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.
Bibliographical noteFunding Information:
HJLH, DLA, GB, RC-R, F-FH, DWK, DK, HM, JJVM, VP, and ST were members of the SONAR study steering committee. HJLH serves as a consultant for AbbVie, Astellas, AstraZeneca, Boehringer Ingelheim, Fresenius, Gilead, Janssen, Merck, Mundi Pharma, and Mitsubishi Tanabe. H-HP was the co-chair of the SONAR study steering committee and serves as a consultant for AbbVie. DLA is a former employee of AbbVie and currently provides independent nephrology consulting services. GB was a study investigator for the SONAR study; he is on the steering committees of CREDENCE, CALM-2, and FIDELIO and is principal investigator of FIDELIO; he is a consultant for Bayer, Relypsa, Janssen, Merck, and Vascular Dynamics. RC-R serves on advisory boards for Boehringer and AstraZeneca and has been a speaker for AstraZeneca, Boehringer Ingelheim, AbbVie, Takeda, Amgen, and Janssen. F-FH was a study investigator, and a consultant for and received honoraria from AbbVie and AstraZeneca. DWK was chair of the Event Adjudication Committee for SONAR; has received grant funding from Bayer, Novartis, and the National Institutes of Health, and has been a consultant for AbbVie, Bayer, Merck, Boehringer Ingelheim, Corvia, CinRx, GlaxoSmithKline (GSK), Duke Clinical Research Institute, St Luke's Medical Center, and AstraZeneca. HM is a consultant for Teijin and Boehringer Ingelheim and receives speaker honoraria from Boehringer Ingelheim. VP has served on Steering Committees for trials funded by AbbVie, Boehringer Ingelheim, GSK, Janssen, Novo Nordisk, Retrophin and Tricida; and has participated in scientific presentations or advisory boards with AbbVie, Astellas, AstraZeneca, Bayer, Baxter, Brisol-Myers Squibb, Boehringer Ingelheim, Dimerix, Durect, Eli Lilly, Gilead, GSK, Janssen, Merck, Mitsubishi Tanabe, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa, Retrophin, Sanofi, Servier, and Tricida. ST was a study investigator in SONAR; and participates on a steering committee for Bayer Fidelio/Figaro studies, and speaker's bureaux with Servier and Pfizer. DdZ was a co-chair of the SONAR study steering committee; serves on advisory boards or is a speaker for Bayer, Boehringer Ingelheim, Fresenius, Mundipharma, and Mitsubishi Tanabe; participates in steering committees or is a speaker for AbbVie and Janssen; and is on the data safety and monitoring committees for Bayer. JZM, MGM, TY, and MW are employees of AbbVie, receiving stock or stock options. PEP was a SONAR study investigator; has been a consultant for and received personal fees from AbbVie, Akebia, AstraZeneca, Keryx, Reata, ExThera, and Vifor; and has served on advisory boards for Akebia, Keryx, and Vifor; his institution and employer, Renal Associates PA, has received research support from many pharmaceutical companies for his work as a principal investigator.
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