Association of SGLT2 Inhibitor Use with Circulating Pyroptosis-Related Biomarkers in Iraqi Patients with Diabetic Kidney Disease: A Cross-Sectional Study

Abstract

Objective: To investigate the association between SGLT2 inhibitor use and circulating pyroptosis-related biomarkers in Iraqi patients with diabetic kidney disease (DKD).

Methods: This cross-sectional study included 170 patients with DKD who were divided into two groups according to SGLT2 inhibitor use. DKD was diagnosed based on estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) according to KDIGO recommendations. Serum levels of NF-κB, ASC, p-AKT, caspase-1, IL-1β and IL-18 were measured using ELISA technique. Primary multivariable linear regression models were adjusted for age, sex, BMI, diabetes duration, HbA1c, eGFR, ACEI/ARB use, and DPP4i use.

Results: SGLT2 inhibitor users had lower serum levels of NF-κB, ASC, p-AKT, caspase-1, IL-1β, and IL-18 than non-users. All six between-group comparisons remained statistically significant after Benjamini–Hochberg false discovery rate correction (FDR-adjusted p < 0.05). In the primary multivariable linear regression analysis, the associations remained statistically significant for ASC, p-AKT, caspase-1, IL-1β, and IL-18, whereas the association with NF-κB was not statistically significant. Sensitivity analyses generally preserved the direction of the associations, although statistical significance varied according to model specification. In the log-transformed analysis with robust standard errors, ASC, p-AKT, and caspase-1 remained statistically significant, whereas IL-1β (p = 0.052), NF-κB, and IL-18 were not statistically significant.

 Conclusion: SGLT2 inhibitor use was associated with a more favorable inflammatory and pyroptosis-related biomarker profile in DKD, but the results were not fully consistent across statistical models. Therefore, the findings do not prove that SGLT2 inhibitors directly suppress pyroptosis or provide causal kidney protection.