The Urinary Glucose Excretion by Sodium–Glucose Cotransporter 2 Inhibitor in Patients With Different Levels of Renal Function: A Systematic Review and Meta-Analysis

Hu, Suiyuan; Lin, Chu; Cai, Xiaoling; Zhu, Xiaoxi; Lv, Fang; Lin, Na; Ji, Linong

doi:10.3389/fendo.2021.814074

Cited by 13 publications

(13 citation statements)

References 25 publications

(25 reference statements)

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“…Conversely, the lower the GFR, the smaller is the glycosuria. Anyway, it was found that the inhibition towards renal glucose reabsorption was constant across all levels of renal function, indicating that, regardless of GFR, inhibition of glucose reabsorption might reach its maximum [ 16 ]. Accordingly, an average of 0.79% reduction in HbA1c is obtained in normal renal function, 0.3–0.4% in the estimated GFR (eGFR) range of 30–59 mL/min/1.73 m 2 , until the total ineffectiveness when the parameter is less than 30 mL/min/1.73 m 2 [ 17 ].…”

Section: The Anti-hyperglycemic Effect Of Sglt2-ismentioning

confidence: 99%

An Overview of the Cardiorenal Protective Mechanisms of SGLT2 Inhibitors

Salvatore

Galiero

Caturano

et al. 2022

IJMS

111

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Sodium-glucose co-transporter 2 (SGLT2) inhibitors block glucose reabsorption in the renal proximal tubule, an insulin-independent mechanism that plays a critical role in glycemic regulation in diabetes. In addition to their glucose-lowering effects, SGLT2 inhibitors prevent both renal damage and the onset of chronic kidney disease and cardiovascular events, in particular heart failure with both reduced and preserved ejection fraction. These unexpected benefits prompted changes in treatment guidelines and scientific interest in the underlying mechanisms. Aside from the target effects of SGLT2 inhibition, a wide spectrum of beneficial actions is described for the kidney and the heart, even though the cardiac tissue does not express SGLT2 channels. Correction of cardiorenal risk factors, metabolic adjustments ameliorating myocardial substrate utilization, and optimization of ventricular loading conditions through effects on diuresis, natriuresis, and vascular function appear to be the main underlying mechanisms for the observed cardiorenal protection. Additional clinical advantages associated with using SGLT2 inhibitors are antifibrotic effects due to correction of inflammation and oxidative stress, modulation of mitochondrial function, and autophagy. Much research is required to understand the numerous and complex pathways involved in SGLT2 inhibition. This review summarizes the current known mechanisms of SGLT2-mediated cardiorenal protection.

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Section: The Anti-hyperglycemic Effect Of Sglt2-ismentioning

confidence: 99%

An Overview of the Cardiorenal Protective Mechanisms of SGLT2 Inhibitors

Salvatore

Galiero

Caturano

et al. 2022

IJMS

111

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“…13 The magnitude of SGLT2 inhibitor-mediated glycosuria is reduced in chronic kidney disease. 14,15 Two-thirds of the filtered sodium is absorbed in the proximal tubule, 16 primarily through the action of NHE3 (sodium-hydrogen exchanger 3). NHE3 is colocalized with and structurally interlinked with SGLT2 in the brush border.…”

Section: Effects Of Sglt2 Inhibition In the Proximal Renal Tubule And...mentioning

confidence: 99%

Critical Analysis of the Effects of SGLT2 Inhibitors on Renal Tubular Sodium, Water and Chloride Homeostasis and Their Role in Influencing Heart Failure Outcomes

2023

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SGLT2 (sodium-glucose cotransporter 2) inhibitors interfere with the reabsorption of glucose and sodium in the early proximal renal tubule, but the magnitude and duration of any ensuing natriuretic or diuretic effect are the result of an interplay between the degree of upregulation of SGLT2 and sodium-hydrogen exchanger 3, the extent to which downstream compensatory tubular mechanisms are activated, and (potentially) the volume set point in individual patients. A comprehensive review and synthesis of available studies reveals several renal response patterns with substantial variation across studies and clinical settings. However, the common observation is an absence of a large acute or chronic diuresis or natriuresis with these agents, either when given alone or combined with other diuretics. This limited response results from the fact that renal compensation to these drugs is rapid and nearly complete within a few days or weeks, preventing progressive volume losses. Nevertheless, the finding that fractional excretion of glucose and lithium (the latter being a marker of proximal sodium reabsorption) persists during long-term treatment with SGLT2 inhibitors indicates that pharmacological tolerance to the effects of these drugs at the level of the proximal tubule does not meaningfully occur. This persistent proximal tubular effect of SGLT2 inhibitors can be hypothesized to produce a durable improvement in the internal set point for volume homeostasis, which may become clinically important during times of fluid expansion. However, it is difficult to know whether a treatment-related change in the volume set point actually occurs or contributes to the effect of these drugs to reduce the risk of major heart failure events. SGLT2 inhibitors exert cardioprotective effects by a direct effect on cardiomyocytes that is independent of the presence of or binding to SGLT2 or the actions of these drugs on the proximal renal tubule. Nevertheless, changes in the volume set point mediated by SGLT2 inhibitors might potentially act cooperatively with the direct favorable molecular and cellular effects of these drugs on cardiomyocytes to mediate their benefits on the development and clinical course of heart failure.

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“…They efficiently lower blood glucose levels by inhibiting renal SGLT2, a Na + -dependent glucose transporter which normally accomplishes complete glucose reabsorption along with SGLT1, another isoform that is not inhibited by specific SGLT2 inhibitors (33)(34)(35). As a consequence, the patients excrete more glucose in their urine (36,37). Recent large clinical studies of high quality have unequivocally proven that SGLT2 inhibition has further significant and diabetes-independent cardio-and nephroprotective effects that are, in many aspects, regarded as a milestone in cardiology and nephrology (38)(39)(40).…”

Section: Introductionmentioning

confidence: 99%

The impact of SGLT2 inhibitors on αKlotho in renal MDCK and HK-2 cells

Wolf

Föller²,

Feger³

2023

Front. Endocrinol.

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αKlotho is a transmembrane protein predominantly expressed in the kidney serving as a co-receptor for phosphate homeostasis-regulating hormone FGF23 and has an extracellular domain that can be cleaved off and is a hormone. αKlotho deficiency results in accelerated aging and early onset of aging-associated diseases while its overexpression strongly expands the lifespan of mice. Moreover, αKlotho exerts health-beneficial anti-inflammatory, anti-neoplastic, anti-fibrotic, and anti-oxidant effects. Higher αKlotho levels are associated with better outcomes in renal and cardiovascular diseases. SGLT2 inhibitors are novel drugs in the treatment of diabetes by inhibiting renal glucose transport and have additional nephro- and cardioprotective effects. We explored whether SGLT2 inhibitors affect αKlotho gene expression and protein secretion. Experiments were performed in renal MDCK and HK-2 cells, and αKlotho transcripts were determined by qRT-PCR and Klotho protein by ELISA. SGLT2 inhibitors canagliflozin, sotagliflozin, and dapagliflozin enhanced whereas empagliflozin reduced αKlotho gene expression in MDCK cells. By the same token, canagliflozin, sotagliflozin, dapagliflozin, but not empagliflozin down-regulated p65 subunit of pro-inflammatory NFκB. In HK-2 cells, all SGLT2 inhibitors reduced αKlotho transcripts. Canagliflozin and sotagliflozin, however, increased Klotho protein concentration in the cell culture supernatant, an effect paralleled by up-regulation of ADAM17. Taken together, our investigations demonstrate complex effects of different SGLT2 inhibitors on αKlotho gene expression and protein secretion in renal MDCK and HK-2 cells.

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The Urinary Glucose Excretion by Sodium–Glucose Cotransporter 2 Inhibitor in Patients With Different Levels of Renal Function: A Systematic Review and Meta-Analysis

Cited by 13 publications

References 25 publications

An Overview of the Cardiorenal Protective Mechanisms of SGLT2 Inhibitors

An Overview of the Cardiorenal Protective Mechanisms of SGLT2 Inhibitors

Critical Analysis of the Effects of SGLT2 Inhibitors on Renal Tubular Sodium, Water and Chloride Homeostasis and Their Role in Influencing Heart Failure Outcomes

The impact of SGLT2 inhibitors on αKlotho in renal MDCK and HK-2 cells

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