Key result
Atrasentan exposure is linked to ~24% lower kidney event risk but higher heart failure.
Why the study?
Atrasentan reduced albuminuria with minimal fluid retention in phase II trials, but whether plasma exposure was associated with long-term kidney protection and heart failure outcomes remained to be evaluated.
Does atrasentan plasma exposure reduce the risk of kidney outcomes in patients with type 2 diabetes and CKD?
Cohort (n=3,668)
Double-blind
1:1
Does atrasentan plasma exposure reduce the risk of kidney outcomes in patients with type 2 diabetes and CKD?
Hazard Ratio: 0.76 (95% CI 0.28–0.85)
Atrasentan 0.75 mg/day provides plasma exposures that appropriately balance long-term kidney protection against the risk of fluid retention and heart failure in patients with diabetic kidney disease.
May inform 0.75 mg/day dosing to balance kidney benefit against HF risk in diabetic CKD; leaves open need for prospective validation.
Atrasentan, an endothelin receptor antagonist, showed clinically significant albuminuria reduction with minimal signs of fluid retention in phase II trials. We evaluated whether plasma exposure was associated with long-term outcomes for kidney protection and heart failure in the phase III SONAR trial (n = 3668) in type 2 diabetics with chronic kidney disease. A population pharmacokinetic model was used to estimate plasma exposure of atrasentan 0.75 mg/day. Parametric time-to-event models were used to quantify the association between plasma exposure and long-term outcomes. Mean atrasentan plasma exposure was 41.4 ng.h/mL (2.5th to 97.5th P: 14.2 to 139.9). Compared with placebo, a mean atrasentan exposure translated in a hazard ratio of 0.76 (95% confidence interval (CI): 0.28-0.85) for kidney events and 1.13 (95% CI: 1.03-2.20) for heart failure events. At the mean atrasentan exposure, the kidney protective effect was larger than the increase in heart failure supporting the atrasentan 0.75 mg/day dose in this population.
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Koomen et al. (2020) conducted a cohort in Type 2 diabetes and chronic kidney disease (n=3,668). Atrasentan plasma exposure vs. Placebo was evaluated on Kidney composite outcome (doubling of serum creatinine, end-stage kidney disease, or renal death) (HR 0.76, 95% CI 0.28-0.85). Mean atrasentan plasma exposure resulting from a 0.75 mg/day dose was associated with a reduced risk of kidney events (HR 0.76) and an increased risk of heart failure events compared to placebo.
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