Direct cardiac or systemic? Reexamining the cardiovascular mechanisms of SGLT2 inhibitors and GLP-1 receptor agonists

Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve cardiovascular (CV) outcomes in type 2 diabetes mellitus, and several agents benefit patients without diabetes, yet their mechanisms remain incompletely understood. This narrative review examines whether these benefits arise from direct cardiac actions, systemic hemodynamic and metabolic effects, or both. We performed a structured PubMed search for CV outcome trials, mediation analyses, human mechanistic and imaging studies, and preclinical studies, classifying each proposed mechanism by its supporting evidence. Outcome trials consistently show that SGLT2 inhibitors reduce heart failure (HF) hospitalization and slow kidney disease progression, whereas GLP-1 RAs reduce atherosclerotic events, but these trials cannot identify the responsible mechanisms. Human data support contributions from natriuresis, decongestion, and renal hemodynamics for SGLT2 inhibitors and from glycemic, vascular, and anti-inflammatory effects for GLP-1 RAs, although mediation analyses explain only part of either class's benefit. Direct myocardial actions remain largely hypothetical in humans. The CV effects of both classes are best viewed as overlapping, interacting hemodynamic, renal, metabolic, vascular, and neurohormonal mechanisms rather than a direct-versus-systemic dichotomy. Clinically, the evidence supports prioritizing SGLT2 inhibitors for HF and chronic kidney disease and GLP-1 RAs for atherosclerotic CV disease and obesity-related risk.