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N Engl J Med. 2013 Dec 26;369(26):2492-503. doi: 10.1056/NEJMoa1306033. Epub 2013 Nov 9.

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

Collaborators (347)

de Zeeuw D, Chertow G, Akizawa T, Audhya P, Bakris G, Krauth M, McMurray J, Meyer C, Parving HH, Remuzzi G, Toto B, Vaziri N, Wanner C, Wittes J, McCullough P, Ivanovich P, Ketteler M, Lachin J, McGill J, Agarwal R, Anker S, Arenillas JF, Januzzi J, Jardine A, Kasner S, Kissela B, Kolansky D, Mann J, Thadhani R, Champion de Crespigny P, Chan DT, D'Almeida E, Fraser I, Gray N, Holt S, Irish A, Isbel N, Kerr P, Packham D, Phoon R, Pollock C, Roger S, Suranyi M, Walker R, Wittert G, Yue D, Balcke P, Prager R, Schernthaner G, Schernthaner G jr, Sunder-Plassmann G, Jadoul M, Krzesinski JM, Peeters P, Van der Niepen P, Van Gaal L, Van Vlem B, Warling X, Chow S, Cournoyer S, Dumas R, Jolly S, Levin A, McMahon A, Mehta H, Ooi TC, Perkins D, Roy L, Sapir D, Tam P, Bartaskova D, Hemzsky L, Kubina D, Szabo M, Tesar V, Combe C, Faller B, Fauvel JP, Halimi JM, Hourmant M, Le Meur Y, Urena-Torres P, Zaoui P, Al-Sarraf S, Burst V, Degenhardt S, Kempe HP, Kleophas W, Kosch C, Krumme B, Kuhlmann M, Pistrosch F, Rambausek M, Schmidt-Guertler H, Segiet T, Sommerer C, Vielhauer V, Wanner C, Beberashvili I, Benchetrit S, Herskovits T, Karnieli E, Levin-Iaina N, Mosenzon O, Tsur A, van Dijk DJ, Wainstein J, Yagil Y, Yerushalmi Y, Colussi G, Conte G, Di Luca M, Giovambatista C, Messa P, Pani A, Pisani A, Rapana MR, Ruggenenti P, Villa G, Zoccali C, Correa-Rotter R, Diaz-Escobedo SL, Garcia P, Gonzalez Galvez G, Obrador Vera GT, Rico R, Calero F, Cigarran S, de Alvaro F, de Francisco AL, Egido J, Fernandez E, Fernandez Vega F, Fort J, Galan Serrano A, Gorriz Teruel JL, Martinez I, Martinez Castelao A, Munar MA, Navarro J, Nieto J, Osuna A, Pascual J, Portoles J, Praga M, Vallés M, Fellstrom B, Frisenette-Fich C, Hadimeri H, Stenvinkel P, Svensson M, Weiss L, Adamson K, Dornhorst A, El Kossi M, Gnudi L, Hendry B, Johnson A, Joseph F, Kalra P, Marshall S, Mikhail A, Myint KS, Soran H, Taal M, Zehnder D, Abbott L, Acharya A, Ahmed Z, Aiello J, Akom M, Ali S, Alzohaili O, Anderson L, Anderson S, Anger M, Appel G, Arakaki RF, Arif A, Assefi AR, Atray N, Awad A, Barranco E, Belledonne MO, Belo D, Bernardo M, Bernstein R, Bhalla V, Bhatia D, Black RM, Block G, Blondin J, Blumenthal SS, Bononi P, Brantley RR Jr, Bresssler P, Broumand V, Brusco O, Buerkert J, Burgos-Calderon R, Campbell R, Canas G, Cangiano J, Cherlin R, Chilakapati V, Comunale R, Coyne D, Crawford PW, Darwish R, Deeb W, Denker PS, Desai S, Desouza C, Diamond S, Dixon BS, Durham JH, Eisner G, Elder JG, El-Shahawy M, Fadda G, Fitz-Patrick D, Fonseca V, Fraser NJ, Frei G, Fried L, Galindo-Ramos E, Germain M, Ghantous W, Gilbert JM Jr, Gillum D, Godwin J, Goel A, Goldfarb DS, Graf RJ, Greenwood T, Guasch A, Hanna A, Harper K, Herman T, Hilton T, Hines T, Hoggard J, Hootkins R, Huseman R, Israelit A, Jamal A, Kant K, Kaptein E, Kathresal A, Kaupke J, Kaveh K, Kaye W, Keightley GE, Keith K, Khairullah Q, Kondle V, Kopyt N, Krishna G, Lawrence MK, LeBeau M, Leehey DJ, Levine MM, Levinson D, Lew SQ, Lewis D, Linfert D, Liss K, Lund R, Madeleine P, Mahmood K, Martin ER, Martinez C, Mayeda SO, Mendez R, Middleton J, Molitch ME, Moncrief J, Moustafa M, Muoneke R, Murray AV, Murugan TS, Nammour TM, Nassar G, Navaneethan S, Newman J, Nossuli A, Nwakoby I, Osama S, Ouseph R, Parker J, Parnes E, Patel N, Pergola P, Perlman A, Perry RG, Petrillo R, Prabhakar S, Purighalla RS, Quesada-Suarez L, Rabiei A, Raskin P, Rastogi A, Reisin E, Rekhi A, Rivera-Colon L, Rizk D, Rodelas R, Roer D, Rosas S, Ross DL, Rovner S, Sackel H, Sader S, Santos P, Schmidt R, Shafik S, Shakeel M, Sharon Z, Silva AL, Silva A, Singh B, Smith M, Solomon R, Soman S, Spinowitz B, Sprague SM, Spry L, Stonesifer L, Streja D, Suchinda P, Sun C, Thakar CV, Trespalacios F, Tumlin JA, Van Buren P, Vernace M, Vicks S, Warren M, Weiss D, Welker J, Winston JA, Wombolt DG, Wood M, Wu M, Wynne A, Yu H, Zabaneh RI.

Author information

1
From the University of Groningen, Groningen, the Netherlands (D.Z., H.J.L.H.); Showa University School of Medicine, Tokyo (T.A.); Reata Pharmaceuticals, Irving, TX (P.A., M.C., A.G., M.K., C.J.M.); University of Chicago (G.L.B.) and AbbVie Pharmaceuticals (M.H.) - both in Chicago; Statistics Collaborative, Washington, DC (H.C.-S., J.W., D.W.); University of Glasgow, Glasgow, United Kingdom (J.J.M.); Rigshospitalet, University of Copenhagen, Copenhagen (H.-H.P.); Istituto di Ricovero e Cura a Carattere Scientifico-Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy (G.R.); University of Texas Southwestern Medical Center, Dallas (R.D.T.); University of California, Irvine (N.D.V.); University of Würzburg, Würzburg, Germany (C.W.); and Stanford University, Palo Alto, CA (G.M.C.).

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.).

PMID:
24206459
PMCID:
PMC4496027
DOI:
10.1056/NEJMoa1306033
[Indexed for MEDLINE]
Free PMC Article

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