SGLT2 inhibition reverses metabolic and inflammatory kidney signatures in youth with type 1 diabetes

Sodium-glucose cotransporter-2 (SGLT2) inhibitors slow progression of diabetic kidney disease, but their intrarenal mechanisms remain unclear, particularly in patients with type 1 diabetes (T1D). In a prespecified ancillary study within the placebo-controlled ATTEMPT trial of dapagliflozin in youth with T1D and well-preserved kidney function (N=98), we integrated sequential kidney biopsies, multiparametric kidney MRI, and proteomics. Single-cell RNA-seq of N=16 baseline and N=11 16-week follow-up biopsies (N=27; 214,415 cells) revealed a coordinated network of metabolic, fibrotic, and inflammatory transcriptional changes across nephron, vascular, and immune compartments. These gene shifts paralleled attenuation of hyperfiltration and improvement in glycemic control (HbA1c and time-in-range), implicating 594 transcripts. MRI indicated a reversal of the medullary hyperoxia characteristic of T1D with dapagliflozin. Urine proteomic profiles echoed the transcriptomic patterns. Together, these multimodal data point to metabolic reprogramming, reduced inflammation, and improved oxygen handling as convergent mechanisms of SGLT2-mediated kidney protection. ClinicalTrials.gov: NCT04333823.