CV events scuttle bardoxolone for diabetic kidney disease

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Beware albuminuria in diabetic kidney disease

The adverse events linked to bardoxolone methyl in this study included excess HF and cardiovascular events, as well as increased rates of high blood pressure, high heart rate, albuminuria, GI symptoms, and muscle-related symptoms, said Dr. Jonathan Himmelfarb and Dr. Katherine R. Tuttle.

"The authors speculate that fluid retention, increased afterload, and higher heart rate contributed to heart failure," but it also is possible that bardoxolone methyl may exert direct toxic effects on the heart, Dr. Himmelfarb and Dr. Tuttle said.

In any case, "caution should be exercised whenever any drug for diabetic kidney disease increases, rather than decreases, albuminuria," they noted.

Dr. Himmelfarb and Dr. Tuttle are at the Kidney Research Institute and the division of nephrology at the University of Washington, Seattle. Dr. Tuttle also is at Providence Sacred Heart Medical Center and Children’s Hospital, Spokane. Dr. Himmelfarb reported ties to Abbott Laboratories, and Dr. Tuttle reported ties to Eli Lilly. These remarks were taken from their editorial accompanying Dr. de Zeeuw’s report (N. Engl. J. Med. 2013 Nov. 9 [doi:10.1056/NEJMe1313104]).



Bardoxolone methyl may have reduced the risk of end-stage renal disease in patients with type 2 diabetes and stage 4 chronic kidney disease in a phase III clinical trial, but researchers stopped the study early after patients taking the drug had an increased rate of cardiovascular deaths, heart failure events, nonfatal myocardial infarction, and nonfatal stroke.

The BEACON trial had only an estimated 40% statistical power to determine bardoxolone methyl’s true effects, given its termination because of safety concerns, according to data reported at the annual Kidney Week meeting sponsored by the American Society of Nephrology.

The findings were simultaneously reported online Nov. 9 in the New England Journal of Medicine (doi:10.1056/NEJMoa1306033).

Bardoxolone methyl, the most potent known activator of a transcription factor that regulates antioxidant genes, was previously shown to raise the estimated glomerular filtration rate (eGFR) in patients with diabetes-related kidney disease. However, it also increased the incidence of albuminuria and induced unintended weight loss.

To determine whether longer-term treatment with bardoxolone methyl might translate that eGFR benefit into a slower progression to end-stage renal disease (ESRD), Dr. Dick de Zeeuw of the University of Groningen (the Netherlands) and his associates performed the double-blind BEACON trial (Bardoxolone Methyl Evaluation in Patients With Chronic Kidney Disease and Type 2 Diabetes Mellitus: The Occurrence of Renal Events).

BEACON was sponsored by Reata Pharmaceuticals and included patients from the United States, Europe, Australia, Canada, Israel, and Mexico, resulting in a diverse patient population with regard to age, race/ethnicity, and area of residence. Both diabetic retinopathy and neuropathy were common comorbidities, as was cardiovascular disease.

The 2,185 study participants had type 2 diabetes and moderate to severe chronic kidney diseases, with a baseline eGFR of 15 to less than 30 mL/min per 1.73 m2 of body surface area. They were randomly assigned to receive either once-daily bardoxolone methyl 20 mg (1,088 patients) or a matching placebo (1,097 patients), along with conventional background therapies given at the discretion of their treating physicians. Those included inhibitors of the renin-angiotensin-aldosterone system, insulin or other hypoglycemic agents, and appropriate cardiovascular medications.

The median duration of exposure was 7 months for bardoxolone methyl and 8 months for placebo, and the median follow-up for both was 9 months.

Bardoxolone significantly improved eGFR, compared with placebo, and fewer patients who took the drug progressed to ESRD. But BEACON was terminated early because of an excess of CV events among patients receiving bardoxolone methyl. That "truncated" study duration limited the trial’s statistical power.

The primary endpoint was a composite of progression to ESRD or cardiovascular death, and it occurred in 6% of both study groups. However, deaths from CV causes were significantly more frequent in the active treatment group (27 patients) than in the placebo group (19 patients), with a hazard ratio of 1.44, Dr. de Zeeuw reported.

In particular, 96 patients in the bardoxolone group had heart failure (HF) events, compared with only 55 patients in the placebo group. Moreover, significantly more of the HF events in the active treatment group were severe enough to require hospitalization or cause death.

Similarly, significantly more patients taking bardoxolone methyl had a composite outcome of nonfatal myocardial infarction, nonfatal stroke, HF hospitalization, or CV death. And the number of deaths from any cause was greater – though not significantly – with bardoxolone methyl (44 deaths) than with placebo (31 deaths) (HR, 1.47; P = .10).

Compared with placebo, bardoxolone methyl also raised blood pressure and heart rate, increased levels of B-type natriuretic peptide, raised the rate of albuminuria, and caused substantial unintended weight loss. The investigators were unable to determine whether there was a loss of body fat, intracellular (that is, skeletal muscle) water, or extracellular (interstitial) water. There was a concomitant fall in serum albumin and hemoglobin levels, which may reflect hemodilution caused by fluid retention, the investigators found.

The increases in blood pressure and heart rate "constitute a potentially potent combination of factors that are likely to precipitate HF in an at-risk population." and the increase in B-type natriuretic peptide "is consistent with an increase in left ventricular wall stress," Dr. de Zeeuw said.

The investigators attempted to identify patient characteristics that might be associated with the development of HF in the bardoxolone methyl recipients, but were unable to do so.

Reata Pharmaceuticals funded the BEACON trial. Dr. de Zeeuw reported ties to AbbVie, Astellas, Chemocentryx, Johnson & Johnson, and Reata, and his associates reported ties to numerous industry sources.

*This article was updated November 11, 2013.

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