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Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis. Stroke Zhou, Z., Jardine, M. J., Li, Q., Neuen, B. L., Cannon, C. P., de Zeeuw, D., Edwards, R., Levin, A., Mahaffey, K. W., Perkovic, V., Neal, B., Lindley, R. I., CREDENCE Trial Investigators, Ahuad Guerrero, R. A., Aizenberg, D., Albisu, J. P., Alvarisqueta, A., Bartolacci, I., Berli, M. A., Bordonava, A., Calella, P., Cantero, M. C., Cartasegna, L. R., Cercos, E., Coloma, G. C., Colombo, H., Commendatore, V., Cuadrado, J., Cuneo, C. A., Cusumano, A. M., Douthat, W. G., Dran, R. D., Farias, E., Fernandez, M. F., Finkelstein, H., Fragale, G., Fretes, J. O., Garcia, N. H., Gastaldi, A., Gelersztein, E., Glenny, J. A., Gonzalez, J. P., Del Carmen Gonzalez Colaso, P., Goycoa, C., Greloni, G. C., Guinsburg, A., Hermida, S., Juncos, L. I., Klyver, M. I., Kraft, F., Krynski, F., Lanchiotti, P. V., Leon de la Fuente, R. A., Marchetta, N., Mele, P., Nicolai, S., Novoa, P. A., Orio, S. I., Otreras, F., Oviedo, A., Raffaele, P., Resk, J. H., Rista, L., Rodriguez Papini, N., Sala, J., Santos, J. C., Schiavi, L. B., Sessa, H., Smith Casabella, T., Ulla, M. R., Valdez, M., Vallejos, A., Villarino, A., Visco, V. E., Wassermann, A., Zaidman, C. J., Cheung, N. W., Droste, C., Fraser, I., Johnson, D., Mah, P. M., Nicholls, K., Packham, D., Proietto, J., Roberts, A., Roger, S., Tsang, V., Abrao Raduan, R., Alves da Costa, F. A., Amodeo, C., Andreotti Turatti, L. A., Bregman, R., Camelo Sanches, F. C., Canani, L. H., Chacra, A. R., Cunha Borges, J. L., Cunha Vencio, S. A., da Silva Franco, R. J., d'Avila, D., de Souza Portes, E., de Souza, P., Deboni, L. M., Fraige Filho, F., Geloneze Neto, B., Gomes, M., Keiko Kohara, S., Keitel, E., Kerr Saraiva, J. F., Kurtz Lisboa, H. R., Loss de Carvalho Contieri, F., Milagres, R., Montenegro Junior, R., Moreira de Brito, C., Nasser Hissa, M., Nazario Sabbag, A. 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V., Turcios Juarez, E., Csecsei, G., Csiky, B., Danos, P., Deak, L., Dudas, M., Harcsa, E., Keltai, K., Keresztesi, S., Kiss, K., Konyves, L., Major, L., Mileder, M., Molnar, M., Mucsi, J., Oroszlan, T., Ory, I., Paragh, G., Peterfai, E., Petro, G., Revesz, K., Takacs, R., Vangel, S., Vasas, S., Zsom, M., Oomman, A., Raju, S. B., Dewan, D., Fernando, M. E., Gopalakrishnan, N., Gracious, N., Alva, H., Jain, D., Keshavamurthy, C. B., Khullar, D., Sahay, M., Peringat, J., Prasad, N., Rao, K. S., Reddy, S., Melemadathil, S., Sudhakar, B., Vyasam, R. C., Bonadonna, R., Castellino, P., Ceriello, A., Chiovato, L., De Cosmo, S., De Nicola, L., Derosa, G., Di Carlo, A., Di Cianni, G., Frasca, G., Fuiano, G., Gambaro, G., Garibotto, G., Giorda, C., Malberti, F., Mandreoli, M., Mannucci, E., Orsi, E., Piatti, P., Santoro, D., Sasso, F. C., Serviddio, G., Stella, A., Trevisan, R., Veronelli, A. 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S., Jimenez Flores, F., Laviada Molina, H., Luna Ceballos, R. I., Martin Del Campo Blanco, B., Morales Franco, G., Moreno Loza, O. T., Mustieles Rocha, C., Obrador Vera, G., Orozco Castellanos, R., Peralta Calcaneo, J., Reyes Rosano, M. A., Rodriguez Pattzi, H., Rosas Guzman, J., Rucker Joerg, I. E., Saavedra Sanchez, S. B., Sanchez Mijangos, J. H., Serrano Sanson, P., Tamayo Y Orozco, J. A., Tellez Chavez, E., Valdes Cepeda, A., Venegas Carrillo, L., Villagordoa Mesa, J., Zamarripa Escobedo, R., Baker, J., Noonan, P., Scott, R., Walker, R., Watson, E., Williams, M., Young, S., Abejuela, Z., Agra, J., Aquitania, G., Caringal, C., Comia, R. S., Delos Santos, L., Gomez, O., Jimeno, C., Santos, F., Tan, G., Tolentino, M., Yao, C., Yap, Y. E., Ygpuara, M. D., Bijata-Bronisz, R., Hotlos, L., Januszewicz, A., Kaczmarek, B., Kaminska, A., Lazuka, L., Madej, A., Mazur, S., Mlodawska-Choluj, D., Nowicki, M., Orlowska-Kowalik, G., Popenda, G., Rewerska, B., Sowinski, D., Angelescu, L. M., Anghel, V., Avram, R., Busegeanu, M., Cif, A., Cosma, D., Crisan, C., Demian, L. D., Ferariu, I. E., Halmagyi, I., Hancu, N., Munteanu, M., Negru, D., Onaca, A. G., Petrica, L., Popa, A. R., Ranetti, A., Serafinceanu, C., Toarba, C., Agafyina, A., Barbarash, O., Barysheva, O., Chizhov, D., Dobronravov, V., Dreval, A., Glinkina, I., Grineva, E., Khirmanov, V., Kolmakova, E., Koroleva, T., Kvitkova, L., Marasaev, V., Mkrtumyan, A., Morugova, T., Nagibovich, G., Nagibovich, O., Nedogoda, S., Osipova, I., Raskina, T., Samoylova, Y., Sazonova, O., Shamkhalova, M., Shutemova, E., Shwartz, Y., Uriasyev, O., Vorobyev, S., Zateyshchikova, A., Zateyshshikov, D., Zykova, T., Antic, S., Djordjevic, M., Kendereski, A., Lalic, K., Lalic, N., Popovic-Radinovic, V., Babikova, J., Benusova, O., Buganova, I., Culak, J., Dzupina, A., Dzuponova, J., Fulop, P., Ilavska, A., Martinka, E., Ochodnicka, Z., Pella, D., Smatanova, I., Ahmed, F., Badat, A., Breedt, J., Distiller, L., Govender, V., Govender, R., Joshi, M., Jurgens, J., Latiff, G., Lombard, L., Mookadam, M., Ngcakani, N., Nortje, H., Oosthuizen, H., Pillay-Ramaya, L., Prozesky, H., Reddy, J., Rheeder, P., Seeber, M., Chae, D., Cho, Y. M., Jeong, I., Kim, S. G., Kim, Y. H., Kwon, H., Kwon, M. J., Lee, B., Lee, J., Lee, M., Nam, M., Oh, K., Park, C., Park, S., Yoon, K. H., Alvarez Garcia, P., Asmarats Mercadal, L., Barrios, C., Cereto Castro, F., Cigarran Guldris, S., Dominguez Lopez, M., Egido de Los Rios, J., Fernandez Fresnedo, G., Galan Serrano, A., Garcia, I., Gonzalez Martinez, F. J., Jodar Gimeno, J. E., Lopez Mendoza, M., Malek Marin, T., Morales Portillo, C., Munar Vila, M. A., Munoz Torres, M., Nieto Iglesias, J., Pantoja Perez, J., Perez Vera, M., Portoles Perez, J. M., Quesada Simon, M. A., Simo Canonge, R., Soto Gonzalez, A., Terns Riera, M., Tinahones Madueno, F. J., Velo Plaza, M., Chang, C., Chuang, L., Hsia, T., Hsieh, C., Hwang, S., Lin, C., Lu, Y., Sheu, W. H., Barna, O., Bilyk, S. D., Botsyurko, V., Dudar, I., Fushtey, I., Godlevska, O., Golovchenko, O., Gyrina, O., Kazmirchuk, A., Kolesnyk, M., Komisarenko, I., Korzh, O., Kravchun, N., Legun, O., Mankovskyy, B., Martynyuk, L., Mostovoy, Y., Pashkovska, N., Pererva, L., Pertseva, T., Samoylov, O., Smirnov, I., Svyshchenko, Y., Tomashkevych, H., Topchii, I., Tryshchuk, N., Tseluyko, V., Vizir, V., Vlasenko, M., Zlova, T., Zub, L., Abusnana, S., Railey, M., Abouglila, K., Ainsworth, P., Ali, Z., Arutchelvam, V., Barnard, M., Bellary, S., Davies, E., Davies, M., Davies, S., Dawson, A., El Kossi, M., English, P., Fraser, D., Gnudi, L., Gunstone, A., Hall, T., Hanif, W., Jackson, A., Johnson, A., Joseph, F., Krishnan, S., Kumwenda, M., MacDougall, I., Nixon, P., O'Hare, J., Philip, S., Ramtoola, S., Saxena, M., Sennik, D., Simon, G., Singh, B., Stephens, J., Strzelecka, A., Symonds, R., Turner, W., Wahba, M., Wakeling, J., Wheeler, D., Winocour, P., Abdallah, J., Abdullah, R., Abramowitz, M., Acosta, I., Aiello, J., Akright, L., Akyea-Djamson, A., Alappan, R., Alicic, R., Al-Karadsheh, A., Allison, D. C., Arauz-Pacheco, C., Arfeen, S., Arif, A., Arvind, M., Atray, N., Awad, A., Bakris, G., Barnhill, P., Barranco, E., Barrera, C., Beacom, M., Behara, V., Belo, D., Bentley-Lewis, R., Berenguer, R., Bermudez, L., Bernardo, M., Biscoveanu, M., Bowman-Stroud, C., Brandon, D., Brusco, O., Busch, R., Canaan, Y., Chilito, A., Christensen, T., Christiano, C., Christofides, E., Chuateco, C., Cohen, K., Cohen, R., Cohen-Stein, D., Cook, C., Coyne, D., Daboul, N., Darwish, R., Daswani, A., Deck, K., Desouza, C., Dev, D., Dhillon, M., Dua, S., Eder, F., Elosegui, A. M., El-Shahawy, M., Ervin, J., Esquenazi, A., Evans, J., Fishbane, S., Frias, J., Galindo-Ramos, E., Galphin, C., Ghazi, A., Gonzalez, E., Gorson, D., Gowda, A., Greco, B., Grubb, S., Gulati, R., Hammoud, J., Handelsman, S., Hartman, I., Hershon, K., Hiser, D., Hon, G., Jacob, R., Jaime, M., Jamal, A., Kaupke, C., Keightley, G., Kern, E., Khanna, R., Khitan, Z., Kim, S., Kopyt, N., Kovesdy, C., Krishna, G., Kropp, J. J., Kumar, A., Kumar, J., Kumar, N., Kusnir, J., Lane, W., Lawrence, M., Lehrner, L., Lentz, J., Levinson, D., Lewis, D., Liss, K., Maddux, A., Maheshwari, H., Mandayam, S., Marar, I., Mehta, B., Middleton, J., Mordujovich, J., Moreda, R., Moustafa, M., Mujica Trenche, S., Narayanan, M., Narvarte, J., Nassar, T., Newman, G., Nichol, B., Nicol, P., Nisnisan, J., Nossuli, A. K., Obialo, C., Olelewe, S., Oliver, M., O'Shaughnessy, A., Padron, J., Pankhaniya, R., Parker, R., Patel, D., Patel, G., Patel, N., Pavon, H., Perez, A., Perez, C., Perlman, A., Pettis, K., Pharr, W., Phillips, A., Purighalla, R., Quesada-Suarez, L., Ranjan, R., Rastogi, S., Reddy, J., Rendell, M., Rich, L., Robinson, M., Rodriguez, H., Rosas, S., Saba, F., Sankaram, R., Sarin, R., Schreiman, R., Scott, D., Sekkarie, M., Sensenbrenner, J., Shakeel, M., Shanik, M., Shaw, S., Smith, S., Solomon, R., Sprague, A., Spry, L., Suchinda, P., Sultan, S., Surampudi, P., Sussman, S., Tan, A., Terrelonge, A., Thompson, M., Trespalacios, F., Trippe, B., Trueba, P., Twahirwa, M., Updegrove, J., Van Buren, P., Vannorsdall, M., Varghese, F., Velasquez-Mieyer, P., Ventrapragada, S., Vukotic, G., Wadud, K., Warren, M., Watson, H., Watts, R., Weiner, D., Welker, J., Welsh, J., Williams, S., Zaniewski-Singh, M. 2021: STROKEAHA120031623
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 (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 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 m2]) subgroup (HRpooled, 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.
View details for DOI 10.1161/STROKEAHA.120.031623
View details for PubMedID 33874750