Effects and Safety of SGLT2 Inhibitors on Cardiovascular and Renal Outcomes in Patients with Chronic Kidney Disease: A Systematic Review and Meta-Analysis of Randomised Controlled Trials

Background: The magnitude of effect of sodium glucose con-transporter 2 inhibitors (SGLT2i) on cardiovascular and renal outcomes in patients with chronic kidney disease (CKD), with or without diabetes, remains unknown. Methods: We conducted a systematic review and meta-analysis using PubMed and Embase for randomised controlled trials (RCTs) comparing the efficacy and safety of SGLT2i in patients with CKD. The major efficacy outcome of interest was the composite of cardiorenal outcomes (including worsening estimated glomerular filtration rate, end-stage kidney disease, renal death, or cardiovascular death). Patients were stratified into those with diabetes or not, and by estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) levels. Findings: We included three trials that met our inclusion criteria (n=19289). SGLT2i reduced the composite of cardiorenal outcomes by 27.5% (RR 0.73 [95 % CI 0.62-0.86], p＜0.01), with similar benefits in patients with an UACR≤1000 mg/g (RR 0.65 [95 % CI 0.45-0.93], p=0.02) and UACR＞1000mg/g (RR 0.69 [95 % CI 0.61-0.78], p＜0.01), and with greater reductions in patients with an eGFR≥45 mL/min per 1.73m2(RR 0.59 [95 % CI 0.43-0.81], p=0.001) and patients without diabetes (RR 0.55 [95 % CI 0.39-0.77], p＜0.01). SGLT2i reduced the composite of renal outcomes by 36.4% (RR 0.64 [95 % CI 0.56-0.73], p＜0.01), with similar benefits in patients with and without diabetes. SGLT2i reduced major adverse cardiovascular events by 21.1%(RR 0.79 [95 % CI 0.71-0.88], p＜0.01). Patients in the SGLT2i group demonstrated no statistical difference in death from any cause (RR 0.85 [95 % CI 0.69-1.04], p=0.10). SGLT2i reduced the risk of hospitalisation for heart failure or cardiovascular death by 27.1% (RR 0.74 [95 % CI 0.67-0.81], p＜0.01), with benefits only seen in patients with diabetes (RR 0.74 [95 % CI 0.67-0.81], p＜0.01) and not in those without diabetes (RR 0.79 [95 % CI 0.41-1.55], p=0.50). For safety outcomes, the event rates of SGLT2i in patients with CKD were low. Interpretation: SGLT2i have robust benefits on the composite of cardiorenal outcomes in patients with chronic kidney disease, regardless of diabetes or not. However, further trials should be performed in patients without diabetes to confirm. Funding: None to declare. Declaration of Interest: None to declare.