Abstract
Cardiovascular-Kidney-Metabolic syndrome, introduced by the American Heart Association in 2023, represents a complex and interconnected spectrum of diseases driven by shared pathophysiological mechanisms. However, this framework notably excludes the liver-an organ fundamental to metabolic regulation. Building on this concept, Cardiovascular-Renal-Hepatic-Metabolic (CRHM) syndrome incorporates the liver's pivotal role in this interconnected disease spectrum, particularly through its involvement via metabolic dysfunction-associated steatotic liver disease (MASLD). Despite the increasing prevalence of CRHM syndrome, unified management strategies remain insufficiently explored. This review addresses the following critical question: How can novel anti-diabetic agents, including sodium-glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dual gastric inhibitory polypeptide (GIP)/GLP-1RA, offer an integrated approach to managing CRHM syndrome beyond the boundaries of traditional specialties? By synthesizing evidence from landmark clinical trials, we highlight the paradigm-shifting potential of these therapies. SGLT2is, such as dapagliflozin and empagliflozin, have emerged as cornerstone guideline-directed treatments for heart failure (HF) and chronic kidney disease (CKD), providing benefits that extend beyond glycemic control and are independent of diabetes status. GLP-1RAs, e.g., semaglutide, have transformed obesity management by enabling weight reductions exceeding 15% and improving outcomes in atherosclerotic cardiovascular disease (ASCVD), diabetic CKD, HF, and MASLD. Additionally, tirzepatide, a dual GIP/GLP-1RA, enables unprecedented weight loss (>20%), reduces diabetes risk by over 90%, and improves outcomes in HF with preserved ejection fraction (HFpEF), MASLD, and obstructive sleep apnea. By moving beyond the traditional organ-specific approach, we propose a unified framework that integrates these agents into holistic management strategies for CRHM syndrome. This paradigm shift moves away from fragmented, organ-centric management toward a more unified approach, fostering collaboration across specialties and marking progress in precision cardiometabolic medicine.