4.8%, respectively(p=0.491). Other blood markers did not differ, and side effects were comparable during the in-hospital period as well as at the end of the year. Conclusion Early administration of Dapagliflozin among non-diabetic patients with primary anterior STEMI is associated with a significant decreasing of heart failure hospitalization rate and NT-proBNP level. Additionally, early administration of dapagliflozin does not impact on safety indicators.

Impact of SGLT2 inhibitor dapagliflozin on myocardial protein profile in rats with long-standing Type 1 diabetes mellitus

Abstract Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial effects on the cardiovascular system in diabetes mellitus (DM) patients. However, as most trials have focused on Type 2 DM, the impact of SGLT2 inhibitors on Type 1 DM remains unclear. Objective To investigate the effects of long-term treatment with SGLT2 inhibitor dapagliflozin on the left ventricular (LV) proteome in Type 1 DM rats. Methods Male Wistar rats were divided into three groups: Control (C, n=7); Diabetes (DM, n=6); and Diabetes treated with Dapagliflozin (DM+DAPA, n=8) for 30 weeks. Diabetes was induced by streptozotocin (40 mg/kg). Dapagliflozin was added to chow at 5 mg/kg/day. Label-free mass spectrometry was used to assess LV proteome using a nanoAcquity UPLC-Xevo QTof MS system and ProteinLynx Global Server (PLGS) software. Cytoscape software, Cluster Marker, and Cluego plugins were used for bioinformatic analysis. Statistical analysis: ANOVA and Tukey or Kruskal-Wallis and Dunn. Results Dapagliflozin increased body weight (C 574±43; DM 339±31*; DM+DAPA 413±30*# g; p<0.05: * vs C; # vs DM) and reduced glycemia [C 108 (101–111); DM 554 (529–562)*; DM+DAPA 343 (237–416)*# mg/dL; p<0.05: * vs C; # vs DM]. One rat died in C and two in DM+DAPA. A total of 252 differentially expressed proteins were identified. Most proteins identified in the networks were downregulated in DM vs C and upregulated in DM+DAPA vs DM. Six proteins related to energy metabolism (Atp5j, P21571; CKm, P00564; Ak1, P39069; Atp5h, P31399; Mdh1, O88989; and Idh2, P56574), four involved in myocyte excitation-contraction (Act1, P68065; Casq2, P51868; SERCA1, Q64578; and SERCA2a, P11507), and two associated with oxidative stress (Sod1, P07632; and Sod2, P07895) were upregulated in DM+DAPA x DM. Comparing DM with C, the KEEG Pathway with the highest percentage of gene associations for upregulated proteins was related to gap junction (25.6%), necroptosis (25.6%), and fatty acid degradation (25.6%), and for downregulated proteins was related to Alzheimer disease (27.3%), cardiac muscle contraction (25%) and glycolysis/gluconeogenesis (13.6%). Comparing DM+DAPA with DM, the KEEG Pathway with the highest percentage of gene associations for upregulated proteins was related to Parkinson disease (18.3%), cardiac muscle contraction (14.2%), citrate acid cycle (9.47%), necroptosis (8.88%), and cGMP-PKG signaling (7.10 %), and for downregulated proteins was related to ketone bodies synthesis and degradation (100%). Conclusion Dapagliflozin is safe and prevents changes in the expression of proteins related to energy metabolism, cardiac muscle contraction, and oxidative stress in Type 1 diabetes mellitus rats. These results offer new insights into the cardioprotective mechanisms of dapagliflozin in Type 1 diabetes mellitus.

Metabolic Effects of the SGLT2 Inhibitor Dapagliflozin in Heart Failure Across the Spectrum of Ejection Fraction.

Mechanisms of benefit with SGLT2is (sodium-glucose cotransporter-2 inhibitors) in heart failure (HF) remain incompletely characterized. Dapagliflozin alters ketone and fatty acid metabolism in HF with reduced ejection fraction though similar effects have not been observed in HF with preserved ejection fraction. We explore whether metabolic effects of SGLT2is vary across the left ventricular ejection fraction spectrum and their relationship with cardiometabolic end points in 2 randomized trials of dapagliflozin in HF. Metabolomic profiling of 61 metabolites was performed in 527 participants from DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) and PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction HF; 12-week, placebo-controlled trials of dapagliflozin in HF with reduced ejection fraction and HF with preserved ejection fraction, respectively). Linear regression was used to assess changes in principal components analysis-defined metabolite factors with treatment from baseline to 12 weeks, as well as the relationship between changes in metabolite clusters and HF-related end points. The mean age was 66±11 years, 43% were female, and 33% were self-identified as Black. Two principal components analysis-derived metabolite factors (which were comprised of ketone and short-/medium-chain acylcarnitines) increased with dapagliflozin compared with placebo. Ketosis (defined as 3-hydroxybutyrate >500 μM) was achieved in 4.5% with dapagliflozin versus 1.2% with placebo (P=0.03). There were no appreciable treatment effects on amino acids, including branched-chain amino acids. Increases in several acylcarnitines were consistent across LVEF (Pinteraction>0.10), whereas the ketogenic effect diminished at higher LVEF (Pinteraction=0.01 for 3-hydroxybutyrate). Increases in metabolites reflecting mitochondrial dysfunction (particularly long-chain acylcarnitines) and aromatic amino acids and decreases in branched-chain amino acids were associated with worse HF-related outcomes in the overall cohort, with consistency across treatment and LVEF. SGLT2is demonstrate common (fatty acid) and distinct (ketogenic) metabolic signatures across the LVEF spectrum. Changes in key pathways related to fatty acid and amino acid metabolism are associated with HF-related end points and may serve as therapeutic targets across HF subtypes. URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT03030235 and NCT02653482.

Evaluation of the SGLT2 Inhibitor Dapagliflozin as an Alternative Treatment of Kidney Impairment in a 5/6 Nephrectomy Model Associated with Obesity

Evaluation of the SGLT2 Inhibitor Dapagliflozin as an Alternative Treatment of Kidney Impairment in a 5/6 Nephrectomy Model Associated with Obesity

From Plan to Pivot: How Model-Informed Drug Development Shaped the Dose Strategy of the Zibotentan/Dapagliflozin ZENITH Trials.

Getting the dose right is a key challenge in drug development; model-informed drug development (MIDD) provides powerful tools to shape dose strategies and inform decision making. In this tutorial, the case study of the ZENITH trials showcases how a set of clinical pharmacology and MIDD approaches informed an impactful dose strategy. The endothelin A receptor antagonist zibotentan, combined with the sodium-glucose co-transporter-2 inhibitor dapagliflozin, has yielded a robust and significant albuminuria reduction in the Phase IIb trial ZENITH-CKD and is being investigated for reduction of kidney function decline in a high-risk chronic kidney disease population in the Phase III trial ZENITH High Proteinuria. Endothelin antagonist treatment has, until now, been limited by the class effect fluid retention. ZENITH-CKD investigated a wide range of zibotentan doses based on pharmacokinetics in renal impairment, competitor-data exposure-response modeling, and clinical trial simulations. Recruitment delays reduced interim analysis data availability; here, supportive dose-response modeling recovered decision-making confidence. At trial completion, the low-dose arm enabled Phase III dose selection between Phase IIb doses. Dose-response modeling of efficacy and Kaplan-Meier analyses of tolerability identified a kidney-function-based low-dose strategy of 0.25 or 0.75 mg zibotentan (with 10 mg dapagliflozin) to balance benefit/risk in ZENITH High Proteinuria. The applied clinical pharmacology and MIDD principles enabled successful Phase IIb dose finding, rationalized and built confidence in the innovative Phase III dosing strategy and identified a potential therapeutic window for zibotentan/dapagliflozin, providing the opportunity for a significant improvement in the treatment of chronic kidney disease with high proteinuria.

Inhibition of the RXRA-PPARα-FABP4 signaling pathway alleviates vascular cellular aging by an SGLT2 inhibitor in an atherosclerotic mice model.

Atherosclerosis is the pathological cause of atherosclerotic cardiovascular disease (ASCVD), which rapidly progresses during the cellular senescence. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduce major cardiovascular events in patients with ASCVD and have potential antisenescence effects. Here, we investigate the effects of the SGLT2 inhibitor dapagliflozin on cellular senescence in atherosclerotic mice. Compared with ApoE-/- control mice treated with normal saline, those in the ApoE-/- dapagliflozin group, receiving intragastric dapagliflozin (0.1 mg kg-1 d-1) for 14 weeks, exhibited the reduction in the total aortic plaque area (48.8%±6.6% vs. 74.6%±8.0%, P<0.05), the decrease in the lipid core area ((0.019±0.0037) mm2vs. (0.032±0.0062) mm2, P<0.05) and in the percentage of senescent cells within the plaques (16.4%±3.7% vs. 30.7%±2.0%, P<0.01), while the increase in the thickness of the fibrous cap ((21.6±2.1) µm vs. (14.6±1.5) µm, P<0.01). Transcriptome sequencing of the aortic arch in the mice revealed the involvement of the PPARα and the fatty acid metabolic signaling pathways in dapagliflozin's mechanism of ameliorating cellular aging and plaque progression. In vitro, dapagliflozin inhibited the expression of PPARα and its downstream signal FABP4, by which the accumulation of senescent cells in human aortic smooth muscle cells (HASMCs) was reduced under high-fat conditions. This effect was accompanied by a reduction in the intracellular lipid content and alleviation of oxidative stress. However, these beneficial effects of dapagliflozin could be reversed by the PPARα overexpression. Bioinformatics analysis and molecular docking simulations revealed that dapagliflozin might exert its effects by directly interacting with the RXRA protein, thereby influencing the expression of the PPARα signaling pathway. In conclusion, the cellular senescence of aortic smooth muscle cells is potentially altered by dapagliflozin through the suppression of the RXRA-PPARα-FABP4 signaling pathway, resulting in a deceleration of atherosclerotic progression.

The Beneficial Effect of the SGLT2 Inhibitor Dapagliflozin in Alleviating Acute Myocardial Infarction-Induced Cardiomyocyte Injury by Increasing the Sirtuin Family SIRT1/SIRT3 and Cascade Signaling.

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.

Dapagliflozin and Right Ventricular–Pulmonary Vascular Interaction in Heart Failure With Preserved Ejection Fraction

Increases in pulmonary capillary wedge pressure (PCWP) during exercise reduce pulmonary artery (PA) compliance, increase pulsatile right ventricular (RV) afterload, and impair RV-PA coupling in patients with heart failure with preserved ejection fraction (HFpEF). The effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on pulmonary vascular properties and RV-PA coupling are unknown. To test the effect of dapagliflozin on right ventricular performance and pulmonary vascular load during exertion in HFpEF. Evaluation of the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction (CAMEO-DAPA) randomized clinical trial demonstrated improvement in PCWP at rest and exercise over 24 weeks with dapagliflozin compared with placebo with participants recruited between February 2021 and May 2022. This secondary analysis evaluates the effects of dapagliflozin on pulsatile pulmonary vascular load and RV-PA coupling using simultaneous echocardiography and high-fidelity invasive hemodynamic testing with exercise. This was a single-center study including patients with hemodynamically confirmed HFpEF with exercise PCWP of 25 mm Hg or greater. Dapagliflozin or placebo for 24 weeks. Pulsatile pulmonary vascular load (PA compliance and elastance) and right ventricular performance (PA pulsatility index, RV systolic velocity [s']/PA mean) during rest and exercise. Among 37 randomized participants (mean [SD] age, 67.4 [8.5] years; 25 female [65%]; mean [SD] body mass index, 34.9 [6.7]; calculated as weight in kilograms divided by height in meters squared), there was no effect of dapagliflozin on PA loading or RV-PA interaction at rest. However, with exercise, dapagliflozin improved PA compliance (placebo-corrected mean difference, 0.57 mL/mm Hg; 95% CI, 0.11-1.03 mL/mm Hg; P = .02) and decreased PA elastance (stiffness; -0.17 mm Hg/mL; 95% CI, -0.28 to -0.07 mm Hg/mL; P = .001). RV function during exercise improved, with increase in PA pulsatility index (0.33; 95% CI, 0.08-0.59; P = .01) and increase in exercise RV s' indexed to PA pressure (0.09 cm·s-1/mm Hg; 95% CI, 0.02-0.16 cm·s-1/mm Hg; P = .01). Improvements in pulsatile RV load and RV-PA coupling were correlated with reduction in right atrial (RA) pressure (PA elastance Pearson r = 0.55; P =.008; RV s'/PA elastance Pearson r = -0.60; P =.002) and PCWP (PA elastance Pearson r = 0.58; P <.001; RV s'/PA elastance Pearson r = -0.47; P = .02). Dapagliflozin increased resistance-compliance time (dapagliflozin, median [IQR] change, 0.06 [0.03-0.15] seconds; placebo, median [IQR] change, 0.01 [-0.02 to 0.05] seconds; P =.046), resulting in higher PA compliance for any exercise pulmonary vascular resistance. Results of this randomized clinical trial reveal that treatment with dapagliflozin for 24 weeks reduced pulsatile pulmonary vascular load and enhanced dynamic RV-PA interaction during exercise in patients with HFpEF, findings that are related to the magnitude of PCWP reduction. Benefits on dynamic right ventricular-pulmonary vascular coupling may partially explain the benefits of SGLT2 inhibitors in HFpEF. ClinicalTrials.gov Identifier: NCT04730947.

Effects of Zibotentan Alone and in Combination with Dapagliflozin on Fluid Retention in Patients with CKD.

Endothelin receptor antagonists (ERAs) reduce albuminuria but are limited by fluid retention risk, particularly in patients with chronic kidney disease (CKD). Combining ERAs with sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have diuretic effects, offers a promising strategy to mitigate fluid retention. In this post-hoc analysis of the ZENITH-CKD trial, we assessed fluid dynamics in patients with CKD treated with the ERA zibotentan alone, and in combination with the SGLT2 inhibitor dapagliflozin. In ZENITH-CKD, 508 patients with CKD (estimated glomerular filtration rate ≥ 20 mL/min/1.73m2 and a urinary albumin-to-creatinine ratio of 150-5000 mg/g) were randomized to treatment with placebo, dapagliflozin 10 mg plus placebo, zibotentan (0.25, 1.5 or 5 mg) plus dapagliflozin 10 mg and zibotentan 5 mg plus placebo. We evaluated correlations between changes in fluid retention markers and bioimpedance-measured extracellular fluid (ECF) in response to zibotentan treatment. We used Cox proportional hazards regression to assess the association between zibotentan/dapagliflozin treatment, baseline characteristics, and fluid retention, and the relationship between zibotentan plasma exposure and fluid retention. After 3 weeks of treatment with zibotentan 0.25, 1.5 or 5 mg plus dapagliflozin 10 mg, changes in body weight (β=0.36 [95%CI 0.26,0.45]) per kg, B-type natriuretic peptide (β=0.38 [95%CI 0.22, 0.54]) per doubling, and hemoglobin (β=-0.29 [95%CI -0.48, -0.10]) per g/dL were independently associated with changes in ECF. Higher doses of zibotentan were associated with significantly higher risk of fluid retention compared to dapagliflozin alone (zibotentan 5 mg HR 8.50 (95%CI 3.40, 21.30). The hazard ratio attenuated when zibotentan was combined with dapagliflozin (HR zibotentan/dapagliflozin 5/10 mg 3.09 [95%CI 1.08, 8.80], zibotentan/dapagliflozin 1.5/10 mg 2.70 [95%CI 1.44, 5.07] and zibotentan/dapagliflozin 0.25/10 mg HR 1.21 [95%CI 0.50, 2.91]). The risk of fluid retention was higher with higher zibotentan exposure and lower eGFR. High doses of zibotentan were associated with a higher risk of fluid retention, which was attenuated with lower doses and the addition of dapagliflozin.

SGLT2 inhibitor dapagliflozin reduces proximal tubular cell damage biomarkers in patients with acute heart failure

SGLT2 inhibitor dapagliflozin reduces proximal tubular cell damage biomarkers in patients with acute heart failure

SGLT2 Inhibitor Dapagliflozin Increases Skeletal Muscle and Brain Fatty Acid Uptake in Individuals With Type 2 Diabetes: A Randomized Double-Blind Placebo-Controlled Positron Emission Tomography Study.

The aim of this study was to investigate the impact of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on tissue fatty acid (FA) uptake in the skeletal muscle, brain, small intestine, and subcutaneous and visceral adipose tissue of individuals with type 2 diabetes by using positron emission tomography (PET). In a 6-week randomized double-blind placebo-controlled trial, 53 patients with type 2 diabetes treated with metformin received either 10 mg dapagliflozin or placebo daily. Tissue FA uptake was quantified at baseline and end of treatment with PET and the long-chain FA analog radiotracer 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid. Treatment effects were assessed using ANCOVA, and the results are reported as least square means and 95% CIs for the difference between groups. A total of 38 patients (dapagliflozin n = 21; placebo n = 17) completed the study. After 6 weeks, skeletal muscle FA uptake was increased by dapagliflozin compared with placebo (1.0 [0.07, 2.0] μmol ⋅ 100 g-1 ⋅ min-1; P = 0.032), whereas uptake was not significantly changed in the small intestine or visceral or subcutaneous adipose tissue. Dapagliflozin treatment significantly increased whole-brain FA uptake (0.10 [0.02, 0.17] μmol ⋅ 100 g-1 ⋅ min-1; P = 0.01), an effect observed in both gray and white matter regions. Six weeks of treatment with dapagliflozin increases skeletal muscle and brain FA uptake, partly driven by a rise in free FA availability. This finding is in accordance with previous indirect measurements showing enhanced FA metabolism in response to SGLT2 inhibition and extends the notion of a shift toward increased FA use to muscle and brain.

SGLT2 inhibitor Dapagliflozin alleviates cardiac dysfunction and fibrosis after myocardial infarction by activating PXR and promoting angiogenesis

BackgroundMyocardial infarction (MI) has emerged as the primary cause of global mortality. Managing blood sugar levels could play a vital role in the treatment of MI. Dapagliflozin (DPG), a commonly used hypoglycemic drug, has demonstrated efficacy in treating heart failure. However, the impact of DPG on MI remains unclear. We aimed to investigate the effects and mechanisms of DPG in relation to MI. Methods and resultsDPG administration alleviated MI-induced cardiac dysfunction and myocardial fibrosis. We also found that DPG administration mitigated cardiomyocyte apoptosis through TUNEL staining. CD31 and α-Sma staining revealed that DPG promotes post-MI angiogenesis in mice. In vitro, using scratch assays, transwell assays, and tube formation assays, we discovered that DPG enhanced HUVEC proliferation capacity. Mechanistically, DPG promoted the expression of extracellular matrix genes and mitochondrial function-related genes. Additionally, molecular docking identified the interaction between DPG and PXR, which activated PXR and recruited it to the promoters of Pgam2 and Tcap, promoting their expressions, thus facilitating angiogenesis and post-MI heart repair. ConclusionsDPG promotes angiogenesis by activating PXR, thereby alleviating cardiac dysfunction and fibrosis after myocardial infarction. This study provides new strategies and targets for the treatment of ischemic disease.

Dapagliflozin administration to a mouse model of type 2 diabetes induces DNA methylation and gene expression changes in pancreatic islets

Decreased pancreatic β-cell volume is a serious problem in patients with type 2 diabetes mellitus, and there is a need to establish appropriate treatments. Increasingly, sodium/glucose cotransporter 2 (SGLT2) inhibitors, which have a protective effect on pancreatic β-cells, are being prescribed to treat diabetes; however, the underlying mechanism is not well understood. We previously administered SGLT2 inhibitor dapagliflozin to a mouse model of type 2 diabetes and found significant changes in gene expression in the early-treated group, which led us to hypothesize that epigenetic regulation was a possible mechanism of these changes. Therefore, we performed comprehensive DNA methylation analysis by methylated DNA immunoprecipitation using isolated pancreatic islets after dapagliflozin administration to diabetic model mice. As a result, we identified 31 genes with changes in expression due to DNA methylation changes. Upon immunostaining, cystic fibrosis transmembrane conductance regulator and cadherin 24 were found to be upregulated in islets in the dapagliflozin-treated group. These molecules may contribute to the maintenance of islet morphology and insulin secretory capacity, suggesting that SGLT2 inhibitors’ protective effect on pancreatic β-cells is accompanied by DNA methylation changes, and that the effect is long-term and not temporary. In future diabetes care, SGLT2 inhibitors may be expected to have positive therapeutic effects, including pancreatic β-cell protection.