Integrated Management of Cardiovascular-Renal-Hepatic-Metabolic Syndrome: Expanding Roles of SGLT2is, GLP-1RAs, and GIP/GLP-1RAs

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.

Keywords: arterial hypertension; cardiometabolic medicine; cardiovascular–kidney–metabolic syndrome; cardiovascular–renal–hepatic–metabolic syndrome; chronic kidney disease; diabetes mellitus; dyslipidemia; heart failure; metabolic dysfunction-associated steatotic liver disease; obesity.

Figure 1

SGLT2is, GLP-1RAs, and GIP/GLP-1RAs for the integrated management of Cardiovascular–Renal–Hepatic–Metabolic syndrome. Abbreviations: CAD (coronary artery disease); CKD (chronic kidney disease); GLP-1RAs (glucagon-like peptide-1 receptor agonists); GIP (Glucose-Dependent Insulinotropic Polypeptide); HF (heart failure); MASLD (metabolic dysfunction-associated steatotic liver disease); PAD (Peripheral Artery Disease); SGLT2is (sodium–glucose cotransporter-2 inhibitors); T2DM (type 2 diabetes mellitus).

Figure 2

The spectrum of Cardiovascular–Renal–Hepatic–Metabolic diseases and its distinction from other frameworks. The spectrum of cardiometabolic diseases encompassing the cardiometabolic (CM), Cardiovascular–Kidney–Metabolic (CKM), and Cardiovascular–Renal–Hepatic–Metabolic (CRHM) frameworks. This figure illustrates the progression from isolated cardiometabolic interactions to the broader integration of renal and hepatic contributions. The CRHM framework uniquely emphasizes the liver’s role in systemic inflammation, insulin resistance, and lipid dysregulation, with metabolic dysfunction-associated steatotic liver disease serving as a central component. This comprehensive model highlights the interconnected pathophysiology across the cardiovascular, renal, hepatic, and metabolic systems, differentiating CRHM from the narrower CKM and CM spectrums.

Figure 3

The key cardioprotective mechanisms of GLP-1RAs and SGLT2is.

Figure 4

A proposed algorithm for the use of SGLT2is, GLP-1RAs, and GIP/GLP-1RAs for the management of CRHM syndrome. This illustration shows our proposed algorithm for the use of established SGLT2is, GLP-1RAs, and GIP/GLP-1RAs across CRHM syndrome based on the available guidelines and phase III randomized controlled trials. The use of GLP-1RAs and GIP/GLP-1RAs in HF, diabetic CKD and MASLD has not yet been recommended by guidelines because the evidence from trials is very recent. Abbreviations ASCVD (atherosclerotic cardiovascular disease); BMI (body mass index); CKD (chronic kidney disease); DM (Diabetes Mellitus); eGFR (estimated glomerular filtration rate); GIP (Glucose-Dependent Insulinotropic Polypeptide); GLP-1RA (glucagon-like peptide-1 receptor agonist); HF (heart failure); HFmrEF (heart failure with mildly reduced ejection fraction); HFpEF (heart failure with preserved ejection fraction); HFrEF (heart failure with reduced ejection fraction); MASLD (metabolic dysfunction-associated steatotic liver disease); SCORE2 (Systematic Coronary Risk Evaluation 2); SGLT2is (sodium–glucose cotransporter-2 inhibitor); TOD (target organ damage); T2DM (Type 2 Diabetes Mellitus); UACR (urinary albumin-to-creatinine ratio).