SGLT2 inhibitors showed no clear effect on total stroke across pooled trials (HR 0.96; 95% CI 0.82-1.12), but significantly reduced hemorrhagic stroke (HR 0.50; 95% CI 0.30-0.83).
Meta-Analysis (n=4,401)
randomized
Yes
Do SGLT2 inhibitors reduce the risk of stroke and atrial fibrillation/flutter in patients with type 2 diabetes mellitus?
SGLT2 inhibitors reduce the risk of hemorrhagic stroke and atrial fibrillation/flutter in patients with type 2 diabetes, and may reduce total stroke risk specifically in those with severe kidney disease (eGFR <45).
Effect estimate: HR 0.77 (95% CI 0.55-1.08)
Absolute Event Rate: 10.9% vs 14.2%
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.
Zhou et al. (Tue,) conducted a meta-analysis in Type 2 diabetes mellitus and chronic kidney disease (n=4,401). SGLT2 inhibitors (canagliflozin) vs. Placebo was evaluated on Fatal or nonfatal stroke (HR 0.77, 95% CI 0.55-1.08). SGLT2 inhibitors showed no clear effect on total stroke across pooled trials (HR 0.96; 95% CI 0.82-1.12), but significantly reduced hemorrhagic stroke (HR 0.50; 95% CI 0.30-0.83).