Integrating the liver into the cardiovascular-kidney-metabolic syndrome: pathophysiology and therapeutic implications

This review examines the mechanistic, epidemiological and therapeutic evidence underpinning liver integration into the cardiovascular-kidney-metabolic (CKM) construct. For the purposes of this review, we use the term cardiovascular-renal-hepatic-metabolic (CRHM) syndrome to denote this expanded framework, acknowledging that consensus nomenclature is yet to be established.

Large cohort data confirm that coexistent metabolic dysfunction-associated steatotic liver disease (MASLD) and CKD confer additive, stage-dependent mortality risk exceeding that of either condition alone, with hepatic fibrosis severity, rather than steatosis, the dominant prognostic driver. The past 12-18 months have seen significant therapeutic developments spanning the full CRHM spectrum. Resmetirom, a hepato-selective thyroid hormone receptor-β (THR-β) agonist, received FDA-accelerated approval (March 2024) and European Commission conditional marketing authorization (August 2025) as the first licensed metabolic dysfunction-associated steatohepatitis (MASH)-specific therapy; UK approval is pending. Incretin-based therapies demonstrated efficacy across the full CRHM spectrum: semaglutide in diabetic and non-diabetic kidney disease across FLOW, SELECT, and SMART trials; tirzepatide in obesity-related heart failure with preserved ejection fraction (HFpEF) in SUMMIT. Semaglutide additionally received accelerated FDA approval and EU marketing authorization for MASH following the ESSENCE trial; UK approval for this indication is pending.

The integration of the liver into CKM staging now has implications for how clinicians stratify risk and select therapy. Early identification of MASLD in CKD cohorts using validated noninvasive fibrosis tools should be considered standard practice in high-risk populations.