Efficacy and Safety of SGLT-2 Inhibitors in Patients With and Without Advanced CKD: A Systematic Review and Meta-Analysis

Background: The efficacy and safety of sodium-glucose co-transporter-2 (SGLT-2) inhibitors in patients with advanced chronic kidney disease (CKD), defined as an estimated glomerular filtration rate (eGFR) <30 ml/min/1.73m 2 , has not been adequately studied. Methods: We conducted a systematic review and meta-analysis of phase 3 randomized controlled trials (RCTs) of SGLT-2 inhibitors in adults. We searched the MEDLINE and Embase databases from inception to April 2024. The primary outcomes were a composite kidney (worsening kidney function, kidney failure, kidney or cardiovascular death) and cardiovascular (cardiovascular death or hospitalization for heart failure) outcome. Secondary outcomes included other reported cardiovascular and kidney outcomes, eGFR slopes, mechanistic and safety outcomes. The relative risks (RR) were estimated using a random effects model. Interaction effects were estimated for treatment effect modification by baseline eGFR (<30 and ≥30 ml/min/1.73m 2 ). Results: A total of 10 RCTs were included (total of 4800 patients with eGFR <30 ml/min/1.73m 2 ). Participants were randomized to receive either placebo or an SGLT-2 inhibitor. Use of SGLT-2 inhibitors was associated with a lower incidence of the primary composite kidney outcome in patients with eGFR <30 ml/min/1.73m 2 [RR 0.79, 95% confidence interval (CI) 0.70-0.89] and ≥30 ml/min/1.73m 2 (RR 0.71, 95% CI 0.64-0.79). The incidence of the primary cardiovascular outcome was numerically lower in the SGLT-2 inhibitor arm in patients with eGFR <30 ml/min/1.73m 2 (RR 0.88, 95% CI 0.71-1.10). In patients with eGFR ≥30 ml/min/1.73m 2 , SGLT-2 inhibitor use was associated with a lower incidence of the composite cardiovascular outcome (RR 0.77, 95% CI 0.71-0.83). However, there was no interaction between advanced CKD status and the effect of SGLT-2 inhibitors on any of the primary or secondary outcomes. The incidence of adverse events was similar in both arms. Conclusion: SGLT-2 inhibitors retain their kidney and cardiovascular protective effect in patients with advanced CKD, with no added safety concerns.