Avosentan for overt diabetic nephropathy.
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, placebo-controlled 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 = 0.225), 17 (3.6%; P = 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.
Mann
Johannes F E
JF
Schwabing General Hospital, and Department of Medicine IV, University of Erlangen and KfH Kidney Centre, Munich, Germany.
Green
Damian
D
Jamerson
Kenneth
K
Ruilope
Luis M
LM
Kuranoff
Susan J
SJ
Littke
Thomas
T
Viberti
Giancarlo
G
D000368:Aged; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000401:mortality; D018450:Disease Progression; D016232:Endothelins / Q000037:antagonists & inhibitors; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006333:Heart Failure / Q000139:chemically induced / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011507:Proteinuria / Q000188:drug therapy* / Q000401:mortality; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects*; D016896:Treatment Outcome; D014883:Water-Electrolyte Imbalance / Q000139:chemically induced / Q000401:mortality
D016232:Endothelins; D011725:Pyridines; D011743:Pyrimidines; C484919:Avosentan