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

2022 ◽  
Author(s):  
Saurabh Nayak ◽  
Vinay Rathore ◽  
Joyita Bharati ◽  
Kamal Kant Sahu
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Sglt2 Inhibitors ◽  
Preclinical Studies ◽  
Diabetic Kidney

Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors

2021 ◽  
Author(s):  
Ralph A. DeFronzo ◽  
W. Brian Reeves ◽  
Alaa S. Awad
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Sglt2 Inhibitors ◽  
Diabetic Kidney ◽  
Disease Impact

scholarly journals Dapagliflozin Ameliorates Diabetic Kidney Disease via Upregulating Crry and Alleviating Complement Over-activation in db/db Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Dong-Yuan Chang ◽  
Xiao-Qian Li ◽  
Min Chen ◽  
Ming-Hui Zhao
Keyword(s):  
Kidney Disease ◽  
Protective Effect ◽  
High Glucose ◽  
Diabetic Kidney Disease ◽  
Membrane Attack Complex ◽  
Sglt2 Inhibitors ◽  
Tubulointerstitial Injury ◽  
Diabetic Kidney ◽  
Proximal Tubular Epithelial Cells ◽  
Complement Regulator

Sodium-glucose cotransporter 2(SGLT2) inhibitors show prominent renal protective effect in diabetic kidney disease (DKD), anti-inflammatory effect being one of its key mechanisms. Over-activation of the complement system, a crucial part of innate immunity, plays an important role in DKD. We aimed to investigate the effect of SGLT2 inhibitors on alleviating complement over-activation in DKD. Db/db mice were randomly divided into two groups, with 7 mice in each group treated with dapagliflozin and vehicle respectively, and 7 mice in m/m mice group. Laboratory and renal pathological parameters were evaluated. Mouse proximal tubular epithelial cells (MPTECs) were cultured and treated with high glucose. Dapagliflozin and dimethyloxallyl glycine (DMOG) were added as conditional treatment. Dapagliflozin-treated db/db mice showed significantly lower urinary albumin than vehicle-treated ones. Besides typical glomerular and tubulointerstitial injury, both C3b and membrane attack complex (MAC) depositions were significantly attenuated in dapagliflozin-treated db/db mice. The expression of complement receptor type 1-related protein y (Crry), a key complement regulator which inhibits complement over-activation, was significantly upregulated by dapagliflozin. Dapagliflozin-mediated Crry upregulation was associated with inhibition of HIF-1α accumulation under high glucose. When HIF-1α expression was stabilized by DMOG, the protective effect of dapagliflozin via upregulating Crry was blocked. In conclusion, dapagliflozin could attenuate complement over-activation in diabetic mice via upregulating Crry, which is associated with the suppression of HIF-1α accumulation in MPTECs.

scholarly journals SGLT2 Inhibitors—Sweet Success for Diabetic Kidney Disease?

2016 ◽  
Vol 28 (1) ◽  
pp. 7-10 ◽  
Author(s):  
Ian H. de Boer ◽  
Steven E. Kahn
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Sglt2 Inhibitors ◽  
Diabetic Kidney

SGLT-2 inhibitors in Diabetic Kidney Disease: What Lies Behind their Renoprotective Properties?

2019 ◽  
Vol 26 (29) ◽  
pp. 5564-5578 ◽  
Author(s):  
Panagiotis I. Georgianos ◽  
Maria Divani ◽  
Theodoros Eleftheriadis ◽  
Peter R. Mertens ◽  
Vassilios Liakopoulos
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Systemic Blood Pressure ◽  
Favorable Effect ◽  
Bibliographic Databases ◽  
Preclinical Studies ◽  
Renal Protection ◽  
Glucose Lowering ◽  
Diabetic Kidney ◽  
High Sodium

Background: Despite optimal management of diabetic kidney disease (DKD) with intensive glycemic control and administration of agents blocking the renin-angiotensinaldosterone- system, the residual risk for nephropathy progression to end-stage-renal-disease (ESRD) remains high. Sodium-glucose co-transporter type 2 (SGLT-2)-inhibitors represent a newly-introduced anti-diabetic drug class with pleiotropic actions extending above their glucose-lowering efficacy. Herein, we provide an overview of preclinical and clinical-trial evidence supporting a protective effect of SGLT-2 inhibitors on DKD. Methods: A systematic literature search of bibliographic databases was conducted to identify preclinical studies and randomized trials evaluating the effects SGLT-2 inhibitors on DKD. Results: Preclinical studies performed in animal models of DKD support the renoprotective action of SGLT-2 inhibitors showing that these agents exert albuminuria-lowering effects and reverse glomerulosclerosis. The renoprotective action of SGLT-2 inhibitors is strongly supported by human studies showing that these agents prevent the progression of albuminuria and retard nephropathy progression to ESRD. This beneficial effect of SGLT-2 inhibitors is not fully explained by their glucose-lowering properties. Attenuation of glomerular hyperfiltration and improvement in a number of surrogate risk factors, including associated reduction in systemic blood pressure, body weight, and serum uric acid levels may represent plausible mechanistic explanations for the cardio-renal protection offered by SGLT-2 inhibitors. Furthermore, the tubular cell metabolism seems to be altered towards a ketone-prone pathway with protective activities. Conclusion: SGLT-2 inhibition emerges as a novel therapeutic approach of diabetic with anticipated benefits towards cardio-renal risk reduction. Additional research efforts are clearly warranted to elucidate this favorable effect in patients with overt DKD.

Diabetic Kidney Disease

2019 ◽  
pp. 277-286
Author(s):  
John Cijiang He
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Early Stage ◽  
Pressure Control ◽  
Sglt2 Inhibitors ◽  
New Drugs ◽  
Diabetic Kidney ◽  
Mesangial Area ◽  
The World ◽  
Effective Drugs

Diabetic kidney disease (DKD) is the most common cause of ESRD in USA as well as in the world. The incidence and the prevalence of DKD have been increasing regardless of current intervention. The pathology of DKD is characterized by accumulation of extracellular matrix in GBM and mesangial area. The pathogenesis of DKD is multi-factorial including genetic, metabolic, and hemodynamic changes, which lead to activation of oxidative stress, inflammation, and fibrosis pathways in the diabetic kidney. Clinically, patients with DKD presents with glomerular hyperfiltration at early stage, then microalbuminuria, macroalbuminuria, and ESRD. However, the disease progression varies greatly among individual patients. Treatment of DKD is limited to hyperglycemic and blood pressure control and use of RAS blockade. Several new drugs such as SGLT2 inhibitors have been on phase 3 clinical trials but research is required to develop more effective drugs to treat DKD.

scholarly journals Targeting Inflammation in Diabetic Kidney Disease: Is There a Role for Pentoxifylline?

Kidney360 ◽  
2020 ◽  
Vol 1 (4) ◽  
pp. 292-299
Author(s):  
David J. Leehey
Keyword(s):  
Clinical Trials ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Standard Of Care ◽  
The United States ◽  
Sglt2 Inhibitors ◽  
Low Grade ◽  
Diabetic Kidney ◽  
Raas Blockade ◽  
Patients With Diabetes

Diabetic kidney disease (DKD) is the most common cause of ESKD in the United States and worldwide. Current treatment for DKD includes strict glycemic control and normalization of BP with renin-angiotensin-aldosterone system (RAAS) blockade. Although RAAS blockers slow progression of disease, they do not generally prevent ESKD and none of the studies with these agents in DKD included patients who were nonproteinuric, which make up an increasingly large percentage of patients with diabetes now seen in clinical practice. Recent studies with glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown beneficial renal effects, and the benefits of SGLT2 inhibitors likely extend to patients who are nonproteinuric. However, there remains a need to develop new therapies for DKD, particularly in those patients with advanced disease. A role of chronic low-grade inflammation in microvascular complications in patients with diabetes has now been widely accepted. Large clinical trials are being carried out with experimental agents such as bardoxolone and selonsertib that target inflammation and oxidative stress. The Food and Drug Administration–approved, nonspecific phosphodiesterase inhibitor pentoxifylline (PTX) has been shown to have anti-inflammatory effects in both animal and human studies by inhibiting the production of proinflammatory cytokines. Small randomized clinical trials and meta-analyses indicate that PTX may have therapeutic benefits in DKD, raising the possibility that a clinically available drug may be able to be repurposed to treat this disease. A large, multicenter, randomized clinical trial to determine whether this agent can decrease time to ESKD or death is currently being conducted, but results will not be available for several years. At this time, the combination of RAAS blockade plus SGLT2 inhibition is considered standard of care for DKD, but it may be reasonable for clinicians to consider addition of PTX in patients whose disease continues to progress despite optimization of current standard-of-care therapies.

scholarly journals Are SGLT2 Inhibitors Safe and Effective in Advanced Diabetic Kidney Disease?

2020 ◽  
Vol 15 (12) ◽  
pp. 1694-1695
Author(s):  
Sophia Zoungas ◽  
Kevan R. Polkinghorne
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Sglt2 Inhibitors ◽  
Diabetic Kidney
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