Received May 12, 2008
Accepted on September 17, 2008

CLINICAL RESEARCH

Avosentan Reduces Albumin Excretion in Diabetics with Macroalbuminuria

René R. Wenzel ^*1, Thomas Littke , Susan Kuranoff , Christiane Jürgens , Heike Bruck , Eberhard Ritz , Thomas Philipp , Anna Mitchell , and for the SPP301 (Avosentan) Endothelin Antagonist Evaluation in Diabetic Nephropathy Study Investigators

*Department of Internal Medicine, A.Ö. Krankenhaus Zell am See, Academic Teaching Hospital of the Paracelsus University Salzburg, Zell am See, Austria; SPEEDEL Pharma AG, Basel, Switzerland; and Department of Nephrology and Hypertension, University Hospital of Essen, Essen, and Department of Nephrology, University of Heidelberg, Heidelberg, Germany

¹ To whom correspondence should be addressed. E-mail: rrwenzel{at}me.com.

	Abstract

Despite the first-line use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), there is still a large need to improve the prevention and progression of diabetic nephropathy and its associated cardiovascular events. Endothelin antagonists have shown anti-inflammatory, antifibrotic, and antiproteinuric effects in experimental studies. This study was a randomized, placebo-controlled, double-blind, parallel-design, dosage-range study of the effect of the endothelin-A antagonist avosentan (SPP301) on urinary albumin excretion rate (UAER) in patients with diabetic nephropathy. We randomly assigned 286 patients with diabetic nephropathy, macroalbuminuria (UAER 0.2 to 5.6 mg/min), and BP <180/110 mmHg to 12 wk of avosentan (5, 10, 25, and 50 mg) or placebo, in addition to standard ACEI/ARB therapy. Relative to baseline, all avosentan dosages decreased mean relative UAER (-16.3 to -29.9%) compared with placebo (35.5%). Median relative UAER decreased with all avosentan dosages (-28.7 to -44.8%) compared with placebo (12.1%). Creatinine clearance and BP were unchanged at 12 wk. The main adverse events were peripheral edema (12%), mainly with high (25 mg) dosages of avosentan; significant increases in liver enzymes did not occur. Twenty-one (7.3%) patients experienced adverse events that led to withdrawal from study medication. In summary, the endothelin-A antagonist avosentan given in addition to standard ACEI/ARB treatment decreases UAER in patients with diabetic nephropathy and macroalbuminuria.