Extending the ambit of SGLT2 inhibitors beyond diabetes: a review of clinical and preclinical studies on non-diabetic kidney disease

Nayak, Saurabh; Rathore, Vinay; Bharati, Joyita; Sahu, Kamal Kant

doi:10.1080/17512433.2021.2028620

Cited by 3 publications

(7 citation statements)

References 123 publications

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“…By using a mathematical model of renal function and volume homeostasis in combination with clinical data, it has been predicted that inhibition of apical proximal tubule sodium hydrogen exchanger type 3 is required for the natriuretic effect induced by SGLT2i in humans ( 97 ). Since sodium and chloride remain the sole solute sensor for macula densa cells, downregulation of sodium hydrogen exchanger type 3 may also play an essential role in TGF activation in nondiabetic patients ( 77 ).…”

Section: Resultsmentioning

confidence: 99%

“…During treatment with SGLT2i, a doubling of ketone bodies in plasma has been observed in nondiabetic patients similar to what is found in diabetic patients ( 100 ). This is accompanied by increased levels of ketone bodies and metabolites from ketogenesis in the urine ( 77 ). Because impaired tissue oxygenation plays an equally crucial role in progression of CKD of various subtypes, its reversal may be important ( 43 ).…”

Section: Resultsmentioning

confidence: 99%

“…SGLT2i may induce erythropoietin due to increased hypoxia at the corticomedullary junction, related to the translocation of tubular transport from cortical segments to medullary thick ascending limbs ( 101 ). Studies showed that this mechanism may stimulate erythropoietin (EPO) producing fibroblasts ( 25 , 77 ). Animal studies support the described mechanisms for example determination of the intrarenal distribution of tissue oxygenation following SGLTi with the use of oxygen microelectrodes ( 102 ).…”

Section: Resultsmentioning

confidence: 99%

“…The restoration of the tubuloglomerular feedback (TGF) mechanism has been considered to be an outstanding explanation why SGLT2i offers nephroprotection, because it targets common steps in the pathogenesis of CKD, in particular the glomerular hyperfiltration (76). Vasodilation of the afferent arteriole which can be observed in patients with diabetes mellitus or in patients with high protein intake causes glomerular hyperfiltration (95).…”

Section: Hemodynamic Mechanismsmentioning

confidence: 99%

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Narrative review investigating the nephroprotective mechanisms of sodium glucose cotransporter type 2 inhibitors in diabetic and nondiabetic patients with chronic kidney disease

Speedtsberg,

Tepel

2023

Front. Endocrinol.

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Background and aimsOutcome trials using sodium glucose cotransporter type 2 inhibitors have consistently shown their potential to preserve kidney function in diabetic and nondiabetic patients. Several mechanisms have been introduced which may explain the nephroprotective effect of sodium glucose cotransporter type 2 inhibitors beyond lowering blood glucose. This current narrative review has the objective to describe main underlying mechanisms causing a nephroprotective effect and to show similarities as well as differences between proposed mechanisms which can be observed in patients with diabetic and nondiabetic chronic kidney disease.MethodsWe performed a narrative review of the literature on Pubmed and Embase. The research string comprised various combinations of items including “chronic kidney disease”, “sodium glucose cotransporter 2 inhibitor” and “mechanisms”. We searched for original research and review articles published until march, 2022. The databases were searched independently and the agreements by two authors were jointly obtained.ResultsSodium glucose cotransporter type 2 inhibitors show systemic, hemodynamic, and metabolic effects. Systemic effects include reduction of blood pressure without compensatory activation of the sympathetic nervous system. Hemodynamic effects include restoration of tubuloglomerular feedback which may improve pathologic hyperfiltration observed in most cases with chronic kidney disease. Current literature indicates that SGLT2i may not improve cortical oxygenation and may reduce medullar oxygenation.ConclusionSodium glucose cotransporter type 2 inhibitors cause nephroprotective effects by several mechanisms. However, several mediators which are involved in the underlying pathophysiology may be different between diabetic and nondiabetic patients.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Hemodynamic Mechanismsmentioning

confidence: 99%

See 2 more Smart Citations

Narrative review investigating the nephroprotective mechanisms of sodium glucose cotransporter type 2 inhibitors in diabetic and nondiabetic patients with chronic kidney disease

Speedtsberg,

Tepel

2023

Front. Endocrinol.

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“…Adequate blood sugar control is beneficial in reducing the risk of malignant tumors. Obese patients with type 2 diabetes have a higher risk of developing cancer such as liver ( 44 ), biliary tract ( 45 ), pancreatic ( 46 ), colorectal ( 47 ), kidney ( 48 ), bladder ( 49 ), breast ( 50 ) and endometrial cancer ( 51 ). Insulin resistance leads to unsatisfactory treatment effects in diabetes, and is a chronic, non-specific inflammatory process.…”

Section: Metformin As An Antitumor Candidate Drugmentioning

confidence: 99%

Metformin: A promising drug for human cancers (Review)

Huang

Zhao

et al. 2022

Oncol Lett

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Small-molecule chemical drugs are of great significance for tumor-targeted and individualized therapies. However, the development of new small-molecule drugs, from basic experimental research and clinical trials to final application in clinical practice, is a long process that has a high cost. It takes at least 5 years for most drugs to be developed in the laboratory to prove their effectiveness and safety. Compared with the development of new drugs, repurposing traditional non-tumor drugs can be a shortcut. Metformin is a good model for a new use of an old drug. In recent years, the antitumor efficacy of metformin has attracted much attention. Epidemiological data and in vivo , and in vitro experiments have shown that metformin can reduce the incidence of cancer in patients with diabetes and has a strong antagonistic effect on metabolism-related tumors. Recent studies have shown that metformin can induce autophagy in esophageal cancer cells, mainly by inhibiting inflammatory signaling pathways. In recent years, studies have shown that the antitumor functions and mechanisms of metformin are multifaceted. The present study aims to review the application of metformin in tumor prevention and treatment.

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SGLT2 inhibitors: from glucose-lowering to cardiovascular benefits

Preda,

Montecucco,

Carbone

et al. 2024

Cardiovascular Research

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An increasing number of individuals is at high risk of type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease (CKD), and premature death. The sodium-glucose cotransporter-2 (SGLT2) protein sits in the proximal tubule of human nephrons to regulate glucose reabsorption, and its inhibition by gliflozins represents the cornerstone of contemporary T2D and HF management. Herein, we aim to provide an updated view on the pleiotropy of gliflozins, provide mechanistic insights and delineate related cardiovascular (CV) benefits. By discussing contemporary evidence obtained in preclinical models and landmark randomized controlled trials, we move from bench to bedside across the broad spectrum of cardio- and cerebrovascular diseases. With robust trials confirming a reduction in major adverse CV events (MACE; composite endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke), SGLT2 inhibitors strongly mitigate the risk for heart failure hospitalization in diabetics and non-diabetics alike while conferring renoprotection in specific patient populations. Along four major pathophysiological axes (ie, at cardiac, vascular, renal, and systemic levels), we provide insights into key mechanisms that may underlie their beneficial effects, including gliflozins’ role in the modulation of vascular inflammation, oxidative stress, cellular energy metabolism and housekeeping mechanisms. We also discuss how this drug class controls hyperglycaemia, ketogenesis, natriuresis, and hyperuricaemia, contributing to their pleiotropic effects. Finally, evolving data in the setting of cerebrovascular diseases and arrythmias are presented, and potential implications for future research and clinical practice are comprehensively reviewed.

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Extending the ambit of SGLT2 inhibitors beyond diabetes: a review of clinical and preclinical studies on non-diabetic kidney disease

Cited by 3 publications

References 123 publications

Narrative review investigating the nephroprotective mechanisms of sodium glucose cotransporter type 2 inhibitors in diabetic and nondiabetic patients with chronic kidney disease

Narrative review investigating the nephroprotective mechanisms of sodium glucose cotransporter type 2 inhibitors in diabetic and nondiabetic patients with chronic kidney disease

Metformin: A promising drug for human cancers (Review)

SGLT2 inhibitors: from glucose-lowering to cardiovascular benefits

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