The principal mechanism of action of sodium-glucose cotransporter 2 (SGLT2) inhibitors is based on the binding to the SGLT2 located in the proximal tubule of nephrons. In healthy subjects, SGLT2 as sodium-dependent glucose transport proteins are responsible for approximately 90% of renal glucose reabsorption [110]. Therefore, inhibition of its function leads to a significant increase in glucose excretion [75]. Additionally, they reduce plasma glucose levels independently of insulin, which may have a protective influence on pancreatic β-cells [85]. A concurrent increase in glucagon secretion has been observed to promote lipolysis and reduce visceral adipose tissue, which results in improvement of insulin resistance and glycemic control [94]. The nephroprotective mechanism of SGLT2 inhibitors depends on the reduction of hyperglycemia-induced glomerular hyperfiltration through the regulation of tubuloglomerular feedback and reduced adenosine triphosphatase activity in the macula densa, followed by afferent arteriolar vasodilation, as empagliflozin treatment increases urinary adenosine excretion and reduces hyperfiltration via afferent arteriolar constriction, effects that are abolished by A1 adenosine receptor blockade [6,14,31,42]. In addition, SGLT2 inhibitors may affect other cells and tissues, such as cardiomyocytes, endothelial cells, adipocytes through regulating inflammation, oxidative stress, senescence and fibrosis [25,56]. It is important to mention that action of SGLT2 inhibitors can affect not only SGLT-2 but also SGLT-1 transporters and as well additional targets. For example, multiple SGLT-2 inhibitors, including empagliflozin, targets also SGLT-1/SLC5A according to binding DB. While ertugliflozin targets additionally SGLT-3/SLC5A11, and dapagliflozin not only SGLT-2, SGLT-1, but also SGLT-3 and SGLT-6/SLC5A11 [108].

MicroRNAs (miRNA, miR) are small (18–25 nt), endogenous, single-stranded, non-coding RNAs (ncRNAs) able to suppress translation and post-translational processes of proteins synthesis via binding to complementary regions of messenger transcripts or less frequently inducing messengerRNAs (mRNA) degradation [23]. They control over half of the mammalian protein-coding genes, affecting significant molecular and cellular processes regulating homeostasis [77]. Several studies showed that miRNAs demonstrate potential as prognostic biomarkers and therapeutic targets. Impaired miRNA abundance has been observed in scientific research and clinical practice in various chronic states, such as diabetes, autoimmune diseases, chronic kidney disease (CKD) and heart failure (HF) [37,93].

Circular RNAs (circRNAs) are a class of endogenous, single-stranded ncRNAs featuring covalently closed continuous loops form. This structure provides stability and results in abundance of the circRNAs in the cytoplasm [29]. It has been proposed that circRNA regulates gene expression at the transcriptional and post-transcriptional level by sponging to miRNAs and by altering interactions between proteins [46]. Increasing number of studies report the effect of SGLT2 inhibitors on modifying circRNAs expression, which may suggest another mechanism of action for this group of drugs [97]. Additionally, the role of circRNAs has been implicated in diabetes mellitus, cardiovascular diseases and cancer (X. [102]).

Therefore, we aim to review the up-to-date knowledge of protective effects of SGLT2 inhibitors action in various states and conditions by affecting ncRNAs expression.