SGLT2 inhibition modulates metabolic, vascular, and inflammatory molecular markers in the kidney in youth with type 1 diabetes.

Summary

In a randomized, placebo-controlled trial (ATTEMPT) of 98 youth with type 1 diabetes and hyperfiltration, dapagliflozin for 16 weeks enabled unprecedented intrarenal profiling with sequential biopsies, MRI, and proteomics. SGLT2 inhibition reshaped metabolic, vascular, and inflammatory molecular signatures within the kidney, offering mechanistic insight into potential renoprotection in type 1 diabetes.

Key Findings

• Randomized 98 youth (12–21 years) with T1D and hyperfiltration to dapagliflozin 5 mg vs placebo for 16 weeks.
• Sequential kidney biopsies (in adults ≥18 years) with MRI and proteomics revealed modulation of metabolic, vascular, and inflammatory pathways by SGLT2 inhibition.
• Study provides direct intrarenal mechanistic evidence in T1D, a population where kidney protection by SGLT2i has not been definitively established.

Clinical Implications

Findings support kidney-targeted mechanisms of SGLT2 inhibition in type 1 diabetes and may inform biomarker development, patient selection, and intermediate endpoints for future renoprotective trials in T1D.

Limitations

• Kidney biopsies were performed only in adult participants (≥18 years), limiting generalizability to younger teens.
• Short intervention duration (16 weeks) and modest sample size restrict inference on long-term clinical renal outcomes and safety.

Future Directions

Validate intrarenal markers as surrogate endpoints, extend to longer trials powered for hard renal outcomes in T1D, and explore age-dependent effects and dose-response.