Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis

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 m²]) 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.

Keywords: atrial fibrillation; canagliflozin; glomerular filtration rate; hemorrhagic stroke; ischemic stroke.

Figure 1.

Effects of canagliflozin on stroke in CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation). CANA indicates canagliflozin; eGFR, estimated glomerular filtration rate; HR, hazard ratio; PBO, placebo; and UACR, urinary albumin:creatinine ratio. *P value for interaction across subgroups.

Figure 2.

Effects of canagliflozin on the incidence of atrial fibrillation (AF) or atrial flutter (AFL) in CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation). CANA indicates canagliflozin; eGFR, estimated glomerular filtration rate; HR, hazard ratio; PBO, placebo; and UACR, urinary albumin:creatinine ratio. *P value for interaction across subgroups. †Events of AF or AFL were identified from site investigator–reported adverse events.

Figure 3.

Meta-analysis of the treatment effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and stroke subtypes. CANA indicates canagliflozin; CANVAS, Canagliflozin Cardiovascular Assessment Study; CREDENCE, Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation; DAPA, dapagliflozin; DECLARE-TIMI-58, Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58; EMPA, empagliflozin; EMPA-REG OUTCOME, EMPA Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; HR, hazard ratio; NR, not reported; and PBO, placebo. *Data on ischemic stroke. †Hazard ratio was estimated by risk ratio.

Figure 4.

Effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke according to baseline kidney function. CANA, canagliflozin; CANVAS, Canagliflozin Cardiovascular Assessment Study; CREDENCE, Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation; DAPA, dapagliflozin; DECLARE-TIMI-58, Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58; eGFR, estimated glomerular filtration rate; EMPA, empagliflozin; EMPA-REG OUTCOME, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; HR, hazard ratio; NR, not reported; and PBO, placebo; *Ischemic stroke only. †Based on screening (rather than baseline) eGFR. ‡The heterogeneity of meta-analysis is I²=36.5% (P=0.19) for all participants, I²=0.0% (P=0.44) for eGFR ≥90 mL/min/1.73 m² I²=0.0% (P=0.65) for eGFR 60–<90 mL/min/1.73 m² I²=24.7% (P=0.26) for eGFR 45–<60 mL/min/1.73 m² and I²=0.0% (P=0.46) for eGFR <45 mL/(min·1.73 m²). §Tested by random-effects meta-regression with the hypothesis of no linear trend across ordered eGFR categories (eGFR ≥90, 60–<90, 45–<60, and <45 mL/min/1.73 m²).