Efficacy and Safety of Sodium-Glucose Cotransporter-2 Inhibitors in Patients with and without Advanced CKD

Key Points Treatment with sodium-glucose cotransporter-2 inhibitor (SGLT-2i) provides kidney and cardiovascular protection in patients with advanced CKD. The glycosuric action of SGLT-2i is attenuated in advanced CKD resulting in no change in glycated hemoglobin and fewer volume depletion events. The use of SGLT-2i did not increase the incidence of AKI, urine infections, fractures, or treatment discontinuation due to adverse events. Background The efficacy and safety of sodium-glucose cotransporter-2 inhibitor (SGLT-2i) in patients with advanced CKD, defined as an eGFR <30 ml/min per 1.73 m 2 , has not been adequately studied. Methods We conducted a systematic review and meta-analysis of phase 3 randomized controlled trials of SGLT-2i in adults. We searched the medical literature analysis and retrieval system online and excerpta medica database databases from inception to April 2024. The primary outcomes were composite kidney (worsening kidney function, kidney failure, and kidney or cardiovascular [CV] death) and CV (CV death or hospitalization for heart failure) outcomes. Secondary outcomes included other reported CV and kidney outcomes, eGFR slopes, mechanistic, and safety outcomes. The risk ratios (RR) were estimated using a random effects model. Interaction effects were estimated for treatment effect modification by baseline eGFR (<30 and ≥30 ml/min per 1.73 m 2 ). Results A total of ten randomized controlled trials were included (total of 4800 patients with eGFR <30 ml/min per 1.73 m 2 ). Participants were randomized to receive either placebo or an SGLT-2i. The use of SGLT-2i was associated with a lower incidence of the primary composite kidney outcome in patients with eGFR <30 ml/min per 1.73 m 2 (RR, 0.79; 95% confidence interval [CI], 0.70 to 0.89) and ≥30 ml/min per 1.73 m 2 (RR, 0.71; 95% CI, 0.64 to 0.79). The incidence of the primary CV outcome was numerically lower in the SGLT-2i arm in patients with eGFR <30 ml/min per 1.73 m 2 (RR, 0.88; 95% CI, 0.71 to 1.10). In patients with eGFR ≥30 ml/min per 1.73 m 2 , SGLT-2i use was associated with a lower incidence of the composite CV outcome (RR, 0.77; 95% CI, 0.71 to 0.83). However, there was no interaction between advanced CKD status and the effect of SGLT-2i on any of the primary or secondary outcomes. The incidence of adverse events was similar in both arms. Conclusions SGLT-2i retain their kidney and CV protective effect in patients with advanced CKD, with no added safety concerns.