Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease
Author:
Zhou Zien12ORCID, Jardine Meg J.13, Li Qiang1, Neuen Brendon L.1ORCID, Cannon Christopher P.4, de Zeeuw Dick5, Edwards Robert6, Levin Adeera7, Mahaffey Kenneth W.8, Perkovic Vlado19, Neal Bruce11011ORCID, Lindley Richard I.1213ORCID, Ahuad Guerrero Rodolfo Andres, Aizenberg Diego, Albisu Juan Pablo, Alvarisqueta Andres, Bartolacci Ines, Berli Mario Alberto, Bordonava Anselmo, Calella Pedro, Cantero Maria Cecilia, Cartasegna Luis Rodolfo, Cercos Esteban, Coloma Gabriela Cecilia, Colombo Hugo, Commendatore Victor, Cuadrado Jesus, Cuneo Carlos Alberto, Cusumano Ana Maria, Douthat Walter Guillermo, Dran Ricardo Dario, Farias Eduardo, Fernandez Maria Florencia, Finkelstein Hernan, Fragale Guillermo, Fretes Jose Osvaldo, Garcia Nestor Horacio, Gastaldi Anibal, Gelersztein Elizabeth, Glenny Jorge Archibaldo, Gonzalez Joaquin Pablo, del Carmen Gonzalez Colaso Patricia, Goycoa Claudia, Greloni Gustavo Cristian, Guinsburg Adrian, Hermida Sonia, Juncos Luis Isaias, Klyver Maria Isabel, Kraft Florencia, Krynski Fernando, Lanchiotti Paulina Virginia, Leon de la Fuente Ricardo Alfonso, Marchetta Nora, Mele Pablo, Nicolai Silvia, Novoa Pablo Antonio, Orio Silvia Ines, Otreras Fabian, Oviedo Alejandra, Raffaele Pablo, Resk Jorge Hector, Rista Lucas, Rodriguez Papini Nelson, Sala Jorgelina, Santos Juan Carlos, Schiavi Lilia Beatriz, Sessa Horacio, Smith Casabella Tomas, Ulla Maria Rosa, Valdez Maria, Vallejos Augusto, Villarino Adriana, Visco Virginia Esther, Wassermann Alfredo, Zaidman Cesar Javier, Cheung Ngai Wah, Droste Carolyn, Fraser Ian, Johnson David, Mah Peak Mann, Nicholls Kathy, Packham David, Proietto Joseph, Roberts Anthony, Roger Simon, Tsang Venessa, Abrão Raduan Roberto, Alves da Costa Fernando Augusto, Amodeo Celso, Andreotti Turatti Luiz Alberto, Bregman Rachel, Camelo Sanches Fernanda Cristina, Canani Luis Henrique, Chacra Antônio Roberto, Cunha Borges João Lindolfo, Cunha Vêncio Sérgio Alberto, da Silva Franco Roberto Jorge, d’Avila Domingos, de Souza Portes Evandro, de Souza Pedro, Deboni Luciane Mônica, Fraige Filho Fadlo, Geloneze Neto Bruno, Gomes Marcus, Keiko Kohara Suely, Keitel Elizete, Kerr Saraiva Jose Francisco, Kurtz Lisboa Hugo Roberto, Loss de Carvalho Contieri Fabiana, Milagres Rosângela, Montenegro Junior Renan, Moreira de Brito Claudia, Nasser Hissa Miguel, Nazario Sabbag Ângela Regina, Noronha Irene, Panarotto Daniel, Pecoits Filho Roberto, Pereira Márcio Antônio, Saporito Wladmir, Scafuto Scotton Antonio, Schuch Tiago, Simões de Almeida Roberto, Slompo Ramos Cássio, Soares Felício João, Thomé Fernando, Tibes Hachmann Jean Carlo, Yamada Sérgio, Yoiti Hayashida Cesar, Zanata Petry Tarissa Beatrice, Zanella Maria Teresa, Andreeva Viktoria, Angelova Angelina, Dimitrov Stefan, Genadieva Veselka, Genova-Hristova Gabriela, Hristozov Kiril, Kamenov Zdravko, Koundurdjiev Atanas, Lozanov Lachezar, Margaritov Viktor, Nonchev Boyan, Rangelov Rangel, Shinkov Alexander, Temelkova Margarita, Velichkova Ekaterina, Yakov Andrian, Aggarwal Naresh, Aronson Ronnie, Bajaj Harpreet, Cherney David, Chouinard Guy, Conway James, Cournoyer Serge, DaRoza Gerald, De Serres Sacha, Dubé François, Goldenberg Ronald, Gupta Anil, Gupta Milan, Henein Sam, Khandwala Hasnain, Leiter Lawrence, Madore François, McMahon Alan, Muirhead Norman, Pichette Vincent, Rabasa-Lhoret Remi, Steele Andrew, Tangri Navdeep, Torshizi Ali, Woo Vincent, Zalunardo Nadia, Fernández Montenegro María Alicia, Godoy Jorquera Juan Gonzalo, Medina Fariña Marcelo, Saavedra Gajardo Victor, Vejar Margarita, Chen Nan, Chen Qinkai, Gan Shenglian, Kong Yaozhong, Li Detian, Li Wenge, Li Xuemei, Lin Hongli, Liu Jian, Lu Weiping, Mao Hong, Ren Yan, Song Weihong, Sun Jiao, Sun Lin, Tu Ping, Wang Guixia, Yang Jinkui, Yin Aiping, Yu Xueqing, Zhao Minghui, Zheng Hongguang, Accini Mendoza Jose Luis, Arcos Edgar, Avendano Jorge, Diaz Ruiz Jorge Ernesto Andres, Garcia Ortiz Luis Hernando, Gonzalez Alexander, Hernandez Triana Eric, Higuera Juan Diego, Malaver Natalia, Molina de Salazar Dora Inés, Rosero Ricardo, Terront Lozano Monica Alexandra, Valderrama Cometa Luis, Valenzuela Alex, Vargas Alonso Ruben Dario, Villegas Ivan, Yupanqui Hernan, Bartaskova Dagmar, Barton Petr, Belobradkova Jana, Dohnalova Lenka, Drasnar Tomas, Ferkl Richard, Halciakova Katarina, Klokocnikova Vera, Kovar Richard, Lastuvka Jiri, Lukac Martin, Pesickova Satu, Peterka Karel, Pumprla Jiri, Rychlik Ivan, Saudek Frantisek, Tesar Vladimir, Valis Martin, Weiner Pavel, Zemek Stanislav, Alamartine Eric, Borot Sophie, Cariou Bertrand, Dussol Bertrand, Fauvel Jean-Pierre, Gourdy Pierre, Klein Alexandre, Le Meur Yannick, Penfornis Alfred, Roussel Ronan, Saulnier Pierre-Jean, Thervet Eric, Zaoui Philippe, Burst Volker, Faghih Markus, Faulmann Grit, Haller Hermann, Jerwan-Keim Reinhold, Maxeiner Stephan, Paschen Björn, Plassmann Georg, Rose Ludger, Gonzalez Orellana Ronaldo Arturo, Haase Franklin Paul, Moreira Diaz Juan Pablo, Ramirez Roca Luis Alberto, Sánchez Arenales Jose Antonio, 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Sazonova Olga, Shamkhalova Minara, Shutemova Elena, Shwartz Yuriy, Uriasyev Oleg, Vorobyev Sergey, Zateyshchikova Anna, Zateyshshikov Dmitry, Zykova Tatyana, Antic Slobodan, Djordjevic Miodrag, Kendereski Aleksandra, Lalic Katarina, Lalic Nebojsa, Popovic-Radinovic Vesna, Babikova Jana, Benusova Olga, Buganova Ingrid, Culak Jan, Dzupina Andrej, Dzuponova Jana, Fulop Peter, Ilavska Adriana, Martinka Emil, Ochodnicka Zuzana, Pella Daniel, Smatanova Iveta, Ahmed Fayzal, Badat Aysha, Breedt Johannes, Distiller Lawrence, Govender Vimladhevi, Govender Ravendran, Joshi Mukesh, Jurgens Jaco, Latiff Gulam, Lombard Landman, Mookadam Mohamed, Ngcakani Nomangesi, Nortje Hendrik, Oosthuizen Helena, Pillay-Ramaya Larisha, Prozesky Hans, Reddy Jeevren, Rheeder Paul, Seeber Mary, Chae Dong-Wan, Cho Young Min, Jeong In-Kyung, Kim Sin Gon, Kim Yeong Hoon, Kwon Hyuk-Sang, Kwon Min Jeong, Lee Byung-Wan, Lee JungEun, Lee Moon-Kyu, Nam Moon-Suk, Oh Kook-Hwan, Park Cheol-Young, Park Sun-Hee, Yoon Kun Ho, 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Affiliation:
1. The George Institute for Global Health, UNSW Sydney, Australia (Z.Z., M.J.J., Q.L., B.L.N., V.P., B.N.). 2. Department of Radiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, China (Z.Z.). 3. Concord Repatriation General Hospital, Sydney, Australia (M.J.J.). 4. Cardiovascular Division, Brigham and Women’s Hospital and Baim Institute for Clinical Research, Boston, MA (C.P.C.). 5. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, the Netherlands (D.d.Z.). 6. Janssen Research & Development, LLC, Raritan, NJ (R.E.). 7. Division of Nephrology, University of British Columbia, Vancouver, BC, Canada (A.L.). 8. Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, CA (K.W.M.). 9. Royal North Shore Hospital, Sydney, Australia (V.P.). 10. Charles Perkins Centre, University of Sydney, Australia (B.N.). 11. Imperial College London, London, United Kingdom (B.N.). 12. Westmead Applied Research Centre, University of Sydney, Sydney, Australia (R.I.L.). 13. The George Institute for Global Health, Sydney, Australia (R.I.L.).
Abstract
Background and Purpose:
Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus.
Methods:
CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis.
Results:
In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55–1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61–1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19–1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20–1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53–1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HR
pooled
, 0.96 [95% CI, 0.82–1.12]), ischemic stroke (HR
pooled
, 1.01 [95% CI, 0.89–1.14]), hemorrhagic stroke (HR
pooled
, 0.50 [95% CI, 0.30–0.83]), undetermined stroke (HR
pooled
, 0.86 [95% CI, 0.49–1.51]), and AF/AFL (HR
pooled
, 0.81 [95% CI, 0.71–0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (
P
=0.01), with protection in the lowest estimated glomerular filtration rate (<45 mL/min/1.73 m
2
]) subgroup (HR
pooled
, 0.50 [95% CI, 0.31–0.79]).
Conclusions:
Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms.
Registration:
URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT02065791.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Advanced and Specialised Nursing,Cardiology and Cardiovascular Medicine,Clinical Neurology
Cited by
77 articles.
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