Cardio-renal protective effect and safety of sodium-glucose cotransporter 2 inhibitors for chronic kidney disease patients with eGFR < 60 mL/min/1.73 m2: a systematic review and meta-analysis.

Objective: This meta-analysis was designed to investigate cardio-renal outcomes and safety of sodium-glucose cotransporter-2 inhibitors (SGLT2i) as a therapeutic option among chronic kidney disease(CKD) patients with GFR < 60 mL/min/1.73 m2, regardless of their diabetic status.

Method: We conducted a full-scale search from MEDLINE, EMBASE and the Cochrane Library database to identify eligible studies up to Jun 2024. All randomized controlled trials (RCTs) comparing cardio-renal outcomes and/or safety of SGLT2i in CKD patients with eGFR < 60 mL/min/1.73 m were involved. The relative risk (RR) and 95% confidence interval (CI) for primary outcomes and adverse events were computed by random-effects mode. We used I statistic to analyze heterogeneity. Publication bias was assessed by Egger's test.

Results: Our study incorporated 17 RCTS, including 27,928 patients. In CKD patients with eGFR < 60 mL/min/1.73 m, SGLT2i decreased risks of cardiovascular events (seven studies, 17,355 participants, RR 0.77, 95% CI 0.70-0.84), hospitalization for heart failure (HHF) (seven studies, 17,869 participants, RR 0.73, 95% CI 0.65-0.82), cardiovascular death (eight studies, 23,079 participants, RR 0.81, 95% CI 0.74 to 0.88) and renal composite outcomes (eight studies, 22,525 participants, RR 0.70, 95% CI 0.61-0.80) with lower risks of any serious adverse effects(fourteen studies, 19,654 participants, RR 0.91, 95% CI 0.87-0.95), hypoglycemia (nine studies, 16,412 participants, RR 0.91, 95% CI 0.84-0.98), hyperkalemia (four studies, 2693 participants, RR 0.68, 95% CI 0.51-0.93) and acute renal injury (five studies, 5424 participants, RR 0.79, 95% CI 0.65-0.95) compared to placebo. SGLT2i also slowed eGFR decline (total slopes: five studies, 10,370 participants, mean difference 1.17, 95%CI 0.86-1.49; chronic slopes: four studies, 8459 participants, mean difference 2.12, 95%CI 1.64-2.61). Further subgroup analyses revealed that SGLT2i decreased relative risks of cardiovascular outcomes(three studies, 1075 participants, RR 0.76, 95% CI 0.54-0.82), HHF(four studies, 1280 participants, RR 0.74, 95% CI 0.55-1.00) and renal composite outcomes (six studies,4375 participants, RR 0.78, 95% CI 0.68-0.88) with no increased adverse events in the CKD 4 patients.

Conclusions: SGLT2i significantly improved cardio-renal outcomes and were generally safe in CKD patients with eGFR < 60 mL/min/1.73 m2 and with eGFR < 30 mL/min/1.73 m2. Future large-scale RCTs are needed to confirm the robustness of these results.