Table 3.

Parameters/markers/systems affected, changes from baseline, and the probable mechanisms of SGLT2 inhibitors.

Parameter/marker/system	Change from baseline	Probable mechanisms according to literature
Plasma glucose levels	Reduced	Glucosuria
Body weight	Reduced	Caloric loss results in reduced body weight.
Systolic and diastolic blood pressure	Reduced	Natriuresis results in reduced extracellular volume and thus lowers systolic and diastolic blood pressure
Plasma uric acid	Reduced	Glucose and uric acid compete with the same GLUT9 transporter. When higher glucose levels are available in the tubular lumen, the transport of uric acid into the blood is reduced.
Sympathetic nerve system	Reduced	No compensatory increase in heart rate despite reduction of extracellular volume. Mediators are only partly known.
Tubuloglomerular feedback	Increased	Increased delivery of sodium to macula densa cells, which is amplified by downregulation of the sodium-proton-exchanger 3 (NHE3), stimulates the release of vasoactive mediators. These affect the glomerular arterioles, thus ameliorating glomerular hyperfiltration.
Renin-angiotensin-aldosterone-system (RAAS)	Increased	The increased release if renin is due to reduced effective vascular volume. In the presence of RAAS blockade with ACEi of ARB several mediators are directed from the vasoconstrictive and pro-inflammatory classical pathway to the vasodilating and anti-inflammatory alternative pathways.
Ketogenesis	Increased	Stimulation of starvation like stages induce transcription factors and decrease insulin secretion. This stimulates ketogenesis. Ketones are energy efficient fuels producing more ATP from oxygen compared to free fatty acids.
Hematocrit	Increased	Partly due to reduced effective vascular volume and enhanced erythropoiesis. That causes compensatory upregulation of SGLT1 in the medulla which results in local hypoxia and stimulates the transformation of erythropoietin-producing fibroblasts.
Renal tissue oxygenation	Cortex: No change. Medulla: Reduced	Reduced oxygen demand in the cortex may be due to reduced sodium transport and increased utilization of ketones. Increased oxygen delivery is partly explained by elevated hematocrit. Furthermore, intensified medullary hypoxia due to reabsorption of glucose and sodium and tubular segments downstream the location of SGLT2.
Autophagia	Increased	Ketones upregulate transcription factors which promote autophagia.
Cellular inflammatory response and inflammasome	Decreased	Ketones inhibit histone deacylases and inflammasomes.
Renal fibrosis	Decreased	On one hand, improved renal cortical oxygenation results in decreased inflammation and fibrosis through downregulation of hypoxia inducible transcription factors and others. On the other hand, there is enhanced medullary hypoxia. Enhanced medullary transport leading to medullary hypoxia occurs in medullary thick limbs in the inner- and outer stripe of the outer medulla, with an increased activity of sodium-potassium-ATPase in the basolateral membrane and sodium-potassium-2-chloride cotransporter at the apical membrane.