A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors

Sen, Taha; Heerspink, Hiddo J L

doi:10.1016/j.cmet.2021.02.016

Cited by 93 publications

(77 citation statements)

References 84 publications

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“…Indeed kidney protective effects of SGLT2 inhibition may be in part explained by increasing haemoglobin and improving mitochondrial function. 24,25 KT patients usually have significant comorbidities that decrease patient and graft survival. 26 In KT patients, T1DM, T2DM and PTDM are major risk factors for the development of cardiovascular disease, shorter graft survival, and premature death, 5 so better management of KT patients' comorbidities may increase graft and patient survival (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Sodium‐glucose cotransporter 2 inhibitors for diabetes mellitus control after kidney transplantation: Review of the current evidence

et al. 2021

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Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) are promising drugs to treat chronic kidney disease patients with or without diabetes mellitus (DM). Besides improving glycemic control, SGLT2i are cardioprotective and kidney protective and decrease bodyweight, serum uric acid, blood pressure, albuminuria and glomerular hyperfiltration. These effects may benefit graft function and survival in kidney transplant (KT) patients. In this review, we evaluate data on the efficacy and safety of SGLT2i for KT patients with DM. Eleven studies with 214 diabetic KT patients treated with SGLT2i have been reported. SGLT2i lowered haemoglobin A1c and bodyweight. While glomerular filtration rate may be reduced in the short-term, it remained similar to baseline after 3-12 months. In two studies, blood pressure decreased and remained unchanged in the others. There were no significant changes in urine protein to creatinine ratio. Regarding safety, 23 patients had urinary tract infections, 2 patients had a genital yeast infection, one had acute kidney injury, and one had mild hypoglycaemia. No cases of ketoacidosis or acute rejection were reported. In conclusion, the limited experience so far suggests that SGLT2i are safe in KT patients with DM, decrease bodyweight and improve glycemic control. However, some of the benefits observed in larger studies in the non-KT population have yet to be demonstrated in KT recipients, including preservation of kidney function, reduction in blood pressure and decreased proteinuria.

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Section: Introductionmentioning

confidence: 99%

Sodium‐glucose cotransporter 2 inhibitors for diabetes mellitus control after kidney transplantation: Review of the current evidence

et al. 2021

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“…However, the protection of SGLT2 inhibitors could not be fully explained by a single mechanism since different clinic treatment strategies targeting different conditions are short of the overall effect of the SGLT2 inhibitors. The effects of the SGLT inhibitors are more likely related to their renal effects (Bertero et al 2017 ; Gerich, 2010 ; Nikolic et al 2021 ; Patel et al 2021 ; Santos et al 2020 ; Sen and Heerspink, 2021 ; Thomson and Vallon 2019 ), and an interplay of modest beneficial effects from different systems. Besides more available data from clinical trials, experiments of molecular mechanisms are much more desired.…”

Section: Introductionmentioning

confidence: 99%

The Na/K-ATPase Signaling and SGLT2 Inhibitor-Mediated Cardiorenal Protection: A Crossed Road?

et al. 2021

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In different large-scale clinic outcome trials, sodium (Na+)/glucose co-transporter 2 (SGLT2) inhibitors showed profound cardiac- and renal-protective effects, making them revolutionary treatments for heart failure and kidney disease. Different theories are proposed according to the emerging protective effects other than the original purpose of glucose-lowering in diabetic patients. As the ATP-dependent primary ion transporter providing the Na+ gradient to drive other Na+-dependent transporters, the possible role of the sodium–potassium adenosine triphosphatase (Na/K-ATPase) as the primary ion transporter and its signaling function is not explored. Graphic Abstract

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“…The energy for the transport capacity of SGLT2 and SGLT1 is derived from the Na + /K + ATPase pump located in the basolateral membrane of the proximal tubule. Therefore, the reabsorption of filtered glucose is also accompanied by Na + reabsorption [ 10 , 18 , 21 ]. SGLT2 knockout mice had glucosuria and polyuria compared with wildtype mice [ 22 ].…”

Section: Pathophysiological and Pharmacologic Roles Of Sglt2 Inhibitionmentioning

confidence: 99%

“…These renoprotective benefits of SGLT2 inhibitors may be attributed to glycemic control, reducing body weight, lipid profiles, blood pressure and uric acid and improving insulin resistance. Moreover, due to the improvement of these cardiovascular risk factors, SGLT2 inhibitors also present cardioprotective effects [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of SGLT2 Inhibitors on Atherosclerosis: Lessons from Cardiovascular Clinical Outcomes in Type 2 Diabetic Patients and Basic Researches

Hirai

Koya

et al. 2021

JCM

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Atherosclerosis-caused cardiovascular diseases (CVD) are the leading cause of mortality in type 2 diabetes mellitus (T2DM). Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective oral drugs for the treatment of T2DM patients. Multiple pre-clinical and clinical studies have indicated that SGLT2 inhibitors not only reduce blood glucose but also confer benefits with regard to body weight, insulin resistance, lipid profiles and blood pressure. Recently, some cardiovascular outcome trials have demonstrated the safety and cardiovascular benefits of SGLT2 inhibitors beyond glycemic control. The SGLT2 inhibitors empagliflozin, canagliflozin, dapagliflozin and ertugliflozin reduce the rates of major adverse cardiovascular events and of hospitalization for heart failure in T2DM patients regardless of CVD. The potential mechanisms of SGLT2 inhibitors on cardioprotection may be involved in improving the function of vascular endothelial cells, suppressing oxidative stress, inhibiting inflammation and regulating autophagy, which further protect from the progression of atherosclerosis. Here, we summarized the pre-clinical and clinical evidence of SGLT2 inhibitors on cardioprotection and discussed the potential molecular mechanisms of SGLT2 inhibitors in preventing the pathogenesis of atherosclerosis and CVD.

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A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors

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Cited by 93 publications

References 84 publications

Sodium‐glucose cotransporter 2 inhibitors for diabetes mellitus control after kidney transplantation: Review of the current evidence

Sodium‐glucose cotransporter 2 inhibitors for diabetes mellitus control after kidney transplantation: Review of the current evidence

The Na/K-ATPase Signaling and SGLT2 Inhibitor-Mediated Cardiorenal Protection: A Crossed Road?

Effects of SGLT2 Inhibitors on Atherosclerosis: Lessons from Cardiovascular Clinical Outcomes in Type 2 Diabetic Patients and Basic Researches

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