Avosentan for Overt Diabetic Nephropathy

Abstract

In the short term, the endothelin antagonist avosentan reduces proteinuria, but whether this translates to protection from progressive loss of renal function is unknown. We examined the effects of avosentan on progression of overt diabetic nephropathy in a multicenter, multinational, double-blind, placebocontrolled trial. We randomly assigned 1392 participants with type 2 diabetes to oral avosentan (25 or 50 mg) or placebo in addition to continued angiotensin-converting enzyme inhibition and/or angiotensin receptor blockade. The composite primary outcome was the time to doubling of serum creatinine, ESRD, or death. Secondary outcomes included changes in albumin-to-creatinine ratio (ACR) and cardiovascular outcomes. We terminated the trial prematurely after a median follow-up of 4 months (maximum 16 months) because of an excess of cardiovascular events with avosentan. We did not detect a difference in the frequency of the primary outcome between groups. Avosentan significantly reduced ACR: In patients who were treated with avosentan 25 mg/d, 50 mg/d, and placebo, the median reduction in ACR was 44.3, 49.3, and 9.7%, respectively. Adverse events led to discontinuation of trial medication significantly more often for avosentan than for placebo (19.6 and 18.2 versus 11.5% for placebo), dominated by fluid overload and congestive heart failure; death occurred in 21 (4.6%; P ϭ 0.225), 17 (3.6%; P ϭ 0.194), and 12 (2.6%), respectively. In conclusion, 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.

Addition of Atrasentan to Renin-Angiotensin System Blockade Reduces Albuminuria in Diabetic Nephropathy

“…9 A recent clinical trial with avosentan, an endothelin receptor antagonist that likely blocked both ET A R and ET B R, reduced albuminuria in patients with macroalbuminuria and type 2 diabetes, although significant safety concerns related to fluid retention resulted in early trial termination. 10 Atrasentan is a highly selective ET A R antagonist with an approximate 1800:1 selectivity for ET A R to ET B R. 11 Such ET A R, as opposed to ET B R, selectivity may be ideal for targeting the ET pathogenicity in DN. The purpose of this randomized, double-blind, placebo-controlled clinical trial was to prospectively evaluate the efficacy and safety of atrasentan for the reduction of residual albuminuria in subjects with type 2 DN who were receiving stable doses of angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs).…”

Diabetic nephropathy: newer therapeutic perspectives

“…ASCEND, a multicentre RCT, was designed to study the effects of avosentan, an endothelin antagonist, on composite renal outcomes including albuminuria [11]. 1392 subjects were randomized to receive placebo and avosentan 25 mg or 50 mg.…”

“…However, there is emerging evidence on newer drugs that could mitigate deleterious effects of diabetes on renal function. DN has been an extremely active area of pharmacological research in the last decade, and multiple drugs targeting various pathways have been studied with only a few encouraging results [11-13]. This review attempts to summarize some of the newer and clinically significant pharmacotherapy.…”

Therapeutic Modalities in Diabetic Nephropathy: Standard and Emerging Approaches

“…200 When the avosentan-treated patients were followed up after 3-and 6-months in the ASCEND (Avosentan on Doubling of Serum Creatinine, End-stage Renal Disease and Death in Diabetic Nephropathy) phase III clinical trial, substantial reductions in albuminuria were seen. 201 Unfortunately, drugrelated adverse events including fluid retention, led to early termination of the ASCEND trial. 201 Much more work will be needed to determine the safety and effectiveness of ET antagonists in preventing or treating DN in humans.…”

“…201 Unfortunately, drugrelated adverse events including fluid retention, led to early termination of the ASCEND trial. 201 Much more work will be needed to determine the safety and effectiveness of ET antagonists in preventing or treating DN in humans.…”