Association of SGLT2 Inhibitors with Reduced Mortality and Improved Clinical Outcomes in Patients with Cancer and CKD: A Real-World Propensity-Matched Analysis

Background: The benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in diabetic and chronic kidney disease (CKD) populations are well-established, but their impact in cancer patients with CKD is unclear. We aimed to evaluate the association of SGLT2i use with mortality and clinically relevant outcomes in cancer patients with CKD stages 3–5. Methods: We conducted a retrospective, propensity-matched cohort study using TriNetX Global Network data (2016–2025). Adult cancer patients with CKD stage 3–5 were included. Patients prescribed SGLT2i (dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, sotagliflozin) were matched 1:1 to controls without SGLT2i. The primary outcome was all-cause mortality. Secondary outcomes included acute kidney injury (AKI), dialysis initiation, progression to advanced CKD (eGFR ≤30), myocardial infarction (MI), heart failure, cardiac arrest, stroke, fatigue, blood transfusion (proxy for worsening anemia of CKD), diabetic ketoacidosis (DKA), outpatient visits, and hospitalizations. Outcomes were assessed by risk difference, hazard ratio (HR), and 95% confidence intervals (CI). Results: After matching (N=20,080), SGLT2i use was associated with significantly lower all-cause mortality (20.2% vs. 44.3%; HR 0.53, 95% CI 0.50–0.56, p<0.001), AKI (23.4% vs. 35.3%; HR 0.76, 0.70–0.82), dialysis initiation (4.7% vs. 8.4%; HR 0.67, 0.60–0.76), advanced CKD (19.3% vs. 28.6%; HR 0.67, 0.63–0.72), MI (2.2% vs. 3.5%; HR 0.63, 0.52–0.76), heart failure (10.1% vs. 15.2%; HR 0.66, 0.59–0.74), cardiac arrest (1.8% vs. 3.8%; HR 0.58, 0.49–0.70), stroke (3.9% vs. 6.0%; HR 0.83, 0.72–0.95), fatigue (19.1% vs. 25.7%; HR 0.88, 0.81–0.95), blood transfusion (4.3% vs. 10.0%; HR 0.48, 0.42–0.54), outpatient visits (4.8% vs. 18.7%; HR 0.21, 0.19–0.24), and hospitalizations (18.0% vs. 30.3%; HR 0.70, 0.66–0.76), all p<0.01. DKA occurred in 11.3% of SGLT2i patients vs. 12.0% of controls (HR 1.29, 1.16–1.44, p<0.001). Conclusion: SGLT2i use in cancer patients with CKD is associated with substantial reductions in mortality and major adverse renal, cardiovascular, and healthcare utilization outcomes, but is linked to a higher hazard of DKA. These findings support SGLT2i therapy as a promising strategy in this vulnerable population, with appropriate DKA risk monitoring.