Nephrology · Medical Literature
SGLT2 inhibition modulates metabolic, vascular, and inflammatory molecular markers in the kidney in youth with type 1 diabetes.
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.
Clinical relevance
SGLT2 inhibitors have demonstrated kidney-protective effects in type 2 diabetes and CKD, but intrarenal mechanisms in type 1 diabetes (T1D) — particularly in pediatric and adolescent populations — remain poorly characterized and kidney protection has not been definitively established. This trial addresses a critical gap by applying single-cell RNA sequencing, multiparametric kidney MRI, and multi-omic profiling to sequential research biopsies in youth with T1D and hyperfiltration, a high-risk early phenotype. Mechanistic clarity in this population is urgently needed to justify expanding SGLT2 inhibitor use to younger T1D patients before irreversible structural injury occurs.
Key findings
1. In a randomized, placebo-controlled trial (ATTEMPT; NCT04333823), 98 youth aged 12–21 years with T1D and hyperfiltration were randomized 1:1 to dapagliflozin 5 mg or placebo for 16 weeks, with sequential research kidney biopsies performed in adult participants (baseline n=16, follow-up n=11). 2. Single-cell RNA sequencing of 214,415 cells across 27 biopsies identified coordinated transcriptional changes across nephron, vascular, and immune compartments in dapagliflozin-treated subjects. 3. In proximal tubular cells (the primary site of SGLT2 expression), dapagliflozin down-regulated transcriptional programs governing glycolysis, gluconeogenesis, and oxidative stress, consistent with metabolic reprogramming away from injury-prone states. 4. Endothelial cells showed reduced profibrotic and inflammatory gene expression alongside upregulation of protective factors; podocytes demonstrated enhanced cytoskeletal reinforcement and suppressed interferon signaling, suggesting multi-compartment glomerular protection. 5. Trajectory analyses demonstrated that dapagliflozin shifted tubular cell states from injury-prone toward healthier phenotypes, and cross-cohort comparison against healthy controls showed that more than 55% of dapagliflozin-responsive genes shifted toward healthy control expression patterns. 6. Clinical improvements paralleled the molecular findings, including attenuation of hyperfiltration, improved glycemic control, normalization of medullary oxygenation on multiparametric MRI, decreased urine injury biomarkers, and increased urinary protective proteins on proteomics; specific effect sizes, confidence intervals, and p-values for these endpoints were not reported in the abstract.
Practice implications
These mechanistic data provide hypothesis-generating, biologically plausible support for renoprotective effects of dapagliflozin in youth with T1D and hyperfiltration, a population not yet covered by definitive outcome trial evidence, and should prompt clinicians to consider SGLT2 inhibitor therapy early in the disease course before structural injury is established. Patient selection should prioritize adolescents and young adults (≥18 years for biopsy-confirmed phenotyping) with documented hyperfiltration, as this appears to be the highest-yield target population based on trial enrollment criteria. Pending confirmatory outcomes data, these findings support ongoing surveillance with functional biomarkers (eGFR trajectory, urine proteomics) and reinforce the importance of enrolling eligible T1D youth in prospective trials to establish definitive kidney-protective efficacy.