scholarly journals SGLT2 Inhibitors for Treatment of Diabetic Nephropathy

2019 ◽  
Vol 12 (3) ◽  
Author(s):  
Nasser Mikhail
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Kidney Disease ◽  
Primary Outcome ◽  
Sglt2 Inhibitors ◽  
Drug Discontinuation ◽  
Protective Effects ◽  
Renal Protection ◽  
Ras Blockers

Background: Sodium-glucose co-transporter 2 (SGLT2) are medications approved for treatment of type 2 diabetes. Recent evidence suggests that these agents exert Reno protective effects. Methods: Review of literature (English, French, Spanish) from January 1990 to November 10, 2019. Searching terms include sodium-glucose co-transporters 2 inhibitors (SGLT2) inhibitors, chronic kidney disease (CKD), end-stage kidney disease (ESKD). Randomized trials, meta-analysis, expert opinions and guidelines are also reviewed. Results: The effects of canagliflozin on renal events were evaluated in patients with type 2 diabetes and albuminuric diabetic nephropathy already on renin-angiotensin (RAS) blockade. The primary outcome was a composite of the incidence of ESKD, doubling of serum creatinine, renal or cardiovascular (CV) death. Canagliflozin was associated with 30% reduction in the incidence of this primary outcome [hazard ratio (HR) 0.70, 95% CI 0.59-0.82, P=0.00001)]. Similar results were generally reported in large CV trials of canagliflozin, empagliflozin and dapagliflozin although renal events were secondary or post-hoc outcomes. Renoprotection by SGLT2 inhibitors was observed in patients with different degrees of renal function at baseline, with or without albuminuria, and taking or not RAS blockers. SGLT2 inhibitors were generally safe with drug discontinuation rates similar to placebo. Canagliflozin was tolerated in patients with eGFR <60 ml/min/1.73 m2. The incidence of acute renal injury was numerically less frequent with SGLT2 inhibitors compared with placebo. Conclusions: SGLT2 inhibitors slow progression of diabetic nephropathy and should be standard of care on top of RAS blockers for renal protection in patients with type 2 diabetes. Regulatory authorities should consider allowing using canagliflozin 100 mg/d in patients with estimated glomerular filtration rate (eGFR) between 30-45 ml/min/1.73 m2./p>

scholarly journals Additive protection by LDR and FGF21 treatment against diabetic nephropathy in type 2 diabetes model

2015 ◽  
Vol 309 (1) ◽  
pp. E45-E54 ◽  
Author(s):  
Minglong Shao ◽  
Lechu Yu ◽  
Fangfang Zhang ◽  
Xuemian Lu ◽  
Xiaokun Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Combination Treatment ◽  
Combined Treatment ◽  
Protective Effects ◽  
Diabetic Mice ◽  
Renal Protection ◽  
Glucose Levels

The onset of diabetic nephropathy (DN) is associated with both systemic and renal changes. Fibroblast growth factor (FGF)-21 prevents diabetic complications mainly by improving systemic metabolism. In addition, low-dose radiation (LDR) protects mice from DN directly by preventing renal oxidative stress and inflammation. In the present study, we tried to define whether the combination of FGF21 and LDR could further prevent DN by blocking its systemic and renal pathogeneses. To this end, type 2 diabetes was induced by feeding a high-fat diet for 12 wk followed by a single dose injection of streptozotocin. Diabetic mice were exposed to 50 mGy LDR every other day for 4 wk with and without 1.5 mg/kg FGF21 daily for 8 wk. The changes in systemic parameters, including blood glucose levels, lipid profiles, and insulin resistance, as well as renal pathology, were examined. Diabetic mice exhibited renal dysfunction and pathological abnormalities, all of which were prevented significantly by LDR and/or FGF21; the best effects were observed in the group that received the combination treatment. Our studies revealed that the additive renal protection conferred by the combined treatment against diabetes-induced renal fibrosis, inflammation, and oxidative damage was associated with the systemic improvement of hyperglycemia, hyperlipidemia, and insulin resistance. These results suggest that the combination treatment with LDR and FGF21 prevented DN more efficiently than did either treatment alone. The mechanism behind these protective effects could be attributed to the suppression of both systemic and renal pathways.

scholarly journals Roles of sodium-glucose cotransporter 2 of mesangial cells in diabetic kidney disease

2021 ◽  
Author(s):  
Masanori Wakisaka ◽  
Kuniyuki Nakamura ◽  
Toshiaki Nakano ◽  
Takanari Kitazono
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Kidney Disease ◽  
Mesangial Cells ◽  
Sglt2 Inhibitor ◽  
Sglt2 Inhibitors ◽  
Urine Sodium ◽  
Sodium Glucose Cotransporter ◽  
Urine Sodium Excretion

Abstract We have been studying the presence of sodium-glucose cotransporter 2 (SGLT2) in mesangial cells and pericytes since 1992. Recent large placebo-controlled studies of SGLT2 inhibitors in patients with type 2 diabetes mellitus have reported desirable effects of the inhibitors on the diabetic kidney and the diabetic heart. Most studies have indicated that these effects of SGLT2 inhibitors could be mediated by the tubuloglomerular feedback (TGF) system. However, a recent study about urine sodium excretion in the presence of an SGLT2 inhibitor did not show any increases in urine sodium excretion. A very small dose of an SGLT2 inhibitor did not inhibit SGLT2 at the S1 segment of proximal tubules. Moreover, SGLT2 inhibition protects against progression in chronic kidney disease with and without type 2 diabetes. In these circumstances, the TGF hypothesis involves several theoretical concerns that must be clarified. The presence of SGLT2 in mesangial cells seems to be very important for diabetic nephropathy. We now propose a novel mechanism by which the desirable effects of SGLT2 inhibitors on diabetic nephropathy are derived from the direct effect on SGLT2 expressed in mesangial cells.

scholarly journals Effects of SGLT2 Inhibitors on Renal Outcomes in Patients With Chronic Kidney Disease: A Meta-Analysis

2021 ◽  
Vol 8 ◽  
Author(s):  
Ning Li ◽  
Dan Lv ◽  
Xiangjun Zhu ◽  
Ping Wei ◽  
Yuan Gui ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Kidney Disease ◽  
Primary Outcome ◽  
Sglt2 Inhibitors ◽  
Atherosclerotic Cardiovascular Disease ◽  
Renal Outcomes ◽  
Underlying Diseases

Introduction: The effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on renal outcomes in patients with chronic kidney disease (CKD) were initially demonstrated in recent trials. However, the magnitude of renal benefits for CKD patients with different baseline features and underlying diseases remains unclear.Method: We systematically searched the Embase, PubMed, Web of Science, and Cochrane library databases from inception to April 15, 2021 to identify eligible trials. The primary outcome was a composite of worsening kidney function, end-stage kidney disease (ESKD), or renal death. Efficacy and safety outcomes were stratified by baseline features, such as type 2 diabetes, heart failure, atherosclerotic cardiovascular disease, proteinuria, and renal function.Results: A total of nine studies were included. These studies included 25,749 patients with estimated glomerular filtration rate (eGFR)&lt;60 mL/min/1.73 m2 and 12,863 patients with urine albumin-to-creatinine ratio (UACR) &gt;300 mg/g. SGLT2 inhibitors reduced the risk of the primary renal outcome by 30% in patients with eGFR&lt;60 mL/min/1.73 m2 (HR 0.70, [95% CI 0.58–0.83], I2 = 0.00%) and by 43% in patients with UACR &gt; 300 mg/g (HR 0.57, [95% CI 0.48–0.67], I2 = 16.59%). A similar benefit was observed in CKD patients with type 2 diabetes. SGLT2 inhibitors had no clear effects on renal outcomes in patients with eGFR&lt;60 mL/min/1.73 m2 combined with atherosclerotic cardiovascular disease (HR 0.74, [95% CI 0.51–1.06], I2 = 0.00%). However, they reduced the risk of major renal outcomes by 46% (HR 0.54, [95% CI 0.38–0.76], I2 = 0.00%) in patients with atherosclerotic cardiovascular disease and macroalbuminuria (defined as UACR &gt; 300 mg/g). SGLT2 inhibitors did not significantly reduce the risk of major renal outcomes in CKD patients with heart failure (eGFR&lt;60 mL/min/1.73 m2: HR 0.81, [95% CI 0.47–1.38], I2 = 0.00%; UACR &gt; 300 mg/g: HR 0.66, [95% CI 0.41–1.07], I2 = 0.00%). SGLT2 inhibitors showed consistent renal benefits across different levels of eGFR (P interaction = 0.48).Conclusion: SGLT2 inhibitors significantly reduced the risk of the primary outcome in CKD patients. However, for patients with different features and underlying diseases, there exists differences in the renal protective effect.

scholarly journals The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin

2018 ◽  
Vol 132 (4) ◽  
pp. 489-507 ◽  
Author(s):  
Keizo Kanasaki
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Kidney Disease ◽  
Dipeptidyl Peptidase ◽  
Renal Effects ◽  
Dipeptidyl Peptidase 4 ◽  
Dipeptidyl Peptidase 4 Inhibitors ◽  
Membrane Bound

Emerging evidence suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors used to treat type 2 diabetes may have nephroprotective effects beyond the reduced renal risk conferred by glycemic control. DPP-4 is a ubiquitous protein with exopeptidase activity that exists in cell membrane-bound and soluble forms. The kidneys contain the highest levels of DPP-4, which is increased in diabetic nephropathy. DPP-4 inhibitors are a chemically heterogeneous class of drugs with important pharmacological differences. Of the globally marketed DPP-4 inhibitors, linagliptin is of particular interest for diabetic nephropathy as it is the only compound that is not predominantly excreted in the urine. Linagliptin is also the most potent DPP-4 inhibitor, has the highest affinity for this protein, and has the largest volume of distribution; these properties allow linagliptin to penetrate kidney tissue and tightly bind resident DPP-4. In animal models of kidney disease, linagliptin elicited multiple renoprotective effects, including reducing albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis, independent of changes in glucagon-like peptide-1 (GLP-1) and glucose levels. At the molecular level, linagliptin prevented the pro-fibrotic endothelial-to-mesenchymal transition by disrupting the interaction between membrane-bound DPP-4 and integrin β1 that enhances signaling by transforming growth factor-β1 and vascular endothelial growth factor receptor-1. Linagliptin also increased stromal cell derived factor-1 levels, ameliorated endothelial dysfunction, and displayed unique antioxidant effects. Although the nephroprotective effects of linagliptin are yet to be translated to the clinical setting, the ongoing Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with Type 2 Diabetes Mellitus (CARMELINA®) study will definitively assess the renal effects of this DPP-4 inhibitor. CARMELINA® is the only clinical trial of a DPP-4 inhibitor powered to evaluate kidney outcomes.

scholarly journals Renal haemodynamic and protective effects of renoactive drugs in type 2 diabetes: Interaction with SGLT2 inhibitors

Nephrology ◽  
2021 ◽  
Author(s):  
Rosalie A. Scholtes ◽  
Michaël J. B. Baar ◽  
Megan D. Kok ◽  
Petter Bjornstad ◽  
David Z. I. Cherney ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Sglt2 Inhibitors ◽  
Protective Effects

scholarly journals Renal and Cardiovascular Effects of Sodium Glucose Co-Transporter 2 Inhibitors in Patients with Type 2 Diabetes and Chronic Kidney Disease: Perspectives on the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation Trial Results

2020 ◽  
Vol 51 (4) ◽  
pp. 276-288 ◽  
Author(s):  
Matthew R. Weir ◽  
Peter A. McCullough ◽  
John B. Buse ◽  
John Anderson
Keyword(s):  
Type 2 Diabetes ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Clinical Evaluation ◽  
Enzyme Inhibitor ◽  
Cardiovascular Effects ◽  
Cardiac Risk ◽  
Renal Protection ◽  
Substantial Impact

Background: Chronic kidney disease (CKD) risk is elevated in patients with type 2 diabetes mellitus (T2DM). Disease management in these patients has been generally focused on glycemic control and controlling other renal and cardiac risk factors as, historically, few protective therapies have been available. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation ­(CREDENCE) trial of canagliflozin was the first study to demonstrate renal protection with a sodium glucose co-transporter 2 inhibitor in patients with T2DM and CKD, and these results could have important implications for clinical practice. Summary: In CREDENCE, participants with T2DM and estimated glomerular filtration rate 30–<90 mL/min/1.73 m2 and urinary albumin-creatinine ratio >300–5,000 mg/g who were treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for ≥4 weeks prior to randomization at either the maximum labeled or tolerated dose were randomized to receive either canagliflozin 100 mg or placebo. Canagliflozin significantly reduced the risk of the primary composite outcome of doubling of serum creatinine, end-stage kidney disease, or renal or cardiovascular (CV) death compared with placebo (hazard ratio 0.70, 95% CI 0.59–0.82; p = 0.00001). Canagliflozin also reduced the risk of secondary renal and CV outcomes. The safety profile of canagliflozin in CREDENCE was generally similar to previous studies of canagliflozin. No imbalances were observed between canagliflozin and placebo in the risk of amputation or fracture in the CREDENCE population. Key Messages: The positive renal and CV effects of canagliflozin observed in the ­CREDENCE trial could have a substantial impact on improving outcomes for patients with T2DM and CKD.

scholarly journals Impact of sodium–glucose cotransporter 2 inhibitors on renal function in participants with type 2 diabetes and chronic kidney disease with normoalbuminuria

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Akinobu Nakamura ◽  
Hideaki Miyoshi ◽  
Hiraku Kameda ◽  
Kumiko Yamashita ◽  
Yoshio Kurihara
Keyword(s):  
Type 2 Diabetes ◽  
Chronic Kidney Disease ◽  
Renal Function ◽  
Kidney Disease ◽  
Sglt2 Inhibitor ◽  
Sglt2 Inhibitors ◽  
Creatinine Ratio ◽  
Sodium Glucose Cotransporter ◽  
Clinical Records

Abstract Background We compared the effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors on renal function in participants with type 2 diabetes and chronic kidney disease (CKD) classified by degree of albuminuria. Methods A retrospective review of the clinical records of Japanese participants with type 2 diabetes (age > 20 years; SGLT2 inhibitor treatment > 2 years; estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2) was conducted. Based on the urinary albumin-to-creatinine ratio (UACR) or urinary protein-to-creatinine ratio (UPCR) at the start of SGLT2 inhibitor administration, participants were categorized into three groups: normoalbuminuria (A1; UACR < 30 mg/g Cr or UPCR < 0.15 g/g Cr), microalbuminuria (A2; UACR 30 to < 300 mg/g Cr or UPCR 0.15 to < 0.50 g/g Cr), and macroalbuminuria (A3; UACR ≥ 300 mg/g Cr or UPCR ≥ 0.50 g/g Cr). The study outcome was a comparison of the rates of change in renal function evaluated by eGFR at 2 years after starting SGLT2 inhibitor among the three groups. Results A total of 87 participants (40 females, 47 males) were categorized into three groups: A1 (n = 46), A2 (n = 25), and A3 (n = 16). eGFR was similarly decreased at 2 years before starting SGLT2 inhibitor in all three groups. However, the decline in eGFR was ameliorated at 2 years after starting SGLT2 inhibitor, and eGFR was rather increased in the A1 and A2 groups. Interestingly, the rate of change in eGFR at 2 years after starting SGLT2 inhibitor in the A1 group was significantly higher than that in the A3 group. Conclusions These results demonstrate that more favorable effects of SGLT2 inhibitors on renal function were observed in participants with type 2 diabetes and CKD with normoalbuminuria compared with those with macroalbuminuria. Trial registration UMIN-CTR: UMIN000035263. Registered 15 December 2018

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