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Avosentan Can Reduce Proteinuria but Serious Adverse Effects Occur in Patients with Type 2 Diabetes

“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,” the study authors write. “Of particular concern was a trend to a higher mortality with avosentan….

“In the short term, the endothelin antagonist avosentan reduces proteinuria, but whether this translates to protection from progressive loss of renal function is unknown,” write Johannes Mann, MD, from Schwabing General Hospital and KfH Kidney Centre in Munchen, Germany, and colleagues from the Avosentan on doubling of Serum Creatinine, End stage renal disease and death in Diabetic Nephropathy (ASCEND) Study Group. “We examined the effects of avosentan on progression of overt diabetic nephropathy in a multicenter, multinational, double-blind, placebo-controlled trial.”

In this study, 1,392 participants with Type 2 diabetes were randomly assigned to receive oral avosentan (25 or 50 mg) or placebo. All patients continued on treatment with angiotensin-converting enzyme inhibition and/or angiotensin receptor blockade. The main composite study endpoint was the time to doubling of serum creatinine, end-stage renal disease, or death, and secondary endpoints were changes in albumin-to-creatinine ratio and cardiovascular outcomes.

After a median follow-up of 4 months (maximum, 16 months), an excess of cardiovascular events with avosentan led to the trial being prematurely terminated. There was no apparent between-group difference in the frequency of the primary outcome. Avosentan significantly reduced albumin-to-creatinine ratio, with a median reduction in albumin-to-creatinine ratio of 44.3% for avosentan 25 mg/day, 49.3% for avosentan 50 mg/day, and 9.7% for placebo.

Discontinuation of trial medication because of adverse events occurred significantly more often for avosentan than for placebo (19.6% and 18.2%, respectively, vs 11.5% for placebo). Adverse events leading to study dropout for avosentan were predominantly fluid overload and congestive heart failure. There were 12 deaths with placebo (2.6%), 21 deaths with avosentan 25 mg/day (4.6%; P = .225), and 17 deaths with avosentan 50 mg/day (3.6%; P = .194).

Anemia, hypoglycemia, and hypotension were also reported more frequently in patients who received avosentan.

“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,” the study authors write. “Of particular concern was a trend to a higher mortality with avosentan.”

The main limitation of this study is the short treatment exposure time.

“Despite its potent albuminuria-lowering effect, it is clear that avosentan at the doses of 25 and 50 mg/d in a population of patients with Type 2 diabetes and 3 to 4 [chronic kidney disease] stage is not a viable therapeutic option,” the study authors conclude. “The clear dosage dependence of the renal and hemodynamic effects of avosentan shown in other studies raises the question as to whether lower dosages of avosentan would maintain the antialbuminuric effect, thereby affording a significantly more favorable risk-benefit ratio, especially at earlier stages of [chronic kidney disease] and with more strict control of sodium balance.”

In an accompanying editorial, Eberhard Ritz, from Ruperto Carola University in Heidelberg, Germany, and René Wenzel, from Zell am See, Austria, note that it is “absolutely necessary” to have more information on the long-term safety of avosentan in the 5- to 10-mg/day dosage range before recommending this therapy.

“There is no question that the high incidence of adverse outcomes in patients with stages 3 to 4 [chronic kidney disease] observed in the study by Mann et al. is a clear contraindication to the use of [endothelin A receptor] blockers in advanced [chronic kidney disease],” Dr. Ritz and Dr. Wenzel write. “Should we continue to use [endothelin A receptor] blockers in all proteinuric kidney disease? Presumably, yes, particularly in earlier stages of diabetic (and possibly nondiabetic) nephropathy in view of the aforementioned impressive experimental and clinical findings, but watch out for clear contraindications (stages 3 and 4 [chronic kidney disease] and pre-existing heart disease), and monitor patients carefully.”

Am Soc Nephrol. Published online February 18, 2010.