Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease

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.

Effects of SGLT2 inhibitors on stroke and its subtypes in patients with type 2 diabetes: a systematic review and meta-analysis

“…The meta-analysis conducted by Zhou et al did not include the VERTIS CV trial for analysis, unlike our study. Both studies revealed consistent results that SGLT2 inhibitors have a neutral effect on the risk of stroke as compared with placebo 19 .…”

Role of Epicardial Adipose Tissue in Cardiovascular Diseases: A Review

“…SGLT2 inhibitors also improved the inflammatory status of EAT [209]. They have been documented to be effective against HF and endothelial dysfunction [212,213]. This group of drugs causes a significant reduction in body weight, and one of the mechanisms of action is the stimulation of visceral fat burn [214].…”

“…Statins anti-inflammatory [160,[162][163][164][165] modulation of EAT [164] ↓ EAT metabolic activity [163] PCSK-9 inhibitors unknown Metformin anti-inflammatory [186,187,[196][197][198]200] ↑ fat oxidation and thermogenesis [193,194] ↓ endothelial dysfunction [195] activation of adenosine monophosphate-activated protein kinase [198,200] Thiazolidinediones anti-inflammatory [190,191,[204][205][206] SGLT2 inhibitors anti-inflammatory [210,217] ↓ endothelial dysfunction [213] stimulation of visceral fat burn [215] ↑ EAT cells sensitivity to insulin [217] GLP-1 agonists ↑ pre-adipocyte differentiation [225] ↑ thermogenesis [226] ↑ adipocyte browning [226] DPP-4 inhibitors anti-inflammatory [231][232][233] downregulation of the receptor for advanced glycation end-products [234] ↑ cyclic adenosine monophosphate/protein kinase A signaling and IL-6 production [235] ↓ ROS generation and intercellular adhesion molecule-1 expression [236] Table 1. Cont.…”

Association Between SGLT2is and Cardiovascular and Respiratory Diseases: A Meta-Analysis of Large Trials

“…Three previous meta-analyses (Li et al, 2021a;Li et al, 2021b;Zhou et al, 2021) identified SGLT2is with the reduced risk of atrial fibrillation, whereas they failed to explore the association between SGLT2is and bradycardia. Our meta-analysis further revealed the association between use of SGLT2is and a lower risk of bradycardia besides that of atrial fibrillation.…”