Avosentan benefits overshadowed by serious adverse events

The endothelin antagonist avosentan substantially reduced urinary protein loss in patients with type 2 diabetes and kidney disease, but the drug is associated with serious adverse events, new research showed.

It has been suggested that lower doses of avosentan may have a more favorable risk-benefit ratio for patients.

ASCEND was a multinational, multicenter, double blind, placebo-controlled study that examined the effects of avosentan on progression of overt diabetic retinopathy. Researchers randomly assigned 1,392 patients with type 2 diabetes and kidney disease to daily oral avosentan (25 mg or 50 mg) or placebo. All patients were also administered standard treatment of angiotensin-converting enzyme inhibition and/or angiotensin receptor blockade.

The primary outcome — time to doubling of serum creatinine, end-stage renal disease or death — was not statistically significant between the avosentan and placebo groups.

Researchers noted significant reductions in albumin-to-creatinine ratios in the avosentan groups (25 mg, 44.3%; 50 mg, 49.3%; P<.0001) compared with the placebo group (9.7%; P<0.0001).

Although avosentan at either dose lowered patients’ urinary protein excretion by 40% to 50%, compared with less than 10% with placebo, patients taking the drug experienced a high incidence of serious adverse events, according to the researchers.

Adverse events associated with avosentan included: higher rates of fluid overload (25 mg, 44.8%; 50 mg, 45.8%; placebo, 30.7%); higher frequency of congestive heart failure rates (25 mg, 5.9%; 50 mg, 6.1%; placebo, 2.2%); and higher mortality (25 mg, 21 deaths; 50 mg, 17 deaths; placebo, 12 deaths).

Patients assigned avosentan were also more likely to end treatment because of the aforementioned adverse events (25 mg, 19.6%; 50 mg, 18.2%) compared with patients assigned placebo (11.5%).

The researchers concluded that data from the ASCEND trial highlight the risks and potential benefits of endothelin antagonists in patients with kidney disease and proteinuria and will help researchers design future studies to test the drug’s potential. Specifically, lower doses of avosentan may generate more positive effects.

Mann JFE. J Am Soc Nephrol. 2010;21:527-535.