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Avosentan trial cut short, but lower doses may reduce proteinuria in diabetics

Reuters Health • The Doctor's Channel Daily Newscast

NEW YORK (Reuters Health) – Researchers cut short a clinical trial of the endothelin blocker avosentan in patients with diabetic nephropathy because it was linked with fluid overload and congestive heart failure. Before the abrupt end, however, it was clear that avosentan cut proteinuria by 40-50%.

Although terminated prematurely, the study provides new information about the effects of a predominant endothelin receptor antagonist in type 2 diabetics with stages 3 to 4 chronic kidney disease, the researchers report in the February 18th online edition of the Journal of the American Society of Nephrology.

Because of the trial’s termination, they couldn’t tell if the reduction of proteinuria could slow the loss of kidney function. They hope to find, eventually, that lower doses of avosentan will be effective, not to mention more tolerable.

In the discontinued trial, researchers at more than 500 centers in 36 countries treated 1,392 diabetic adults either with avosentan, in doses of 25 or 50 mg per day, or with placebo. All subjects had overt kidney disease. Throughout the trial, all patients continued taking their standard medication, either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.

Although scheduled for 42 months, the trial was stopped after a median of four months for those taking avosentan and five months for the placebo group. There was no difference between the groups in the percentages of patients who met the primary composite end point (death, end-stage renal disease, or doubling of baseline creatinine level).

In the avosentan groups, fewer patients progressed to end-stage renal disease, but more died, mainly of cardiovascular causes. Cardiovascular outcomes in general, and particularly congestive heart failure, were more frequent with both doses of avosentan.

Compared to the placebo group, significantly more avosentan patients withdrew from the trial due to adverse effects (19.6% of the 25-mg group, 18.2% of the 50-mg group, and 11.5% of the placebo group).

Albumin-to-creatinine ratios (ACR) fell by a median of 44.3% in the 25-mg group, 49.3% in the 50-mg group, and 9.7% in the placebo group.

“The effect on albuminuria is likely due to inhibition of the renal ETA (endothelin) receptor, because other researchers have found that the mixed type ETA/B receptor antagonists have a weaker or no effect on proteinuria,” the researchers write.

In another secondary outcome, the estimated glomerular filtration rate (eGFR) declined in all three groups by 2.5 to 4 ml/min/1.73 m2. The decrease was slightly greater in the group that took the 50-mg dose compared to the placebo group after three months (p = 0.03) and six months (p = 0.02).

“Whether the faster fall in eGFR was the result of avosentan-induced lower intraglomerular pressure, an effect that could translate into long-term benefit, remains a moot point,” the authors say, given that any benefit for the kidney “was outweighed by increased early mortality.”

In an editorial, Dr. Eberhard Ritz of Ruperto Carola University in Heidelberg, Germany and Dr. Rene Wenzel of A.O. Krankenhaus in Zell am See, Austria write, “We suspect that lower dosages of (endothelin receptor) blockers may be associated with fewer adverse effects, and hopefully those dosages will be clinically effective.”

But, they emphasize, “Before making any sweeping suggestions…it is absolutely necessary to have more information on the long-term safety of avosentan in the 5- to 10-mg/d dosage range.”

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