Key result
SGLT2 inhibitors and GLP-1 RAs offer distinct cardioprotection through hemodynamic versus antiatherosclerotic mechanisms.
Why the study?
Although SGLT2 inhibitors and GLP-1 RAs improve CV outcomes in patients with and without type 2 diabetes mellitus, whether their benefits arise from direct cardiac actions or systemic effects remains incompletely understood.
Do SGLT2 inhibitors and GLP-1 receptor agonists improve cardiovascular outcomes through direct cardiac actions, systemic hemodynamic and metabolic effects, or both?
Do SGLT2 inhibitors and GLP-1 receptor agonists improve cardiovascular outcomes through direct cardiac actions, systemic hemodynamic and metabolic effects, or both?
This narrative review synthesizes mechanistic evidence showing that the cardiovascular benefits of SGLT2 inhibitors and GLP-1 RAs arise from overlapping systemic hemodynamic, renal, metabolic, and vascular pathways rather than isolated direct myocardial effects, supporting the prioritization of SGLT2 inhibitors for heart failure/CKD and GLP-1 RAs for ASCVD/obesity.
Answers are grounded in this paper and cite their sources.
Direct cardiac effects of SGLT2 inhibitors and GLP-1 RAs cannot yet be isolated from systemic benefits; leaves open the dominant mechanism in CV protection.
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.
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Osmanlli et al. (2026) conducted a review in Type 2 diabetes mellitus, heart failure, chronic kidney disease, atherosclerotic cardiovascular disease, and obesity-related risk. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) was evaluated on Cardiovascular mechanisms, heart failure hospitalization, kidney disease progression, and atherosclerotic events. SGLT2 inhibitors reduce heart failure hospitalization and kidney disease progression via systemic hemodynamic effects, while GLP-1 RAs reduce atherosclerotic events via metabolic and vascular actions.
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