Sodium-Glucose Co-transporter 2 inhibitors (SGLT2i) have demonstrated profound cardio-renal protection in randomized controlled trials (RCTs). However, real-world data are essential to confirm these benefits across heterogeneous patient populations afflicted by multiple chronic conditions, particularly when accounting for confounding by indication (channeling bias) and competing mortality risk.1

This retrospective observational cohort study utilized propensity score matching (PSM) to compare the risk of Chronic Renal Syndrome (CARDIO-RENAL SYNDROME) and Hemodialysis/Peritoneal Dialysis (HD/PD) initiation between SGLT2i users (N=2,998) and non-SGLT2i users (N=2,998) in a chronic disease (CD) patient cohort. Robust statistical adjustment included over 30 baseline variables, including the Charlson Comorbidity Index (CCI) and Diabetes Comorbidity Severity Index (DCSI).2 Primary outcome assessment employed the Fine-Gray Competing Risks Regression model, reporting adjusted Subhazard Ratios (aSHR) to account for all-cause mortality as a competing risk.2 Sensitivity analyses included assessment of lag time and stratification by follow-up duration.

SGLT2i use was associated with a statistically significant reduction in the risk of CARDIO-RENAL SYNDROME (Incidence Rate: 515.22 per 1000 person-years vs. 590.72 per 1000 PY; aSHR, 0.87; 95% CI, 0.81–0.92; P<0.001). Conversely, the overall risk of the rare outcome of HD/PD was elevated but not statistically significant (IR: 2.00 per 1000 PY vs. 1.23 per 1000 PY; aSHR, 2.29; 95% CI, 0.89–5.90; P=0.0867). Time-varying analysis for HD/PD revealed substantial non-proportional hazards, with a highly significant spike in risk observed only during the intermediate follow-up period (1.5–2.5 years: aHR, 10.0; 95% CI, 1.65–61.51; P=0.0124).

SGLT2 inhibitor therapy provides substantial real-world protection against Chronic Renal Syndrome. The observed transient elevation in HD/PD risk is interpreted not as an adverse drug effect but as a pronounced statistical artifact resulting from unavoidable residual channeling bias. SGLT2i were preferentially initiated in patients with clinically aggressive disease trajectories toward end-stage kidney failure, underscoring the severe challenges inherent in studying rare, high-mortality outcomes in observational cohorts.