The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy

Abstract

Despite optimal treatment, including renin-angiotensin system (RAS) inhibitors, patients with type 2 diabetic nephropathy have high cardiorenal morbidity and mortality related to residual albuminuria. We evaluated whether or not atrasentan, a selective endothelin A receptor antagonist, further reduces albuminuria when administered concomitantly with maximum tolerated labeled doses of RAS inhibitors. We enrolled 211 patients with type 2 diabetes, urine albumin/creatinine ratios of 300-3500 mg/g, and eGFRs of 30-75 ml/min per 1.73 m(2) in two identically designed, parallel, multinational, double-blind studies. Participants were randomized to placebo (n=50) or to 0.75 mg/d (n=78) or 1.25 mg/d (n=83) atrasentan for 12 weeks. Compared with placebo, 0.75 mg and 1.25 mg atrasentan reduced urine albumin/creatinine ratios by an average of 35% and 38% (95% confidence intervals of 24 to 45 and 28 to 47, respectively) and reduced albuminuria≥30% in 51% and 55% of participants, respectively. eGFR and office BP measurements did not change, whereas 24-hour systolic and diastolic BP, LDL cholesterol, and triglyceride levels decreased significantly in both treatment groups. Use of atrasentan was associated with a significant increase in weight and a reduction in hemoglobin, but rates of peripheral edema, heart failure, or other side effects did not differ between groups. However, more patients treated with 1.25 mg/d atrasentan discontinued due to adverse events. After stopping atrasentan for 30 days, measured parameters returned to pretreatment levels. In conclusion, atrasentan reduced albuminuria and improved BP and lipid spectrum with manageable fluid overload-related adverse events in patients with type 2 diabetic nephropathy receiving RAS inhibitors.

Figure 1.

Consolidated Standards of Reporting Trials diagram. This is a summary of the disposition of study participants.

Figure 2.

Atrasentan treatment significantly decreases albuminuria. (A) UACR change in the percent geometric mean from baseline to recovery for the placebo (●), 0.75 mg/d atrasentan (▪), and 1.25 mg/d atrasentan (▲) groups. (B) Degree of UACR reduction from baseline to final in the placebo (squares), 0.75 mg/d atrasentan (open bars), and 1.25 mg/d atrasentan (filled bars) groups. ***P<0.001.

Figure 3.

Atrasentan treatment modulates office and 24-hour ambulatory blood pressure. Mean office SBP/DBP over 12 weeks and after recovery (A) and mean 24-hour ambulatory SBP/DBP over 6 and 10 weeks (B) for the placebo (circles), 0.75 mg/d atrasentan (squares), and 1.25 mg/d atrasentan (triangles) groups. Overall P values are as follows: 0.63 and 0.23 for 0.75 and 1.25 mg/d atrasentan, respectively, for SBP; 0.07 and 0.01 for 0.75 and 1.25 mg/d atrasentan, respectively, for DBP; 0.03 and 0.01 for 0.75 and 1.25 mg/d atrasentan, respectively, for 24-hour SBP; and <0.001 for 0.75 and 1.25 mg/d atrasentan, respectively, for 24-hour DBP.

Figure 4.

Atrasentan treatment exerts lipid-lowering effects. Mean changes in total cholesterol (A), LDL cholesterol (B), HDL cholesterol (C), and triglycerides (D) after placebo (●), 0.75 mg/d atrasentan (▪), and 1.25 mg/d atrasentan (▲) treatment for 12 weeks and after recovery.

Figure 5.

Atrasentan treatment affects body weight. Mean changes in weight and new incidence of edema after placebo (●), 0.75 mg/d atrasentan treatment (▪), and 1.25 mg/d atrasentan treatment (▲) and after recovery.