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Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease.

ABSTRACT: Although inhibitors of the renin-angiotensin-aldosterone system can slow the progression of diabetic kidney disease, the residual risk is high. Whether nuclear 1 factor (erythroid-derived 2)-related factor 2 activators further reduce this risk is unknown.We randomly assigned 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease (estimated glomerular filtration rate [GFR], 15 to <30 ml per minute per 1.73 m(2) of body-surface area) to bardoxolone methyl, at a daily dose of 20 mg, or placebo. The primary composite outcome was end-stage renal disease (ESRD) or death from cardiovascular causes.The sponsor and the steering committee terminated the trial on the recommendation of the independent data and safety monitoring committee; the median follow-up was 9 months. A total of 69 of 1088 patients (6%) randomly assigned to bardoxolone methyl and 69 of 1097 (6%) randomly assigned to placebo had a primary composite outcome (hazard ratio in the bardoxolone methyl group vs. the placebo group, 0.98; 95% confidence interval [CI], 0.70 to 1.37; P=0.92). In the bardoxolone methyl group, ESRD developed in 43 patients, and 27 patients died from cardiovascular causes; in the placebo group, ESRD developed in 51 patients, and 19 patients died from cardiovascular causes. A total of 96 patients in the bardoxolone methyl group were hospitalized for heart failure or died from heart failure, as compared with 55 in the placebo group (hazard ratio, 1.83; 95% CI, 1.32 to 2.55; P<0.001). Estimated GFR, blood pressure, and the urinary albumin-to-creatinine ratio increased significantly and body weight decreased significantly in the bardoxolone methyl group, as compared with the placebo group.Among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, bardoxolone methyl did not reduce the risk of ESRD or death from cardiovascular causes. A higher rate of cardiovascular events with bardoxolone methyl than with placebo prompted termination of the trial. (Funded by Reata Pharmaceuticals; BEACON ClinicalTrials.gov number, NCT01351675.).

SUBMITTER: de Zeeuw D

PROVIDER: S-EPMC4496027 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease.

de Zeeuw Dick D Akizawa Tadao T Audhya Paul P Bakris George L GL Chin Melanie M Christ-Schmidt Heidi H Goldsberry Angie A Houser Mark M Krauth Melissa M Lambers Heerspink Hiddo J HJ McMurray John J JJ Meyer Colin J CJ Parving Hans-Henrik HH Remuzzi Giuseppe G Toto Robert D RD Vaziri Nosratola D ND Wanner Christoph C Wittes Janet J Wrolstad Danielle D Chertow Glenn M GM

The New England journal of medicine 20131109 26

<h4>Background</h4>Although inhibitors of the renin-angiotensin-aldosterone system can slow the progression of diabetic kidney disease, the residual risk is high. Whether nuclear 1 factor (erythroid-derived 2)-related factor 2 activators further reduce this risk is unknown.<h4>Methods</h4>We randomly assigned 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease (estimated glomerular filtration rate [GFR], 15 to <30 ml per minute per 1.73 m(2) of body-surface area) to ba ...[more]

PMID: 24206459

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Project description:IntroductionCell-based therapies potentially delay the trajectory toward end-stage kidney disease (ESKD) in late stage 4 diabetic chronic kidney disease (DKD). We describe the trial design, baseline patient characteristics, and early results of an IRB-approved phase II multicenter clinical trial, utilizing Renal Autologous Cell Therapy (REACT) in adults with pre-ESKD due to type 2 DKD. The trial objectives were safety and tolerability of REACT by assessment of the procedure, product administration, and renal-specific adverse events in addition to evaluate the impact on renal function following injection.MethodsTen adults with an eGFR of 14-20 mL/min/1.73 m2 were enrolled in a single-arm open-label trial. Following a percutaneous kidney biopsy, an ex vivo expansion of selected renal cells that form the REACT was injected into the cortex of the biopsied kidney with CT image guidance. Each participant received two doses of the REACT product at 6-month intervals. A 6-month observation pre-trial was required to establish patients' "own" baseline and rate of DKD progression.ResultsFive men and 5 women underwent 19 REACT injections (1 participant received only one injection). Their baseline characteristics were as follows: 3 Hispanic/Latino, 7 non-Hispanic, 7 white; mean (SD) age: 58.9 years (5.22), BMI 35.8 (8.2), eGFR (sCR) 15.5 (2.72), eGFR (sCR + Cys-C) 17.7 (3.67) mL/min/1.73 m2, sCr 3.6 mg/mL (0.73), Cys-C 2.6 mg/mL (0.52), and log random UACR 7.9 mg/g (1.01). The pre- and post-injection eGFR slope was -6.5 mL/min/1.73 m2 and -3.9 mL/min/1.73 m2. No cell-related adverse events occurred, and two procedure-related hematomas required observation without transfusion or angiographic interventions. Dialysis was delayed a mean of 16 months (range 6-28 months). At 15 months, 2 patients (20%) have eGFR slope stability and have not commenced renal replacement therapy.ConclusionTrials that include patients with an eGFR of <20 mL/min/1.73 m2 are uncommon, and none to date involve autologous homologous cell-based treatments. REACT has the potential to stabilize or delay dialysis in high-risk late stage 4 DKD.

Project description:INTRODUCTION:Ertugliflozin is a sodium-glucose cotransporter 2 inhibitor in development for type 2 diabetes mellitus (T2DM). The safety and efficacy of ertugliflozin were evaluated over 52 weeks in patients with chronic kidney disease (CKD). METHODS:In this double-blind randomized study (NCT01986855), patients with glycated hemoglobin (A1C) 7.0-10.5% and stage 3 CKD [estimated glomerular filtration rate (eGFR) ≥ 30 to < 60 mL/min/1.73 m2] who were undergoing treatment with standard diabetes therapy (or therapies) including insulin and/or sulfonylureas were randomized to once-daily ertugliflozin 5 mg, 15 mg, or placebo. Patients on metformin underwent a pre-randomization ≥ 10-week wash-off period. The primary endpoint was change from baseline in A1C at week 26 in the overall cohort. Secondary efficacy endpoints were assessed in the stage 3A CKD cohort (eGFR ≥ 45 to < 60 mL/min/1.73 m2) at weeks 26 and 52. Safety was assessed in the overall cohort. RESULTS:468 patients were randomized (baseline mean A1C 8.2%). At week 26, reductions from baseline in A1C were observed across groups in the overall cohort [least squares mean changes (95% confidence interval) - 0.3% (- 0.4, - 0.1), - 0.3% (- 0.4, - 0.1), and - 0.4% (- 0.6, - 0.3) for placebo and for ertugliflozin 5 mg and 15 mg, respectively]. Prohibited use of metformin was identified in ~ 17% of patients and impacted evaluation of the primary endpoint. Greater reductions from baseline in body weight, fasting plasma glucose, and systolic blood pressure were observed with ertugliflozin versus placebo at week 26 (stage 3A CKD cohort). The incidences of urinary tract infections, genital mycotic infections, and hypoglycemia adverse events were not meaningfully different between groups. The incidence of hypovolemia-related adverse events was higher with ertugliflozin relative to placebo. CONCLUSION:Although surreptitious metformin use impacted the primary analysis, reductions in blood glucose and body weight were observed with ertugliflozin in patients with T2DM and stage 3 CKD; ertugliflozin had an acceptable safety profile. FUNDING:Merck Sharp & Dohme Corp. a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and Pfizer Inc. TRIAL REGISTRATION:Clinicaltrials.gov identifier NCT01986855.

Project description:IntroductionBardoxolone methyl significantly increases estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease (CKD). However, the phase 3 study, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus: the Occurrence of Renal Events (BEACON), was terminated prematurely because bardoxolone methyl increased the risk for early-onset fluid overload in patients with identifiable risk factors for heart failure (elevated baseline B-type natriuretic peptide levels >200 pg/ml and prior history of hospitalization for heart failure). The Phase 2 Study of Bardoxolone Methyl in Patients with Chronic Kidney Disease and Type 2 Diabetes (TSUBAKI) study aimed to determine if patients without risk factors can mitigate the risk for fluid overload and whether changes in eGFR with bardoxolone methyl reflect true increases in GFR.MethodsThis phase 2, randomized, multicenter, double-blind, placebo-controlled study enrolled patients with type 2 diabetes and stage 3-4 CKD. Patients were randomized 1:1 to bardoxolone methyl (n = 41) or placebo (n = 41) (cohort G3), or 2:1 to bardoxolone methyl (n = 24) or placebo (n = 14) (cohort G4), administered orally once daily for 16 weeks using a dose-titration scheme. The primary efficacy endpoint was change from baseline in GFR measured by inulin clearance at week 16 in the cohort G3.ResultsA total of 40 patients were evaluated for the prespecified primary efficacy analysis. Mean change (95% confidence interval [CI]) from baseline in GFR was 5.95 (2.29 to 9.60) and -0.69 (-3.83 to 2.45) ml/min per 1.73 m2 for patients randomized to bardoxolone methyl and placebo, respectively, with a significant intergroup difference of 6.64 ml/min per 1.73 m2 (P = 0.008). Increases in the albumin/creatinine ratio were observed in the bardoxolone methyl group vs the placebo group. The most common adverse events (≥15% in either group) were viral upper respiratory tract infection, increased alanine aminotransferase, increased aspartate aminotransferase, increased γ-glutamyltransferase, and constipation. Peripheral edema was reported by 4 patients receiving bardoxolone methyl and by 1 patient receiving placebo; all events were mild and self-limiting. No patient died or experienced heart failure. The study discontinuation rate was higher in the bardoxolone methyl group (cohort G3, n = 8; cohort G4, n = 7) than the placebo group (cohort G3, n = 1; cohort G4, n = 0).ConclusionBardoxolone methyl significantly increased measured GFR, and further investigation is ongoing to evaluate whether it provides clinical benefit without major safety concerns in selected patients with CKD.

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Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease.

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Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease.

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