Proteins and signalling pathways targeted by dapagliflozin and finerenone: Insights from DAPA-CKD and FIGARO-DKD
A proteomic analysis of the DAPA-CKD and FIGARO-DKD trials shows dapagliflozin and finerenone act largely through distinct molecular pathways, giving mechanistic support for why the two drug classes deliver complementary, additive kidney protection.
Study design
A post hoc analysis used Olink Explore proteomic data from 1616 DAPA-CKD and 929 FIGARO-DKD participants with type 2 diabetes and CKD. Analysis of covariance and linear mixed models assessed the effect of dapagliflozin and finerenone versus placebo on plasma protein levels, followed by pathway enrichment analysis.
Key findings
Individual proteins affected by finerenone and dapagliflozin showed very little overlap. Finerenone enriched coagulation, inflammatory and immune-signalling pathways, whereas dapagliflozin enriched lipid metabolism, erythrocyte gas exchange and leukocyte migration pathways. Both agents modulated the endothelin-1 pathway and extracellular matrix remodelling pathways such as hepatic fibrosis and BMP signalling.
Clinical implications
The divergent proteomic signatures provide a mechanistic basis for the independent and possibly additive cardiorenal effects of SGLT2 inhibitors and finerenone, supporting combination therapy; direct proteomic analysis of the CONFIDENCE combination trial is needed to confirm the findings.
Category
Research
Source
Diabetes, Obesity & Metabolism
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