The effects of atrasentan on urinary metabolites in patients with type 2 diabetes and nephropathy

We assessed the effect of atrasentan therapy on a pre-specified panel of 13 urinary metabolites known to reflect mitochondrial function in patients with diabetic kidney disease. This post-hoc analysis was performed using urine samples collected during the RADAR study which was a randomized, double-blind, placebo-controlled trial that tested the effects of atrasentan on albuminuria reduction in patients with type 2 diabetes and nephropathy. At baseline, four of the 13 metabolites, quantified by gas-chromatography mass spectrometry, were below detectable levels, and six were reduced in patients with eGFR <60 ml/min/1.73 m(2) . After 12-weeks of atrasentan treatment in patients with eGFR <60 ml/min/1.73 m(2) , a single-value index of the metabolites changed by -0.31 (95%CI -0.60 to -0.02; p = 0.035), -0.08 (-12 to 0.29; p = 0.43) and 0.01 (-0.21 to 0.19; p = 0.913) in placebo, atrasentan 0.75 mg/d and 1.25 mg/d, respectively. The metabolite index difference compared to placebo was 0.13 (-0.17 to 0.43; p = 0.40) and 0.35 (0.05 to 0.65; p = 0.02) for atrasentan 0.75 mg/d and 1.25 mg/d, respectively. These data corroborate previous findings of mitochondrial dysfunction in patients with type 2 diabetes, nephropathy, and eGFR <60 ml/min/1.73 m(2) , suggesting that atrasentan may prevent the progression of mitochondrial dysfunction common to this specific patient population. Future studies of longer treatment duration with atrasentan are indicated.