Avosentan, an endothelin-A antagonist, decreases the urinary albumin excretion rate (UAER) in patients with diabetes and macroalbuminuria when added to standard therapy with an angiotensin-converting enzyme (ACE) inhibitor and/or angiotensin receptor blocker (ARB), according to results of a new study at 58 centers.
The results indicate that avosentan may help slow the progression of diabetic end-stage renal disease (ESRD).
Despite the use of ACE inhibitors and ARBs, as well as a new renin inhibitor (aliskiren), “There is still a large need to improve prevention of [diabetic nephropathy] and reduce its progression to ESRD and associated cardiovascular events,” write René R. Wenzel, MD, from the Academic Teaching Hospital of the Paracelsus University Salzburg, Zell am See, Austria.
The study was designed to investigate the effects of 12 weeks of treatment with a new strategy of endothelin-A antagonism with avosentan when added to standard therapy. The primary endpoint was change in UAER, an indicator of progression of diabetic nephropathy.
Of 501 patients with type 1 or 2 diabetes and diabetic nephropathy who were screened, 286 were randomly assigned to 5 mg (n = 59), 10 mg (n = 57), 25 mg (n = 60), 50 mg (n = 53), or placebo (n = 57). All but six patients were pretreated with an ACE inhibitor or ARB, and concomitant antihypertensive and antidiabetic therapy was similar among all treatment groups.
At baseline, mean UAER levels ranged from 0.79 mg/minute in the avosentan 10-mg group to 1.21 mg/minute in the avosentan 50-mg group. Median UAER levels were similar across all treatment groups and ranged from 0.49 to 0.78 mg/minute. At 12 weeks, the mean absolute change in UAER was significant compared with baseline in each of the treatment groups (−15% to −21%) compared with placebo (5%), with an apparent dose-related response. The mean relative change in UAER was similar (−16.3% to −29.9%) compared with placebo (12.1%).
When median values were used, the findings differed somewhat. Median absolute decreases in UAER with avosentan were similar for the 5- and 10-mg groups (−0.15 mg/minute) and for the 25- and 50-mg groups (−0.21 mg/minute) compared with a median absolute increase of 0.05 mg/minute in the placebo group. Median relative changes showed a flat dose-response curve, and similar efficacy was seen with all doses of avosentan except the 5-mg dose. Creatinine clearance and blood pressure were unchanged at week 12.
The authors write, “As relative median UAER values show, there seems to be no additional antiproteinuric effect with dosages of avosentan above 25 mg; thus, the optimal dosage in terms of risk-benefit ratio may be defined at ≤10 mg.”
An analysis of secondary efficacy parameters showed that total cholesterol and mean urinary protein excretion rate were significantly decreased by avosentan compared with placebo.
Overall, all avosentan doses were well tolerated, and adverse events were generally minor over the 12-week study period. About 25% of patients reported adverse events that were potentially related to study medication. The main adverse event was peripheral edema in 12% of patients who received avosentan, mainly in patients who received high doses (≥25 mg). Of five deaths that occurred during the safety analysis, only one was considered possibly related to avosentan. No significant elevations of liver enzymes were reported.
“A large outcome trial is mandatory to confirm these findings and to determine whether avosentan’s antiproteinuric effects can be translated into long-term benefits also with lower doses of avosentan, which are likely to have an optimal tolerability,” the authors conclude. “Nevertheless, the marked and significant reduction in macroalbuminuria after 12 weeks of avosentan treatment suggests a clinically valuable nephroprotective effect.”
J Am Soc Nephrol. 2009;20:655-664.