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Colin J Meyer - One of the best experts on this subject based on the ideXlab platform.

  • effect of Bardoxolone Methyl on the urine albumin to creatinine ratio in patients with type 2 diabetes and stage 4 chronic kidney disease
    Kidney International, 2019
    Co-Authors: Peter Rossing, Melanie P Chin, Angie Goldsberry, Colin J Meyer, Pablo E Pergola, Hiddo J L Heerspink, Geoffrey A Block, Peter Mccullough, David K Packham, Bruce Spinowitz
    Abstract:

    Bardoxolone Methyl attenuates inflammation by inducing nuclear factor erythroid-derived 2-related factor 2 and suppressing nuclear factor κB. The Bardoxolone Methyl Evaluation in Patients With Chronic Kidney Disease and Type 2 Diabetes (BEACON) trial was a phase 3 placebo-controlled, randomized, double-blind, parallel-group, international, multicenter trial in 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease. BEACON was terminated because of safety concerns, largely related to a significant increase in early heart failure events in patients randomized to Bardoxolone Methyl. Bardoxolone Methyl resulted in increased estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio. Herein, we present post hoc analyses characterizing the relation between the urine albumin-to-creatinine ratio and eGFR. The urine albumin-to-creatinine ratio and eGFR were assessed every four weeks through Week 12, followed by assessments every eight weeks thereafter, and 4 weeks after the last dose of Bardoxolone Methyl was administered. The initial increases in urine albumin-to-creatinine ratio observed in patients randomized to Bardoxolone Methyl were attenuated after six months. Multivariable regression analysis identified baseline eGFR and eGFR over time as the dominant factors associated with change in the urine albumin-to-creatinine ratio. Relative to placebo, Bardoxolone Methyl resulted in a significant decrease in albuminuria when indexed to eGFR (least-squared means: −0.035 [95% confidence interval −0.031 to −0.039]). Thus, among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with Bardoxolone Methyl, changes in albuminuria are directly related to changes in eGFR, challenging the conventional construct that increases in albuminuria universally reflect kidney injury and denote harm.

  • effects of Bardoxolone Methyl on qt interval in healthy volunteers
    CardioRenal Medicine, 2019
    Co-Authors: Melanie P Chin, Shannon Rich, Angie Goldsberry, Megan Ogrady, Colin J Meyer
    Abstract:

    Background Bardoxolone Methyl has been shown to increase eGFR in several clinical trials, including a phase 3 trial in patients with type 2 diabetes and stage 4 CKD (BEACON), which was terminated early due to an increase in heart failure events in Bardoxolone Methyl-treated patients. A separate, "thorough QT" study was conducted in parallel with BEACON to evaluate the cardiovascular safety of Bardoxolone Methyl in healthy subjects. Methods Subjects in the "thorough QT" study were randomized to receive Bardoxolone Methyl 20 mg (therapeutic dose) or 80 mg (supratherapeutic dose), placebo, or moxifloxacin (400 mg; an active comparator). ECG results and supine blood pressure measurements were analyzed. The effects of Bardoxolone Methyl on QT interval changes from baseline were quantified compared to the effect of placebo by calculating mean, time-matched, placebo-corrected, baseline-adjusted QTcF values (ΔΔQTcF) after 6 days of daily administration of Bardoxolone Methyl. Results The study was halted early due to emerging safety information from the BEACON trial; however, 142/179 patients received all doses of the study drug and completed the study. For both Bardoxolone Methyl-treated groups (20 and 80 mg), the upper limits of the 2-sided 90% confidence interval for ΔΔQTcF were less than the significance limit (10 ms) at all time points. Changes in blood pressure were similar in all treatment groups, and no serious adverse events were reported. Conclusions In healthy subjects, treatment with 20 or 80 mg Bardoxolone Methyl did not affect the QTcF interval.

  • effects of Bardoxolone Methyl on magnesium in patients with type 2 diabetes mellitus and chronic kidney disease
    CardioRenal Medicine, 2019
    Co-Authors: Dana V Rizk, Melanie P Chin, Angie Goldsberry, Megan Ogrady, Colin J Meyer, Pablo E Pergola, Robert D Toto, David G Warnock, Arnold L Silva, Peter A Mccullough
    Abstract:

    Background: Treatment with Bardoxolone Methyl (Bard) in a multinational phase 3 trial, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), resulted in increases in estimated glomerular filtration rate with concurrent reductions in serum magnesium. We analyzed data from several trials to characterize reductions in magnesium with Bard. Methods: BEACON randomized patients (n = 2,185) with type 2 diabetes (T2DM) and stage 4 chronic kidney disease (CKD) 1:1 to receive Bard (20 mg) or placebo once daily. In a separate open-label study, magnesium levels from 24-hour urine and sublingual epithelial cell samples were analyzed in patients with stage 3b-4 CKD and T2DM administered 20 mg Bard for 56 consecutive days. Results: BEACON patients randomized to Bard experienced significant reductions in serum magnesium from baseline relative to patients randomized to placebo (–0.17 mEq/L, 95% CI –0.18 to –0.60 mEq/L; p < 0.001). A separate study showed intracellular and urinary magnesium levels were unchanged with Bard treatment. Conclusions: Bard treatment results in significant decreases in serum magnesium that are not associated with changes in intracellular and urinary magnesium levels, indicating that magnesium decreases are not due to renal magnesium wasting or total body magnesium depletion. Importantly, the decreases in serum magnesium with Bard are not associated with adverse effects on QT interval.

  • effects of Bardoxolone Methyl on body weight waist circumference and glycemic control in obese patients with type 2 diabetes mellitus and stage 4 chronic kidney disease
    Journal of Diabetes and Its Complications, 2018
    Co-Authors: Glenn M Chertow, Melanie P Chin, Angie Goldsberry, Colin J Meyer, Geoffrey A Block, Gerald B Appel, Daniel W Coyne, Kamyar Kalantarzadeh, Mark E Molitch, Pablo E Pergola
    Abstract:

    Abstract Aims Obesity is associated with progression of chronic kidney disease (CKD). Treatment with Bardoxolone Methyl in a multinational phase 3 trial, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), resulted in increases in estimated glomerular filtration rate (eGFR) with concurrent reductions in body weight. We performed post-hoc analyses to further characterize reductions in body weight with Bardoxolone Methyl. Methods Eligible patients with type 2 diabetes (T2DM) and CKD stage 4 (eGFR 15 to Results BEACON enrolled 2185 patients. Patients randomized to Bardoxolone Methyl experienced significant reductions in body weight from baseline relative to patients randomized to placebo (−5.7 kg; 95% CI: −6.0 to −5.3 kg; p  Conclusions Bardoxolone Methyl resulted in significant weight loss in a generally obese patient population with T2DM and stage 4 CKD, with the magnitude and rate dependent on baseline BMI.

  • a food effect study and dose proportionality study to assess the pharmacokinetics and safety of Bardoxolone Methyl in healthy volunteers
    Clinical pharmacology in drug development, 2014
    Co-Authors: Nathan S Teuscher, Richard J Kelley, Emily O Dumas, Cheri E Klein, Walid M Awni, Colin J Meyer
    Abstract:

    This study investigated the effect of food on the plasma pharmacokinetics of Bardoxolone Methyl, an antioxidant inflammation modulator, at a 20mg dose, and the dose proportionality of Bardoxolone Methyl pharmacokinetics from 20 to 80mg. It was a single‐dose study conducted at a single center in 32 healthy volunteers aged 18–45 years using an amorphous spray‐dried dispersion formulation of Bardoxolone Methyl. In Part A, 16 subjects received single 20mg doses of Bardoxolone Methyl under fasting and non‐fasting conditions. In Part B, 16 subjects received a single 60 or 80mg dose of Bardoxolone Methyl and a matching placebo dose under fasting conditions.Blood samples for pharmacokinetic analysis were taken over 120hours following dose administration. Single dose administration of 20, 60, and 80mg Bardoxolone Methyl was safe and well‐tolerated in healthy volunteers. Total Bardoxolone Methyl exposure was unchanged in the presence of food. However, doses of Bardoxolone Methyl above 20mg appear to have a saturated dissolution or absorption process and are associated with less than proportional increases in drug exposure.

Xu-feng Huang - One of the best experts on this subject based on the ideXlab platform.

  • Bardoxolone Methyl prevents obesity and hypothalamic dysfunction
    Chemico-Biological Interactions, 2016
    Co-Authors: Danielle Camer, Chi H. L Dinh, Alexander M Szabo, Hongqin Wang, Xu-feng Huang
    Abstract:

    High-fat (HF) diet-induced obesity is associated with hypothalamic leptin resistance and low grade chronic inflammation, which largely impairs the neuroregulation of negative energy balance. Neuroregulation of negative energy balance is largely controlled by the mediobasal and paraventricular nuclei regions of the hypothalamus via leptin signal transduction. Recently, a derivative of oleanolic acid, Bardoxolone Methyl (BM), has been shown to have anti-inflammatory effects. We tested the hypothesis that BM would prevent HF diet-induced obesity, hypothalamic leptin resistance, and inflammation in mice fed a HF diet. Oral administration of BM via drinking water (10 mg/kg daily) for 21 weeks significantly prevented an increase in body weight, energy intake, hyperleptinemia, and peripheral fat accumulation in mice fed a HF diet. Furthermore, BM treatment prevented HF diet-induced decreases in the anorexigenic effects of peripheral leptin administration. In the mediobasal and paraventricular nuclei regions of the hypothalamus, BM administration prevented HF diet-induced impairments of the downstream protein kinase b (Akt) pathway of hypothalamic leptin signalling. BM treatment also prevented an increase in inflammatory cytokines, tumour necrosis factor alpha (TNFα) and interleukin 6 (IL-6) in these two hypothalamic regions. These results identify a potential novel neuropharmacological application for BM in preventing HF diet-induced obesity, hypothalamic leptin resistance, and inflammation.

  • Research Article Bardoxolone Methyl Prevents Mesenteric Fat Deposition and Inflammation in High-Fat Diet Mice
    2016
    Co-Authors: Chi H. L Dinh, Danielle Camer, Hongqin Wang, Er Szabo, Xu-feng Huang
    Abstract:

    Copyright © 2015 Chi H. L. Dinh et al.This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mesenteric fat belongs to visceral fat. An increased deposition of mesenteric fat contributes to obesity associated complications such as type 2 diabetes and cardiovascular diseases. We have investigated the therapeutic effects of Bardoxolone Methyl (BARD) on mesenteric adipose tissue of mice fed a high-fat diet (HFD). Male C57BL/6J mice were administered oral BARD during HFD feeding (HFD/BARD), only fed a high-fat diet (HFD), or fed low-fat diet (LFD) for 21 weeks. Histology and immunohistochemistry were used to analyse mesenteric morphology and macrophages, while Western blot was used to assess the expression of inflammatory, oxidative stress, and energy expenditure proteins. Supplementation of drinking water with BARD prevented mesenteric fat deposition, as determined by a reduction in large adipocytes. BARD prevented inflammation as there were fewer inflammatory macrophages and reduced proinflammatory cytokines (interleukin-1 beta and tumour necrosis factor alpha). BARD reduced the activation of extracellular signal-regulated kinase (ERK) and Akt, suggesting an antioxidative stress effect. BARD upregulates energy expenditure proteins, judged by the increased activity of tyrosine hydroxylase (TH) and AMP-activated protein kinase (AMPK) and increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-

  • Bardoxolone Methyl prevents high fat diet induced colon inflammation in mice
    Journal of Histochemistry and Cytochemistry, 2016
    Co-Authors: Chi H. L Dinh, Alexander M Szabo, Qingsheng Zhang, Peng Zhang, Xu-feng Huang
    Abstract:

    Obesity induces chronic, low-grade inflammation, which increases the risk of colon cancer. We investigated the preventive effects of Bardoxolone Methyl (BARD) on high-fat diet (HFD)-induced inflammation in a mouse colon. Male C57BL/6J mice (n=7) were fed a HFD (HFD group), HFD plus BARD (10 mg/kg) in drinking water (HFD/BARD group), or normal laboratory chow diet (LFD group) for 21 weeks. In HFD mice, BARD reduced colon thickness and decreased colon weight per length. This was associated with an increase in colon crypt depth and the number of goblet cells per crypt. BARD reduced the expression of F4/80 and CD11c but increased CD206 and IL-10, indicating an anti-inflammatory effect. BARD prevented an increase of the intracellular pro-inflammatory biomarkers (NF-қB, p NF-қB, IL-6, TNF-α) and cell proliferation markers (Cox2 and Ki67). BARD prevented fat deposition in the colon wall and prevented microbial population changes. Overall, we report the preventive effects of BARD on colon inflammation in HFD-fed mice through its regulation of macrophages, NF-қB, cytokines, Cox2 and Ki67, fat deposition and microflora.

  • Bardoxolone Methyl prevents the development and progression of cardiac and renal pathophysiologies in mice fed a high fat diet
    Chemico-Biological Interactions, 2016
    Co-Authors: Danielle Camer, Chi H. L Dinh, Alexander M Szabo, Hongqin Wang, Xu-feng Huang
    Abstract:

    Obesity caused by the consumption of a high-fat (HF) diet is a major risk factor for the development of associated complications, such as heart and kidney failure. A semi-synthetic triterpenoid, Bardoxolone Methyl (BM) was administrated to mice fed a HF diet for 21 weeks to determine if it would prevent the development of obesity-associated cardiac and renal pathophysiologies. Twelve week old male C57BL/6J mice were fed a lab chow (LC), HF (40% fat), or a HF diet supplemented with 10 mg/kg/day BM in drinking water. After 21 weeks, the left ventricles of hearts and cortex of kidneys of mice were collected for analysis. Histological analysis revealed that BM prevented HF diet-induced development of structural changes in the heart and kidneys. BM prevented HF diet-induced decreases in myocyte number in cardiac tissue, although this treatment also elevated cardiac endothelin signalling molecules. In the kidneys, BM administration prevented HF diet-induced renal corpuscle hypertrophy and attenuated endothelin signalling. Furthermore, in both the hearts and kidneys of mice fed a HF diet, BM administration prevented HF diet-induced increases in fat accumulation, macrophage infiltration and tumour necrosis factor alpha (TNFα) gene expression. These findings suggest that BM prevents HF diet-induced developments of cardiac and renal pathophysiologies in mice fed a chronic HF diet by preventing inflammation. Moreover, these results suggest that BM has the potential as a therapeutic for preventing obesity-induced cardiac and renal pathophysiologies.

  • Bardoxolone Methyl Prevents Mesenteric Fat Deposition and Inflammation in High-Fat Diet Mice
    TheScientificWorldJournal, 2015
    Co-Authors: Chi H. L Dinh, Alexander M Szabo, Danielle Camer, Hongqin Wang, Xu-feng Huang
    Abstract:

    Mesenteric fat belongs to visceral fat. An increased deposition of mesenteric fat contributes to obesity associated complications such as type 2 diabetes and cardiovascular diseases. We have investigated the therapeutic effects of Bardoxolone Methyl (BARD) on mesenteric adipose tissue of mice fed a high-fat diet (HFD). Male C57BL/6J mice were administered oral BARD during HFD feeding (HFD/BARD), only fed a high-fat diet (HFD), or fed low-fat diet (LFD) for 21 weeks. Histology and immunohistochemistry were used to analyse mesenteric morphology and macrophages, while Western blot was used to assess the expression of inflammatory, oxidative stress, and energy expenditure proteins. Supplementation of drinking water with BARD prevented mesenteric fat deposition, as determined by a reduction in large adipocytes. BARD prevented inflammation as there were fewer inflammatory macrophages and reduced proinflammatory cytokines (interleukin-1 beta and tumour necrosis factor alpha). BARD reduced the activation of extracellular signal-regulated kinase (ERK) and Akt, suggesting an antioxidative stress effect. BARD upregulates energy expenditure proteins, judged by the increased activity of tyrosine hydroxylase (TH) and AMP-activated protein kinase (AMPK) and increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and uncoupling protein 2 (UCP2) proteins. Overall, BARD induces preventive effect in HFD mice through regulation of mesenteric adipose tissue.

Melanie P Chin - One of the best experts on this subject based on the ideXlab platform.

  • study design and baseline characteristics of the cardinal trial a phase 3 study of Bardoxolone Methyl in patients with alport syndrome
    American Journal of Nephrology, 2021
    Co-Authors: Glenn M Chertow, Melanie P Chin, Angie Goldsberry, Geoffrey A Block, Gerald B Appel, Sharon P Andreoli, Sripal Bangalore, Arlene B Chapman, Keisha L Gibson, Kazumoto Iijima
    Abstract:

    INTRODUCTION Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons ( 200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to Bardoxolone Methyl or placebo, with stratification by baseline UACR. RESULTS A total of 371 patients were screened, and 157 patients were randomly assigned to receive Bardoxolone Methyl (n = 77) or placebo (n = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m2, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was -4.9 mL/min/1.73 m2 despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy. DISCUSSION/CONCLUSION CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.

  • effect of Bardoxolone Methyl on the urine albumin to creatinine ratio in patients with type 2 diabetes and stage 4 chronic kidney disease
    Kidney International, 2019
    Co-Authors: Peter Rossing, Melanie P Chin, Angie Goldsberry, Colin J Meyer, Pablo E Pergola, Hiddo J L Heerspink, Geoffrey A Block, Peter Mccullough, David K Packham, Bruce Spinowitz
    Abstract:

    Bardoxolone Methyl attenuates inflammation by inducing nuclear factor erythroid-derived 2-related factor 2 and suppressing nuclear factor κB. The Bardoxolone Methyl Evaluation in Patients With Chronic Kidney Disease and Type 2 Diabetes (BEACON) trial was a phase 3 placebo-controlled, randomized, double-blind, parallel-group, international, multicenter trial in 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease. BEACON was terminated because of safety concerns, largely related to a significant increase in early heart failure events in patients randomized to Bardoxolone Methyl. Bardoxolone Methyl resulted in increased estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio. Herein, we present post hoc analyses characterizing the relation between the urine albumin-to-creatinine ratio and eGFR. The urine albumin-to-creatinine ratio and eGFR were assessed every four weeks through Week 12, followed by assessments every eight weeks thereafter, and 4 weeks after the last dose of Bardoxolone Methyl was administered. The initial increases in urine albumin-to-creatinine ratio observed in patients randomized to Bardoxolone Methyl were attenuated after six months. Multivariable regression analysis identified baseline eGFR and eGFR over time as the dominant factors associated with change in the urine albumin-to-creatinine ratio. Relative to placebo, Bardoxolone Methyl resulted in a significant decrease in albuminuria when indexed to eGFR (least-squared means: −0.035 [95% confidence interval −0.031 to −0.039]). Thus, among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with Bardoxolone Methyl, changes in albuminuria are directly related to changes in eGFR, challenging the conventional construct that increases in albuminuria universally reflect kidney injury and denote harm.

  • effects of Bardoxolone Methyl on qt interval in healthy volunteers
    CardioRenal Medicine, 2019
    Co-Authors: Melanie P Chin, Shannon Rich, Angie Goldsberry, Megan Ogrady, Colin J Meyer
    Abstract:

    Background Bardoxolone Methyl has been shown to increase eGFR in several clinical trials, including a phase 3 trial in patients with type 2 diabetes and stage 4 CKD (BEACON), which was terminated early due to an increase in heart failure events in Bardoxolone Methyl-treated patients. A separate, "thorough QT" study was conducted in parallel with BEACON to evaluate the cardiovascular safety of Bardoxolone Methyl in healthy subjects. Methods Subjects in the "thorough QT" study were randomized to receive Bardoxolone Methyl 20 mg (therapeutic dose) or 80 mg (supratherapeutic dose), placebo, or moxifloxacin (400 mg; an active comparator). ECG results and supine blood pressure measurements were analyzed. The effects of Bardoxolone Methyl on QT interval changes from baseline were quantified compared to the effect of placebo by calculating mean, time-matched, placebo-corrected, baseline-adjusted QTcF values (ΔΔQTcF) after 6 days of daily administration of Bardoxolone Methyl. Results The study was halted early due to emerging safety information from the BEACON trial; however, 142/179 patients received all doses of the study drug and completed the study. For both Bardoxolone Methyl-treated groups (20 and 80 mg), the upper limits of the 2-sided 90% confidence interval for ΔΔQTcF were less than the significance limit (10 ms) at all time points. Changes in blood pressure were similar in all treatment groups, and no serious adverse events were reported. Conclusions In healthy subjects, treatment with 20 or 80 mg Bardoxolone Methyl did not affect the QTcF interval.

  • effects of Bardoxolone Methyl on magnesium in patients with type 2 diabetes mellitus and chronic kidney disease
    CardioRenal Medicine, 2019
    Co-Authors: Dana V Rizk, Melanie P Chin, Angie Goldsberry, Megan Ogrady, Colin J Meyer, Pablo E Pergola, Robert D Toto, David G Warnock, Arnold L Silva, Peter A Mccullough
    Abstract:

    Background: Treatment with Bardoxolone Methyl (Bard) in a multinational phase 3 trial, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), resulted in increases in estimated glomerular filtration rate with concurrent reductions in serum magnesium. We analyzed data from several trials to characterize reductions in magnesium with Bard. Methods: BEACON randomized patients (n = 2,185) with type 2 diabetes (T2DM) and stage 4 chronic kidney disease (CKD) 1:1 to receive Bard (20 mg) or placebo once daily. In a separate open-label study, magnesium levels from 24-hour urine and sublingual epithelial cell samples were analyzed in patients with stage 3b-4 CKD and T2DM administered 20 mg Bard for 56 consecutive days. Results: BEACON patients randomized to Bard experienced significant reductions in serum magnesium from baseline relative to patients randomized to placebo (–0.17 mEq/L, 95% CI –0.18 to –0.60 mEq/L; p < 0.001). A separate study showed intracellular and urinary magnesium levels were unchanged with Bard treatment. Conclusions: Bard treatment results in significant decreases in serum magnesium that are not associated with changes in intracellular and urinary magnesium levels, indicating that magnesium decreases are not due to renal magnesium wasting or total body magnesium depletion. Importantly, the decreases in serum magnesium with Bard are not associated with adverse effects on QT interval.

  • effects of Bardoxolone Methyl on body weight waist circumference and glycemic control in obese patients with type 2 diabetes mellitus and stage 4 chronic kidney disease
    Journal of Diabetes and Its Complications, 2018
    Co-Authors: Glenn M Chertow, Melanie P Chin, Angie Goldsberry, Colin J Meyer, Geoffrey A Block, Gerald B Appel, Daniel W Coyne, Kamyar Kalantarzadeh, Mark E Molitch, Pablo E Pergola
    Abstract:

    Abstract Aims Obesity is associated with progression of chronic kidney disease (CKD). Treatment with Bardoxolone Methyl in a multinational phase 3 trial, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), resulted in increases in estimated glomerular filtration rate (eGFR) with concurrent reductions in body weight. We performed post-hoc analyses to further characterize reductions in body weight with Bardoxolone Methyl. Methods Eligible patients with type 2 diabetes (T2DM) and CKD stage 4 (eGFR 15 to Results BEACON enrolled 2185 patients. Patients randomized to Bardoxolone Methyl experienced significant reductions in body weight from baseline relative to patients randomized to placebo (−5.7 kg; 95% CI: −6.0 to −5.3 kg; p  Conclusions Bardoxolone Methyl resulted in significant weight loss in a generally obese patient population with T2DM and stage 4 CKD, with the magnitude and rate dependent on baseline BMI.

Danielle Camer - One of the best experts on this subject based on the ideXlab platform.

  • Bardoxolone Methyl prevents obesity and hypothalamic dysfunction
    Chemico-Biological Interactions, 2016
    Co-Authors: Danielle Camer, Chi H. L Dinh, Alexander M Szabo, Hongqin Wang, Xu-feng Huang
    Abstract:

    High-fat (HF) diet-induced obesity is associated with hypothalamic leptin resistance and low grade chronic inflammation, which largely impairs the neuroregulation of negative energy balance. Neuroregulation of negative energy balance is largely controlled by the mediobasal and paraventricular nuclei regions of the hypothalamus via leptin signal transduction. Recently, a derivative of oleanolic acid, Bardoxolone Methyl (BM), has been shown to have anti-inflammatory effects. We tested the hypothesis that BM would prevent HF diet-induced obesity, hypothalamic leptin resistance, and inflammation in mice fed a HF diet. Oral administration of BM via drinking water (10 mg/kg daily) for 21 weeks significantly prevented an increase in body weight, energy intake, hyperleptinemia, and peripheral fat accumulation in mice fed a HF diet. Furthermore, BM treatment prevented HF diet-induced decreases in the anorexigenic effects of peripheral leptin administration. In the mediobasal and paraventricular nuclei regions of the hypothalamus, BM administration prevented HF diet-induced impairments of the downstream protein kinase b (Akt) pathway of hypothalamic leptin signalling. BM treatment also prevented an increase in inflammatory cytokines, tumour necrosis factor alpha (TNFα) and interleukin 6 (IL-6) in these two hypothalamic regions. These results identify a potential novel neuropharmacological application for BM in preventing HF diet-induced obesity, hypothalamic leptin resistance, and inflammation.

  • Research Article Bardoxolone Methyl Prevents Mesenteric Fat Deposition and Inflammation in High-Fat Diet Mice
    2016
    Co-Authors: Chi H. L Dinh, Danielle Camer, Hongqin Wang, Er Szabo, Xu-feng Huang
    Abstract:

    Copyright © 2015 Chi H. L. Dinh et al.This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mesenteric fat belongs to visceral fat. An increased deposition of mesenteric fat contributes to obesity associated complications such as type 2 diabetes and cardiovascular diseases. We have investigated the therapeutic effects of Bardoxolone Methyl (BARD) on mesenteric adipose tissue of mice fed a high-fat diet (HFD). Male C57BL/6J mice were administered oral BARD during HFD feeding (HFD/BARD), only fed a high-fat diet (HFD), or fed low-fat diet (LFD) for 21 weeks. Histology and immunohistochemistry were used to analyse mesenteric morphology and macrophages, while Western blot was used to assess the expression of inflammatory, oxidative stress, and energy expenditure proteins. Supplementation of drinking water with BARD prevented mesenteric fat deposition, as determined by a reduction in large adipocytes. BARD prevented inflammation as there were fewer inflammatory macrophages and reduced proinflammatory cytokines (interleukin-1 beta and tumour necrosis factor alpha). BARD reduced the activation of extracellular signal-regulated kinase (ERK) and Akt, suggesting an antioxidative stress effect. BARD upregulates energy expenditure proteins, judged by the increased activity of tyrosine hydroxylase (TH) and AMP-activated protein kinase (AMPK) and increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-

  • Bardoxolone Methyl prevents the development and progression of cardiac and renal pathophysiologies in mice fed a high fat diet
    Chemico-Biological Interactions, 2016
    Co-Authors: Danielle Camer, Chi H. L Dinh, Alexander M Szabo, Hongqin Wang, Xu-feng Huang
    Abstract:

    Obesity caused by the consumption of a high-fat (HF) diet is a major risk factor for the development of associated complications, such as heart and kidney failure. A semi-synthetic triterpenoid, Bardoxolone Methyl (BM) was administrated to mice fed a HF diet for 21 weeks to determine if it would prevent the development of obesity-associated cardiac and renal pathophysiologies. Twelve week old male C57BL/6J mice were fed a lab chow (LC), HF (40% fat), or a HF diet supplemented with 10 mg/kg/day BM in drinking water. After 21 weeks, the left ventricles of hearts and cortex of kidneys of mice were collected for analysis. Histological analysis revealed that BM prevented HF diet-induced development of structural changes in the heart and kidneys. BM prevented HF diet-induced decreases in myocyte number in cardiac tissue, although this treatment also elevated cardiac endothelin signalling molecules. In the kidneys, BM administration prevented HF diet-induced renal corpuscle hypertrophy and attenuated endothelin signalling. Furthermore, in both the hearts and kidneys of mice fed a HF diet, BM administration prevented HF diet-induced increases in fat accumulation, macrophage infiltration and tumour necrosis factor alpha (TNFα) gene expression. These findings suggest that BM prevents HF diet-induced developments of cardiac and renal pathophysiologies in mice fed a chronic HF diet by preventing inflammation. Moreover, these results suggest that BM has the potential as a therapeutic for preventing obesity-induced cardiac and renal pathophysiologies.

  • Bardoxolone Methyl Prevents Mesenteric Fat Deposition and Inflammation in High-Fat Diet Mice
    TheScientificWorldJournal, 2015
    Co-Authors: Chi H. L Dinh, Alexander M Szabo, Danielle Camer, Hongqin Wang, Xu-feng Huang
    Abstract:

    Mesenteric fat belongs to visceral fat. An increased deposition of mesenteric fat contributes to obesity associated complications such as type 2 diabetes and cardiovascular diseases. We have investigated the therapeutic effects of Bardoxolone Methyl (BARD) on mesenteric adipose tissue of mice fed a high-fat diet (HFD). Male C57BL/6J mice were administered oral BARD during HFD feeding (HFD/BARD), only fed a high-fat diet (HFD), or fed low-fat diet (LFD) for 21 weeks. Histology and immunohistochemistry were used to analyse mesenteric morphology and macrophages, while Western blot was used to assess the expression of inflammatory, oxidative stress, and energy expenditure proteins. Supplementation of drinking water with BARD prevented mesenteric fat deposition, as determined by a reduction in large adipocytes. BARD prevented inflammation as there were fewer inflammatory macrophages and reduced proinflammatory cytokines (interleukin-1 beta and tumour necrosis factor alpha). BARD reduced the activation of extracellular signal-regulated kinase (ERK) and Akt, suggesting an antioxidative stress effect. BARD upregulates energy expenditure proteins, judged by the increased activity of tyrosine hydroxylase (TH) and AMP-activated protein kinase (AMPK) and increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and uncoupling protein 2 (UCP2) proteins. Overall, BARD induces preventive effect in HFD mice through regulation of mesenteric adipose tissue.

  • Bardoxolone Methyl prevents insulin resistance and the development of hepatic steatosis in mice fed a high fat diet
    Molecular and Cellular Endocrinology, 2015
    Co-Authors: Danielle Camer, Chi H. L Dinh, Alexander M Szabo, Hongqin Wang, Licai Cheng, Xu-feng Huang
    Abstract:

    High-fat (HF) diet-induced obesity is a major risk factor for the development of insulin resistance and hepatic steatosis. We examined the hypothesis that Bardoxolone Methyl (BM) would prevent the development of insulin resistance and hepatic steatosis in mice fed a HF diet. C57BL/6J male mice were fed a lab chow (LC), HF (40% fat), or HF diet supplemented with 10 mg/kg/day BM orally for 21 weeks. Glucose metabolism was assessed using a glucose tolerance test (GTT) and insulin sensitivity test (IST). Signalling molecules involved in insulin resistance, inflammation, and lipid metabolism were examined in liver tissue via western blotting and RT-PCR. BM prevented HF diet-induced insulin resistance and alterations in the protein levels of protein tyrosine phosphatase 1B (PTP1B), forkhead box protein O1 (FOXO1) and BDNF, and expression of the insulin receptor (IR), IRS-1 and glucose-6-phosphatase (G6Pase) genes. Furthermore, BM prevented fat accumulation in the liver and decreases in the β-oxidation gene, peroxisomal acyl-coenzyme A oxidase 1 (ACOX) in mice fed a HF diet. In the livers of HF fed mice, BM administration prevented HF diet-induced macrophage infiltration, inflammation as indicated by reduced IL-6 and signal transducer and activator of transcription 3 (STAT3) protein levels and TNFα mRNA expression, and increased nuclear factor-like 2 (Nrf2) mRNA expression and nuclear protein levels. These findings suggest that BM prevents HF diet induced insulin resistance and the development of hepatic steatosis in mice fed a chronic HF diet through modulation of molecules involved in insulin signalling, lipid metabolism and inflammation in the liver.

Angie Goldsberry - One of the best experts on this subject based on the ideXlab platform.

  • study design and baseline characteristics of the cardinal trial a phase 3 study of Bardoxolone Methyl in patients with alport syndrome
    American Journal of Nephrology, 2021
    Co-Authors: Glenn M Chertow, Melanie P Chin, Angie Goldsberry, Geoffrey A Block, Gerald B Appel, Sharon P Andreoli, Sripal Bangalore, Arlene B Chapman, Keisha L Gibson, Kazumoto Iijima
    Abstract:

    INTRODUCTION Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons ( 200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to Bardoxolone Methyl or placebo, with stratification by baseline UACR. RESULTS A total of 371 patients were screened, and 157 patients were randomly assigned to receive Bardoxolone Methyl (n = 77) or placebo (n = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m2, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was -4.9 mL/min/1.73 m2 despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy. DISCUSSION/CONCLUSION CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.

  • effect of Bardoxolone Methyl on the urine albumin to creatinine ratio in patients with type 2 diabetes and stage 4 chronic kidney disease
    Kidney International, 2019
    Co-Authors: Peter Rossing, Melanie P Chin, Angie Goldsberry, Colin J Meyer, Pablo E Pergola, Hiddo J L Heerspink, Geoffrey A Block, Peter Mccullough, David K Packham, Bruce Spinowitz
    Abstract:

    Bardoxolone Methyl attenuates inflammation by inducing nuclear factor erythroid-derived 2-related factor 2 and suppressing nuclear factor κB. The Bardoxolone Methyl Evaluation in Patients With Chronic Kidney Disease and Type 2 Diabetes (BEACON) trial was a phase 3 placebo-controlled, randomized, double-blind, parallel-group, international, multicenter trial in 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease. BEACON was terminated because of safety concerns, largely related to a significant increase in early heart failure events in patients randomized to Bardoxolone Methyl. Bardoxolone Methyl resulted in increased estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio. Herein, we present post hoc analyses characterizing the relation between the urine albumin-to-creatinine ratio and eGFR. The urine albumin-to-creatinine ratio and eGFR were assessed every four weeks through Week 12, followed by assessments every eight weeks thereafter, and 4 weeks after the last dose of Bardoxolone Methyl was administered. The initial increases in urine albumin-to-creatinine ratio observed in patients randomized to Bardoxolone Methyl were attenuated after six months. Multivariable regression analysis identified baseline eGFR and eGFR over time as the dominant factors associated with change in the urine albumin-to-creatinine ratio. Relative to placebo, Bardoxolone Methyl resulted in a significant decrease in albuminuria when indexed to eGFR (least-squared means: −0.035 [95% confidence interval −0.031 to −0.039]). Thus, among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with Bardoxolone Methyl, changes in albuminuria are directly related to changes in eGFR, challenging the conventional construct that increases in albuminuria universally reflect kidney injury and denote harm.

  • effects of Bardoxolone Methyl on qt interval in healthy volunteers
    CardioRenal Medicine, 2019
    Co-Authors: Melanie P Chin, Shannon Rich, Angie Goldsberry, Megan Ogrady, Colin J Meyer
    Abstract:

    Background Bardoxolone Methyl has been shown to increase eGFR in several clinical trials, including a phase 3 trial in patients with type 2 diabetes and stage 4 CKD (BEACON), which was terminated early due to an increase in heart failure events in Bardoxolone Methyl-treated patients. A separate, "thorough QT" study was conducted in parallel with BEACON to evaluate the cardiovascular safety of Bardoxolone Methyl in healthy subjects. Methods Subjects in the "thorough QT" study were randomized to receive Bardoxolone Methyl 20 mg (therapeutic dose) or 80 mg (supratherapeutic dose), placebo, or moxifloxacin (400 mg; an active comparator). ECG results and supine blood pressure measurements were analyzed. The effects of Bardoxolone Methyl on QT interval changes from baseline were quantified compared to the effect of placebo by calculating mean, time-matched, placebo-corrected, baseline-adjusted QTcF values (ΔΔQTcF) after 6 days of daily administration of Bardoxolone Methyl. Results The study was halted early due to emerging safety information from the BEACON trial; however, 142/179 patients received all doses of the study drug and completed the study. For both Bardoxolone Methyl-treated groups (20 and 80 mg), the upper limits of the 2-sided 90% confidence interval for ΔΔQTcF were less than the significance limit (10 ms) at all time points. Changes in blood pressure were similar in all treatment groups, and no serious adverse events were reported. Conclusions In healthy subjects, treatment with 20 or 80 mg Bardoxolone Methyl did not affect the QTcF interval.

  • effects of Bardoxolone Methyl on magnesium in patients with type 2 diabetes mellitus and chronic kidney disease
    CardioRenal Medicine, 2019
    Co-Authors: Dana V Rizk, Melanie P Chin, Angie Goldsberry, Megan Ogrady, Colin J Meyer, Pablo E Pergola, Robert D Toto, David G Warnock, Arnold L Silva, Peter A Mccullough
    Abstract:

    Background: Treatment with Bardoxolone Methyl (Bard) in a multinational phase 3 trial, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), resulted in increases in estimated glomerular filtration rate with concurrent reductions in serum magnesium. We analyzed data from several trials to characterize reductions in magnesium with Bard. Methods: BEACON randomized patients (n = 2,185) with type 2 diabetes (T2DM) and stage 4 chronic kidney disease (CKD) 1:1 to receive Bard (20 mg) or placebo once daily. In a separate open-label study, magnesium levels from 24-hour urine and sublingual epithelial cell samples were analyzed in patients with stage 3b-4 CKD and T2DM administered 20 mg Bard for 56 consecutive days. Results: BEACON patients randomized to Bard experienced significant reductions in serum magnesium from baseline relative to patients randomized to placebo (–0.17 mEq/L, 95% CI –0.18 to –0.60 mEq/L; p < 0.001). A separate study showed intracellular and urinary magnesium levels were unchanged with Bard treatment. Conclusions: Bard treatment results in significant decreases in serum magnesium that are not associated with changes in intracellular and urinary magnesium levels, indicating that magnesium decreases are not due to renal magnesium wasting or total body magnesium depletion. Importantly, the decreases in serum magnesium with Bard are not associated with adverse effects on QT interval.

  • effects of Bardoxolone Methyl on body weight waist circumference and glycemic control in obese patients with type 2 diabetes mellitus and stage 4 chronic kidney disease
    Journal of Diabetes and Its Complications, 2018
    Co-Authors: Glenn M Chertow, Melanie P Chin, Angie Goldsberry, Colin J Meyer, Geoffrey A Block, Gerald B Appel, Daniel W Coyne, Kamyar Kalantarzadeh, Mark E Molitch, Pablo E Pergola
    Abstract:

    Abstract Aims Obesity is associated with progression of chronic kidney disease (CKD). Treatment with Bardoxolone Methyl in a multinational phase 3 trial, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), resulted in increases in estimated glomerular filtration rate (eGFR) with concurrent reductions in body weight. We performed post-hoc analyses to further characterize reductions in body weight with Bardoxolone Methyl. Methods Eligible patients with type 2 diabetes (T2DM) and CKD stage 4 (eGFR 15 to Results BEACON enrolled 2185 patients. Patients randomized to Bardoxolone Methyl experienced significant reductions in body weight from baseline relative to patients randomized to placebo (−5.7 kg; 95% CI: −6.0 to −5.3 kg; p  Conclusions Bardoxolone Methyl resulted in significant weight loss in a generally obese patient population with T2DM and stage 4 CKD, with the magnitude and rate dependent on baseline BMI.