TY - JOUR
T1 - Effect of SGLT2 inhibitors on stroke and atrial fibrillation in diabetic kidney disease
T2 - Results from the CREDENCE trial and meta-analysis
AU - CREDENCE Trial Investigators
AU - Zhou, Zien
AU - Jardine, Meg J.
AU - Li, Qiang
AU - Neuen, Brendon L.
AU - Cannon, Christopher P.
AU - De Zeeuw, Dick
AU - Edwards, Robert
AU - Levin, Adeera
AU - Mahaffey, Kenneth W.
AU - Perkovic, Vlado
AU - Neal, Bruce
AU - Lindley, Richard I.
AU - Guerrero, Rodolfo Andres Ahuad
AU - Aizenberg, Diego
AU - Albisu, Juan Pablo
AU - Alvarisqueta, Andres
AU - Bartolacci, Ines
AU - Berli, Mario Alberto
AU - Bordonava, Anselmo
AU - Calella, Pedro
AU - Cantero, Maria Cecilia
AU - Cartasegna, Luis Rodolfo
AU - Cercos, Esteban
AU - Coloma, Gabriela Cecilia
AU - Colombo, Hugo
AU - Commendatore, Victor
AU - Cuadrado, Jesus
AU - Cuneo, Carlos Alberto
AU - Cusumano, Ana Maria
AU - Douthat, Walter Guillermo
AU - Dran, Ricardo Dario
AU - Farias, Eduardo
AU - Fernandez, Maria Florencia
AU - Finkelstein, Hernan
AU - Fragale, Guillermo
AU - Fretes, Jose Osvaldo
AU - Garcia, Nestor Horacio
AU - Gastaldi, Anibal
AU - Gelersztein, Elizabeth
AU - Glenny, Jorge Archibaldo
AU - Gonzalez, Joaquin Pablo
AU - Del Carmen Gonzalez Colaso, Patricia
AU - Goycoa, Claudia
AU - Greloni, Gustavo Cristian
AU - Guinsburg, Adrian
AU - Hermida, Sonia
AU - Juncos, Luis Isaias
AU - Klyver, Maria Isabel
AU - Kraft, Florencia
AU - Lin, Chih Ching
N1 - Publisher Copyright:
© 2021 EDP Sciences. All rights reserved.
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
KW - atrial fibrillation
KW - canagliflozin
KW - glomerular filtration rate
KW - hemorrhagic stroke
KW - ischemic stroke
UR - http://www.scopus.com/inward/record.url?scp=85104993066&partnerID=8YFLogxK
U2 - 10.1161/STROKEAHA.120.031623
DO - 10.1161/STROKEAHA.120.031623
M3 - Article
C2 - 33874750
AN - SCOPUS:85104993066
SN - 0039-2499
VL - 52
SP - 1545
EP - 1556
JO - Stroke
JF - Stroke
IS - 5
ER -