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Review
. 2021 Apr 23;22(9):4416.
doi: 10.3390/ijms22094416.

Multi-Organ Protective Effects of Sodium Glucose Cotransporter 2 Inhibitors

Hidekatsu Yanai  1 , Mariko Hakoshima  1 , Hiroki Adachi  1 , Hisayuki Katsuyama  1
Affiliations
Review

Multi-Organ Protective Effects of Sodium Glucose Cotransporter 2 Inhibitors

Hidekatsu Yanai et al. Int J Mol Sci. .

Abstract

Sodium glucose cotransporter 2 inhibitors (SGLT2i) block the reabsorption of glucose by inhibiting SGLT2, thus improving glucose control by promoting the renal excretion of glucose, without requiring insulin secretion. This pharmacological property of SGLT2i reduces body weight and improves insulin resistance in diabetic patients. Such beneficial metabolic changes caused by SGLT2i are expected to be useful not only for glucose metabolism, but also for the protection for various organs. Recent randomized controlled trials (RCTs) on cardiovascular diseases (EMPA-REG OUTCOME trial and CANVAS program) showed that SGLT2i prevented cardiovascular death and the development of heart failure. RCTs on renal events (EMPA-REG OUTCOME trial, CANVAS program, and CREDENCE trial) showed that SGLT2i suppressed the progression of kidney disease. Furthermore, SGLT2i effectively lowered the liver fat content, and our study demonstrated that SGLT2i reduced the degree of hepatic fibrosis in patients at high-risk of hepatic fibrosis. Such promising properties of SGLT2i for cardiovascular, renal, and hepatic protection provide us the chance to think about the underlying mechanisms for SGLT2i-induced improvement of multiple organs. SGLT2i have various mechanisms for organ protection beyond glucose-lowering effects, such as an increase in fatty acids utilization for hepatic protection, osmotic diuresis for cardiac protection, an improvement of insulin resistance for anti-atherogenesis, and an improvement of tubuloglomerular feedback for renal protection.

Keywords: cardiovascular diseases; diabetes; hepatic fibrosis; nephropathy; sodium glucose cotransporter 2.

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Conflict of interest statement

The authors declare no conflict of interest in relation to the present review paper.

Figures

Figure 1
Figure 1
Possible anti-atherosclerotic mechanisms of sodium glucose cotransporter 2 inhibitors (SGLT2i) inhibitors. The bold down arrows indicate a decrease.
Figure 2
Figure 2
Possible renal protective mechanisms of SGLT2 inhibitors. The up and down arrows in white boxes indicate an increase and a decrease, respectively.
Figure 3
Figure 3
Possible hepatic protective mechanisms by SGLT2 inhibitors. ACC, acetyl-CoA carboxylase; AMPK, adenosine monophosphate-activated protein kinase; FA, fatty acids. The up and down arrows in white boxes indicate an increase and a decrease, respectively.
Figure 4
Figure 4
Unique multi-organ protective effects beyond the hypoglycemic effect of SGLT2 inhibitors.
See this image and copyright information in PMC

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