Table 1.

Putative Extra-Glycemic Effects of SGLT2i

Action	Putative Mechanism	Source of the Evidence
Blood pressure reduction	Osmotic diuresis and Natriuresis Reduction of arterial stiffness Improved endothelial function	RCTs and CVOTs10–13,47,52,53 Small human studies93–95 Small human studies94,96
Body weight reduction	Increased glucose excretion	RCTs and CVOTs10–13,47–49
Uric acid reduction	Reduced urate reabsorption	RCTs and CVOTs59,60
Ketone bodies increase	Glucagon secretion and suppression of insulin production due to lower plasma glucose level Direct effect on alfa cells	Small human studies62 Human alfa cells63
LDL and HDL cholesterol increase, triglycerides reduction	Increased lipoprotein lipase activity Accelerated clearance of VLDL Delayed turnover LDL	RCTs and CVOTs10–13,77 Animal model (mice)78
Liver steatosis amelioration	Reduction of liver fat content Reduction in hepatocyte injury biomarkers (AST, ALT, GGT)	Small human studies81–84 Large RCTs85,86
Hematocrit increase	Reduction in plasma volume Increase in erythropoietin	RCTs and CVOTs87,89 Small RCTs88
Cytoplasmic sodium and calcium concentration decreased, mitochondrial calcium concentration increased	Na+/H+ exchange inhibition	Animal models (rabbits, rats and mice)98,101
Cardiac fibrosis reduction	Reduction of oxidative stress M2 macrophage polarization Reduction of TGF-β	Animal models (rats and mice)105,106
Epicardial adipose tissue volume reduction	Weight loss? Unknown mechanism	Small human study108
Oxidative stress reduction	Decrease in NADPH oxidase activity Lowering AGEs generation Improving mitochondrial function Improvement of glycemic control	Animal models (mice, rats)70–75
Lowering proinflammatory cytokine expression	Improvement of glycemic control Weight loss Decrease in reactive oxygen species production	Animal models, RCTs70,72,76
Arterial stiffness reduction	Weight loss Improvement of glycemic control Oxidative stress reduction Direct effects on vascular smooth muscle relaxation?	Small human studies93–95
Endothelial dysfunction amelioration	Oxidative stress reduction Glucotoxicity reduction Direct effect on endothelium?	Small human studies94,96