Discovery of Tofogliflozin, a NovelC-Arylglucoside with anO-Spiroketal Ring System, as a Highly Selective Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

2012 ◽  
Vol 55 (17) ◽  
pp. 7828-7840 ◽  
Author(s):  
Yoshihito Ohtake ◽  
Tsutomu Sato ◽  
Takamitsu Kobayashi ◽  
Masahiro Nishimoto ◽  
Naoki Taka ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Sglt2 Inhibitor ◽  
Ring System ◽  
Sodium Glucose Cotransporter

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

scholarly journals Inhibition of Sodium Glucose Cotransporter 2 Attenuates the Dysregulation of Kelch-Like 3 and NaCl Cotransporter in Obese Diabetic Mice

2019 ◽  
Vol 30 (5) ◽  
pp. 782-794 ◽  
Author(s):  
Kenichi Ishizawa ◽  
Qin Wang ◽  
Jinping Li ◽  
Ning Xu ◽  
Yoshikazu Nemoto ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cultured Cells ◽  
Sglt2 Inhibitor ◽  
Distal Convoluted Tubule ◽  
Protective Effects ◽  
Human Embryonic Kidney Cells ◽  
Sodium Glucose Cotransporter ◽  
Tubule Cells ◽  
Nacl Cotransporter

BackgroundMechanisms underlying the frequent association between salt-sensitive hypertension and type 2 diabetes remain obscure. We previously found that protein kinase C (PKC) activation phosphorylates Kelch-like 3 (KLHL3), an E3 ubiquitin ligase component, at serine 433. We investigated whether impaired KLHL3 activity results in increased renal salt reabsorption via NaCl cotransporter (NCC).MethodsWe used the db/db diabetes mouse model to explore KLHL3′s role in renal salt handling in type 2 diabetes and evaluated mechanisms of KLHL3 dysregulation in cultured cells.ResultsWe observed PKC activity in the db/db mouse kidney and phosphorylation of serine 433 in KLHL3 (KLHL3S433-P). This modification prevents binding of with-no-lysine (WNK) kinases; however, total KLHL3 levels were decreased, indicating severely impaired KLHL3 activity. This resulted in WNK accumulation, activating NCC in distal convoluted tubules. Ipragliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, lowered PKC activity in distal convoluted tubule cells and reduced KLHL3S433-P and NCC levels, whereas the thiazolidinedione pioglitazone did not, although the two agents similarly reduced in blood glucose levels. We found that, in human embryonic kidney cells expressing KLHL3 and distal convoluted tubule cells, cellular glucose accumulation increased KLHL3S433-P levels through PKC. Finally, the effect of PKC inhibition in the kidney of db/db mice confirmed PKC’s causal role in KLHL3S433-P and NCC induction.ConclusionsDysregulation of KLHL3 is involved in the pathophysiology of type 2 diabetes. These data offer a rationale for use of thiazide in individuals with diabetes and provide insights into the mechanism for cardiorenal protective effects of SGLT2 inhibitors.

scholarly journals New SGLT2 inhibitor ertugliflozin: safe and effective in the management of type 2 diabetes

2020 ◽  
pp. 32-41
Author(s):  
V. V. Salukho ◽  
T. A. Ilyinskay
Keyword(s):  
Type 2 Diabetes ◽  
Body Mass ◽  
Clinical Studies ◽  
Sglt2 Inhibitor ◽  
Evidence Base ◽  
Sglt2 Inhibitors ◽  
Adverse Outcomes ◽  
Positive Effects ◽  
Sodium Glucose Cotransporter

Type 2 diabetes mellitus (T2DM) is closely associated with the risk of developing cardiovascular complications. A new approach to treatment of T2DM, based on the inhibition of the sodium-glucose cotransporter type 2 (SGLT2) ensures reliable insulin-independent glycemic control with quick overcome of glucotoxicity, reduction of insulin resistance, and positive effects on body mass, blood pressure and other rates. Besides, pronounces clinical efficacy of SGLT2 inhibitor is marked by its use safety and minimized frequency of adverse events. Along with this, the results of carried-out, randomized clinical studies of cardiovascular safety of different SGLT2 inhibitors showed, that apart from bearing on the risk factors, the inhibition of sodium-glucose cotransporter type 2 leads to cardioand renoprotective effects. In addition, their influence on cardiovascular and renal outcomes is the stronger the more different the pre-existing status of cardiovascular diseases of the patient is, the condition of his renal function and the severity of albuminuria. This article summarizes the main results of carried-out randomized clinical studies of SGLT2 inhibitors, which demonstrate their cardiovascular advantages and compile encouraging results of multicentered studies VERTIS, examining different aspects of the use of the ertugliflazine SGLT2 inhibitor in patients with type 2 diabetes. There is data provided demonstrating a powerful glucoselowering, body-mass lowering and hypotensive impacts of ertugliflazine comparable to the same performance of the best representatives of the class. This article describes an evidence base of the use of the drug in monotherapy and its ability to be combined with other oral hypoglycemic agentsand highlightes a high level of safety of the use of ertugliflazine correspondinding to minimized frequency of adverse outcomes of SGLT2 inhibition and so the potential of SGLT2 inhibitors as a new promising class for the treatment of patients with type 2 diabetes and established cardiovascular disease is revealed.

scholarly journals The Cardiovascular Benefits Associated with the Use of Sodium-glucose Cotransporter 2 Inhibitors – Real-world Data

2018 ◽  
Vol 14 (1) ◽  
pp. 17 ◽  
Author(s):  
Baptist Gallwitz
Keyword(s):  
Type 2 Diabetes ◽  
Real World ◽  
Sglt2 Inhibitor ◽  
Cardiovascular Outcomes ◽  
Health Improvement ◽  
Published Data ◽  
Class Effect ◽  
Sodium Glucose Cotransporter ◽  
Cardiovascular Assessment

Type 2 diabetes (T2D) is associated with numerous comorbidities that significantly reduce quality of life, increase mortality and complicate treatment decisions. In a recent cardiovascular outcomes trial, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME), the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin was shown to reduce cardiovascular (CV) mortality and heart failure in high-risk patients with T2D with a previous CV event or with established CV disease (CVD). Recently published data from the Canagliflozin Cardiovascular Assessment Study (CANVAS-PROGRAM) study suggested that the cardiovascular benefits of empagliflozin are also seen with the SGLT2-inhibitor canagliflozin, indicating a class effect of SGLT2 inhibitors. Evidence for a class effect has also been shown by meta-analyses and real-world studies, including the Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL) and The Health Improvement Network (THIN) databases. These findings also suggest the results of EMPA-REG OUTCOME can be applied to patients with T2D with a broader CV risk profile, including people at low risk of CVD.

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 Exposure−response modelling for empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes

2014 ◽  
Vol 78 (6) ◽  
pp. 1407-1418 ◽  
Author(s):  
Matthew M. Riggs ◽  
Leo J. Seman ◽  
Alexander Staab ◽  
Thomas R. MacGregor ◽  
William Gillespie ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Sglt2 Inhibitor ◽  
Exposure Response ◽  
Sodium Glucose Cotransporter ◽  
Response Modelling

scholarly journals Nephrology Consultation for Severe SGLT2 Inhibitor-Induced Ketoacidosis in Type 2 Diabetes: Case Report

Medicina ◽  
2019 ◽  
Vol 55 (8) ◽  
pp. 462 ◽  
Author(s):  
Felice Nappi ◽  
Antonietta La Verde ◽  
Giovanni Carfora ◽  
Carlo Garofalo ◽  
Michele Provenzano ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Ketoacidosis ◽  
Sglt2 Inhibitor ◽  
Delayed Diagnosis ◽  
Kidney Injury ◽  
Dialysis Unit ◽  
New Class ◽  
Sodium Glucose Cotransporter ◽  
Euglycemic Diabetic Ketoacidosis

Euglycemic diabetic ketoacidosis (euDKA) related to sodium-glucose cotransporter 2 inhibitor (SGLT2-I), despite being reported as consistent, though infrequent, adverse effect in all trials on SGLT2-I in type 2 diabetes mellitus (T2D), still remains poorly known in the real world. On the other hand, the use of this new class of antihyperglycemic agents is expected to increase based on the recent solid evidence of remarkable cardiorenal protection. Therefore, improving awareness on risk factors, diagnosis, and treatment of euDKA is essential to allow correct implementation of SGLT2-I in clinical practice. We here report a T2D patient admitted to the emergency department and then transferred to the nephrology-dialysis unit because of severe euglycemic diabetic ketoacidosis (euDKA) related to sodium-glucose cotransporter 2 inhibitor (SGLT2-I). In our patient, a concurrent acute kidney injury at presentation, initially attributed to excessive use of nonsteroid anti-inflammatory agents, and the absence of severe hyperglycemia led to delayed diagnosis and proper therapy. The detailed description of decision-making process for diagnosis and therapy, and the analysis of precipitating factors as well, discloses the helpful contribution of nephrologist to optimize prevention and management of euDKA.

scholarly journals The Effect of Long-term Sodium-glucose Cotransporter 2 Inhibitor Treatment on Renal Function in the Patients with Type 2 Diabetes

2020 ◽  
Vol 95 (4) ◽  
pp. 236-243
Author(s):  
Jong Ha Baek ◽  
Tae Jung Oh ◽  
Ju-Young Moon ◽  
Taehee Kim ◽  
Seung Hyu Ko ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Renal Function ◽  
Kidney Disease ◽  
Sglt2 Inhibitor ◽  
Sglt2 Inhibitors ◽  
Renal Outcomes ◽  
Sodium Glucose Cotransporter ◽  
Inhibitor Treatment

Chronic kidney disease is developed commonly in type 2 diabetes mellitus (T2DM) and is the most common cause of end-stage renal disease and related cardiovascular complications. Meanwhile, despite the current standard of care including optimized glucose control and the use of single-agent blockade of the renin-angiotensin-aldosterone system (RAAS), patients with T2DM remain at increased risk for death and complications from cardiorenal causes. The recent studies using sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown not only glucose lowering effect, but also a reduction in blood pressure, weight loss, and a lowering cardiovascular risk. Regarding renal outcomes, the use of SGLT2 inhibitor slows the progression of kidney disease compared to placebo when added to standard care. However, concern has been raised that currently available SGLT2 inhibitors in Korea may be also associated with improved renal outcomes with long-term treatment. As a result, we aimed to evaluate the effect of long-term SGLT2 inhibitor treatment on renal function in the patients with T2DM using meta-analysis. (Korean J Med 2020;95:236-243)

scholarly journals Potential mechanisms underlying cardiovascular protection by sodium glucose cotransporter 2 inhibitors (empagliflozin)

2021 ◽  
Vol 10 (3) ◽  
pp. 79-89
Author(s):  
I. S. Sabirov ◽  
I. T. Murkamilov ◽  
V. V. Fomin
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Risk ◽  
Cardiovascular Diseases ◽  
Sglt2 Inhibitor ◽  
Sglt2 Inhibitors ◽  
Controlled Clinical Trial ◽  
Sodium Glucose Cotransporter ◽  
Pubmed Database ◽  
Urinary Glucose

The presented literature review is devoted to the cardioprotective capabilities of a new class of antihyperglycemic drugs - sodium-glucose cotransporter 2 inhibitors (SGLT2), which improve glycemic control through an insulin-independent mechanism of action associated with an increase in urinary glucose excretion. The article presents the results of large-scale clinical trials on the use of SGLT2 inhibitors in patients with and without diabetes, and with cardiovascular diseases or multiple cardiovascular risk factors. A number of the most frequently discussed cardiac specific mechanisms mediated by the SGLT2 inhibitor affecting the Abstract           state of the cardiovascular system are presented. Moreover, the article presents the results of a placebo-controlled clinical trial entitled “Empagliflozin reduces mortality in patients with type 2 diabetes at high cardiovascular risk” (EMPA-REG oUtcOmE) to analyze the cardioprotective capabilities of SGLT2 inhibitor empagliflozin in patients with type 2 diabetes and concomitant cardiovascular diseases. The article emphasizes the importance of further research to determine the degree of contribution of the above-mentioned mechanisms to the cardioprotective potential of SGLT2 inhibitors. PubMed database was used to identify relevant studies and systematic reviews.

Sign in / Sign up

Export Citation Format

Share Document