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Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

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@article{47f52745c2a44e80992537e7482c1e12,
title = "Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial",
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 m 2 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 m 2 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.",
keywords = "Administration, Oral, Adult, Aged, Aged, 80 and over, Atrasentan/administration & dosage, Creatinine/blood, Diabetes Mellitus, Type 2/drug therapy, Diabetic Nephropathies/blood, Double-Blind Method, Endothelin A Receptor Antagonists/administration & dosage, Female, Glomerular Filtration Rate, Humans, Male, Middle Aged, Renal Insufficiency, Chronic/blood, Serum Albumin, Human/urine, Treatment Outcome, Young Adult",
author = "Heerspink, {Hiddo J.L.} and Parving, {Hans Henrik} and Andress, {Dennis L.} and George Bakris and Ricardo Correa-Rotter and Hou, {Fan Fan} and Kitzman, {Dalane W.} and Donald Kohan and Hirofumi Makino and McMurray, {John J.V.} and Melnick, {Joel Z.} and Miller, {Michael G.} and Pergola, {Pablo E.} and Vlado Perkovic and Sheldon Tobe and Tingting Yi and Melissa Wigderson and {de Zeeuw}, Dick and Alicia Elbert and Augusto Vallejos and Andres Alvarisqueta and Laura Maffei and Luis Juncos and {de Arteaga}, Javier and Gustavo Greloni and Eduardo Farias and Alfredo Zucchini and Daniel Vogel and Ana Cusumano and Juan Santos and Margaret Fraenkel and Martin Gallagher and Tim Davis and Shamasunder Acharya and Duncan Cooke and Michael Suranyi and Simon Roger and Nigel Toussaint and Carol Pollock and Doris Chan and Stephen Stranks and Richard MacIsaac and Zoltan Endre and Alice Schmidt and Rudolf Prager and Gert Mayer and Xavier Warling and Michel Jadoul and Peter Rossing and Kim, {Min Seon} and {SONAR Committees and Investigators}",
note = "Copyright {\circledC} 2019 Elsevier Ltd. All rights reserved.",
year = "2019",
month = "5",
day = "11",
doi = "10.1016/S0140-6736(19)30772-X",
language = "English",
volume = "393",
pages = "1937--1947",
journal = "Lancet",
issn = "0140-6736",
publisher = "The/Lancet Publishing Group",
number = "10184",

}

RIS

TY - JOUR

T1 - Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR)

T2 - a double-blind, randomised, placebo-controlled trial

AU - Heerspink, Hiddo J.L.

AU - Parving, Hans Henrik

AU - Andress, Dennis L.

AU - Bakris, George

AU - Correa-Rotter, Ricardo

AU - Hou, Fan Fan

AU - Kitzman, Dalane W.

AU - Kohan, Donald

AU - Makino, Hirofumi

AU - McMurray, John J.V.

AU - Melnick, Joel Z.

AU - Miller, Michael G.

AU - Pergola, Pablo E.

AU - Perkovic, Vlado

AU - Tobe, Sheldon

AU - Yi, Tingting

AU - Wigderson, Melissa

AU - de Zeeuw, Dick

AU - Elbert, Alicia

AU - Vallejos, Augusto

AU - Alvarisqueta, Andres

AU - Maffei, Laura

AU - Juncos, Luis

AU - de Arteaga, Javier

AU - Greloni, Gustavo

AU - Farias, Eduardo

AU - Zucchini, Alfredo

AU - Vogel, Daniel

AU - Cusumano, Ana

AU - Santos, Juan

AU - Fraenkel, Margaret

AU - Gallagher, Martin

AU - Davis, Tim

AU - Acharya, Shamasunder

AU - Cooke, Duncan

AU - Suranyi, Michael

AU - Roger, Simon

AU - Toussaint, Nigel

AU - Pollock, Carol

AU - Chan, Doris

AU - Stranks, Stephen

AU - MacIsaac, Richard

AU - Endre, Zoltan

AU - Schmidt, Alice

AU - Prager, Rudolf

AU - Mayer, Gert

AU - Warling, Xavier

AU - Jadoul, Michel

AU - Rossing, Peter

AU - Kim, Min Seon

AU - SONAR Committees and Investigators

N1 - Copyright © 2019 Elsevier Ltd. All rights reserved.

PY - 2019/5/11

Y1 - 2019/5/11

N2 - 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 m 2 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 m 2 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.

AB - 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 m 2 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 m 2 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.

KW - Administration, Oral

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Atrasentan/administration & dosage

KW - Creatinine/blood

KW - Diabetes Mellitus, Type 2/drug therapy

KW - Diabetic Nephropathies/blood

KW - Double-Blind Method

KW - Endothelin A Receptor Antagonists/administration & dosage

KW - Female

KW - Glomerular Filtration Rate

KW - Humans

KW - Male

KW - Middle Aged

KW - Renal Insufficiency, Chronic/blood

KW - Serum Albumin, Human/urine

KW - Treatment Outcome

KW - Young Adult

UR - http://www.scopus.com/inward/record.url?scp=85065234142&partnerID=8YFLogxK

U2 - 10.1016/S0140-6736(19)30772-X

DO - 10.1016/S0140-6736(19)30772-X

M3 - Journal article

VL - 393

SP - 1937

EP - 1947

JO - Lancet

JF - Lancet

SN - 0140-6736

IS - 10184

ER -

ID: 58478661