Review prioritizes SGLT2 inhibitors and incretin agonists for stage-specific cardiovascular-kidney-metabolic syndrome management.

Cardiovascular-kidney-metabolic (CKM) syndrome represents a complex, interdependent continuum linking metabolic risk factors like diabetes and obesity with chronic kidney disease (CKD) and cardiovascular disease (CVD), significantly impacting global health. The escalating prevalence of type 2 diabetes (T2D) highlights an urgent need for therapeutic strategies that extend beyond mere glycemic control to address the intricate pathophysiology underlying these interconnected conditions. Traditional approaches often fall short in providing integrated, multi-organ protection, leaving a critical gap in comprehensive CKM management.

This narrative review synthesized evidence to provide a phenotype-oriented perspective on the cardiovascular-kidney-metabolic (CKM) syndrome spectrum. Researchers conducted a structured literature search to identify relevant studies, scientific statements, consensus documents, clinical guidelines, and pivotal randomized controlled trials. The review evaluated the expanding role of newer antidiabetic drug classes, specifically sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dual or triple-incretin agonists, across the CKM continuum, focusing on their benefits beyond glucose lowering.

The review found that SGLT2 inhibitors, GLP-1RAs, and dual/triple-incretin agonists offer significant benefits in reducing major adverse cardiovascular events (MACEs), attenuating CKD progression, and enhancing metabolic health, largely independent of their glucose-lowering properties. A stage-specific treatment paradigm for CKM syndrome was delineated:

For CKM stage 0-1 (obesity/prediabetes), weight-centric incretin therapy (GLP-1RAs or dual incretins) is prioritized. In CKM stage 2, SGLT2 inhibitors are recommended first for patients with albuminuric CKD and/or heart failure risk, with early addition of GLP-1RAs when CVD or obesity predominates. For CKM stage 3, a layered combination therapy, typically an SGLT2 inhibitor plus a GLP-1RA/dual incretin (with optional finerenone for persistent albuminuria), is advised to maximize cardiovascular and kidney protection.