SGLT2-inhibitors and Kidney Markers in Youth with T1D
Petter Bjornstad, Ye Ji Choi, Phoom Narongkiatikhun, Anil Karihaloo Pottumarthi V Prasad, Lu-Ping Li, ……., Daniël H van Raalte, David Z I Cherney, Laura Pyle, Farid H Mahmud, Matthias Kretzler
SGLT2 inhibition modulates metabolic, vascular, and inflammatory molecular markers in the kidney in youth with type 1 diabetes. Sci Transl Med. 2026 Jul 22;18(859):eaee1005.
Adults with type 1 diabetes (T1D) experience a moderate but clinically relevant decline in Sodium-glucose cotransporter-2 (SGLT2) inhibitors are known to slow the progression of diabetic kidney disease, but exactly how they protect the kidney in type 1 diabetes (T1D) has remained unclear. This ancillary mechanistic study, conducted within the ATTEMPT trial (a 16-week, placebo-controlled trial of dapagliflozin in 98 adolescents and young adults with T1D and hyperfiltration), used paired kidney biopsies, single-cell RNA sequencing, kidney MRI, and plasma/urine proteomics to map the drug's effects at the cellular level. Findings were further validated against an independent cohort of people with T1D and healthy controls (the CROCODILE study).
Key findings:
- Dapagliflozin reduced hyperfiltration and improved metabolic control: Compared with placebo, dapagliflozin significantly lowered measured GFR (attenuating hyperfiltration), reduced HbA1c, and improved time-in-range, confirming the clinical benefits seen in the parent trial.
- Proximal tubule cells shifted toward a healthier metabolic state: Dapagliflozin down-regulated genes tied to glycolysis, gluconeogenesis, and oxidative stress, reducing the "hypermetabolic," injury-prone profile characteristic of diabetic tubular cells.
- Endothelial cells showed reduced inflammation and fibrosis risk: Genes promoting fibrosis and vascular inflammation were suppressed, while protective, anti-inflammatory factors increased, suggesting improved blood vessel health within the kidney.
- Podocytes (filtration cells) were reinforced and protected: Structural genes supporting the cell's cytoskeleton increased, while stress and injury-related signaling decreased, indicating a protective effect on the kidney's filtration barrier.
- Kidney oxygen handling was normalized: MRI showed changes in oxygenation patterns consistent with correction of the abnormal "hyperoxygenated" medulla seen in diabetic kidneys, aligning with a healthier oxygen supply-demand balance.
- Molecular changes matched a shift toward the non-diabetic, healthy kidney state: When benchmarked against the independent healthy-control cohort, more than half of the diabetes-associated genes affected by dapagliflozin moved in the direction of healthy kidney tissue.
- Effects were localized to the kidney, not systemic: Urine proteomics showed clear reductions in injury and fibrosis markers, while plasma protein levels remained largely unchanged, suggesting the drug's molecular effects are concentrated within the kidney itself.
This hypothesis-generating study provides some of the first direct human tissue evidence for how SGLT2 inhibitors may protect the kidney in type 1 diabetes, reinforcing their potential role as an early, targeted therapy to prevent diabetic kidney disease.
Concluding, the authors state
"In conclusion, this work provides a multimodal view of how the
kidney of a person with T1D responds to SGLT2 inhibition."
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