Sodium-glucose cotransporter 2 inhibitors in the context of cardiorenal-metabolic comorbidity. Part 2: Metabolomic aspects of nephroprotection

Abstract

The article is the second part of a review series devoted to metabolomic aspects of nephroprotection in cardiorenal-metabolic comorbidity and the pleiotropic effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors. Cardiorenal-metabolic syndrome, which integrates hypertension, type 2 diabetes mellitus, ischemic heart disease, and obesity, represents a pathological continuum associated with a high risk of chronic kidney disease (CKD) progression and cardiovascular events. Although SGLT2 inhibitors have fundamentally changed the organ-protective paradigm, clinical response remains heterogeneous, underscoring the need for predictive tools and personalized strategies. This review summarizes current clinical, experimental, and metabolomic evidence regarding the mechanisms underlying SGLT2 inhibitor–mediated nephroprotection. Patients with CKD in the setting of metabolic comorbidity demonstrate a characteristic metabolomic profile marked by mitochondrial dysfunction, impaired energy metabolism, accumulation of branched-chain amino acids, dysregulation of tricarboxylic acid cycle intermediates, oxidative stress, and chronic inflammation. Urinary 8-hydroxy-2′-deoxyguanosine is highlighted as a marker of DNA damage associated with albuminuria and glomerular filtration rate decline. SGLT2 inhibitors induce metabolic reprogramming toward more energy-efficient substrate utilization, restore mitochondrial bioenergetics, reduce renal hypoxia, and modulate lipidomic and inflammatory pathways. Identified metabolomic shifts correlate with regression of albuminuria and improved cardiovascular outcomes. Emerging data on biomarker panels, SLC5A2 genetic variants, and epigenetic mechanisms further support the concept of precision nephroprotection. Metabolomics is therefore evolving from a research tool into a promising clinical approach for patient stratification within the cardiorenal-metabolic continuum.