Sodium-glucose Cotransporter 2 Inhibitor Dapagliflozin Research Articles

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.

Dapagliflozin enhances arterial and venous compliance during exercise in heart failure with preserved ejection fraction

Abstract 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 (SGLT2i) reduce hemodynamic congestion and improve clinical outcomes in patients with HFpEF, but the mechanisms remain unclear. Purpose This study tested the hypothesis that SGLT2i dapagliflozin would improve systemic arterial compliance and venous capacitance during exercise in patients with HFpEF. Methods In this secondary analysis from the RCT trial, patients with HFpEF underwent invasive hemodynamic exercise testing at baseline and following treatment for 24 weeks with dapagliflozin or placebo. Patients were required to display pulmonary capillary wedge pressure (PCWP) ≥25 mmHg during exercise at the time of baseline evaluation. 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 (eSBV) from hemodynamic indices fit to a comprehensive cardiovascular model. Results A total of 37 patients completed the study and were included in this analysis (21 dapagliflozin and 16 placebo). Patients were predominantly women (24/37, 65%) and older (mean age 67 years). 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 mmHg, 95% CI: -33.9 to -3.7, P=0.016) (Figure 1A). Dapagliflozin improved exertional total arterial compliance (TAC) index (ETD, 0.06 mL/mmHg/m2, 95% CI: 0.003 to 0.11, P=0.039) (Figure 1B) and aortic root characteristic impedance (ETD, -2.6 mmHg/ml*sec, 95% CI: -5.1 to -0.03, P=0.048) during peak exercise, with no significant effect on systemic vascular resistance. Dapagliflozin reduced eSBV at rest and during peak exercise (ETD, -292 mmHg, 95% CI: -530 to -53, P=0.018) (Figure 1C), and improved venous capacitance evidenced by a decline in ratio of eSBV to total blood volume (ETD, -7.3%, 95% CI -13.3 to -1.3, P=0.020). Each of these effects of dapagliflozin during peak exercise were also observed during matched 20W exercise intensity. Improvements in TAC index and eSBV were correlated with decreases in body weight, and reduction in systolic BP with treatment was correlated with the change in eSBV during exercise (r=0.40, P=0.019) (Figure 2A). Decreases in BP were correlated with reduction in PCWP during exercise (r=0.56, P<0.001) (Figure 2B). Conclusion 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 SGLT2i in HFpEF.

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.

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.

The impact of using SGLT-2 inhibitor on left ventricular longitudinal strain and NT-proBNP levels during six-month follow-up in diabetic patients with and without coronary artery disease with preserved ejection fraction.

Optimal glycemic control is necessary to prevent cardiovascular events in patients with type 2 diabetes. The positive impact of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on cardiovascular events and mortality in these patients has been demonstrated by previous studies although the mechanism is unclear. We aimed to compare the influence of SGLT2i on left ventricular remodeling and strain in diabetic patients with coronary artery disease (CAD) and without CAD during 6-month follow-up. Between October 2021 and June 2022, 100 diabetic patients with preserved ejection fraction (HbA1c levels 6.5-10%) were started on SGLT2i (empagliflozin or dapagliflozin) and were prospectively followed up. Conventional and speckle-tracking echocardiography was performed by blinded sonographers, at baseline and then at 1 month and 6 months of treatment. After 6 months, the initial and biochemical blood tests were administered, and N-terminal pro-B-type natriuretic peptide levels of the patients were measured. Patients with CAD were older (P = 0.008), more frequently hypertensive (P = 0.035), and had dyslipidemia (P = 0.021). N-terminal pro-B-type natriuretic peptide levels did not change significantly after treatment in both groups. Left ventricular ejection fraction, global, 2-chamber, and 3-chamber strain values were improved significantly following SGLTi administration for the overall patient cohort, regardless of CAD status (P < 0.05 for all groups). Treatment with SGLT2i resulted in improvement in left ventricular strain parameters, which indicates that they might have a positive impact on outcomes for diabetic patients with preserved EF.

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.

Sodium-Glucose Cotransporter 2 Inhibitor Combined with Conventional Diuretics Ameliorate Body Fluid Retention without Excessive Plasma Volume Reduction.

We previously reported that sodium-glucose cotransporter 2 (SGLT2) inhibitors exert sustained fluid homeostatic actions through compensatory increases in osmotic diuresis-induced vasopressin secretion and fluid intake. However, SGLT2 inhibitors alone do not produce durable amelioration of fluid retention. In this study, we examined the comparative effects of the SGLT2 inhibitor dapagliflozin (SGLT2i group, n = 53) and the combined use of dapagliflozin and conventional diuretics, including loop diuretics and/or thiazides (SGLT2i + diuretic group, n = 23), on serum copeptin, a stable, sensitive, and simple surrogate marker of vasopressin release and body fluid status. After six months of treatment, the change in copeptin was significantly lower in the SGLT2i + diuretic group than in the SGLT2i group (-1.4 ± 31.5% vs. 31.5 ± 56.3%, p = 0.0153). The change in the estimated plasma volume calculated using the Strauss formula was not significantly different between the two groups. Contrastingly, changes in interstitial fluid, extracellular water, intracellular water, and total body water were significantly lower in the SGLT2i + diuretic group than in the SGLT2i group. Changes in renin, aldosterone, and absolute epinephrine levels were not significantly different between the two groups. In conclusion, the combined use of the SGLT2 inhibitor dapagliflozin and conventional diuretics inhibited the increase in copeptin levels and remarkably ameliorated fluid retention without excessively reducing plasma volume and activating the renin-angiotensin-aldosterone and sympathetic nervous systems.

Effect of sodium-glucose cotransporter 2 inhibitor dapagliflozin on ejection fraction reduction, myocardial and renal NF-κB expression and systemic pro-inflammatory biomarkers in models of short-term doxorubicin cardiotoxicity.

e24013 Background: Anthracycline-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in cancer patients. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) exerts multiple cardiometabolic benefits in patients with/without type 2 diabetes, chronic kidney disease and heart failure with reduced and preserved ejection fraction. We hypothesized that the SGLT2i Dapagliflozin administered before and during doxorubicin therapy, could improve cardiac function and reduce pro-inflammatory pathways in preclinical models. Methods: Female C57Bl/6 mice were treated for 10 days with a saline solution or DOXO (2.17 mg/kg), DAPA (10 mg/kg) or DOXO combined to DAPA. Systemic levels of ferroptosis-related biomarkers, galectin-3, hs-CRP and pro-inflammatory chemokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF) were quantified. After treatments, immunohistochemical staining of myocardial and renal p65/NF-kB was performed. Results: DAPA prevented the reduction of radial and longitudinal strain and ejection fraction after 10 days of treatment with DOXO. A reduced myocardial expression of NLRP-3 and MyD-88 was seen in DOXO-DAPA group compared to DOXO mice. Systemic levels of IL-1β, IL-6, TNF-α, G-CSF and GM-CSF were significantly reduced after treatment with DAPA. Serum levels of galectine-3 and hs-CRP were strongly enhanced in DOXO group; contrary, their expression were reduced in DAPA-DOXO group. Troponin-T, BNP and NT-pro-BNP were strongly reduced in DOXO-DAPA group, revealing cardioprotective properties of SGLT2-i. Mice treated with DOXO and DAPA exhibited reduced myocardial and renal NF-kB expression. Conclusions: The overall picture of the study encourages the use of DAPA in primary prevention of cardiomyopathies induced by anthracyclines in cancer patients.

#2661 High albuminuria in CKD: prevalence and characteristics in a real-world clinical setting

Abstract Background and Aims Chronic kidney disease (CKD) is estimated to affect 1 in 10 adults globally. CKD is associated with increased morbidity, mortality and decreased quality of life, and places a financial burden on the healthcare system. Furthermore, persistently high albuminuria is associated with an especially high risk of renal and cardiovascular complications in patients with CKD. With recent advances in therapeutic approaches for CKD management, both with sodium–glucose co-transporter-2 inhibitors (SGLT2i) and endothelin receptor antagonists as add-on to renin–angiotensin system blockade, it is important to highlight patients with persistent urine albumin-creatinine ratio (UACR; ≥700 mg/g). In patients with UACR &amp;gt;700 mg/g, a novel and highly selective endothelin receptor A antagonist (zibotentan) plus the SGLT2i dapagliflozin significantly reduced albuminuria versus dapagliflozin plus placebo (ZENITH-CKD trial). Hence, it is important to understand the prevalence and characteristics of patients with CKD and high albuminuria in a real-world clinical setting. Methods We used a large USA claims database (Optum's de-identified Clinformatics® Data Mart Database [CDM]) to identify patients aged ≥18 years with a CKD diagnosis and a UACR measurement ≥200 mg/g. Patients were indexed on 1st January 2022 and grouped into two UACR groups: ≥700UACR group (≥700 mg/g) and &amp;lt;700UACR group (200–699 mg/g). Continuous variables were calculated as medians with interquartile range (IQR). Baseline characteristics and comorbidities included age, sex, median UACR, median estimated glomerular filtration rate (eGFR) and a history of heart failure. Results Of 53,306 patients with CKD and UACR ≥200 mg/g, 22,504 (42%) were in the ≥700UACR group and 30,802 (58%) in the &amp;lt;700UACR group (Fig. 1). Patients were more frequently men in both groups (57%). Median UACR was 1459 mg/g (IQR 977–2473) in the ≥700UACR group and 341 mg/g (IQR 256–474) in the &amp;lt;700UACR group. Patients in the ≥700UACR group were slightly younger (72 vs 74 years), had a higher frequency of heart failure (42% vs 34%) and lower eGFR (37 mL/min/1.73 m2 [IQR 21–55] vs 49 mL/min/1.73 m2 [IQR 34–67]) compared to the &amp;lt;700UACR group. Conclusions In this contemporary study of patients with albuminuric CKD, more than 4 out of 10 had UACR levels ≥700 mg/g. These patients were slightly younger, had more severe CKD, and greater prevalence of cardiorenal disease compared to those with UACR 200–699 mg/g. Patients with UACR levels ≥700 mg/g have an urgent need for improved risk management.

Sodium-glucose cotransporter 2 inhibitor dapagliflozin prevents ejection fraction reduction, reduces myocardial and renal NF-κB expression and systemic pro-inflammatory biomarkers in models of short-term doxorubicin cardiotoxicity.

Anthracycline-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in patients with cancer. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) exert multiple cardiometabolic benefits in patients with/without type 2 diabetes, chronic kidney disease, and heart failure with reduced and preserved ejection fraction. We hypothesized that the SGLT2i dapagliflozin administered before and during doxorubicin (DOXO) therapy could prevent cardiac dysfunction and reduce pro-inflammatory pathways in preclinical models. Cardiomyocytes were exposed to DOXO alone or combined with dapagliflozin (DAPA) at 10 and 100 nM for 24 h; cell viability, iATP, and Ca++ were quantified; lipid peroxidation products (malondialdehyde and 4-hydroxy 2-hexenal), NLRP3, MyD88, and cytokines were also analyzed through selective colorimetric and enzyme-linked immunosorbent assay (ELISA) methods. Female C57Bl/6 mice were treated for 10 days with a saline solution or DOXO (2.17 mg/kg), DAPA (10 mg/kg), or DOXO combined with DAPA. Systemic levels of ferroptosis-related biomarkers, galectin-3, high-sensitivity C-reactive protein (hs-CRP), and pro-inflammatory chemokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF) were quantified. After treatments, immunohistochemical staining of myocardial and renal p65/NF-kB was performed. DAPA exerts cytoprotective, antioxidant, and anti-inflammatory properties in human cardiomyocytes exposed to DOXO by reducing iATP and iCa++ levels, lipid peroxidation, NLRP-3, and MyD88 expression. Pro-inflammatory intracellular cytokines were also reduced. In preclinical models, DAPA prevented the reduction of radial and longitudinal strain and ejection fraction after 10 days of treatment with DOXO. A reduced myocardial expression of NLRP-3 and MyD-88 was seen in the DOXO-DAPA group compared to DOXO mice. Systemic levels of IL-1β, IL-6, TNF-α, G-CSF, and GM-CSF were significantly reduced after treatment with DAPA. Serum levels of galectine-3 and hs-CRP were strongly enhanced in the DOXO group; on the other hand, their expression was reduced in the DAPA-DOXO group. Troponin-T, B-type natriuretic peptide (BNP), and N-Terminal Pro-BNP (NT-pro-BNP) were strongly reduced in the DOXO-DAPA group, revealing cardioprotective properties of SGLT2i. Mice treated with DOXO and DAPA exhibited reduced myocardial and renal NF-kB expression. The overall picture of the study encourages the use of DAPA in the primary prevention of cardiomyopathies induced by anthracyclines in patients with cancer.

Real-world effectiveness of sodium-glucose cotransporter-2 inhibitors on the progression of chronic kidney disease in patients without diabetes, with and without albuminuria.

To examine the renal effects of sodium-glucose cotransporter-2 (SGLT2) inhibition among non-diabetic individuals with chronic kidney disease (CKD) in a real-world setting. We collected de-identified data on adults without diabetes and with an estimated glomerular filtration rate (eGFR) of 25-60 mL/min/1.73 m2, who initiated the SGLT2 inhibitors dapagliflozin or empagliflozin between September 2020 and November 2022 at Maccabi Healthcare Services, an Israeli health maintenance organization. We assessed the effects of SGLT2 inhibitors on renal function (changes in eGFR slope/time). Index date was defined as the date of the first dispensing of SGLT2 inhibitors. Annual baseline slope was calculated using all eGFR measurements during the 2 years prior to index date (median = 7 measurements), while annual follow-up slope was calculated from all evaluations during 90-900 days post index date, along with baseline measurement at index date (median = 6 measurements). Paired t tests were used to compare differences between baseline and follow-up annual slopes. Of a total of 354 participants with CKD, without diabetes, who received SGLT2 inhibitors and were followed for a median of 527 days, the mean age was 72.8 ± 11.8 years, 26% were female, and 91% used renin-angiotensin system blockade. The mean eGFR was 45.4 ± 9.5 mL/min/1.73 m2. The mean body mass index was 29.1 ± 5.4 kg/m2. During the year before index date, 146 participants (41%) had a urinary albumin to creatinine ratio (UACR) <30 mg/g, 81 (23%) had a UACR of 30-300 mg/g, 74 (21%) had a UACR >300 mg/g, and 53 (15%) had no UACR evaluation. The mean eGFR slope over time was -5.6 ± 7.7 mL/min/1.73 m2 per year at baseline, which improved to -1.7 ± 6.8 mL/min/1.73 m2 per year after SGLT2 inhibitor administration (p <0.001). This effect was independent of UACR. In a real-world study of primarily older non-diabetic adults with CKD, SGLT2 inhibition was associated with a slower rate of kidney function decline, regardless of baseline UACR level.

Mathematical Models of the Effect of Glucagon on Glycemia in Individuals With Type 2 Diabetes Treated With Dapagliflozin.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels by promoting urinary glucose excretion, but their overall effects on hormonal and metabolic status remain unclear. We here investigated the roles of insulin and glucagon in the regulation of glycemia in individuals treated with an SGLT2 inhibitor using mathematical model analysis. Hyperinsulinemic-euglycemic clamp and oral glucose tolerance tests were performed in 68 individuals with type 2 diabetes treated with the SGLT2 inhibitor dapagliflozin. Data previously obtained from such tests in 120 subjects with various levels of glucose tolerance and not treated with an SGLT2 inhibitor were examined as a control. Mathematical models of the feedback loops connecting glucose and insulin (GI model) or glucose, insulin, and glucagon (GIG model) were generated. Analysis with the GI model revealed that the disposition index/clearance, which is defined as the product of insulin sensitivity and insulin secretion divided by the square of insulin clearance and represents the glucose-handling ability of insulin, was significantly correlated with glycemia in subjects not taking an SGLT2 inhibitor but not in those taking dapagliflozin. Analysis with the GIG model revealed that a metric defined as the product of glucagon sensitivity and glucagon secretion divided by glucagon clearance (designated production index/clearance) was significantly correlated with blood glucose level in subjects treated with dapagliflozin. Treatment with an SGLT2 inhibitor alters the relation between insulin effect and blood glucose concentration, and glucagon effect may account for variation in glycemia among individuals treated with such drugs.

Early use of SGLT2 inhibitors reduces the progression of diabetic kidney disease: a retrospective cohort study.

To evaluate the potential of sodium-glucose cotransporter 2 (SGLT2) inhibitors in preventing the progression of diabetic kidney disease and to provide guidance for clinical practice to improve renal health management strategies for diabetic patients. A retrospective analysis was conducted on 178 patients with diabetic kidney disease admitted to Baoji High Tech Hospital from March 2023 to March 2024. Of these, 88 patients who received early treatment with the SGLT2 inhibitor dapagliflozin were included in the early SGLT2-i group, while 90 patients receiving later treatment with SGLT2 inhibitor dapagliflozin were included in the late SGLT2-i group. Clinical data, overall effectiveness, adverse reactions, blood glucose, renal function, lipid levels, and inflammatory markers were compared between the two groups. Prior to treatment, there were no differences in blood glucose indicators between the two groups (all P > 0.05). Following treatment, both groups showed reductions in 2-hour postprandial blood glucose (2hPG), fasting plasma glucose (FPG), and glycosylated hemoglobin (HbA1c), with the early SGLT2-i group demonstrating significantly lower values compared to the late SGLT2-i group (all P < 0.05). Similarly, there were no differences in renal function indicators between the two groups before treatment (all P > 0.05). However, following treatment, the early SGLT2-i group showed more noticeable improvements compared to the late SGLT2-i group (P < 0.05). Inflammatory markers and lipid levels followed similar patterns. The overall effectiveness of the early SGLT2-i group was higher than that of the late SGLT2-i group (92.05% vs. 78.89%, P < 0.05), while the incidence of adverse reactions did not differ statistically between the two groups (6.82% vs. 10.00%, P > 0.05). Early use of SGLT2 inhibitors in diabetic kidney disease patients effectively controls blood glucose and lipid levels, improves renal function, reduces inflammatory responses, and exhibits a low incidence of adverse reactions. This demonstrates high safety and an important role in delaying disease progression. Therefore, it is worth considering clinical promotion and use for this patient population.

Post-Coronary Artery Bypass Grafting Outcomes of Patients with/without Type-2 Diabetes Mellitus and Chronic Kidney Disease Treated with SGLT2 Inhibitor Dapagliflozin: A Single-Center Experience Analysis.

Increasingly, SGLT2 inhibitors save patients with heart failure and comorbidities such as type-2 diabetes mellitus (T2DM) and chronic kidney disease (CKD); the inhibition of sodium-glucose cotransporter 2 (SGLT2) was first studied in patients with diabetes as a solution to lower glucose levels by preventing glucose reabsorption and facilitating its elimination; in the process, researchers took notice of how SGLT2 inhibitors also seemed to have beneficial cardiovascular effects in patients with both diabetes and cardiovascular disease. Our single-center prospective study assesses outcomes of post-coronary artery bypass grafting (CABG) rehabilitation and SLGT2 inhibition in CABG patients with/without T2DM and with/without CKD. One hundred twenty consecutive patients undergoing CABG were included in the analysis. Patients were divided into four subgroups: diabetes patients with chronic kidney disease (T2DM + CKD), diabetes patients without chronic kidney disease (T2DM-CKD), prediabetes patients with chronic kidney disease (PreD+CKD), and prediabetes patients without chronic kidney disease (PreD-CKD). Echocardiographic and laboratory investigations post-surgery (phase I) and 6 months later (phase II) included markers for cardiac ischemia, glycemic status, and renal function, and metabolic equivalents were investigated. One hundred twenty patients participated, mostly men, overweight/obese, hypertensive, smokers; 65 had T2DM (18 with CKD), and 55 were prediabetic (17 with CKD). The mean ejection fraction increased by 8.43% overall but significantly more in the prediabetes group compared to the T2DM group (10.14% vs. 6.98%, p < 0.05). Overall, mean heart-type fatty-acid-binding protein (H-FABP) levels returned to normal levels, dropping from 68.40 ng/mL to 4.82 ng/mL (p = 0.000), and troponin data were more nuanced relative to an overall, strongly significant decrease of 44,458 ng/L (p = 0.000). Troponin levels in patients with CKD dropped more, both in the presence of T2DM (by 82,500 ng/L, p = 0.000) and in patients without T2DM (by 73,294 ng/L, p = 0.047). As expected, the overall glycated hemoglobin (HbA1c) levels improved significantly in those with prediabetes (from 6.54% to 5.55%, p = 0.000); on the other hand, the mean HbA1c changed from 7.06% to 6.06% (p = 0.000) in T2DM, and the presence or absence of CKD did not seem to make any difference: T2DM+CKD 7.01-6.08% (p = 0.000), T2DM-CKD 7.08-6.04% (p = 0.000), PreD+CKD 5.66-4.98% (p = 0.014), and PreD-CKD 6.03-4.94% (p = 0.00). Compared to an overall gain of 11.51, the GFRs of patients with CKD improved by 18.93 (68.15-87.07%, p = 0.000) in the presence of established diabetes and 14.89 (64.75-79.64%, p = 0.000) in the prediabetes group. Regarding the patients' cardiac statuses, the results from our single-center analysis revealed a significant decrease in ischemic risk (H-FABP and hs-cTnI levels) with improvements in mean ejection fraction, glycemic status, and renal function in patients post-CABG with/without T2DM, with/without CKD, and with SGLT2 inhibitor dapagliflozin treatment while undergoing cardiac rehabilitation.

Single-Cell RNA Sequencing Reveals Metabolic Stress-Dependent Activation of Cardiac Macrophages in a Model of Dyslipidemia-Induced Diastolic Dysfunction.

Metabolic distress is often associated with heart failure with preserved ejection fraction (HFpEF) and represents a therapeutic challenge. Metabolism-induced systemic inflammation links comorbidities with HFpEF. How metabolic changes affect myocardial inflammation in the context of HFpEF is not known. We found that ApoE knockout mice fed a Western diet recapitulate many features of HFpEF. Single-cell RNA sequencing was used for expression analysis of CD45+ cardiac cells to evaluate the involvement of inflammation in diastolic dysfunction. We focused bioinformatics analysis on macrophages, obtaining high-resolution identification of subsets of these cells in the heart, enabling us to study the outcomes of metabolic distress on the cardiac macrophage infiltrate and to identify a macrophage-to-cardiomyocyte regulatory axis. To test whether a clinically relevant sodium glucose cotransporter-2 inhibitor could ameliorate the cardiac immune infiltrate profile in our model, mice were randomized to receive the sodium glucose cotransporter-2 inhibitor dapagliflozin or vehicle for 8 weeks. ApoE knockout mice fed a Western diet presented with reduced diastolic function, reduced exercise tolerance, and increased pulmonary congestion associated with cardiac lipid overload and reduced polyunsaturated fatty acids. The main immune cell types infiltrating the heart included 4 subpopulations of resident and monocyte-derived macrophages, determining a proinflammatory profile exclusively in ApoE knockout- Western diet mice. Lipid overload had a direct effect on inflammatory gene activation in macrophages, mediated through endoplasmic reticulum stress pathways. Investigation of the macrophage-to-cardiomyocyte regulatory axis revealed the potential effects on cardiomyocytes of multiple inflammatory cytokines secreted by macrophages, affecting pathways such as hypertrophy, fibrosis, and autophagy. Finally, we describe an anti-inflammatory effect of sodium glucose cotransporter-2 inhibitor in this model. Using single-cell RNA sequencing , in a model of diastolic dysfunction driven by hyperlipidemia, we have determined the effects of metabolic distress on cardiac inflammatory cells, in particular on macrophages, and suggest sodium glucose cotransporter-2 inhibitors as potential therapeutic agents for the targeting of a specific phenotype of HFpEF.

Dapagliflozin treatment is associated with a reduction of epicardial adipose tissue thickness and epicardial glucose uptake in human type 2 diabetes

ObjectiveWe recently demonstrated that treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) leads to an increase in myocardial flow reserve in patients with type 2 diabetes (T2D) with stable coronary artery disease (CAD). The mechanism by which this occurs is, however, unclear. One of the risk factors for cardiovascular disease is inflammation of epicardial adipose tissue (EAT). Since the latter is often increased in type 2 diabetes patients, it could play a role in coronary microvascular dysfunction. It is also well known that SGLT-2i modify adipose tissue metabolism. We aimed to investigate the effects of the SGLT-2i dapagliflozin on metabolism and visceral and subcutaneous adipose tissue thickness in T2D patients with stable coronary artery disease and to verify whether these changes could explain observed changes in myocardial flow.MethodsWe performed a single-center, prospective, randomized, double-blind, controlled clinical trial with 14 T2D patients randomized 1:1 to SGLT-2i dapagliflozin (10 mg daily) or placebo. The thickness of visceral (epicardial, mediastinal, perirenal) and subcutaneous adipose tissue and glucose uptake were assessed at baseline and 4 weeks after treatment initiation by 2-deoxy-2-[18F]fluoro-D-glucose Positron Emission Tomography/Computed Tomography during hyperinsulinemic euglycemic clamp.ResultsThe two groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, BMI, renal and heart function). Dapagliflozin treatment significantly reduced EAT thickness by 19% (p = 0.03). There was a significant 21.6% reduction in EAT glucose uptake during euglycemic hyperinsulinemic clamp in the dapagliflozin group compared with the placebo group (p = 0.014). There were no significant effects on adipose tissue thickness/metabolism in the other depots explored.ConclusionsSGLT-2 inhibition selectively reduces EAT thickness and EAT glucose uptake in T2D patients, suggesting a reduction of EAT inflammation. This could explain the observed increase in myocardial flow reserve, providing new insights into SGLT-2i cardiovascular benefits.

Fluid homeostatic action of dapagliflozin in patients with chronic kidney disease: the DAPA-BODY Trial.

Sodium glucose cotransporter 2 (SGLT2) inhibitors have both glucose-lowering and diuretic effects. We recently reported that the SGLT2 inhibitor dapagliflozin exerts short-term fluid homeostatic action in patients with chronic kidney disease (CKD). However, the long-term effects of SGLT2 inhibitors on body fluid status in patients with CKD remain unclear. This was a prospective, non-randomized, open-label study that included a dapagliflozin treatment group (n = 73) and a control group (n = 24) who were followed for 6 months. Body fluid volume was measured using a bioimpedance analysis device. The extracellular water-to-total body water ratio (ECW/TBW), a predictor of renal outcomes, was used as a parameter for body fluid status (fluid retention, 0.400 ≤ ECW/TBW). Six-month treatment with dapagliflozin significantly decreased ECW/TBW compared with the control group (-0.65% ± 2.03% vs. 0.97% ± 2.49%, p = 0.0018). Furthermore, dapagliflozin decreased the ECW/TBW in patients with baseline fluid retention, but not in patients without baseline fluid retention (-1.47% ± 1.93% vs. -0.01% ± 1.88%, p = 0.0017). Vasopressin surrogate marker copeptin levels were similar between the control and dapagliflozin groups at 6 months (32.3 ± 33.4 vs. 30.6 ± 30.1 pmol/L, p = 0.8227). However, dapagliflozin significantly increased the change in copeptin levels at 1 week (39.0% ± 41.6%, p = 0.0010), suggesting a compensatory increase in vasopressin secretion to prevent hypovolemia. Renin and aldosterone levels were similar between the control and dapagliflozin groups at 6 months, while epinephrine and norepinephrine (markers of sympathetic nervous system activity) were significantly lower in the dapagliflozin group than in the control group. In conclusion, the SGLT2 inhibitor dapagliflozin ameliorated fluid retention and maintained euvolemic fluid status in patients with CKD, suggesting that SGLT2 inhibitors exert sustained fluid homeostatic actions in patients with various fluid backgrounds. Clinical trial registration: https://www.umin.ac.jp/ctr/, identifier [UMIN000048568].

The SGLT2I Dapagliflozin reverses metabolic stress driving myocardial inflammation in a mouse model of heart failure with preserved ejection fraction: insights from single-cell RNA sequencing

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is often associated with metabolic distress and represents a therapeutic challenge. Metabolism-induced systemic inflammation links comorbidities with HFpEF. How metabolic changes impact myocardial inflammation in the context of HFpEF is not known. Methods We generated a model of metabolic HFpEF by feeding ApoE knockout (ApoE KO) mice a high-fat diet (HFD), and used single-cell expression analysis (scRNA-seq) on CD45+ cardiac cells to evaluate the involvement of inflammation. By focusing our analysis on macrophages, we obtained high-resolution identification of subsets of these cells in the heart, enabling us to study the outcomes of metabolic distress on the cardiac macrophage infiltrate and identify a macrophage-to-cardiomyocyte (CMC) regulatory axis. To test whether a clinically relevant sodium glucose cotransporter-2 inhibitor (SGLT2i) could ameliorate the cardiac immune infiltrate profile in our model, ApoE KO-HDF mice were randomized to receive the SGLT2i dapagliflozin (DAPA) or vehicle for 8 weeks. Results We describe a new metabolic HFpEF model: mice present with reduced diastolic function, reduced exercise tolerance, and increased pulmonary congestion associated with cardiac lipid overload and reduced polyunsaturated fatty acids. The main immune cell types infiltrating the heart included 4 sub-populations of resident and monocyte-derived macrophages displaying a pro-inflammatory profile exclusively in ApoE KO-HFD mice. Lipid overload had a direct effect on inflammatory gene activation in macrophages, mediated through endoplasmic-reticulum stress pathways. Investigation of the macrophage-to-CMC regulatory axis revealed the potential effects on CMCs of multiple inflammatory cytokines secreted by macrophages, impacting pathways such as hypertrophy, fibrosis, and autophagy. Finally, we describe the anti-inflammatory effect of SGLT2i. Conclusions Through a newly described model of HFpEF based on metabolic stress, and using scRNA-seq, we have determined the effects of metabolic distress on cardiac inflammatory cells, in particular on macrophages, and suggest SGLT2i as potential therapeutic agents for the targeting of a specific phenotype of HFpEF.

New-onset syncope in diabetic patients treated with sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase 4 inhibitors: A Chinese population-based cohort study

Abstract Background and Aims Type 2 diabetes mellitus (T2DM) is an independent risk factor for syncope. Sodium-glucose cotransporter-2 inhibitor (SGLT2i) shows strong cardiovascular benefits, but a therapeutic benefit on syncope has not been previously investigated. This study aims to investigate the incidence of new-onset syncope in T2DM patients treated with SGLT2i v.s. dipeptidyl peptidase-4 inhibitors (DPP4i) in a Chinese population. Methods This was a retrospective cohort study of T2DM patients treated with SGLT2i or DPP4i between January 1st, 2016, and December 31st, 2020, in Hong Kong. The study outcomes were new-onset syncope, cardiovascular mortality and all-cause mortality. Results A total of 55370 patients (50.48% male; median age: 62.78 years) were included with a median follow-up of 5.56 years. In the matched cohort (SGLT2i: n=18751; DPP4i: n=18751), SGLT2i use was significantly associated with lower risks of syncope (HR: 0.49, 95%CI: [0.41, 0.57], P &amp;lt; 0.0001), cardiovascular mortality (HR: 0.35, 95%CI: [0.26, 0.46], P &amp;lt; 0.001) and all-cause mortality (HR: 0.30, 95%CI: [0.26, 0.34], P &amp;lt; 0.0001). Of the SGLT2i types, empagliflozin (HR: 0.79, 95%CI: [0.59, 1.05], P = 0.0999), dapagliflozin (HR: 0.70, 95%CI: [0.58, 0.85], P = 0.0004), canagliflozin (HR: 0.48, 95%CI: [0.36, 0.63], P &amp;lt; 0.0001) and ertugliflozin (HR: 0.45, 95%CI: [0.30, 0.68], P = 0.0001) were all associated with significantly lower risks of syncope. Conclusions SGLT2i is associated with lower risk of new-onset syncope, cardiovascular death and all-cause death compared to DPP4i. Of the different SGLT2i, dapagliflozin, canagliflozin and ertuglifolzin were significantly associated with lower risks of new-onset syncope.

Correction of the prooxidant-antioxidant balance disorders in patients with diabetic kidney disease

The present study aimed to evaluate the effect of sodium-glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin therapy on the prooxidant-antioxidant balance (PAB) in patients with diabetic kidney disease.&#x0D; Methods. A total of 88 patients with type 2 diabetes mellitus (DM) and diabetic nephropathy (DN) were included in this single-center randomized open-label prospective study. All patients were randomly divided into 2 groups: 45 patients received a standard course of treatment, which included antidiabetic drugs, renin-angiotensin-aldosterone system blockers, and HMG-CoA reductase inhibitors (statins). In addition to the standard therapy, the remaining 43 patients were prescribed the SGLT2 inhibitor dapagliflozin 10 mg per day. Patients were re-examined after 6 months of treatment. The blood PAB was calculated as the ratio of total hydroperoxides (THP) to total antioxidant activity (TAA). The level of THP and TAA was determined by the colorimetric method.&#x0D; Results. PAB was significantly elevated in type 2 DM patients with nephropathy due to TAA decrease and THP level increase when compared to the control group. The highest values of PAB were found in the late stages of DN in patients with glomerular filtration rates &lt;60 ml/min/1.73m2. In patients who received dapagliflozin, significant PAB elevation by 30,55% (р &lt; 0.05) was observed as well as THP decrease and TAA increase in blood. In the standard therapy group, no significant changes in PAB parameters were detected.&#x0D; Conclusions. Add-on treatment with dapagliflozin resulted in a more significant improvement of the PAB in patients with DN in comparison with standard treatment.