Stratifying Cardiovascular–Kidney–Metabolic Syndrome by Metabolic Dysfunction-Associated Steatotic Liver Disease: A Pathophysiology-Anchored, India-Contextualized Framework for Node-Directed Pharmacotherapy

Abstract

Abstract

The same drug can protect the heart, the kidney and the liver at once—not by coincidence, but because these organs share a small set of molecular failure points. Cardiovascular–kidney–metabolic (CKM) syndrome, formalized by the American Heart Association in 2023^1,2 and codified in the first-ever 2026 AHA/ACC/ADA/ASN multisociety guideline³, describes the progression from dysfunctional adiposity through cardiorenal and metabolic injury. Its staging construct, however, incorporates the liver only implicitly, despite metabolic dysfunction-associated steatotic liver disease (MASLD)⁴ being both a near-universal companion of CKM and an independent, pharmacologically actionable amplifier of its trajectory. This review advances a pathophysiology-anchored framework positioning MASLD as the hepatic node of CKM and liver fibrosis stage as a quantitative modifier that reclassifies cardiorenal-metabolic risk. We first deconstruct the shared molecular nodes linking liver, heart, kidney and adipose tissue—adipose lipotoxicity, hepatic de novo lipogenesis and the thyroid/ATP-citrate lyase axis, stellate-cell fibrosis, NLRP3-inflammasome inflammation, the mineralocorticoid–fibrotic axis, the cardiorenal hemodynamic–tubular axis, and the gut–liver axis. We then map the contemporary pharmacopoeia—incretin and multi-agonists, sodium–glucose cotransporter-2 (SGLT2) inhibitors, pioglitazone, the thyroid hormone receptor-β agonist resmetirom, fibroblast growth factor 21 (FGF21) analogues, the nonsteroidal mineralocorticoid antagonist finerenone, bempedoic acid, low-dose colchicine, and microbiome-directed strategies—onto these nodes rather than onto organ silos; two agents (resmetirom³⁶ and semaglutide²⁴) now carry regulatory approval for steatohepatitis with fibrosis. Because the epidemiology, phenotype, genetics, diet and drug-access realities of South Asia materially alter how the framework applies, we integrate an India-specific analysis throughout^59,62. Synthesising the evidence into a CKM-stage × fibrosis-stage selection matrix (rendered as an India-adapted therapeutic ladder) and a tiered evidence appraisal, we argue that fibrosis stage, not organ label, should guide individualised pharmacotherapy across the CKM spectrum.