Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease
Authors: Zhou Zien , Jardine Meg J. , Li Qiang , Neuen Brendon L. , Cannon Christopher P. , de Zeeuw Dick , Edwards Robert , Levin Adeera , Mahaffey Kenneth W. , Perkovic Vlado , Neal Bruce , Lindley Richard I. , 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 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, Osipova Irina , Raskina Tatiana , Samoylova Yulia , 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 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Ivan , Godlevska Olga , Golovchenko Oleksandr , Gyrina Olga , Kazmirchuk Anatoliy , Kolesnyk Mykola , Komisarenko Iuliia , Korzh Oleksii , Kravchun Nonna , Legun Oleg , Mankovskyy Borys , Martynyuk Liliya , Mostovoy Yuriy , Pashkovska Nataliia , Pererva Larysa , Pertseva Tetyana , Samoylov Oleksandr , Smirnov Ivan , Svyshchenko Yevgeniya , Tomashkevych Halyna , Topchii Ivan , Tryshchuk Nadiya , Tseluyko Vira , Vizir Vadym , Vlasenko Maryna , Zlova Tetiana , Zub Liliia , Abusnana Salah , Railey Mohamed , Abouglila Kamal , Ainsworth Paul , Ali Zishan , Arutchelvam Vijayaraman , Barnard Maria , Bellary Srikanth , Davies Emyr , Davies Mark , Davies Simon , Dawson Alison , El Kossi Mohsen , English Patrick , Fraser Donald , Gnudi Luigi , Gunstone Anthony , Hall Timothy , Hanif Wasim , Jackson Alan , Johnson Andrew , Joseph Franklin , Krishnan Singhan , Kumwenda Mick , MacDougall Iain , Nixon Paul , O’Hare Joseph , Philip Sam , Ramtoola Shenaz , Saxena Manish , Sennik Davesh , Simon Godwin , Singh Baldev , Stephens Jeffrey , Strzelecka Anna , Symonds Rehan , Turner Wayne , Wahba Mona , Wakeling John , Wheeler David , Winocour Peter , Abdallah Joseph , Abdullah Raied , Abramowitz Matthew , Acosta Idalia , Aiello Joseph , Akright Laura , Akyea-Djamson Ayim , Alappan Rajendran , Alicic Radica , Al-Karadsheh Amer , Allison Dale Crawford , Arauz-Pacheco Carlos , Arfeen Shahabul , Arif Ahmed , Arvind Moogali , Atray Naveen , Awad Ahmed , Bakris George , Barnhill Peggy , Barranco Elizabeth , Barrera Carlos , Beacom Matthew , Behara Venkata , Belo Diogo , Bentley-Lewis Rhonda , Berenguer Ramon , Bermudez Lidia , Bernardo Marializa , Biscoveanu Mihaela , Bowman-Stroud Cynthia , Brandon Donald , Brusco Osvaldo , Busch Robert , Canaan Yamil , Chilito Alicia , Christensen Tom , Christiano Cynthia , Christofides Elena , Chuateco Caroucel , Cohen Kenneth , Cohen Robert , Cohen-Stein Debbie , Cook Charles , Coyne Daniel , Daboul Nizar , Darwish Riad , Daswani Adarsh , Deck Kenneth , Desouza Cyrus , Dev Devasmita , Dhillon Monika , Dua Sohan , Eder Frank , Elosegui Ana Maria , El-Shahawy Mohamed , Ervin John , Esquenazi Alberto , Evans John , Fishbane Steven , Frias Juan , Galindo-Ramos Eugenia , Galphin Claude , Ghazi Adline , Gonzalez Enrique , Gorson David , Gowda Anupama , Greco Barbara , Grubb Stephen , Gulati Rakesh , Hammoud Jamal , Handelsman Stuart , Hartman Israel , Hershon Kenneth , Hiser Daniel , Hon George , Jacob Radu , Jaime Maria , Jamal Aamir , Kaupke Charles , Keightley Gerald , Kern Elizabeth , Khanna Rakhi , Khitan Zeid , Kim Sun , Kopyt Nelson , Kovesdy Csaba , Krishna Gopal , Kropp Jeffrey (Jay) , Kumar Amrendra , Kumar Jayant , Kumar Neil , Kusnir Jorge , Lane Wendy , Lawrence Mary , Lehrner Lawrence , Lentz John , Levinson Dennis , Lewis Derek , Liss Kenneth , Maddux Andreas , Maheshwari Hiralal , Mandayam Sreedhar , Marar Isam , Mehta Bhasker , Middleton John , Mordujovich Jorge , Moreda Ramon , Moustafa Moustafa , Mujica Trenche Samuel , Narayanan Mohanram , Narvarte Javier , Nassar Tareq , Newman George , Nichol Brian , Nicol Philip , Nisnisan Josier , Nossuli A. Kaldun , Obialo Chamberlain , Olelewe Sarah , Oliver Michael , O’Shaughnessy Andrew , Padron John , Pankhaniya Rohit , Parker Reginald , Patel Devesh , Patel Gnyandev , Patel Nina , Pavon Humberto , Perez Armando , Perez Carlos , Perlman Alan , Pettis Karlton , Pharr Walter , Phillips Andrea , Purighalla Raman , Quesada-Suarez Luis , Ranjan Rajiv , Rastogi Sanjeev , Reddy Jakkidi , Rendell Marc , Rich Lisa , Robinson Michael , Rodriguez Hector , Rosas Sylvia , Saba Fadi , Sankaram Rallabhandi , Sarin Ravi , Schreiman Robert , Scott David , Sekkarie Mohamed , Sensenbrenner John , Shakeel Muhammad , Shanik Michael , Shaw Sylvia , Smith Stephen , Solomon Richard , Sprague Amy , Spry Leslie , Suchinda Pusadee , Sultan Senan , Surampudi Prasanth , Sussman Sherry , Tan Anjanette , Terrelonge Antonio , Thompson Michael , Trespalacios Fernando , Trippe Bruce , Trueba Pilar , Twahirwa Marcel , Updegrove John , Van Buren Peter , Vannorsdall Mark , Varghese Freemu , Velasquez-Mieyer Pedro , Ventrapragada Sailaja , Vukotic Goga , Wadud Khurram , Warren Mark , Watson Henry , Watts Ronald , Weiner Daniel , Welker James , Welsh Jean , Williams Shelley , Zaniewski-Singh Michelle 
Published: April 2021

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.