Sodium–Glucose Cotransporter-2 (SGLT-2) Inhibitors for Slowing the Progression of Chronic Kidney Disease: A Systematic Review of Randomized Controlled Trials and Primary Studies

Abstract

Introduction: Chronic kidney disease (CKD) is a progressive disorder leading to kidney failure and cardiovascular death, with substantial residual risk persisting despite renin–angiotensin system (RAS) blockade. Sodium–glucose cotransporter-2 (SGLT-2) inhibitors have demonstrated kidney-protective effects apparently independent of glycaemic control. This systematic review synthesized randomized controlled trial (RCT) evidence on efficacy and safety of SGLT-2 inhibitors for slowing CKD progression across diabetic and non-diabetic aetiologies.

Methods: The study strictly adhered to the Preferred Reporting Items for Systematic Review and  (PRISMA) 2020 guidelines to 30 June 2026 for RCTs comparing SGLT-2 inhibitors with placebo or active control in adults with CKD or at risk of progression, reporting at least one kidney outcome. Two reviewers independently screened records, extracted data, appraised risk of bias with Cochrane RoB 2, and rated certainty with GRADE. Effect estimates were synthesised narratively; trial-level hazard ratios were pooled using DerSimonian–Laird random-effects models.

Results: Eighteen reports from fourteen unique trials enrolling >80,000 participants met inclusion criteria. In the three dedicated CKD outcome trials, the pooled hazard ratio for the primary kidney–cardiovascular composite was 0.68 (95% CI 0.62–0.75; I²=17.5%; p<0.0001); across six independent trials, the kidney-specific composite was 0.62 (95% CI 0.56–0.70; I²=34.3%; p<0.0001). Empagliflozin halved the chronic eGFR slope from −2.75 to −1.37 mL/min/1.73 m² per year; dapagliflozin attenuated total eGFR decline by 0.95 mL/min/1.73 m² per year. Albuminuria fell by 16–38%, all-cause mortality was reduced in DAPA-CKD (HR 0.69, 95% CI 0.53–0.88), and acute kidney injury was reduced rather than increased. Benefits were consistent across diabetes status, primary kidney diagnosis, baseline eGFR down to 20 mL/min/1.73 m², and the full spectrum of albuminuria. Ten reports were at low overall risk of bias; none at high risk.

Discussion: The renoprotective signal is mechanistically coherent: restoration of tubuloglomerular feedback lowers intraglomerular pressure, reduced proximal tubular workload and improved cortical oxygenation, natriuresis, uricosuria, erythropoietic stimulation, and attenuation of tubulointerstitial inflammation and fibrosis contribute. Mediation analyses attribute the largest fractions of the treatment effect to erythrocyte concentration, serum urate, and systolic blood pressure rather than glycaemia, explaining benefit in non-diabetic participants and those with minimal albuminuria. Key limitations include median follow-up of only two to four years and incomplete representation of eGFR below 20 mL/min/1.73 m².

Conclusion: High-certainty randomized evidence establishes that SGLT-2 inhibitors safely and substantially slow CKD progression, reduce kidney failure, cardiovascular death, and heart-failure hospitalisation, with consistent effects irrespective of diabetes or underlying kidney diagnosis. SGLT-2 inhibitors should be regarded as foundational therapy alongside maximally tolerated RAS blockade for patients with albuminuric or progressive CKD.