Endothelin A receptor antagonist reduces renal events in selected high-risk T2DM patients
Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trialLiterature - Lambers Heerspink HJ, Parving H-H, Andress DL, et al., - The Lancet 2019. April 14. https://doi.org/10.1016/S0140-6736(19)30772-X
Presented during ISN-WCN 2019 in Melbourne, Australia on April 15, 2019.
Introduction and methods
People with type 2 diabetes (T2DM) are at high risk of developing end-stage kidney disease (ESKD) and CV complications, despite treatment, especially when albuminuria is high [1,2].
Endothelin receptor antagonists reduce albuminuria and blood pressure, but they can cause sodium retention. Avosentan is a non-selective endothelin receptor antagonist, and was studied at high dose in a trial that was stopped prematurely, because of an increased incidence of heart failure . Atrasentan is a more selective endothelin A receptor antagonist that was found to reduce albuminuria at low doses during short-term treatment, without causing significant fluid retention [4,5].
The Study of Diabetic Nephropathy with Atrasentan (SONAR) aimed to evaluate the efficacy and safety of atrasentan in patients with T2DM and chronic kidney disease (CKD). SONAR was a double-blind, randomized, placebo-controlled event-driven trial in adults with T2DM and eGFR 25-75 mL/min/1.73m², a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g, serum albumin ≥25 g/L, brain natriuretic peptide (BNP) concentration ≤200 pg/mL, serum potassium ≥3.5 mmol/L and systolic BP 110-180 mmHg. Those who showed evidence of fluid retention were excluded from SONAR, to minimize the risk of heart failure.
Responders to treatment were selected, based on the extent of reduction in albuminuria during an 6-week open-label period of treatment with atrasentan (0.75 mg orally once daily). After this enrichment period, responders to atrasentan were randomized to atrasentan or placebo. A subset of non-responders was also randomized to atrasentan or placebo, to evaluate whether the drug yielded renal benefit in this population.
The primary outcome was the efficacy to delay progression of CKD, defined as time from randomization to the first occurrence of any of the following components of a composite endpoint: doubling of serum creatinine, onset of ESKD (chronic dialysis for >90 days, kidney transplantation, eGFR <15 mL/min/1.73m², or death from kidney failure). The trial was stopped prematurely after it had become apparent that the rate of the primary outcome was much lower than anticipated.
At completion of the trial, 184 primary renal events had occurred (as opposed to the 425 aimed for). 2648 Patients out of 4711 who completed the enrichment period, were responders, and subsequently randomized to atrasentan (n=1325) or placebo (n=1323). 1020 Non-responders were randomized (n=509 to atrasentan, n=511 to placebo). Responders were followed for a median of 2.2 years (IQR: 1.4-2.9).
- UACR increased more during follow-up in the placebo group than the atrasentan group (difference: 33.6%, 95%CI: 29.1-38.2, P<0.0001). Increase in BNP was higher with atrasentan than with placebo (difference: 10.5%, 95%CI: 5.1-15.4, P<0.0001).
- The composite primary outcome occurred significantly less often in the atrasentan group (6.05% vs. 7.95%, HR: 0.65, 95%CI: 0.49-0.88, P=0.0047).
- The risk of doubling of serum creatinine was lower with atrasentan (HR: 0.61, 95%CI: 0.43-0.87, P=0.0055).HR for ESKD was 0.73 (95%CI: 0.53-1.01, P=0.06).
- The first secondary endpoint of ≥50% eGFR decline showed a risk reduction with atrasentan (HR: 0.73, 95%CI: 0.55-0.98, P=0.038).
- HR for the cardiorenal composite outcome was 0.80 (95%CI: 0.64-0.999, P=0.049), and no effect of atrasentan on the cardiovascular composite outcome was seen (HR: 0.88, 95%CI: 0.64-1.22, P=0.448).
- In the atrasentan group, the mean rate of change in eGFR during the trial was -2.4 mL/min/1.73m² per year, as compared with -3.1 mL/min/1.73m² per year (P=0.00049).
- Among non-responders, no significant effect of atrasentan on the primary renal outcome was seen (14.3% vs. 17.0%, HR: 0.75, 95%CI: 0.55-1.03, P=0.079).
- No interaction of being a responder or non-responder on the effect of atrasentan on the primary renal outcome was seen (P-interaction: 0.41). When the two groups were combined, the primary renal outcome was seen in 8.3% of patients treated with atrasentan and in 10.5% of the placebo group (HR: 0.72, 95%CI: 0.58-0.89, P=0.0023).
- Fluid retention and anemia were the most frequently reported adverse events, and more often in the atrasentan group. Serious adverse events occurred more frequently in the atrasentan group (36.3% vs. 32.6%). Admission for HF occurred in 3.5% of patients on atrasentan and in 2.6% of those on placebo (HR: 1.33, 95%CI: 0.85-2.07, P=0.208). 4.5% And 3.9% patients died, respectively (HR: 1.09, 95%CI: 0.75-1.59, P=0.65).
In a selected population of patients with T2DM and CKD, long-term low-dose treatment with atrasentan significantly reduced the risk of the primary composite renal outcome of doubling of serum creatinine or end-stage kidney disease, as compared with placebo. These findings were obtained after these patients had demonstrated a substantial UACR reduction and minimal clinical signs of sodium retention during short-term treatment with atrasentan. Thus, in clinical setting, strict interpretation of these results would imply that monitoring of UACR response after atrasentan initiation is required. This study was only adequately powered to assess the effect of atrasentan in responders, but the consistent effect in the combined analysis of responders and non-responders may suggest a broader indication. These findings inform the position of endothelin receptor antagonists as a future treatment option in diabetes patients at high renal and CV risk.