SONAR results support atrasentan for preserving renal function in type 2 diabetes
medwireNews: The endothelin receptor antagonist atrasentan may reduce the risk for kidney disease progression among certain high-risk patients with type 2 diabetes and kidney disease, indicate findings from the SONAR trial.
Investigator Dick de Zeeuw (University of Groningen, the Netherlands) told delegates at the ISN World Congress of Nephrology 2019 in Melbourne, Victoria, Australia, that trial participants “were selected for a substantial albuminuria reduction and minimal clinical signs of sodium retention.”
The selection process involved an initial 6-week enrichment period in which 4711 adults with type 2 diabetes, an estimated glomerular filtration rate (eGFR) of 25–75 mL/min per 1.73 m², and a urine albumin-to-creatinine ratio (UACR) of 300–5000 mg/g, who had received stable treatment with renin–angiotensin system blockade for at least 4 weeks were given oral atrasentan 0.75 mg/day. The 2648 atrasentan responders – defined as those with at least a 30% reduction in UACR, no substantial fluid retention, and an increase in serum creatinine of no more than 0.5 mg/dL and 20% from baseline – then entered the randomized part of the trial.
As reported simultaneously at the congress and in The Lancet, 6.0% of the 1325 responders who were randomly assigned to continue atrasentan 0.75 mg/day experienced the primary composite renal endpoint – defined as doubling of serum creatinine or onset of end-stage kidney disease – over a median-follow up of 2.2 years, compared with 7.9% of the 1323 given placebo. These results translated into annual rates of 2.8% and 3.7%, respectively, and a significant hazard ratio (HR) of 0.65 favoring atrasentan.
The investigators note that the trial was terminated earlier than planned due to “much lower than expected” rates of the primary endpoint.
Participants in the atrasentan group were significantly less likely to experience a decline in eGFR of at least 50% (HR=0.73) and had a significantly lower risk for the cardiorenal composite outcome of doubling serum creatinine, end-stage kidney disease, cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (HR=0.80) compared with those given placebo.
Serious adverse events occurred significantly more frequently among people treated with atrasentan versus placebo (36.3 vs 32.6%), as did the treatment-emergent adverse events of fluid retention (36.6 vs 32.3%) and anemia (18.5 vs 10.3%), which the SONAR (Study of Diabetic Nephropathy with Atrasentan) investigators say “have been previously attributed to endothelin receptor antagonists.”
Rates of hospital admission for heart failure (3.5 vs 2.6%) and death (4.4 vs 3.9%) were also numerically higher in the atrasentan group, but the difference did not reach statistical significance.
Taken together, these results “suggest that endothelin antagonism could play a role in preventing kidney failure in diabetic patients with kidney disease,” study co-author Ricardo Correa-Rotter (National Medical Science and Nutrition Institute Salvador Zubirán, Mexico City) said in his presentation.
Writing in an accompanying comment, Katherine Tuttle (University of Washington, Seattle, USA) said that SONAR “demonstrates a turning point in trial innovation,” and “succeeded in shifting trial design to match patients with treatment on the basis of safety and response assessments during a prerandomisation enrichment period.”
Noting the positive findings from the CREDENCE trial of the sodium-glucose cotransporter (SGLT)2 inhibitor canagliflozin, she says that atrasentan, alongside SGLT2 inhibitors and glucagon-like peptide 1 agonists, “is poised to join the selection of drugs for treatment of patients with diabetes and chronic kidney disease.”
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