Sodium-glucose cotransporter 2 inhibitors in the context of cardiorenal-metabolic comorbidity. Part 1: Pathophysiology and key clinical studies

Abstract

This article is the first in a series of reviews on modern concepts of nephroprotection within the cardiorenal–metabolic continuum and the pleiotropic effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors. It summarizes the pathophysiological mechanisms linking arterial hypertension, type 2 diabetes mellitus, chronic kidney disease, ischemic heart disease, and obesity into an integrated system of metabolic and vascular injury. Key drivers of target organ damage include insulin resistance, glucotoxicity, lipotoxicity, oxidative stress, systemic inflammation, endothelial dysfunction, and glomerular hemodynamic instability, forming a self-perpetuating cycle that accelerates renal and cardiac decline.

The review outlines molecular and cellular mechanisms of nephroprotection mediated by SGLT2 inhibition-restoration of tubuloglomerular feedback, reduction of intraglomerular pressure, modulation of energy metabolism through a ketone shift, attenuation of oxidative stress and inflammation, and inhibition of the renin–angiotensin–aldosterone system. The role of oxidative stress biomarkers such as 8-oxo-2′-deoxyguanosine is highlighted as a potential tool for early diagnosis and therapy monitoring.

Particular attention is given to adipose tissue dysfunction, adipokine imbalance, and sarcopenic obesity as contributors to insulin resistance and vascular aging. Against this background, SGLT2 inhibitors emerge not only as pharmacological agents but as metabolic modulators capable of restoring kidney–heart-vessel-metabolism interactions. Understanding these unified mechanisms forms the basis for personalized therapeutic strategies and sets the stage for the second part of this review, focused on multi-omics approaches to individualized organ protection.