Benefits of SGLT2 inhibitors combining with renin-angiotensin-system blockers on cardiovascular outcomes in chronic kidney disease patients: A systemic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors in combination with renin-angiotensin-system (RAS) blockers for CKD remains controversial. We conducted this meta-analysis to explore the effect of SGLT2 inhibitors combining with RAS blockers on cardiovascular outcomes in chronic kidney disease (CKD) patients. METHODS: We searched Embase, PubMed, Web of Science, and Cochrane Library databases with the following keywords. "Renal Insufficiency, Chronic" or "Diabetic Nephropathies" and "Sodium-glucose cotransporter 2 inhibitors". We included randomized controlled trials (RCTs) based on angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy. The outcome events included cardiac and renal outcomes and other adverse events. This study is registered with PROSPERO: CRD42020218337. RESULTS: Ten RCTs including 16,983 CKD patients met the inclusion criteria. Compared with placebo plus RAS blockers, SGLT2 inhibitors plus RAS blockers significantly reduced cardiovascular mortality and heart failure-related hospitalization rates (RR=0.78, 95% CI: 0.66-0.91, p=0.002; RR=0.7, 95% CI: 0.61-0.8, p=0.000). We also performed trials sequential analysis (TSA) and the results indicated that our results are reliable. Additionally, it significantly reduced the 24-h urinary albumin excretion rate (24hUAE) and the creatinine elevation rate (WMD=-0.19, 95% CI: -0.24 to -0.14; RR=0.61, 95% CI: 0.51-0.74, p=0.000), delayed progression to end-stage renal disease (ESRD) (RR=0.69, 95% CI: 0.59-0.81, p=0.000). Further, it had no significant effect on the incidence of renal-related adverse events or renal-related mortality. Although it decreased the estimated glomerular filtration rate (eGFR) (WMD=-5.4, 95% CI: -7.24 to -3.57), this effect was reversible. CONCLUSIONS: These data provide a well-document testimonial of the benefits of the combined use of SGLT2 inhibitors and RAS blockers for cardiovascular and renal outcomes in CKD patients.