Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial - PubMed (original) (raw)
Randomized Controlled Trial
. 2019 May 11;393(10184):1937-1947.
doi: 10.1016/S0140-6736(19)30772-X. Epub 2019 Apr 14.
Hans-Henrik Parving 2, Dennis L Andress 3, George Bakris 4, Ricardo Correa-Rotter 5, Fan-Fan Hou 6, Dalane W Kitzman 7, Donald Kohan 8, Hirofumi Makino 9, John J V McMurray 10, Joel Z Melnick 3, Michael G Miller 3, Pablo E Pergola 11, Vlado Perkovic 12, Sheldon Tobe 13, Tingting Yi 3, Melissa Wigderson 3, Dick de Zeeuw 14; SONAR Committees and Investigators
Collaborators, Affiliations
- PMID: 30995972
- DOI: 10.1016/S0140-6736(19)30772-X
Randomized Controlled Trial
Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial
Hiddo J L Heerspink et al. Lancet. 2019.
Erratum in
- Department of Error.
[No authors listed] [No authors listed] Lancet. 2019 May 11;393(10184):1936. doi: 10.1016/S0140-6736(19)30939-0. Lancet. 2019. PMID: 31084966 No abstract available.
Abstract
Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes.
Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1·73 m2 of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days) or end-stage kidney disease (eGFR <15 mL/min per 1·73 m2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532.
Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4-2·9). 79 (6·0%) of 1325 patients in the atrasentan group and 105 (7·9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0·65 [95% CI 0·49-0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%) of 1325 patients in the atrasentan group and 34 (2·6%) of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85-2·07]; p=0·208). 58 (4·4%) patients in the atrasentan group and 52 (3·9%) in the placebo group died (HR 1·09 [95% CI 0·75-1·59]; p=0·65).
Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease.
Funding: AbbVie.
Copyright © 2019 Elsevier Ltd. All rights reserved.
Comment in
- A turning point for chronic kidney disease in diabetes.
Tuttle KR. Tuttle KR. Lancet. 2019 May 11;393(10184):1913-1914. doi: 10.1016/S0140-6736(19)30855-4. Epub 2019 Apr 14. Lancet. 2019. PMID: 30995973 No abstract available. - SONAR propels endothelin A receptor antagonists to success.
Pollock JS, Pollock DM. Pollock JS, et al. Nat Rev Nephrol. 2019 Aug;15(8):461-462. doi: 10.1038/s41581-019-0169-9. Nat Rev Nephrol. 2019. PMID: 31217497 No abstract available. - Atrasentan in patients with diabetes and chronic kidney disease.
Liu D, Liu Z. Liu D, et al. Lancet. 2020 Jan 25;395(10220):269-270. doi: 10.1016/S0140-6736(19)33021-1. Lancet. 2020. PMID: 31982064 No abstract available. - Atrasentan in patients with diabetes and chronic kidney disease.
Sepe V, Libetta C. Sepe V, et al. Lancet. 2020 Jan 25;395(10220):269. doi: 10.1016/S0140-6736(19)33020-X. Lancet. 2020. PMID: 31982065 No abstract available. - The SONAR study-is there a future for endothelin receptor antagonists in diabetic kidney disease?
Cahn A, Cernea S, Raz I. Cahn A, et al. Ann Transl Med. 2019 Dec;7(Suppl 8):S330. doi: 10.21037/atm.2019.09.117. Ann Transl Med. 2019. PMID: 32016048 Free PMC article. No abstract available.
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