Evaluation of SGLT2 inhibitor therapeutic efficacy and identification of IL-18/IL-18R1 signaling as a predictive biomarker in patients with T2DM

We hypothesised that circulating proteins predict inter-individual variability in the metabolic and cardiorenal benefits obtained from sodium-glucose co-transporter-2 inhibitor (SGLT2i) therapy in type 2 diabetes mellitus (T2DM). To test this, we combined longitudinal clinical phenotyping with plasma proteomics (Olink ® panels) and PBMC RNA-seq in up to 70 adults initiating SGLT2i treatment and followed for six months.

What the Data Show
- Clinical outcomes: Significant improvements in HbA1c (median −0.9 %), UACR (−26 %), body-weight (−1.8 kg) and related metabolic indices.
- Proteomics: Baseline IL-18R1 and its six-month reduction correlated with glycaemic change, fat-mass loss and albuminuria improvement (AUC = 0.75 for overall response). Macrophage-linked proteins (CD163, CHI3L1, CD93) and inflammasome‐related IL-1R2 also declined after therapy.
- Transcriptomics: RNA-seq of paired PBMC samples confirmed down-regulation of pro-inflammatory genes (CCR2, TNFAIP8L2, VIP) and up-regulation of reparative markers (SELENBP1, HIF1A), supporting an anti-inflammatory shift.