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 m2 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. Copyright © 2013 Massachusetts Medical Society.
Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease
De Zeeuw, Dick; Akizawa, Tadao; Audhya, Paul; Bakris, George L.; Chin, Melanie; Christ-Schmidt, Heidi; Goldsberry, Angie; Houser, Mark; Krauth, Melissa; Lambers Heerspink, Hiddo J.; McMurray, John J.; Meyer, Colin J.; Parving, Hans-Henrik; Remuzzi, Giuseppe; Toto, Robert D.; Vaziri, Nosratola D.; Wanner, Christoph; Wittes, Janet; Wrolstad, Danielle; Chertow, Glenn M.; Toto, B.; McCullough, P.; Ivanovich, P.; Ketteler, M.; Lachin, J.; McGill, J.; Agarwal, R.; Anker, S.; Arenillas, J. F.; Januzzi, J.; Jardine, A.; Kasner, S.; Kissela, B.; Kolansky, D.; Mann, J.; Thadhani, R.; Champion de Crespigny, P.; Chan, D. T.; 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.; Sunder-Plassmann, G.; Jadoul, M.; Krzesinski, J. M.; 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, T. C.; Perkins, D.; Roy, L.; Sapir, D.; Tam, P.; Bartaskova, D.; Hemzsky, L.; Kubina, D.; Szabo, M.; Tesar, V.; Combe, C.; Faller, B.; Fauvel, J. P.; Halimi, J. M.; Hourmant, M.; Le Meur, Y.; Urena-Torres, P.; Zaoui, P.; Al-Sarraf, S.; Burst, V.; Degenhardt, S.; Kempe, H. P.; 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, D. J.; Wainstein, J.; Yagil, Y.; Yerushalmi, Y.; Colussi, G.; Conte, G. ;Di Luca, M.; Giovambatista, C.; Messa, P.; Pani, A.; Pisani, A.; Rapana, M. R.; Ruggenenti, P.; Villa, G.; Zoccali, C.; Correa-Rotter, R.; Diaz-Escobedo, S. L.; Garcia, P.; Gonzalez Galvez, G.; Obrador Vera, G. T.; Rico, R.; Calero, F.; Cigarran, S.; de Alvaro, F.; de Francisco, A. L.; Egido, J.; Fernandez, E.; Fernandez Vega, F.; Fort, J.; Galan Serrano, A.; Gorriz Teruel, J. L.; Martinez, I.; Martinez Castelao, A.; Munar, M. A.; 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, K. S.; 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, R. F.; Arif, A.; Assefi, A. R.; Atray, N.; Awad, A.; Barranco, E.; Belledonne, M. O.; Belo, D.; Bernardo, M.; Bernstein, R.; Bhalla, V.; Bhatia, D.; Black, R. M.; Block, G.; Blondin, J.; Blumenthal, S. S.; Bononi, P.; Brantley, R. R.; 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, P. W.; Darwish, R.; Deeb, W.; Denker, P. S.; Desai, S.; Desouza, C.; Diamond, S.; Dixon, B. S.; Durham, J. H.; Eisner, G.; Elder, J. G.; El-Shahawy, M.; Fadda, G.; Fitz-Patrick, D.; Fonseca, V.; Fraser, N. J.; Frei, G.; Fried, L.; Galindo-Ramos, E.; Germain, M.; Ghantous, W.; Gilbert, J. M.; Gillum, D.; Godwin, J.; Goel, A.; Goldfarb, DS.; Graf, R. J.; 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, G. E.; Keith, K.; Khairullah, Q.; Kondle, V.; Kopyt, N.; Krishna, G.; Lawrence, M. K.; LeBeau, M.; Leehey, D. J.; Levine, M. M.; Levinson, D.; Lew, S. Q.; Lewis, D.; Linfert, D.; Liss, K.; Lund, R.; Madeleine, P.; Mahmood, K.; Martin, E. R.; Martinez, C.; Mayeda, S. O.; Mendez, R.; Middleton, J.; Molitch, M. E.; Moncrief, J.; Moustafa, M.; Muoneke, R.; Murray, A. V.; Murugan, T. S.; Nammour, T. M.; 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, R. G.; Petrillo, R.; Prabhakar, S.; Purighalla, R. S.; 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, D. L.; Rovner, S.; Sackel, H.; Sader, S.; Santos, P.; Schmidt, R.; Shafik, S.; Shakeel, M.; Sharon, Z.; Silva, A. L.; Silva, A.; Singh, B.; Smith, M.; Solomon, R.; Soman, S.; Spinowitz, B.; Sprague, S. M.; Spry, L.; Stonesifer, L.; Streja, D.; Suchinda, P.; Sun, C.; Thakar, C. V.; Trespalacios, F.; Tumlin, J. A.; Van Buren, P.; Vernace, M.; Vicks, S.; Warren, M.; Weiss, D.; Welker, J.; Winston, J. A.; Wombolt, D. G.; Wood, M.; Wu, M.; Wynne, A.; Yu, H.; Zabaneh, R. I.
2013
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 m2 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. Copyright © 2013 Massachusetts Medical Society.
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