The George Institute for Global Health, UNSW Sydney, Australia (Z.Z., M.J.J., Q.L., B.L.N., V.P., B.N.).
Department of Radiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, China (Z.Z.).
Stroke. 2021 May;52(5):1545-1556. doi: 10.1161/STROKEAHA.120.031623. Epub 2021 Apr 20.
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.
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.
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, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HR, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HR, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HR, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HR, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (=0.01), with protection in the lowest estimated glomerular filtration rate (<45 mL/min/1.73 m]) subgroup (HR, 0.50 [95% CI, 0.31-0.79]).
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.
患有估算肾小球滤过率降低或白蛋白尿升高的慢性肾脏病会增加缺血性和出血性中风的风险。本研究评估了钠-葡萄糖共转运蛋白 2 抑制剂（SGLT2i）在 CREDENCE（卡格列净和已确诊肾病的 2 型糖尿病患者中的肾脏事件临床评估）和大型心血管结局试验（CVOT）的荟萃分析中对中风和心房颤动/扑动（AF/AFL）的影响。
CREDENCE 将 4401 名患有 2 型糖尿病和慢性肾脏病的患者随机分为卡格列净或安慰剂组。事后，我们估计了对致命或非致命性中风、中风亚型以及中风风险的中间标志物（包括 AF/AFL）的影响。使用随机效应荟萃分析汇总了来自其他 3 个已完成的大型 CVOT 和 CREDENCE 的中风和 AF/AFL 数据。
在 CREDENCE 中，142 名参与者在随访期间发生了中风（卡格列净组为 10.9/1000 患者-年，安慰剂组为 14.2/1000 患者-年；风险比 [HR]，0.77 [95%置信区间，0.55-1.08]）。按中风亚型进行的效果为：缺血性（HR，0.88 [95%置信区间，0.61-1.28]；n=111）、出血性（HR，0.50 [95%置信区间，0.19-1.32]；n=18）和未确定的（HR，0.54 [95%置信区间，0.20-1.46]；n=17）。AF/AFL 无明显影响（HR，0.76 [95%置信区间，0.53-1.10]；n=115）。4 个 CVOT 联合的总体效果为：总中风（HR，0.96 [95%置信区间，0.82-1.12]）、缺血性中风（HR，1.01 [95%置信区间，0.89-1.14]）、出血性中风（HR，0.50 [95%置信区间，0.30-0.83]）、未确定的中风（HR，0.86 [95%置信区间，0.49-1.51]）和 AF/AFL（HR，0.81 [95%置信区间，0.71-0.93]）。有证据表明，SGLT2i 对总中风的影响因基线估算肾小球滤过率而异（P=0.01），在最低估算肾小球滤过率（<45 mL/min/1.73 m2）亚组中具有保护作用（HR，0.50 [95%置信区间，0.31-0.79]）。
尽管我们在 CREDENCE 或联合试验中未发现 SGLT2i 对总中风有明显影响，但在预防出血性中风和 AF/AFL 以及最低估算肾小球滤过率的总中风方面，存在一定的益处。未来的研究应集中在证实这些数据并探索潜在机制。注册：网址：https://www.clinicaltrials.gov；唯一标识符：NCT02065791。
