Proteomic insights into dapagliflozin in CKD
Sodium–glucose cotransporter 2 (SGLT2) inhibitors, such as dapagliflozin, have emerged as a cornerstone therapy for slowing chronic kidney disease (CKD) progression and reducing cardiorenal complications. However, the biological mechanisms underlying these clinical benefits remain incompletely understood. To address this knowledge gap, investigators conducted a large-scale proteomic analysis to identify plasma proteins and molecular pathways associated with CKD progression, and to determine which of these are modulated by dapagliflozin treatment.
Participants were drawn from the double-blind, placebo-controlled, randomised DAPA-CKD trial evaluating the safety and efficacy of dapagliflozin in individuals with CKD (eGFR 25–75 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio 200–5000 mg/g), with or without type 2 diabetes. They were randomly allocated in a 1:1 ratio to dapagliflozin or placebo.
Plasma samples from 2485 of 4304 (57.5%) participants collected at baseline and at 1 year were analysed using the Olink Explore 3072 platform. 2402 proteins were included in the final analyses. Associations were assessed between baseline protein concentrations and a pre-specified composite kidney outcome, defined as the first occurrence of a sustained decline in eGFR of ≥50%, kidney failure, dialysis or kidney transplantation, or death from kidney failure. The effects of dapagliflozin on protein expression after 1 year were also compared with those of placebo. Pathway analyses were subsequently used to identify relevant biological mechanisms.
During a median follow-up of 2.5 years, 224 composite kidney events occurred. A total of 377 proteins were significantly associated with the composite kidney outcome, with associations largely consistent irrespective of diabetes status. Pathway analysis identified hepatic fibrosis, regulation of insulin-like growth factor transport and tumour necrosis factor signalling as the pathways most strongly associated with the outcome. Collectively, these pathways were related predominantly to fibrosis and inflammation.
After 12 months, dapagliflozin treatment changed the plasma concentrations of 216 proteins compared with placebo. The most pronounced reduction was observed in kidney injury molecule-1 (KIM-1), a marker of tubular injury (−14.9%). Of the 137 pathways associated with the composite kidney outcome, 35 (25%) were modulated by dapagliflozin, indicating that the treatment directly influences biological processes implicated in disease progression. Among these, dapagliflozin reversed the activity of 11 pathways (31%) but also increased the activity of 10 pathways (29%) that were positively associated with CKD progression. These pathways were predominantly related to extracellular matrix remodelling, inflammation and fibrosis, and immune–vascular interactions.
This proteomic analysis provides mechanistic insights into the effects of dapagliflozin on CKD progression, which may be mediated through modulation of inflammatory and fibrotic pathways. These findings strengthen the biological rationale for SGLT2 inhibition in CKD and highlight potential therapeutic targets for interventions aimed at slowing disease progression.
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