Newer and novel antidiabetic drug classes across the cardiovascular-kidney-metabolic continuum

Cardiovascular-kidney-metabolic (CKM) syndrome represents an intricate and interdependent nexus among metabolic risk factors, such as diabetes and obesity, chronic kidney disease (CKD), and cardiovascular disease (CVD), collectively exerting a profound impact on global morbidity and mortality. The rising prevalence of type 2 diabetes (T2D) underscores the urgent need for therapeutic strategies that transcend glycemic control to target the intricate pathophysiology underlying these conditions. This review examines the expanding role of novel antidiabetic drug classes, including sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dual or triple-incretin agonists, across the CKM continuum. These agents have demonstrated significant benefits in reducing major adverse cardiovascular events (MACEs), attenuating CKD progression, and enhancing metabolic health, independent of their glucose-lowering properties. Across the CKM continuum, we prioritize weight-centric incretin therapy (GLP-1RAs or dual incretins) in stage 0-1 (obesity/prediabetes), SGLT2 inhibitors first for albuminuric CKD and/or heart failure risk in stage 2 (with early addition of GLP-1RAs when CVD/obesity predominates), and layered combination therapy in stage 3, typically SGLT2 inhibitor + GLP-1RA/dual incretin (± finerenone for persistent albuminuria), to maximize cardiovascular and kidney protection. By synthesizing evidence from pivotal clinical trials, evaluating emerging combination therapies, and delineating the evolving treatment paradigm, this review aims to provide a comprehensive perspective on how these antidiabetic therapies influence CKM syndrome management. As research advances, an integrated, multifaceted approach to diabetes care leveraging these agents may lead to substantial improvements in cardiovascular, kidney, and metabolic outcomes.