SGLT2 Inhibitors Confer Cardiovascular Protection via the Gut-Kidney-Heart Axis: Mechanisms and Translational Perspectives
Yimei Tao, Ning Zhang, Zhaoxiang Wang, Ying Pan, Shao Zhong, Hongying Liu
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated significant cardiovascular and renal benefits beyond glycemic control, yet their integrated mechanisms remain incompletely understood. Emerging evidence highlights the gut-kidney-heart axis as a pivotal pathological network, wherein gut dysbiosis, toxic metabolite accumulation, intestinal barrier disruption, and systemic inflammation synergistically drive cardiorenal injury. This review systematically elucidates how SGLT2i modulate this axis through multi-level interventions: reshaping gut microbiota composition, enriching short-chain fatty acid-producing bacteria, suppressing trimethylamine and other toxin-generating microbes, restoring tight junction integrity, and regulating bile acid metabolism. These upstream effects reduce systemic inflammatory and metabolic stress, interrupt kidney-derived toxin amplification, and mitigate myocardial remodeling. Unlike previous reviews focusing on single-organ pathways, this work integrates microecological regulation, metabolite reprogramming, and cross-organ protection into a unified "three-axis convergence to the heart" framework. We also highlight potential species-specific microbiota regulatory profiles among different SGLT2i and propose future directions, including fecal microbiota transplantation and microbiota-targeted co-therapies, to clarify causal relationships and optimize therapeutic strategies. By positioning the gut as a modifiable upstream driver, this framework provides novel mechanistic insight and translational potential for expanding SGLT2i applications in metabolic cardiovascular disease, including in non-diabetic populations.