Identification of IL18/IL18R1 signaling as a predictive biomarker of SGLT2 inhibitor efficacy in type 2 diabetes

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are widely used to manage type 2 diabetes mellitus (T2DM) to ameliorate hyperglycemia, albuminuria, and obesity, with established cardiorenal benefits. However, predictive biomarkers for therapeutic responses remain limited. In this study, seventy patients initiating SGLT2i therapy were evaluated clinically and through plasma proteomics and transcriptomics. Treatment significantly improved HbA1c (71.2%), albuminuria (47.5%), and weight (58.6%), with benefits in insulin resistance, β-cell function, blood pressure, uric acid, and body composition. Proteomic analysis identified IL-18R1 reduction linked to improved glycemic control, albuminuria, fat mass, and liver function. Transcriptomic profiling revealed genetic alterations in blood mononuclear cells, reinforcing anti-inflammatory changes. Receiver operating characteristic analysis indicated high baseline IL-18/IL-18R1 predicted overall response (area under the curve: 0.75, <i>p</i> = 0.005; cutoffs: IL-18 = 244.29 pg/mL, IL-18R1 = 325.97 pg/mL). IL-18/IL-18R1 signaling emerges as a promising biomarker for predicting therapeutic responses, guiding clinical decisions regarding SGLT2i use in T2DM management.