SGLT2 inhibition modulates metabolic, vascular, and inflammatory molecular markers in the kidney in youth with type 1 diabetes
In brief
Dapagliflozin restores healthy kidney gene patterns in 55% of youth
In a 16-week placebo-controlled trial of 98 adolescents with type 1 diabetes and hyperfiltration, dapagliflozin shifted more than half of altered kidney genes toward normal expression, accompanied by reduced hyperfiltration, better glucose control, and improved medullary oxygenation. These molecular and clinical changes suggest a potential kidney-protective mechanism, but longer-term outcome data are still needed.
- Journal
- Science translational medicine (Q1)
- Published
- 22 July 2026
- Study design
- Randomized controlled trial
- Evidence level
- Level 1, High (CEBM 1b)
- Authors
- Petter Bjornstad, Ye Ji Choi, Phoom Narongkiatikhun, Anil Karihaloo, Pottumarthi V Prasad, Lu-Ping Li, et al.
- PMID
- 42485434
- DOI
- 10.1126/scitranslmed.aee1005
Why clinicians should know about it
- Picked for Biochemistry (medical) (top studies of the week, 26 July 2026).
- Picked for Immunology and Allergy (top studies of the week, 26 July 2026).
- Picked for Radiology, Radiation Oncology, Nuclear Medicine, Medical Physics and Imaging (top studies of the week, 26 July 2026): High-quality evidence in a top journal
- Picked for Endocrinology, Diabetes and Metabolism (paper of the day, 23 July 2026).
Abstract
Sodium-glucose cotransporter-2 (SGLT2) inhibitors slow diabetic kidney disease progression, but their intrarenal mechanisms remain incompletely understood, particularly in type 1 diabetes (T1D), where kidney protection has not been definitively established. ATTEMPT (NCT04333823) was a placebo-controlled trial in which 98 youth (ages 12 to 21) with T1D and hyperfiltration were randomized 1:1 to dapagliflozin (5 milligrams) or placebo for 16 weeks. Participants underwent sequential kidney biopsies, multiparametric kidney MRI, and plasma and urine proteomics. The sequential research kidney biopsies were performed on adults 18 years or older at one of three sites (baseline n = 16, follow-up n = 11). Single-cell RNA sequencing of 214,415 cells across 27 biopsies revealed coordinated transcriptional shifts across nephron, vascular, and immune compartments. In the proximal tubule, the primary site of SGLT2 expression, dapagliflozin down-regulated glycolysis, gluconeogenesis, and oxidative stress markers. Endothelial cells showed reduced profibrotic and inflammatory gene expression with increased protective factors. Podocytes demonstrated enhanced cytoskeletal reinforcement and suppressed interferon signaling. These molecular changes paralleled clinical improvements, including attenuation of hyperfiltration, improved glycemic control, and normalization of medullary oxygenation. Trajectory analyses revealed dapagliflozin shifted tubular cells from injury-prone toward healthier phenotypes. Cross-cohort comparison against healthy controls showed that more than 55% of dapagliflozin-responsive genes shifted toward healthy control expression patterns. Urine proteomics mirrored tissue changes with decreased injury markers and increased protective proteins. These convergent molecular mechanisms, metabolic reprogramming, dampened inflammation, and normalized oxygen handling provide hypothesis-generating mechanistic insights into potential kidney-protective mechanisms of SGLT2 inhibitor therapy in youth with T1D.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.