Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease
Zien Zhou, Meg Jardine, Qiang Li, Brendon L. Neuen, Christopher P. Cannon, Dick de Zeeuw, Robert Edwards, Adeera Levin, Kenneth W. Mahaffey, Vlado Perkovic, Bruce Neal, Richard I. Lindley, Rodolfo Andrés Ahuad Guerrero, Diego Aizenberg, Juan Pablo Albisu, Andres Alvarisqueta, Ines Bartolacci, Mario Alberto Berli, Anselmo P. Bordonava, Pedro Calella, Maria Cecilia Cantero, Luis R Cartasegna, Esteban Cercos, Gabriela Cecilia Coloma, Hugo Colombo, Víctor Commendatore, Jesus Cuadrado, Carlos Alberto Cuneo, Ana María Cusumano, Walter Douthat, Ricardo D. Dran, Eduardo Farias, María Florencia Fernández, Hernan Finkelstein, Guillermo Fragale, Jose Osvaldo Fretes, Néstor H. García, Anibal Gastaldi, Elizabeth Gelersztein, Jorge Archibaldo Glenny, Joaquin Pablo Gonzalez, Patricia del Carmen Gonzalez Colaso, Claudia Goycoa, Gustavo Greloni, Adrián Guinsburg, Sonia Hermida, Luis I. Juncos, Maria Isabel Klyver, Florencia Kraft, Fernando Krynski, Paulina Virginia Lanchiotti, Ricardo Alfonso Leon de la Fuente, Nora Marchetta, Pablo G. Mele, Silvia Nicolai, P. Novoa, Silvia Ines Orio, Fabián Otreras, Alejandra Oviedo, Pablo Raffaele, Jorge Hector Resk, Lucas Rista, Nelson Papini, Jorgelina Sala, Juan Carlos Santos, Lilia Beatriz Schiavi, Horacio Sessa, Tomas Smith Casabella, María Rosa Ulla, María Valdez, Augusto Vallejos, Adriana Villarino, Virginia Esther Visco, Alfredo Wassermann, Cesar Javier Zaidman, N. Wah Cheung, Carolyn Droste, I. W. Fraser, David W. Johnson, Peak Mann Mah, Kathy Nicholls, David Packham, Joseph Proietto, A. J. Roberts, Simon D. Roger, Venessa Tsang, Roberto Abrão Raduan, Fernando Costa, Celso Amodeo, Luiz Alberto Andreotti Turatti, Rachel Bregman, Fernanda Cristina Camelo Sanches, Luís Henrique Santos Canani, Antônio Roberto Chacra, João Borges, Sérgio Vencio, Roberto Jorge da Silva Franco, Domingos O. d’Avila, Evandro de Souza Portes, Pedro de Souza
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.