Supplementary file 1_Soluble guanylate cyclase modulation in heart failure and chronic kidney disease: mechanisms, clinical evidence, and translational boundaries.docx

In VICTORIA, the reduction in the composite endpoint of cardiovascular death or first HF hospitalization was primarily driven by fewer HF hospitalizations, with no statistically significant reduction in cardiovascular death alone. Conversely, the VICTOR trial was neutral for its primary endpoint in stable ambulatory HFrEF, and HFpEF studies of vericiguat or praliciguat did not improve their prespecified biomarker, health-status, or exercise endpoints.

In CKD populations, runcaciguat and avenciguat have shown short-term albuminuria reductions, but these surrogate signals have not established durable kidney protection, including long-term preservation of eGFR or prevention of kidney failure. To contextualize heterogeneous evidence, we propose an evidence-interpretation framework incorporating HF phenotype and clinical state, CKD phenotype, putative sGC redox biology, and endpoint domain.

This framework is intended for evidence interpretation and hypothesis generation rather than patient-level treatment selection; no validated clinical assay defines tissue sGC redox state, and no prospective treatment-by-biomarker interaction has established redox-guided selection. Future studies should prioritize phenotype-enriched HF–CKD populations, contemporary background therapy, and prespecified cardiovascular and kidney outcomes to define the clinical role of sGC modulation.</p>