Semaglutide combined with empagliflozin vs. monotherapy for non-alcoholic fatty liver disease in type 2 diabetes: Study protocol for a randomized clinical trial.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is strongly associated with type 2 diabetes mellitus (T2DM). Lifestyle intervention remains a preferred treatment modality for NAFLD. The glucagon-like peptide (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been developed as new glucose-lowering drugs, which can improve fatty liver via an insulin-independent glucose-lowering effect. However, studies exploring the efficacy of GLP-1 receptor agonists combined with SGLT-2 inhibitors in patients with NAFLD and T2DM are scanty. Thus, the present randomised controlled trial aims at comparing the efficacy and safety of semaglutide plus empagliflozin with each treatment alone in patients with NAFLD and T2DM. METHODS: This 52-week double-blinded, randomised, parallel-group, active-controlled trial evaluates the effects of semaglutide, empagliflozin and semaglutide + empagliflozin in 105 eligible overweight/obese subjects with NAFLD and T2DM. The primary outcome will be a change from baseline to week 52 in the controlled attenuation parameter, free fatty acid and glucagon. Secondary endpoints include changes in liver stiffness measurement, liver enzymes, blood glucose, lipid levels, renal function, electrolyte balances, minerals and bone metabolism, cytokines, high-sensitivity C-reactive protein, ferritin, anthropometric indicators, nonalcoholic fatty liver fibrosis score, fibrosis 4 score and homeostatic model assessment for insulin resistance. In addition, intention-to-treat, interim analysis and safety analysis will be performed. DISCUSSION: This double-blinded, randomised, clinical trial involves a multi-disciplinary approach and aims to explore the synergistic effects of the combination of semaglutide and empagliflozin. The results can provide important insights into mechanisms of GLP-1 receptor agonists and/or SGLT-2 inhibitors in patients with NAFLD and T2DM. TRIAL REGISTRATION: This study has been registered with Chinese Clinical Trial Registry (ChiCTR2300070674).

Comparative Genitourinary Safety of In-class Sodium-Glucose Cotransporter-2 Inhibitors among Patients with Heart Failure with Preserved Ejection Fraction: A Cohort Study.

PURPOSE: The American Heart Association recommended sodium-glucose cotransporter-2 inhibitors (SGLT2i) for the management of heart failure with preserved ejection fraction (HFpEF). However, little is known about their real-world in-class comparative safety in patients with HFpEF. We aimed to assess the comparative safety of SGLT2i in the risk of urinary tract infection (UTI) or genital infection separately or as a composite outcome among patients with HFpEF. METHODS: This cohort study using MarketScan® Commercial and Medicare supplemental databases (2012-2020) included patients aged ≥ 18 years with a diagnosis of HFpEF who initiated SGLT2i therapy. Three pairwise comparison groups were established: cohort 1, dapagliflozin versus canagliflozin; cohort 2, empagliflozin versus canagliflozin; and cohort 3, dapagliflozin versus empagliflozin. After stabilized inverse probability treatment weighting, Cox proportional hazards regression was used to compare the risk of UTI or genital infection separately or as a composite outcome in each cohort. RESULTS: The risk of the composite outcome did not significantly differ between canagliflozin and dapagliflozin (adjusted hazard ratio [aHR] 0.64; 95% confidence interval [CI] 0.36-1.14) or between empagliflozin and canagliflozin (aHR 1.25; 95% CI 0.77-2.05). Similarly, there was no evidence of difference between dapagliflozin and empagliflozin in this risk (aHR 0.76; 95% CI 0.48-1.21). The results of analyses separately assessing UTI or genital infection were similar. CONCLUSIONS: There was no significant difference in the risk of UTI or genital infection among patients with HFpEF who initiated canagliflozin, dapagliflozin, or empagliflozin.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are used for the management of heart failure with preserved ejection fraction (HFpEF). It is important to assess their comparative risk of urinary tract infection (UTI) or genital infection among patients with HFpEF. We compared patients with HFpEF using SGLT2i in three pairwise groups: cohort 1, dapagliflozin versus canagliflozin; cohort 2, empagliflozin versus canagliflozin; and cohort 3, dapagliflozin versus empagliflozin. We found that there was no significant difference in the risk of genitourinary infections including UTI or genital infections among dapagliflozin, empagliflozin, and canagliflozin.

Risk of acute pancreatitis among new users of empagliflozin compared to sulfonylureas in patients with type 2 diabetes: A post-authorization safety study.

PURPOSE: This study was undertaken to evaluate the potential risk of acute pancreatitis with empagliflozin in patients with type 2 diabetes (T2D) newly initiating empagliflozin. METHODS: Data from two large US claims databases were analyzed in an observational study of patients with T2D receiving metformin who were newly prescribed empagliflozin versus sulfonylurea (SU). Because dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists have been associated with the risk of acute pancreatitis in some studies, patients on these agents were excluded. Using pooled analyses of data from the two databases (2014-2021), patients initiating empagliflozin were matched 1:1 within database to patients initiating SU using propensity scores (PS) that incorporated relevant demographic and clinical characteristics. Prespecified sensitivity analyses were performed for design parameters. RESULTS: The analyses identified 72 661 new users of empagliflozin and 422 018 new users of SUs, with both patient groups on concurrent metformin therapy. Baseline characteristics within treatment groups appeared to be similar across the 72 621 matched pairs. After mean follow-up of ~6 months, incidence rates of acute pancreatitis in the pooled matched cohort were 10.30 (95% confidence interval [CI] 9.29-11.39) events per 1000 patient-years (PY) for empagliflozin and 11.65 (95% CI 10.59-12.77) events per 1000 PY for SUs. On a background of metformin, patients newly initiating empagliflozin did not have an increased risk of acute pancreatitis compared with those initiating an SU (pooled PS matched hazard ratio 0.88 [0.76-1.02]) across 75621.42 PY of follow-up. CONCLUSIONS: The results of this voluntary post-approval safety study provide additional evidence that the use of empagliflozin for the treatment of T2D is not associated with an increased risk of acute pancreatitis.

Salidroside Ameliorates Lung Injury Induced by PM 2.5by Regulating SIRT1-PGC-1α in Mice.

Objective: This study aimed to clarify the intervention effect of salidroside (SAL) on lung injury caused by PM 2.5 in mice and illuminate the function of SIRT1-PGC-1ɑ axis. Methods: Specific pathogen-free (SPF) grade male C57BL/6 mice were randomly assigned to the following groups: control group, SAL group, PM 2.5 group, SAL+PM 2.5 group. On the first day, SAL was given by gavage, and on the second day, PM 2.5 suspension was given by intratracheal instillation. The whole experiment consist of a total of 10 cycles, lasting 20 days. At the end of treatment, blood samples and lung tissues were collected and analyzed. Observation of pathological changes in lung tissue using inverted microscopy and transmission electron microscopy. The expression of inflammatory, antioxidants, apoptosis, and SIRT1-PGC-1ɑ proteins were detected by Western blotting. Results: Exposure to PM 2.5 leads to obvious morphological and pathologica changes in the lung of mice. PM 2.5 caused a decline in levels of antioxidant-related enzymes and protein expressions of HO-1, Nrf2, SOD2, SIRT1 and PGC-1ɑ, and an increase in the protein expressions of IL-6, IL-1ß, Bax, caspase-9 and cleaved caspase-3. However, SAL reversed the aforementioned changes caused by PM 2.5 by activating the SIRT1-PGC-1α pathway. Conclusion: SAL can activate SIRT1-PGC-1ɑ to ameliorate PM 2.5-induced lung injury.

Comparative Outcomes of Empagliflozin to Dapagliflozin in Patients With Heart Failure.

Importance: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to have benefits when used in patients with heart failure. The comparative outcomes of SGLT2 inhibitors relative to each other has not been well defined and may impact medication selection. Objective: To determine the comparative outcomes of empagliflozin and dapagliflozin on reducing the composite of all-cause mortality and hospitalizations in patients with heart failure. Design, Setting, and Participants: This multicenter retrospective cohort study included patients with heart failure from August 18, 2021, and December 6, 2022, in the TriNetX Research Collaborative, a centralized database of deidentified electronic medical record data from a network of 81 health care organizations. Eligible patients had a diagnosis of heart failure, had never received an SGLT2 inhibitor previously, and were newly started on empagliflozin or dapagliflozin. Patients were followed up for 1 year. Exposure: Initiation of dapagliflozin or empagliflozin. Main Outcomes and Measures: The primary outcome was the time to the composite of all-cause mortality or hospitalization between study days 1 to 365. Kaplan-Meier analyses, hazard ratios (HRs), and 95% CIs were used to assess the primary outcome. Results: Among 744 914 eligible patients, 28 075 began empagliflozin (15 976 [56.9%]) or dapagliflozin (12 099 [43.1%]). After nearest-neighbor matching for demographics, diagnoses, and medication use, there were 11 077 patients in each group. Of patients who received empagliflozin, 9247 (57.9%) were male, 3130 (19.6%) were Black individuals, and 9576 (59.9%) were White individuals. Similarly, of those who received dapagliflozin, 7439 (61.5%) were male, 2445 (20.2%) were Black individuals, and 7131 (58.9%) were White individuals. Patients receiving empagliflozin were less likely to experience the composite of all-cause mortality or hospitalization compared with those initiated on dapagliflozin (3545 [32.2%] vs 3828 [34.8%] events; HR, 0.90 [95% CI, 0.86-0.94]) in the year following SGLT2 inhibitor initiation and less likely to be hospitalized (HR, 0.90 [95% CI, 0.86-0.94]). All-cause mortality did not differ between exposure groups (HR, 0.91 [95% CI, 0.82-1.00]). There was no difference in mean hemoglobin A1c or adverse events between groups. Conclusions and Relevance: In this cohort study, patients who initiated empagliflozin were less likely to experience the composite of all-cause mortality or hospitalization compared with patients who started dapagliflozin. Additional studies are needed to confirm these finding.

Dapagliflozin added to metformin reduces perirenal fat layer in type 2 diabetic patients with obesity.

Sodium-glucose co-transporters type 2 inhibitors (SLGT2i) are highly effective in controlling type 2 diabetes, but reported beneficial cardiovascular effects suggest broader actions on insulin resistance. Weight loss may be initially explained by glycosuria-induced net caloric output and secondary volumetric reduction, but its maintenance could be due to loss of visceral fat mass. Structured ultrasound (US) imaging of abdominal adipose tissue ("eco-obesity") is a recently described methodology used to measure 5 consecutive layers of abdominal fat, not assessable by DEXA or CT scan: superficial subcutaneous (SS), deep subcutaneous (DS), preperitoneal (PP), omental (Om) and right perirenal (RK). PP, Om and RK are predictors of metabolic syndrome (MS) with defined cut-off points. To assess the effect of SLGT2i on every fat depot we enrolled 29 patients with type 2 Diabetes (HbA1c 6.5-9%) and Obesity (IMC > 30 kg/m2) in an open-label, randomized, phase IV trial (EudraCT: 2019-000979-16): the Omendapa trial. Diabetes was diagnosed < 12 months before randomization and all patients were treatment naïve. 14 patients were treated with metformin alone (cohort A) and 15 were treated with metformin + dapaglifozin (cohort B). Anthropometric measures and laboratory tests for glucose, lipid profile, insulin, HOMA, leptin, ultrasensitive-CRP and microalbuminuria (MAL) were done at baseline, 3rd and 6th months. At 6th month, weight loss was -5.5 ± 5.2 kg (5.7% from initial weight) in cohort A and -8.4 ± 4.4 kg (8.6%) in cohort B. Abdominal circumference showed a -2.7 ± 3.1 cm and -5.4 ± 2.5 cm reduction, respectively (p = 0.011). Both Metformin alone (-19.4 ± 20.1 mm; -21.7%) or combined with Dapaglifozin (-20.5 ± 19.4 mm; -21.8%) induced significant Om fat reduction. 13.3% of cohort A patients and 21.4% of cohort's B reached Om thickness below the cut-off for MS criteria. RK fat loss was significantly greater in cohort B group compared to cohort A, at both kidneys. Only in the Met + Dapa group, we observed correlations between Om fat with leptin/CRP/MAL and RK fat with HOMA-IR. US is a useful clinical tool to assess ectopic fat depots. Both Metformin and Dapaglifozin induce fat loss in layers involved with MS but combined treatment is particularly effective in perirenal fat layer reduction. Perirenal fat should be considered as a potential target for cardiovascular dapaglifozin beneficial effects.

The impact of empagliflozin and metformin on cardiac parameters in patients with mid-range ejection fraction heart failure without diabetes.

Heart failure (HF) remains a significant problem for healthcare systems, requiring the use of intervention and multimodal management strategies. We aimed to assess the short-term effect of empagliflozin (EMPA) and metformin on cardiac function parameters, including ventricular dimension-hypertrophy, septal thickness, ejection fraction (EF), and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in patients with HF and mildly reduced EF. A case-control study included 60 newly diagnosed patients with HF. Patients were divided into two groups: Group E received standard HF treatment (carvedilol, bumetanide, sacubitril-valsartan, spironolactone) plus EMPA 10 mg daily, and Group M received standard HF treatment plus metformin 500 mg daily. After three months of treatment, Group E had a significantly higher EF than Group M compared to initial measurements (a change of 9.2% versus 6.1%, respectively). We found similar results in the left ventricular end-systolic dimension (LVESD), with mean reductions of 0.72 mm for Group E and 0.23 mm for Group M. Regarding cardiac indicators, the level of NT-proBNP was considerably decreased in both groups. However, the reduction was significantly greater in group E than in group M compared to the initial level (mean reduction: 719.9 vs. 973.6, respectively). When combined with quadruple anti-heart failure therapy, metformin enhanced several echocardiographic parameters, showing effects similar to those of EMPA when used in the same treatment regimen. However, the benefits of EMPA were more pronounced, particularly regarding improvements in EF and LVESD.

Wogonoside alleviates microglia-mediated neuroinflammation via TLR4/MyD88/NF-κB signaling axis after spinal cord injury.

Wogonoside (WG) is a natural flavonoid extracted from Scutellariae Radix, recognized for its established anti-inflammatory properties. However, the role of WG in the context of neuroinflammation after spinal cord injury (SCI) remains inadequately elucidated. This study employed in silico, in vitro, and in vivo methodologies to investigate the impact of WG on microglia-mediated neuroinflammation after SCI. In the in silico experiment, we identified 15 potential target genes of WG associated with SCI. These genes were linked to the regulation of inflammatory response and immune defense. Molecular docking maps revealed toll-like receptor 4 as a molecular target for WG, demonstrating binding through a hydrogen bond (Lys263, Ser120). In lipopolysaccharide-stimulated BV2 cells and SCI mice, WG significantly attenuated microglial activation and facilitated a phenotype shift from M1 to M2. This was evidenced by the reversal of the increased expressions of Iba1, GFAP, and iNOS, as well as the decreased expression of Arg1. WG also suppressed the production of pro-inflammatory mediators (NO, TNF-α, IL-6, IL-1α, IL-1ß, C1q). WG exerted these effects by suppressing the TLR4/MyD88/NF-κB signaling axis in microglia. Furthermore, by reducing levels of TNF-α, IL-1α, and C1q in supernatant of LPS-induced microglia, WG indirectly induced astrocytes change to A2 phenotype, evidenced by transcriptome sequencing result of primary mouse astrocytes. All these events above collectively created a favorable microenvironment, contributing to a significant alleviation of weight loss and neuronal damage at the lesion site of SCI mice. Our findings substantiate the efficacy of WG in mitigating neuroinflammation after SCI, thereby warranting further exploration.

ELUCIDATE Trial: A Single-Center Randomized Controlled Study.

BACKGROUND: Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, is an epochal oral antidiabetic drug that improves cardiorenal outcomes. However, the effect of early dapagliflozin intervention on left ventricular (LV) remodeling in patients with type 2 diabetes free from cardiovascular disease remains unclear. METHODS AND RESULTS: The ELUCIDATE trial was a prospective, open-label, randomized, active-controlled study that enrolled 76 patients with asymptomatic type 2 diabetes with LV ejection fraction ≥50%, randomized to the dapagliflozin 10 mg/day add-on or standard-of-care group. Speckle-tracking echocardiography-based measurements of the cardiac global longitudinal strain were performed at baseline and 24 weeks after treatment initiation. Patients who received dapagliflozin had a greater reduction in LV dimension (1.68 mm [95% CI, 0.53-2.84]; P=0.005), LV end-systolic volume (5.51 mL [95% CI, 0.86-10.17]; P=0.021), and LV mass index (4.25 g/m2.7 [95% CI, 2.42-6.09]; P<0.0001) compared with standard of care in absolute mean differences. Dapagliflozin add-on therapy led to a significant LV global longitudinal strain increment (0.74% [95% CI, 1.00-0.49]; P<0.0001) and improved LV systolic and early diastolic strain rates (0.27/s [95% CI, 0.17-0.60]; and 0.11/s [95% CI, 0.06-0.16], respectively; both P<0.0001) but not in global circumferential strain. No significant changes were found in insulin resistance, NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, or other biomarkers at 6 months after the dapagliflozin administration. CONCLUSIONS: Dapagliflozin add-on therapy could lead to more favorable cardiac remodeling accompanied by enhanced cardiac mechanical function among patients with asymptomatic type 2 diabetes. Our findings provide evidence of the efficacy of dapagliflozin use for the primary prevention of diabetic cardiomyopathy. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03871621.

Gastrodin alleviates the deterioration of depressive-like behavior and glucolipid metabolism promoted by chronic stress in type 2 diabetic mice.

The growing burden of psychological stress among diabetes patients has contributed to a rising incidence of depression within this population. It is of significant importance to conduct research on the impact of stress on diabetes patients and to explore potential pharmacological interventions to counteract the stress-induced exacerbation of their condition. Gastrodin is a low molecular weight bioactive compound extracted from the rhizome of Gastrodiae elata Blume, and it may be a preventive strategy for diabetes and a novel treatment for depression symptoms. However, its relevant pharmacological mechanisms for protecting against the impacts of psychological stress in diabetic patients are unclear. In this study, we performed 5 weeks CUMS intervention and simultaneously administered gastrodin (140 mg/kg, once daily) on T2DM mice, to investigate the potential protective effects of gastrodin. The protective effect of gastrodin was evaluated by behavioral tests, biochemical analysis, histopathological examination, RT-qPCR and gut microbiota analysis. We found that the depressive-like behavior and glucolipid metabolism could be deteriorated by chronic stress in type 2 diabetic mice, while gastrodin showed a protective effect against these exacerbations by regulating HPA hormones, activating FXR and Cyp7a1, reducing inflammatory and oxidative stress responses, and regulating ileal gut microbiota abundance. Gastrodin might be a potential therapeutic agent for mitigating the deterioration of diabetes conditions due to chronic stress.

Ketone body levels and its associations with cardiac markers following an acute myocardial infarction: a post hoc analysis of the EMMY trial.

BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been suggested to exert cardioprotective effects in patients with heart failure, possibly by improving the metabolism of ketone bodies in the myocardium. METHODS: This post hoc analysis of the EMMY trial investigated the changes in serum ß-hydroxybutyrate (3-ßOHB) levels after acute myocardial infarction (AMI) in response to 26-week of Empagliflozin therapy compared to the usual post-MI treatment. In addition, the association of baseline and repeated measurements of 3-ßOHB with cardiac parameters and the interaction effects of Empagliflozin were investigated. Cardiac parameters included N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), left ventricle end-systolic volume (LVESV), left ventricle end-diastolic volume (LVEDV), and left ventricular filling pressure (E/é ratio). RESULTS: The mean 3-ßOHB levels increased from baseline (46.2 ± 3.0 vs. 51.7 ± 2.7) to 6 weeks (48.8 ± 2.2 vs. 42.0 ± 2.3) and 26 weeks (49.3 ± 2.2 vs. 35.8 ± 1.9) in the Empagliflozin group compared to a consistent decline in placebo over 26 weeks (pinteraction < 0.001). Baseline and longitudinal measurements of 3-ßOHB were not significantly associated with NT-proBNP and E/é ratio. Baseline 3-ßOHB value was negatively associated with LVEF (coefficient: - 0.464, 95%CI - 0.863;- 0.065, p = 0.023), while an increase in its levels over time was positively associated with LVEF (0.595, 0.156;1.035, 0.008). The baseline 3-ßOHB was positively associated with LVESV (1.409, 0.186;2.632, 0.024) and LVEDV (0.640, - 1.170;- 2.449, 0.488), while an increase in its levels over time was negatively associated with these cardiac parameters (LVESV: - 2.099, - 3.443;- 0.755, 0.002; LVEDV: - 2.406, - 4.341;- 0.472, 0.015). Empagliflozin therapy appears to modify the association between 3-ßOHB, LVEF (pinteraction = 0.090), LVESV (pinteraction = 0.134), and LVEDV (pinteraction = 0.168), particularly at 26 weeks; however, the results were not statistically significant. CONCLUSION: This post hoc analysis showed that SGLT2i increased 3-ßOHB levels after AMI compared to placebo. Higher baseline 3-ßOHB levels were inversely associated with cardiac function at follow-up, whereas a sustained increase in 3-ßOHB levels over time improved these markers. This highlights the importance of investigating ketone body metabolism in different post-MI phases. Although more pronounced effect of 3-ßOHB on cardiac markers was observed in the SGLT2i group, further research is required to explore this interaction effect.

Empagliflozin after Acute Myocardial Infarction.

BACKGROUND: Empagliflozin improves cardiovascular outcomes in patients with heart failure, patients with type 2 diabetes who are at high cardiovascular risk, and patients with chronic kidney disease. The safety and efficacy of empagliflozin in patients who have had acute myocardial infarction are unknown. METHODS: In this event-driven, double-blind, randomized, placebo-controlled trial, we assigned, in a 1:1 ratio, patients who had been hospitalized for acute myocardial infarction and were at risk for heart failure to receive empagliflozin at a dose of 10 mg daily or placebo in addition to standard care within 14 days after admission. The primary end point was a composite of hospitalization for heart failure or death from any cause as assessed in a time-to-first-event analysis. RESULTS: A total of 3260 patients were assigned to receive empagliflozin and 3262 to receive placebo. During a median follow-up of 17.9 months, a first hospitalization for heart failure or death from any cause occurred in 267 patients (8.2%) in the empagliflozin group and in 298 patients (9.1%) in the placebo group, with incidence rates of 5.9 and 6.6 events, respectively, per 100 patient-years (hazard ratio, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P = 0.21). With respect to the individual components of the primary end point, a first hospitalization for heart failure occurred in 118 patients (3.6%) in the empagliflozin group and in 153 patients (4.7%) in the placebo group (hazard ratio, 0.77; 95% CI, 0.60 to 0.98), and death from any cause occurred in 169 (5.2%) and 178 (5.5%), respectively (hazard ratio, 0.96; 95% CI, 0.78 to 1.19). Adverse events were consistent with the known safety profile of empagliflozin and were similar in the two trial groups. CONCLUSIONS: Among patients at increased risk for heart failure after acute myocardial infarction, treatment with empagliflozin did not lead to a significantly lower risk of a first hospitalization for heart failure or death from any cause than placebo. (Funded by Boehringer Ingelheim and Eli Lilly; EMPACT-MI ClinicalTrials.gov number, NCT04509674.).

Dapagliflozin and Empagliflozin in Paediatric Indications: A Systematic Review.

INTRODUCTION: In adults, sodium-glucose cotransporter type 2 inhibitors have revolutionised the treatment of type 2 diabetes mellitus, heart failure, and chronic kidney disease. OBJECTIVE: We aimed to review information on compassionate use, clinical pharmacology, efficacy, and safety of dapagliflozin and empagliflozin in children. METHODS: We conducted a systematic review of published clinical trials, case reports, and observational studies in Medline, Excerpta Medica, and Web of Science databases from inception to September 2023. For the two randomised controlled trials on type 2 diabetes mellitus (T2DM), we implemented a meta-analysis on the primary outcome (mean difference in glycosylated haemoglobin [HbA1c] between intervention and placebo groups). Review Manager (RevMan), version 5.4.1, was used for this purpose. RESULTS: Thirty-five articles (nine case reports, ten case series, one prospective non-controlled trial, four controlled randomised trials, two surveys, six pharmacokinetic studies, and three pharmacovigilance studies) were selected, in which 415 children were exposed to either dapagliflozin or empagliflozin: 189 diabetic patients (mean age 14.7 ± 2.9 years), 32 children with glycogen storage disease type Ib (GSD Ib), glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency, or severe congenital neutropenia type 4 (8.5 ± 5.1 years), 47 children with kidney disease or heart failure (11.2 ± 6.1 years), 84 patients in pharmacokinetic studies (15.1 ± 2.3 years), and 63 patients in toxicological series. The effect of dapagliflozin and empagliflozin in T2DM was demonstrated by HbA1c reduction in two randomised trials among a total of 177 adolescents, with a mean HbA1c difference of -0.82% (95% confidence interval -1.34 to -0.29) as compared to placebo (no heterogeneity, I2 = 0%). Dosage ranged between 5 and 20 mg (mean 11.4 ± 3.7) once daily for dapagliflozin and between 5 and 25 mg (mean 15.4 ± 7.4) once daily for empagliflozin. Among the paediatric cases of GSD Ib, empagliflozin 0.1-1.3 mg/kg/day improved neutropenia, infections, and gastrointestinal health. Dapagliflozin (mean dosage 6.9 ± 5.2 mg once daily) was well-tolerated in children with chronic kidney disease and heart failure. Side effects were generally mild, the most frequent being hypoglycaemia in children with GSD Ib (33% of patients) or T2DM (14% of patients) on concomitant hypoglycaemic drugs. Diabetic ketoacidosis is rare in children. CONCLUSION: Early evidence suggests that dapagliflozin and empagliflozin are well tolerated in children. A clinical pharmacology rationale currently exists only for adolescents with diabetes mellitus. PROSPERO REGISTRATION NUMBER: CRD42023438162.

A review regarding the article 'Targeting inflammatory signaling pathways with SGLT2 inhibitors: Insights into cardiovascular health and cardiac cell improvement'.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have emerged as a novel category of blood glucose-lowering drugs in clinical recommendations for a wide range of diseases. SGLT2 inhibitors are promising anti-inflammatory agents by acting either indirectly via improving metabolism and reducing stress conditions or via direct modulation of inflammatory signaling pathways. The SGLT2 inhibitors empagliflozin and dapagliflozin better vascular function and avert vascular aging by decreasing the reactive oxygen species (ROS) content and increasing nitric oxide bioavailability, respectively. It was discovered that ipragliflozin has the ability to prevent dysfunction of the endothelium, and this effect was connected with oxidative stress. According to published data, SGLT2 inhibitors may delay vascular aging and arrest the development of endothelial dysfunction in animal models of type 2 diabetes (T2D) by reducing inflammation, oxidative stress, and glucose toxicity and increasing the survival of hyperglycemic endothelial cells. The adenosine monophosphate-activated protein kinase (AMPK) molecule plays a vital role in the regulation of bioenergy metabolism and is pivotal in our understanding of diabetes mellitus and other metabolic disorders. It has been hypothesized that SGLT2 inhibitors may indirectly affect AMPK to reduce mammalian target of rapamycin (mTOR) activity. Numerous studies have demonstrated that SGLT2 inhibitors can activate AMPK by restoring the AMP/ATP balance in favor of AMP, which is assumed to be the mechanism by which these medications have positive effects on the cardiac structure and microvessel.

Dapagliflozin Reduces Urinary Kidney Injury Biomarkers in Chronic Kidney Disease Irrespective of Albuminuria Level.

The beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with chronic kidney disease (CKD) with low albuminuria levels have not been established. This study aimed to compare the effects of dapagliflozin on kidney injury biomarkers in patients with CKD stratified by albuminuria level. We prospectively enrolled healthy volunteers (HVs; n = 20) and patients with CKD (n = 54) with and without diabetes mellitus. Patients with CKD were divided into two age-matched and sex-matched subgroups according to urinary albumin-creatinine ratio (uACR) levels (<300 mg/g and ≥300 mg/g). The CKD group received dapagliflozin (10 mg/day). Urine samples were collected before treatment and after 3 and 6 months of dapagliflozin. Urinary kidney injury molecule-1 (KIM-1), interleukin-1ß (IL-1ß), and mitochondrial DNA nicotinamide adenine dinucleotide dehydrogenase subunit-1 (mtND1) copy number were measured. The estimated glomerular filtration rate (eGFR) of patients with CKD was lower than that of HVs (P < 0.001). During the study period, eGFR decreased and uACR did not change in the CKD group. Kidney injury markers were significantly elevated in patients with CKD compared with those in HVs. Dapagliflozin reduced urinary KIM-1, IL-1ß, and mtDNA copy number in patients with CKD after 6 months of treatment. In further, the levels of urinary KIM-1 and IL-1ß, patients with CKD decreased after 6 months of dapagliflozin treatment regardless of albuminuria level. Dapagliflozin reduced urinary kidney injury biomarkers in patients with CKD, regardless of albuminuria level. These findings suggest that SGLT2 inhibitors may also attenuate the progression of low albuminuric CKD.

Anti-diabetic effect of anthocyanin cyanidin-3-O-glucoside: data from insulin resistant hepatocyte and diabetic mouse.

BACKGROUND: Anthocyanins are a group of natural products widely found in plants. They have been found to alleviate the disorders of glucose metabolism in type 2 diabetes mellitus (T2DM), while the underlying mechanisms remain unclear. METHODS: HepG2 and L02 cells were incubated with 0.2 mM PA and 30 mM glucose for 24 h to induce IR, and cells treated with 5 mM glucose were used as the control. C57BL/6 J male mice and db/db male mice were fed with a chow diet and gavaged with pure water or cyanidin-3-O-glucoside (C3G) solution (150 mg/kg/day) for 6 weeks. RESULTS: In this study, the anthocyanin C3G, extracted from red bayberry, was found to alleviate disorders of glucose metabolism, which resulted in increased insulin sensitivity in hepatocytes, and achieved by enhancing the glucose consumption as well as glycogen synthesis in insulin resistance (IR) hepatpcytes. Subsequently, the expression of key proteins involved in IR was detected by western blotting analysis. Protein tyrosine phosphatase-1B (PTP1B), a negative regulator of insulin signaling, could reduce cellular sensitivity to insulin by inhibiting the phosphorylation of insulin receptor substrate-2 (IRS-2). Results of this study showed that C3G inhibited the increase in PTP1B after high glucose and palmitic acid treatment. And this inhibition was accompanied by increased phosphorylation of IRS proteins. Furthermore, the effect of C3G on improving IR in vivo was validated by using a diabetic db/db mouse model. CONCLUSION: These findings demonstrated that C3G could alleviate IR in vitro and in vivo to increase insulin sensitivity, which may offer a new insight for regulating glucose metabolism during T2DM by using the natural dietary bioactive components. C3G promotes the phosphorylation of IRS-2 proteins by suppressing the expression of PTP1B, and then enhances the sensitivity of hepatocyte to insulin.

Quercetin-3-O-glc-1-3-rham-1-6-glucoside decreases Aß production, inhibits Aß aggregation and neurotoxicity, and prohibits the production of inflammatory cytokines.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with the hallmark of aggregation of beta-amyloid (Aß) into extracellular fibrillar deposition. Accumulating evidence suggests that soluble toxic Aß oligomers exert diverse roles in neuronal cell death, oxidative stress, neuroinflammation, and the eventual pathogenesis of AD. Aß is derived from the sequential cleavage of amyloid-ß precursor protein (APP) by ß-secretase (BACE1) and γ-secretase. The current effect of single targeting is not ideal for the treatment of AD. Therefore, developing multipotent agents with multiple properties, including anti-Aß generation and anti-Aß aggregation, is attracting more attention for AD treatment. Previous studies indicated that Quercetin was able to attenuate the effects of several pathogenetic factors in AD. Here, we showed that naturally synthesized Quercetin-3-O-glc-1-3-rham-1-6-glucoside (YCC31) could inhibit Aß production by reducing ß-secretase activity. Further investigations indicated that YCC31 could suppress toxic Aß oligomer formation by directly binding to Aß. Moreover, YCC31 could attenuate Aß-mediated neuronal death, ROS and NO production, and pro-inflammatory cytokines release. Taken together, YCC31 targeting multiple pathogenetic factors deserves further investigation for drug development of AD.

Empagliflozin and pirfenidone confer renoprotection through suppression of glycogen synthase kinase-3ß and promotion of tubular regeneration in rats with induced metabolic syndrome.

Metabolic syndrome (MetS) is largely coupled with chronic kidney disease (CKD). Glycogen synthase kinase-3ß (GSK-3ß) pathway drives tubular injury in animal models of acute kidney injury; but its contribution in CKD is still elusive. This study investigated the effect empagliflozin and/or pirfenidone against MetS-induced kidney dysfunction, and to clarify additional underpinning mechanisms particularly the GSK-3ß signaling pathway. Adult male rats received 10%w/v fructose in drinking water for 20 weeks to develop MetS, then treated with either drug vehicle, empagliflozin (30 mg/kg/day) and/or pirfenidone (100 mg/kg/day) via oral gavage for subsequent 4 weeks, concurrently with the high dietary fructose. Age-matched rats receiving normal drinking water were used as controls. After 24 weeks, blood and kidneys were harvested for subsequent analyses. Rats with MetS showed signs of kidney dysfunction, structural changes and interstitial fibrosis. Activation of GSK-3ß, decreased cyclinD1 expression and enhanced apoptotic signaling were found in kidneys of MetS rats. There was abundant alpha-smooth muscle actin (α-SMA) expression along with up-regulation of TGF-ß1/Smad3 in kidneys of MetS rats. These derangements were almost alleviated by empagliflozin or pirfenidone, with evidence that the combined therapy was more effective than either individual drug. This study emphasizes a novel mechanism underpinning the beneficial effects of empagliflozin and pirfenidone on kidney dysfunction associated with MetS through targeting GSK-3ß signaling which can mediate the regenerative capacity, anti-apoptotic effects and anti-fibrotic properties of such drugs. These findings recommend the possibility of using empagliflozin and pirfenidone as promising therapies for management of CKD in patients with MetS.