Sodium-glucose cotransporter-2 inhibitors protect tissues via cellular and mitochondrial pathways: Experimental and clinical evidence

Table 1 Major scientific studies demonstrating tissue protection by sodium-glucose cotransporter-2 inhibitors

SGLT2i	Study design	Animal/human	Protected tissue	Effect	Ref.
Dapagliflozin	Animal study	Rabbits	Blood vessels	Activation of Kv channels and PKG	[16]
Empagliflozin	Animal study	Mice	Adipose tissue, and liver	Induction of anti-inflammatory macrophage 2 phenotype of macrophages	[18]
Canagliflozin	Animal study	Mice	Adipose tissue	Induction of AMPK-SIRT1-Pgc-1α signalling pathway	[19]
Canagliflozin	Animal study	Mice	Liver	Enhancing FGF21-ERK1/2 pathway activity	[21]
Empagliflozin	Animal study	Mice	Pancreas	Activation of the NLRP3/caspase-1/GSDMD pathway	[23]
Canagliflozin	Animal study	Mice	Kidney	Normalized Pin1 expression and AMPK activation	[25]
Canagliflozin	Animal study	Mice	Kidney	Autophagy modulation	[26]
Empagliflozin and canagliflozin	Cell culture	Renal cells	Kidney	Block basal and TGF-β1-induced expression	[27]
Luseogliflozin	Human study and animal study	Human and xenopus laevis oocytes	Kidney	Uric acid transport activity	[28]
Empagliflozin	Animal study	Mice	Heart	Improving mitochondrial homeostasis	[30]
Empagliflozin	Animal study	Mice	Heart	Modulation of the Beclin 1-TLR9-SIRT3 complexes in the mitochondria	[32]
Empagliflozin	Human study	Human	Heart	Reduced the combined risk of cardiovascular death or hospitalization for heart failure	[36]
Dapagliflozin	Animal study	Mice	Kidney, liver, and heart	Induction of the AMPK-mTORC1 signaling	[41]

AMPK: Adenosine monophosphate-activated protein kinase; ERK: Extracellular signal-regulated kinase; FGF21: Fibroblast growth factor 21; GSDMD: Gasdermin D; mTORC1: Mechanistic target of rapamycin complex 1; NLRP3: Nucleotide-binding oligomerization domain-like receptor protein 3; SIRT: Sirtuin; SGLT2i: Sodium-glucose cotransporter-2 inhibitors; TGF-β: Transforming growth factor beta; TLR9: Toll-like receptor 9.