Avosentan reduced albuminuria (median reduction 44.3-49.3% vs 9.7% for placebo) but induced significant fluid overload and heart failure, leading to premature trial termination.
RCT (n=1,392)
Double-blind
Randomized
Yes
Does oral avosentan reduce the composite of doubling of serum creatinine, ESRD, or death in patients with type 2 diabetes and overt diabetic nephropathy?
While avosentan reduces albuminuria in patients with diabetic nephropathy, it causes unacceptable rates of fluid overload and congestive heart failure, precluding its use in this population.
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.
Mann et al. (Fri,) conducted a rct in Type 2 diabetes with overt diabetic nephropathy (n=1,392). Avosentan vs. Placebo was evaluated on Time to doubling of serum creatinine, ESRD, or death. Avosentan reduced albuminuria (median reduction 44.3-49.3% vs 9.7% for placebo) but induced significant fluid overload and heart failure, leading to premature trial termination.