A Precision Framework Uses Biomarkers to Target Heart, Kidney and Metabolic Drugs

Cardiovascular-kidney-metabolic syndrome was formally defined by the American Heart Association in 2023, yet it already touches nearly nine in ten American adults at measurable stages. Managing it requires navigating an expanding arsenal of drug classes whose mechanisms overlap across the heart, kidneys, and metabolic tissues — a complexity that demands smarter decision tools.

This comprehensive review from researchers at Sun Yat-sen University, Zhejiang University, Shanxi Medical University, and Temple University proposes a three-dimensional biomarker framework for precision pharmacotherapy. Rather than treating biomarkers as passive diagnostic flags, the authors position them as active guides for drug selection, mechanistic interpretation, and therapeutic monitoring.

The organ-specific dimension clarifies molecular mechanisms: SGLT2 inhibitors shift myocardial fuel use toward ketone bodies and may inhibit NHE1, explaining cardioprotection; sacubitril/valsartan's neprilysin selectivity accounts for differential natriuretic peptide responses; and tubuloglomerular feedback underlies SGLT2 inhibitors' renoprotective hemodynamic effects. The pathway-specific dimension identifies cross-organ biomarkers — hs-CRP, IL-6, galectin-3, GDF-15, FGF21 — that point to shared targets including the NLRP3 inflammasome axis (canakinumab, colchicine), IL-6 trans-signaling (ziltivekimab), and FGF21/β-klotho metabolic pathways. The temporal dimension shows how serial biomarker changes, such as the transient eGFR dip after SGLT2 inhibitor initiation or natriuretic peptide shifts during combination therapy, distinguish expected pharmacodynamic effects from true disease worsening.

The authors coin the term 'pharmacological phenotyping' — using multi-biomarker panels to define drug-responsive physiological states analogous to oncology companion diagnostics. They pair this with a drug-biomarker interaction matrix and highlight pipeline agents including RNA-based Lp(a) therapies, FGF21 analogues, galectin-3 inhibitors, and in vivo CAR-T anti-fibrotic strategies.

As a narrative review relying primarily on existing literature and preclinical data, prospective validation of this framework in clinical populations will be essential before widespread adoption.