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, 4 of the 13 metabolites, quantified by gas-chromatography mass spectrometry, were below detectable levels, and 6 were reduced in patients with eGFR < 60 mL/min/1.73 m². After 12 weeks of atrasentan treatment in patients with eGFR < 60 mL/min/1.73 m², a single-value index of the metabolites changed by −0.31 (95%CI −0.60 to −0.02; P =.035), −0.08 (−12 to 0.29; P =.43) and 0.01 (−0.21 to 0.19; P =.913) in placebo, atrasentan 0.75 and 1.25 mg/d, respectively. The metabolite index difference compared to placebo was 0.13 (−0.17 to 0.43; P =.40) and 0.35 (0.05-0.65; P =.02) for atrasentan 0.75 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 m², 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.