- Design
- Proteomic secondary analysis of a randomised placebo-controlled trial
- Population
- 2,485 DAPA-CKD participants with eGFR 25–75 and albuminuria
- Primary outcome
- Plasma proteins and pathways linked to kidney outcomes and modified by dapagliflozin
- Effect
- 216 proteins modified; KIM-1 −14.9% (−17.9 to −11.7); 35 of 137 progression pathways modified
Published in Kidney International in July 2026, this analysis measured 3,072 plasma proteins in 2,485 DAPA-CKD participants with eGFR 25–75 and albuminuria. It identified pathways linked to the composite kidney outcome — chiefly fibrosis, insulin-like growth factor transport and TNF signalling — and asked which dapagliflozin changed.
After 12 months, dapagliflozin modified 216 proteins compared with placebo. Kidney injury molecule-1 fell most (−14.9%, 95% CI −17.9 to −11.7). Of 137 pathways linked to kidney progression, 35 were modified, mostly related to extracellular matrix remodelling, inflammation, fibrosis and immune-vascular interactions.
This is mechanism-generating work. It adds biological plausibility to the clinical benefit already shown in DAPA-CKD but does not change who should receive the drug.
- The clinical case for SGLT2 inhibitors in CKD rests on outcome trials; this adds mechanism, not a new indication.
- Kidney injury molecule-1 fell by about 15% on dapagliflozin, suggesting less tubular stress.
- Pathways modified were mostly inflammatory and fibrotic, beyond glucose and haemodynamic effects.
- Proteomic markers are research tools and are not used to guide treatment.
Why it matters
It helps explain why SGLT2 inhibitors protect kidneys in people without diabetes.
Don't overread it
Protein pathway changes are associations with mechanism, not proof of how the drug protects kidneys.
The statistics, in plain English
A 14.9% placebo-corrected fall in KIM-1 with a narrow interval is a precise biomarker change. Pathway analysis tests many hypotheses at once, so individual pathway findings need replication.
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