CARDIOPROTECTIVE EFFECTS OF SGLT INHIBITORS IN ADULTS WITH ADVANCED CHRONIC KIDNEY DISEASE (EGFR A SYSTEMATIC REVIEW OF RANDOMIZED CONTROLLED TRIALS, META-ANALYSES, AND REAL-WORLD EVIDENCE

Abstract

Background. SGLT inhibitors have transformed the treatment of heart failure and chronic kidney disease (CKD), yet their role in patients with severely reduced kidney function—eGFR below 30 ml/min/1.73m²—remains poorly defined. Most landmark trials either excluded these patients or enrolled too few to draw firm cardiovascular conclusions. This evidence gap matters because cardiovascular disease causes roughly half of all deaths in CKD Stage 4–5, and clinicians lack robust evidence precisely where it is most needed.

Methods. We conducted a systematic review (PROSPERO: CRD420261377175) following PRISMA 2020 guidance. PubMed, EMBASE, and Cochrane CENTRAL were searched from January 2015 through March 2026, supplemented by ClinicalTrials.gov and manual reference mining. We included randomised controlled trials (RCTs) and their prespecified subgroup analyses reporting eGFR <30 outcomes, individual patient data and aggregate meta-analyses, and propensity score matched cohort studies with at least 12 weeks of follow-up. Two reviewers independently screened studies and extracted data. Risk of bias was assessed using the Cochrane RoB 2.0 tool, and certainty of evidence was rated using GRADE. The primary outcomes were hospitalisation for heart failure (HHF) and major adverse cardiovascular events (MACE).

Results. Twenty-two publications met the inclusion criteria: 9 landmark RCTs (~31,900 patients), 5 meta-analyses (pooling up to 97,412), 4 RCT subgroup analyses, and 4 real-world cohort studies. More than 17,000 patients with eGFR <30 or CKD Stage 4–5 contributed direct outcome data. Hazard ratios for HHF/CV death ranged from 0.69 to 0.84 across individual RCTs, converging on a pooled estimate near 0.74. No trial or meta-analysis demonstrated a significant interaction between baseline eGFR and treatment effect (P-trend = 0.16 in SMART-C; P >0.10 in DAPA-CKD subgroups). The Spiazzi 2024 meta-analysis showed that MACE reduction was largest in KDIGO Very High Risk patients (HR 0.72; P-interaction = 0.038). DAPA-CKD was the only individual trial to demonstrate a significant mortality reduction (HR 0.69; P = 0.004); pooled estimates from adequately powered analyses also reached significance (RR 0.87; 95% CI 0.80–0.95). Sotagliflozin demonstrated unique reductions in MI (HR 0.68) and stroke (HR 0.66), likely reflecting dual SGLT1/2 inhibition. Safety was reassuring overall: no DKA events occurred with dapagliflozin in DAPA-CKD, and AKI was consistently lower with SGLT inhibitors (RR 0.77–0.82). Evidence certainty was Moderate for HHF/CV death and mortality, and High for kidney progression.

Conclusions. Available evidence consistently points toward meaningful cardioprotection with SGLT inhibitors in patients with eGFR <30, with no attenuation of benefit at lower eGFR. These findings argue for extending guideline recommendations into CKD Stage 4–5 and highlight the need for adequately powered RCTs enrolling this population