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.