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loss; and more gastrointestinal and muscle-related symptomatology. The reasons for these adverse events are unclear. The authors speculate that fluid retention, increased afterload, and higher heart rate contributed to heart failure in patients in the bardoxolone methyl group. In addition, direct toxic effects are possible. What lessons can be learned from the bardoxolone methyl studies? First, more extensive analysis of preclinical data might have led to greater caution before clinical trials were conducted with this agent. Notably, in one study, the administration of bardoxolone analogues to diabetic rats was associated with increased occurrences of kidney injury, hypertension, proteinuria, and weight loss, which is analogous to some clinical trial findings.9 However, these data were published only after the BEACON trial was terminated. Second, it is not surprising that a potent activator of a transcription factor might have off-target effects. In addition to Nrf2, bardoxolone methyl activates peroxisome proliferatoractivated receptor , which may contribute to fluid retention and heart failure, especially in persons with advanced diabetic kidney disease. Third, caution should be exercised whenever any drug for diabetic kidney disease increases, rather than decreases, the degree of albuminuria. Unfortunately, the failure rate of new drug therapies in clinical trials is extraordinarily high, exceeding 90% overall; even in phase 3 trials, it is still approximately 50%. In addition to bardoxolone methyl, a series of other new therapies for diabetic kidney disease have foundered over the course of drug development. Examples include inhibitors of advanced glycation end products, aldose reductase inhibitors, sulodexide, antifibrotic treatments, and inhibitors of protein kinase C. Increasing the success rate for drug development requires reengineering how we translate discovery science into clinical trials.10 Efforts are under way to increase thorough reporting of preclinical studies, and the development of new
tools such as human organs on microchips may augment the assessment of potential offtarget toxic effects. Additional key areas for focus are rigorous evaluations of dosing, suitable biomarkers for disease processes and therapeutic responses, and business and regulatory environments that foster innovation. If new therapies for diabetic kidney disease are to benefit patients, fresh approaches will be critical. Given the escalating human and societal costs of diabetic kidney disease, efforts to find new safe and effective therapies remain vital.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. From the Kidney Research Institute and Division of Nephrology, Uni versity of Washington School of Medicine, Seattle (J.H., K.R.T.), and Providence Sacred Heart Medical Center and Childrens Hospital, Spokane (K.R.T.) both in Washington. This article was published on November 9, 2013, at NEJM.org.
1. Afkarian M, Sachs MC, Kestenbaum B, et al. Kidney disease
and increased mortality risk in type 2 diabetes. J Am Soc Nephrol 2013;24:302-8. 2. Groop PH, Thomas MC, Moran JL, et al. The presence and severity of chronic kidney disease predicts all-cause mortality in type 1 diabetes. Diabetes 2009;58:1651-8. 3. National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 update. Am J Kidney Dis 2012;60:850-86. [Erratum, Am J Kidney Dis 2013;61:1049.] 4. de Boer IH, Rue TC, Hall YN, Heagerty PJ, Weiss NS, Himmelfarb J. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA 2011;305:2532-9. 5. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59. 6. Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012;367:2204-13. 7. Pergola PE, Raskin P, Toto RD, et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med 2011;365:327-36. 8. de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med 2013. DOI: 10.1056/NEJMoa1306033. 9. Zoja C, Corna D, Nava V, et al. Analogs of bardoxolone methyl worsen diabetic nephropathy in rats with additional adverse effects. Am J Physiol Renal Physiol 2013;304:F808-19. 10. Collins FS. Reengineering translational science: the time is right. Sci Transl Med 2011;3:90 cm17.
DOI: 10.1056/NEJMe1313104
Copyright 2013 Massachusetts Medical Society.
The New England Journal of Medicine Downloaded from nejm.org on November 14, 2013. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved.