Cardiovascular protection by SGLT2 inhibitors: an integrative review of mechanistic networks, clinical evidence, and safety considerations

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were originally developed as glucose-lowering agents for type 2 diabetes mellitus, but accumulating evidence has demonstrated their broad cardiovascular and cardiorenal benefits beyond glycemic control. In particular, empagliflozin and dapagliflozin have shown robust prognostic benefits in heart failure with reduced ejection fraction (HFrEF) and expanding therapeutic value in heart failure with preserved ejection fraction (HFpEF). However, their cardiovascular protection cannot be fully explained by glucose lowering alone and is likely mediated through a multilayered network of systemic, metabolic, vascular, and cellular mechanisms. This integrative narrative review summarizes current mechanistic and clinical evidence regarding SGLT2 inhibitors in cardiovascular disease and proposes a translational framework linking hemodynamic rebalancing, cardiometabolic reprogramming, vascular protection, redox homeostasis, mitochondrial quality control, immunometabolic modulation, and attenuation of adverse myocardial remodeling. Clinically, the strongest evidence has been established in heart failure, whereas data in ischemic heart disease, post-myocardial infarction remodeling, and arrhythmias remain promising but less definitive. In post-myocardial infarction settings, SGLT2 inhibitors may improve N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, ventricular remodeling parameters, and heart failure-related outcomes, although effects on hard clinical endpoints remain inconsistent. For atrial arrhythmias, emerging evidence suggests a potential reduction in atrial fibrillation or flutter risk, but dedicated trials are still required. Safety considerations, including genital infections, volume depletion, renal function changes, euglycemic ketoacidosis, and perioperative management, should also be incorporated into individualized clinical decision-making. Overall, SGLT2 inhibitors should be viewed as cardiovascular-metabolic modulators acting through interconnected mechanisms, with future research needed to clarify phenotype-specific benefits and optimize their precision use in cardiovascular disease.