Long-term efficacy and renal safety of SGLT2 inhibitors in patients with heart failure and advanced chronic kidney disease (stage 4): a propensity score-matched retrospective cohort study

Objective Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a cornerstone of heart failure (HF) therapy; however, landmark trials systematically excluded patients with severe renal impairment. Consequently, prescribing SGLT2i for HF patients with advanced chronic kidney disease (CKD stage 4) remains a clinical “blind spot” due to fears of acute kidney injury. This study aimed to evaluate the long-term efficacy and renal safety of SGLT2i in this vulnerable, real-world population. Methods This single-center, retrospective observational cohort study evaluated HF patients with a baseline estimated glomerular filtration rate (eGFR) of 15–29 mL/min/1.73 m 2 treated between January 2021 and December 2024. To minimize confounding by indication, a rigorous 1:1 propensity score matching (PSM) was performed. The primary efficacy outcome was a composite of heart failure hospitalization (HHF) or cardiovascular death. The primary safety outcome was major adverse kidney events (MAKE), defined as a sustained ≥40% eGFR decline, initiation of dialysis, or renal death. Long-term eGFR slopes were analyzed using linear mixed-effects models. Results Following PSM, the final analysis cohort comprised 320 balanced patients (160 in the SGLT2i group and 160 in the control group), with a median baseline eGFR of 22.4 mL/min/1.73 m 2 . Over a median follow-up of 2.1 years, the SGLT2i group demonstrated a 38% relative risk reduction in the primary efficacy composite outcome compared to controls (30.6% vs. 45.6%; adjusted HR 0.62, 95% CI 0.44–0.87, P = 0.005). The incidence of the primary safety outcome (MAKE) was statistically comparable between the two groups (14.4% vs. 16.9%; adjusted HR 0.86, 95% CI 0.52–1.43, P = 0.550), with no significant excess in severe acute kidney injury or hyperkalemia. Following an initial early “dip” in eGFR (−2.1 mL/min/1.73 m 2 ), SGLT2i utilization was associated with a significantly shallower annualized eGFR decline trajectory compared to standard care (−1.2 vs. −3.5 mL/min/1.73 m 2 per year, P < 0.001). Conclusions In high-risk, real-world HF patients complicated by advanced CKD (Stage 4), SGLT2i therapy appears to be associated with substantial cardiovascular benefits and may attenuate long-term renal function decline. These findings suggest that severe renal impairment should not instinctively preclude the utilization of this life-saving therapy.