Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Issue 10184 (11th May 2019)

• Record Type: Journal Article
• Authors: Heerspink, Hiddo J L; Parving, Hans-Henrik; Andress, Dennis L; Bakris, George; Correa-Rotter, Ricardo; Hou, Fan-Fan; Kitzman, Dalane W; Kohan, Donald; Makino, Hirofumi; McMurray, John J V; Melnick, Joel Z; Miller, Michael G; Pergola, Pablo E; Perkovic, Vlado; Tobe, Sheldon; Yi, Tingting; Wigderson, Melissa; de Zeeuw, Dick; Elbert, Alicia; Vallejos, Augusto; Alvarisqueta, Andres; Maffei, Laura; Juncos, Luis; de Arteaga, Javier; Greloni, Gustavo; Farias, Eduardo; Zucchini, Alfredo; Vogel, Daniel; Cusumano, Ana; Santos, Juan; Fraenkel, Margaret; Gallagher, Martin; Davis, Tim; Acharya, Shamasunder; Cooke, Duncan; Suranyi, Michael; Roger, Simon; Toussaint, Nigel; Pollock, Carol; Chan, Doris; Stranks, Stephen; MacIsaac, Richard; Endre, Zoltan; Schmidt, Alice; Prager, Rudolf; Mayer, Gert; Warling, Xavier; Jadoul, Michel; Hougardy, Jean; Vercammen, Chris; Van Vlem, Bruno; Gillard, Pieter; Costa e Forti, Adriana; Borges, Joao Lindolfo; Santos Canani, Luis; Eliaschewitz, Freddy; Leite, Silmara; Fraige Filho, Fadlo; Paschoalin, Raphael; Moura Neto, Jose Andrade; Deboni, Luciane; de Lourdes Noronha, Irene; Cercato, Cintia; Prompt, Carlos Alberto; Zanella, Maria; Rassi, Nelson; D'Avila, Domingos; Milagres, Rosangela; Felicio, Joao; Pecoits Filho, Roberto; Riella, Miguel Carlos; Salles, Joao; Keitel, Elizete; Draibe, Sergio; Amodeo, Celso; Youmbissi, Joseph; Roy, Louise; Cournoyer, Serge; Jolly, Shivinder; Pichette, Vincent; Nesrallah, Gihad; Bajaj, Harpreet Singh; Khandwala, Hasnain; Aronson, Ronnie; Goluch, Richard; Tam, Paul; Rabbat, Christian; Tobe, Sheldon; Bailey, Gordon; Chow, Stephen; Castillo, Alvaro; Danin Vargas, Alfredo; Gonzalez, Fernando; Munoz, Rodrigo; Gutierrez, Vicente; Godoy, Gonzalo; Zhao, Hongwen; Liu, Zhangsuo; Zhao, Minghui; Guo, Xiaohui; Su, Benli; Fu, Shuxia; Xu, Yan; Yang, Jinkui; Shi, Bingyin; Xiao, Guanqing; Shi, Wei; Hao, Chuanming; Xing, Changying; Hou, Fanfan; Luo, Qun; Li, Yuxiu; Ji, Linong; Zuo, Li; Wang, Song; Ni, Zhaohui; Ding, Guohua; Chen, Nan; Zhao, Jiajun; Jia, Weiping; Yu, Shengqiang; Weng, Jian; Xu, Gang; Fu, Ping; Sun, Shiren; Liu, Bicheng; Ding, Xiaoqiang; Rychlik, Ivan; Oplustilova, Alexandra; Bartaskova, Dagmar; Honova, Vaclava; Chmelickova, Hana; Petr, Martin; Bucek, Petr; Tesar, Vladimir; Zahumensky, Emil; Povlsen, Johan; Egstrup, Kenneth; Oczachowska-Kulik, Anna; Rossing, Peter; Lahtela, Jorma; Strand, Jorma; Kantola, Ilkka; Petit, Catherine; Combe, Christian; Zaoui, Philippe; Esnault, Vincent; Urena Torres, Pablo; Halimi, Jean-Michel; Dussol, Bertrand; Bieler, Tasso; Budde, Klemens; Dellanna, Frank; Segiet, Thomas; Kosch, Christine; Schmidt-Guertler, Hans; Schenkenberger, Isabelle; Vielhauer, Volker; Pistrosch, Frank; Alscher, Mark; Hasslacher, Christoph; Hugo, Christian; Muehlfeld, Anja; Wanner, Christoph; Passadakis, Ploumis; Apostolou, Theofanis; Tentolouris, Nikolaos; Stefanidis, Ioannis; Mavromatidis, Konstantinos; Liakopoulos, Vasilios; Goumenos, Dimitrios; Siamopoulos, Konstantinos; Yeung, Vincent; Ozaki, Risa; Fung, Samuel; Tan, Kathryn; Tang, Sydney; Lui, Sing Leung; Cheung, Siu Fai; Sreenan, Seamus; Eustace, Joseph; O'Shea, Donal; Lavin, Peter; Stack, Austin; Yagil, Yoram; Wainstein, Julio; Knobler, Hilla; Cohen, Josef; Kenis, Irina; Daoud, Deeb; Bar-Dayan, Yosefa; Frajewicki, Victor; Adawi, Faiad; Gesualdo, Loreto; Santoro, Domenico; Marino, Francesco; Galfre, Andrea; Brunati, Chiara; Ruggenenti, Piero; Rombola, Giuseppe; Pugliese, Giuseppe; Ravera, Maura; Malberti, Fabio; Pontoriero, Giuseppe; Rampino, Teresa; De Cosmo, Salvatore; Esposito, Ciro; Nappi, Felice; Abaterusso, Cataldo; Conte, Giuseppe; Panichi, Vincenzo; Lauro, Davide; Capasso, Giovambattista; Russo, Domenico; Anzai, Jiichi; Naka, Motoji; Ato, Keita; Tsujimoto, Tetsuro; Nimura, Toshinori; Nakashima, Eitaro; Takeda, Tetsuro; Fujii, Shinya; Kobayashi, Kunihisa; Iwaoka, Hideaki; Nagayama, Koji; Harada, Hiroyuki; Maeda, Hajime; Kishimoto, Rui; Iitsuka, Tadashi; Itabashi, Naoki; Furuya, Ryuichi; Maeda, Yoshitaka; Yamada, Daishiro; Sasaki, Nobuhiro; Sasaki, Hiromitsu; Ueda, Shinichiro; Kashihara, Naoki; Watanabe, Shuichi; Nakamura, Takehiro; Kanai, Hidetoshi; Makita, Yuichiro; Ono, Keiko; Iehara, Noriyuki; Goto, Daisuke; Kosuge, Keiichiro; Tsuchida, Kenichi; Sato, Toshiaki; Sekikawa, Takashi; Okamoto, Hideki; Tanaka, Tsuyoshi; Ikeda, Naoko; Tadika, Takenobu; Mukasa, Koji; Osonoi, Takeshi; Hirano, Fuminori; Nishimura, Motonobu; Yambe, Yuko; Tanaka, Yukio; Ujihara, Makoto; Sakai, Takashi; Imura, Mitsuo; Umayahara, Yutaka; Makino, Shinya; Nakazawa, Jun; Yamaguchi, Yukinari; Kashine, Susumu; Miyaoka, Hiroaki; Suzuki, Katsunori; Inoue, Toshihiko; Nagai, Sou; Sato, Nobuyuki; Yamamoto, Masahiro; Taya, Noriyasu; Fujita, Akira; Matsutani, Akira; Shibagaki, Yugo; Sato, Yuichi; Yamauchi, Akira; Tsutsui, Masahiro; Ishiko, Tamayo; Kaneko, Shizuka; Azuma, Nobuyuki; Matsuda, Hirofumi; Hashiguchi, Yasuhiro; Onishi, Yukiko; Tokui, Mikiya; Matsuhisa, Munehide; Kiyosue, Arihiro; Shinoda, Junji; Ishikawa, Kazuo; Ahmad, Ghazali; Vijayasingham, Shalini; Aziz, Nor Azizah; Hussein, Zanariah; Fung, Yin Khet; Hassan, Wan Hasnul Halimi Wan; Wong, Hin Seng; Goh, Bak Leong; Ali, Norhaliza Mohd; Merican, Nor Shaffinaz Yusuf Azmi; Vaithilingam, Indralingam; Nik Ahmad, Nik Nur Fatnoon; Adam, Noor; Sukor, Norlela; Vengadasalam, V Paranthaman P; Abdul Kadir, Khalid; Mohamed, Mafauzy; Renoirte Lopez, Karina; Leguizamo-Dimas, Aniceto; Chew Wong, Alfredo; Chevaile-Ramos, Jose; Gonzalez Gonzalez, Jose; Rico Hernandez, Raul; Nino-Cruz, Jose; Sauque Reyna, Leobardo; Gonzalez-Galvez, Guillermo; Madero Rovalo, Magdalena; Bochicchio-Ricardelli, Tomasso; Aldrete, Jorge; Carranza-Madrigal, Jaime; Vogt, Liffert; Smak Gregoor, Peter; Barendregt, JNM; Luik, Peter; Gansevoort, Ronald; Laverman, Gozewijn; Pilmore, Helen; Lunt, Helen; Baker, John; Miller, Steven; Rabindranath, Kannaiyan; Zapata-Rincon, Luis; Vargas-Gonzales, Rolando; Calderon Ticona, Jorge; Dextre Espinoza, Augusto; Burga Nunez, Jose; Zea-Nunez, Carlos Antonio; Herrada Orue, Benjamin; Medina-Santander, Boris; Delgado-Butron, Cesar; Farfan-Aspilcueta, Julio; Mazur, Stanislaw; Necki, Miroslaw; Wruk, Michal; Klodawska, Katarzyna; Popenda, Grazyna; Skokowska, Ewa; Arciszewska, Malgorzata; Wiecek, Andrzej; Ciechanowski, Kazimierz; Nowicki, Michal; Birne, Rita; Cabrita, Antonio; Ramos, Aura; Antunes Ferreira, Manuel Anibal; Matta Fontanet, Evelyn; Alcantara-Gonzalez, Altagracia Aurora; Comulada-Rivera, Angel; Galindo Ramos, Eugenia; Cangiano, Jose; Quesada-Suarez, Luis; Calderon Ortiz, Ricardo; Vazquez-Tanus, Jose; Burgos-Calderon, Rafael; Rosado, Carlos; Hancu, Nicolae; Pintilei, Ella; Mistodie, Cristina; Bako, Gabriel; Ionutiu, Lavinia; Petrica, Ligia; Timar, Romulus; Tuta, Liliana; Duma, Livia; Tutescu, Adriana; Ivanova, Svetlana; Essaian, Ashot; Zrazhevskiy, Konstantin; Tomilina, Natalia; Smolyarchuk, Elena; Kuzin, Anatoly; Lantseva, Olga; Karpova, Irina; Shamkhalova, Minara; Liberanskaya, Natalia; Yavdosyuk, Andrey; Shvarts, Yuri; Bardymova, Tatiana; Blagoveshchenskaya, Olga; Solovev, Oleg; Rechkova, Elena; Pikalova, Natalia; Pavlova, Maria; Kolmakova, Elena; Sayfutdinov, Rustam; Villevalde, Svetlana; Koziolova, Natalya; Martynenko, Vladimir; Marasaev, Vyacheslav; Maksudova, Adelya; Sigitova, Olga; Mordovin, Viktor; Klimontov, Vadim; Samoylova, Yulia; Karonova, Tatiana; Yeoh, Lee Ying; Teo, Boon Wee; Foo, Marjorie Wai Yin; Liew, Adrian; Tkac, Ivan; Oroszova, Aniko; Fekete, Jozef; Rosenberger, Jaroslav; Obetkova, Ida; Fulopova, Alla; Kolesarova, Eva; Raslova, Katarina; Smolko, Peter; Oksa, Adrian; Distiller, Larry; Trokis, Julien; Adams, Luthando; Makan, Hemant; Ramlachan, Padaruth; Mitha, Essack; Coetzee, Kathleen; Punt, Zelda; Bhorat, Qasim; Naiker, Puvenesvari; Ellis, Graham; Van Zyl, Louis; Lee, Kwan Woo; Kim, Min Seon; Yoo, Soon-Jib; Yoon, Kun Ho; Cho, Yong-Wook; Park, Tae-Sun; Kim, Sang Yong; Choi, Moon-Gi; Oh, Tae Keun; Lee, Kang-Wook; Shon, Ho Sang; Suh, Sung Hwan; Kim, Byung-Joon; Doo-Man, Kim; Yi, Joo Hark; Lee, Sang Ah; Cho, Ho Chan; Kim, Sin-Gon; Cha, Dae-Ryong; Seo, Ji A; Choi, Kyung Mook; Woo, Jeong-Taek; Ahn, Kyu Jeung; Lee, Jae Hyuk; Kim, In-Joo; Lee, Moon-Kyu; Jang, Hak Chul; Park, Kyong-Soo; Kim, Beom Seok; Mok, Ji Oh; Shin, Mijung; Yoon, Sun Ae; Nam-Goong, Il-Seong; Chung, Choon Hee; Yu, Tae Yang; Lee, Hyoung Woo; Soto Gonzalez, Alfonso; Almirall, Jaume; Egido, Jesus; Calero Gonzalez, Francesca; Fernandez Fresnedo, Gema; Valera Cortes, Ildefonso; Praga Terente, Manuel; Garcia Mendez, Isabel; Navarro Gonzalez, Juan; Herrero Calvo, Jose; Cigarran Guldris, Secundino; Prieto Velasco, Mario; Minguela Pesquera, Jose Ignacio; Galan, Antonio; Pascual, Julio; Marques Vidas, Maria; Martins Munoz, Judith; Rodriguez-Perez, Jose; Castro-Alonso, Cristina; Bonet Sol, Josep; Seron, Daniel; Fernandez Giraldez, Elvira; Arrieta Lezama, Javier; Montero, Nuria; Hernandez-Jaras, Julio; Santamaria Olmo, Rafael; Molas Coten, Jose Ramon; Hellberg, Olof; Fellstrom, Bengt; Bock, Andreas; Pei, Dee; Lin, Ching-Ling; Tien, Kai-Jen; Chen, Ching-Chu; Huang, Chien-Ning; Jiang, Ju-Ying; Wu, Du-An; Chu, Chih-Hsun; Tseng, Shih-Ting; Chen, Jung-Fu; Bau, Cho-Tsan; Sheu, Wayne; Wu, Mai-Szu; Sari, Ramazan; Sezer, Siren; Yildiz, Alaattin; Satman, Ilhan; Kalender, Betul; Mankovskyy, Borys; Fushtey, Ivan; Stanislavchuk, Mykola; Kolenyk, Mykola; Dudar, Iryna; Zolotaikina, Viktoriia; Abrahamovych, Orest; Kostynenko, Tetyana; Petrosyan, Olena; Kuskalo, Petro; Galushchak, Olga; Legun, Oleg; Topchii, Ivan; Martynyuk, Liliya; Stryzhak, Vasyl; Panina, Svitlana; Tkach, Sergii; Korpachev, Vadym; Maxwell, Peter; Gnudi, Luigi; Kon, Sui Phin; Tindall, Hilary; Kalra, Phillip; Mark, Patrick; Patel, Dipesh; El-Shahawy, Mohamed; Bai, Liqun; Nica, Romanita; Lien, Yeong-Hau; Menefee, Judson; Busch, Robert; Miller, Alan; Ahmed, Azazuddin; Arif, Ahmed; Lee, Joseph; Desai, Sachin; Bansal, Shweta; Bentsianov, Marie; Belledonne, Mario; Jere, Charles; Gaona, Raul; Greenwood, Gregory; Brusco, Osvaldo; Boiskin, Mark; Belo, Diogo; Minasian, Raffi; Atray, Naveen; Lawrence, Mary; Taliercio, John; Pergola, Pablo; Scott, David; Alvarez, German; Marder, Bradley; Powell, Thomas; Bakdash, Wa'el; Stoica, George; McFadden, Christopher; Rendell, Marc; Wise, Jonathan; Jones, Audrey; Jardula, Michael; Madu, Ivy-Joan; Varghese, Freemu; Tulloch, Brian; Ahmed, Ziauddin; Hames, Melanie; Nazeer, Imran; Shahid, Newman; John, Rekha; Montero, Manuel; Fitz-Patrick, David; Phillips, Lawrence; Guasch, Antonio; Christofides, Elena; Gundroo, Aijaz; Amin, Mohammad; Bowman-Stroud, Cynthia; Link, Michael; Mulloy, Laura; Nammour, Michael; Lalwani, Tarik; Hanson, Lenita; Whaley-Connell, Adam; Herman, Lee; Chatha, Rupi; Osama, Sayed; Liss, Kenneth; Kayali, Zeid; Bhargava, Anuj; Israel, Ezra; Peguero-Rivera, Alfredo; Fang, Michael; Slover, Judith; Barengolts, Elena; Flores, Jose; Muoneke, Rosemary; Savin, Virginia; Awua-Larbi, Stella; Levine, Andrew; Newman, George; Golestaneh, Laden; Bohm, Guillermo; Reisin, Efrain; Cruz, Lucita; Weiss, Robert; Zieve, Franklin; Horwitz, Edward; Chuang, Peale; Mersey, James; Manley, John; Graf, Ronald; Bedros, Fadi; Joshi, Sudhir; Frias, Juan; Assefi, Ali; O'Shaughnessy, Andrew; Brantley, Roman; Minga, Todd; Tietjen, David; Kantor, Samuel; Jamal, Aamir; Guadiz, Ramon; Hershon, Kenneth; Bressler, Peter; Kopyt, Nelson; Cathcart, Harold; Bloom, Scott; Reichel, Ronald; Nakhle, Samer; Dulude, Emily; Tarkan, Joshua; Baker, Penelope; Zeig, Steven; Moya Hechevarria, Jaynier; Ropero-Cartier, Armando; De la Calle, Gilda; Doshi, Ankur; Saba, Fadi; Sligh, Teresa; Shaw, Sylvia; Kumar, Jayant; Szerlip, Harold; Bayliss, George; Perlman, Alan; Sakhrani, Lakhi; Gouge, Steven; Argoud, Georges; Acosta, Idalia; Elder, John; Joshi, Sucharit; Sensenbrenner, John; Vicks, Steven; Mangoo-Karim, Roberto; Galphin, Claude; Leon-Forero, Carlos; Gilbert, John; Brown, Eric; Ijaz, Adeel; Butt, Salman; Markell, Mariana; Arauz-Pacheco, Carlos; Sloan, Lance; Alvarado, Odilon; Jabbour, Serge; Simon, Eric; Rastogi, Anjay; James, Sam; Bakris, George; Hall, Karen; Melish, John; Dixon, Brad; Adolphe, Allen; Kovesdy, Csaba; Beddhu, Srinivasan; Solomon, Richard; Fernando, Ronald; Levin, Ellis; Thakar, Charuhas; Robey, Brooks; Goldfarb, David; Fried, Linda; Maddukuri, Geetha; Thomson, Stephen; Annand, Andrew; Kronfli, Saeed; Kalirao, Paramjit; Schmidt, Rebecca; Dahl, Neera; Blumenthal, Samuel; Weinstein, Debra; Ostergaard, Ove; Weinstein, Talia; Ono, Yasuhiro; Yalcin, Murat; Karim, Shahana;
• Is Part Of: Lancet. Volume 393:Issue 10184(2019)
• Page Start: 1937
• Page End: 1947
• Publication Date: 2019-05-11
• Subjects: Medicine -- Periodicals; Medicine -- Periodicals; Medicine; Medicine; Electronic journals; Periodicals; 610.5
• DOI: 10.1016/S0140-6736(19)30772-X
• Languages: English
• ISSNs: 0140-6736

Abstract

Summary: 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.