Avosentan for overt diabetic nephropathy

Abstract

In the short term, the endothelin antagonist avosentan reduces proteinuria, but whether this translates to protection from progressive loss of renal function is unknown. We examined the effects of avosentan on progression of overt diabetic nephropathy in a multicenter, multinational, double-blind, placebo-controlled trial. We randomly assigned 1392 participants with type 2 diabetes to oral avosentan (25 or 50 mg) or placebo in addition to continued angiotensin-converting enzyme inhibition and/or angiotensin receptor blockade. The composite primary outcome was the time to doubling of serum creatinine, ESRD, or death. Secondary outcomes included changes in albumin-to-creatinine ratio (ACR) and cardiovascular outcomes. We terminated the trial prematurely after a median follow-up of 4 months (maximum 16 months) because of an excess of cardiovascular events with avosentan. We did not detect a difference in the frequency of the primary outcome between groups. Avosentan significantly reduced ACR: In patients who were treated with avosentan 25 mg/d, 50 mg/d, and placebo, the median reduction in ACR was 44.3, 49.3, and 9.7%, respectively. Adverse events led to discontinuation of trial medication significantly more often for avosentan than for placebo (19.6 and 18.2 versus 11.5% for placebo), dominated by fluid overload and congestive heart failure; death occurred in 21 (4.6%; P = 0.225), 17 (3.6%; P = 0.194), and 12 (2.6%), respectively. In conclusion, avosentan reduces albuminuria when added to standard treatment in people with type 2 diabetes and overt nephropathy but induces significant fluid overload and congestive heart failure.

Figure 1.

Screen failure was almost exclusively due to an ACR below the inclusion criterion of 35 mg/mmol or a serum creatinine outside the inclusion criteria. For definitions and details of primary and secondary outcomes, see Table 2 and the Concise Methods section. CV, cardiovascular; CHF, a component of the CV outcome (typical signs and/or symptoms of heart failure and having received new therapy for CHF and being admitted to hospital for at least 24 hours). Fluid overload was not defined by the trial protocol but taken from the adverse event reports of the local investigators.

Figure 2.

Kaplan-Meier plot shows time to doubling of serum creatinine, ESRD, or death in patients who had type 2 diabetes and diabetic nephropathy and were treated with avosentan 25 mg/d, avosentan 50 mg/d, or placebo (n = 1392). There were no significant differences among groups. The plots were truncated at 6 months because of premature termination of the trial.

Figure 3.

Urine ACR changed significantly (P < 0.0001; see Table 3) in the avosentan (av)-treated groups during the first 6 months of the trial. Medians and interquartile ranges are given. Similar differences were found for fractional excretion of urine albumin (see Supplemental Appendix 2).

Figure 4.

Fluid overload occurred in the avosentan-treated groups. Fluid overload was not defined by the trial protocol but taken from the adverse event reports of the local investigators. All participants were followed at monthly intervals and examined for adverse events. The individual signs and symptoms on the adverse event forms indicating fluid overload are detailed in the Concise Methods section.