Characterization and comparison of SGLT2 inhibitors: Part 3. Effects on diabetic complications in type 2 diabetic mice

Tahara, Atsuo; Takasu, Toshiyuki; Yokono, Masanori; Imamura, Masakazu; Kurosaki, Eiji

doi:10.1016/j.ejphar.2017.05.019

Cited by 43 publications

(28 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The present study suggests that, in addition to these effects, SGLT2 inhibition with canagliflozin exerts anti-inflammatory and antifibrotic effects and protects against extracellular matrix deregulation. These findings are in line with experimental studies demonstrating that in kidney tissues of animals treated with SGLT2 inhibitors markers of inflammation and fibrosis, including NF-κB, CCL2 and IL-6 decreased [ 8 , 9 ].…”

Section: Discussionsupporting

confidence: 87%

“…The exact mechanisms by which SGLT2 inhibitors reduce the risk of cardiovascular and kidney disease are not completely understood but are thought to involve natriuresis, restoration of tubuloglomerular feedback and amelioration of intrarenal hypoxia [ 7 ]. In addition, experimental studies have suggested possible anti-inflammatory and antifibrotic effects for SGLT2 inhibitors [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease

et al. 2019

View full text Add to dashboard Cite

Aims/hypothesis The sodium–glucose cotransporter 2 (SGLT2) inhibitor canagliflozin slows progression of kidney function decline in type 2 diabetes. The aim of this study was to assess the effect of the SGLT2 inhibitor canagliflozin on biomarkers for progression of diabetic kidney disease (DKD). Methods A canagliflozin mechanism of action (MoA) network model was constructed based on an in vitro transcriptomics experiment in human proximal tubular cells and molecular features linked to SGLT2 inhibitors from scientific literature. This model was mapped onto an established DKD network model that describes molecular processes associated with DKD. Overlapping areas in both networks were subsequently used to select candidate biomarkers that change with canagliflozin therapy. These biomarkers were measured in 296 stored plasma samples from a previously reported 2 year clinical trial comparing canagliflozin with glimepiride. Results Forty-four proteins present in the canagliflozin MoA molecular model overlapped with proteins in the DKD network model. These proteins were considered candidates for monitoring impact of canagliflozin on DKD pathophysiology. For ten of these proteins, scientific evidence was available suggesting that they are involved in DKD progression. Of these, compared with glimepiride, canagliflozin 300 mg/day decreased plasma levels of TNF receptor 1 (TNFR1; 9.2%; p < 0.001), IL-6 (26.6%; p = 0.010), matrix metalloproteinase 7 (MMP7; 24.9%; p = 0.011) and fibronectin 1 (FN1; 14.9%; p = 0.055) during 2 years of follow-up. Conclusions/interpretation The observed reduction in TNFR1, IL-6, MMP7 and FN1 suggests that canagliflozin contributes to reversing molecular processes related to inflammation, extracellular matrix turnover and fibrosis. Trial registration ClinicalTrials.gov NCT00968812 Electronic supplementary material The online version of this article (10.1007/s00125-019-4859-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

show abstract

Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Repeated administration of ipragliflozin lowered HbA 1c levels by increasing urinary glucose excretion. Further, ipragliflozin improved glucose tolerance, hyperinsulinemia, and insulin resistance, similar to findings reported in previous studies in type 2 diabetes models (Tahara et al, 2013(Tahara et al, , 2017. Additionally, no hypoglycemic symptoms such as excessive weight loss or decreased locomotor activity were noted throughout the present study period.…”

Section: Discussionsupporting

confidence: 91%

“…We have investigated the therapeutic effects of the SGLT2 inhibitor ipragliflozin on NASH using a number of animal models. We found that ipragliflozin significantly attenuated various diabetic features such as hyperglycemia, insulin resistance, and obesity, and NASH‐related features such as liver inflammation and steatosis in KK/A y or high‐fat diet‐ and streptozotocin–nicotinamide‐induced type 2 diabetic mice (Tahara et al, ; Tahara, Takasu, Yokono, Imamura, & Kurosaki, ). While these mice exhibit obesity, insulin resistance, and hepatic steatosis, they do not exhibit hepatic fibrosis, which is observed in human NASH.…”

Section: Introductionmentioning

confidence: 93%

SGLT2 inhibitor ipragliflozin alone and combined with pioglitazone prevents progression of nonalcoholic steatohepatitis in a type 2 diabetes rodent model

Tahara

Takasu

2019

Physiol Rep

Self Cite

View full text Add to dashboard Cite

Nonalcoholic steatohepatitis (NASH) has become the most common cause of chronic liver disease worldwide in recent years. The pathogenesis of NASH is closely linked to metabolic diseases such as insulin resistance, obesity, dyslipidemia, and type 2 diabetes. However, there is currently no pharmacological agent for preventing the progression of NASH. Sodium–glucose cotransporter (SGLT) 2 inhibitors increase urinary glucose excretion by inhibiting renal glucose reabsorption, and improve various pathological conditions of type 2 diabetes, including insulin resistance. In the present study, we examined the effects of ipragliflozin, a SGLT2‐selective inhibitor, alone and in combination with pioglitazone on NASH in high‐fat diet‐fed KK/Ay type 2 diabetic mice. Type 2 diabetic mice with NASH exhibited steatosis, inflammation, and fibrosis in the liver as well as hyperglycemia, insulin resistance, and obesity, features that are observed in human NASH. Four‐week repeated administration of ipragliflozin (0.1–3 mg/kg) led to significant improvements in hyperglycemia, insulin resistance, and obesity in addition to hyperlipidemia and liver injury including hepatic steatosis and fibrosis. Moreover, ipragliflozin reduced inflammation and oxidative stress in the liver. Repeated administration of pioglitazone (3–30 mg/kg) also significantly improved various parameters of diabetes and NASH, excluding obesity. Furthermore, combined treatment comprising ipragliflozin (1 mg/kg) and pioglitazone (10 mg/kg) additively improved these parameters. These findings indicate that the SGLT2‐selective inhibitor ipragliflozin improves hyperglycemia as well as NASH in type 2 diabetic mice. Therefore, treatment with ipragliflozin monotherapy or coadministered with pioglitazone is expected to be a potential therapeutic option for the treatment of type 2 diabetes with NASH.

show abstract

“…Investigation has shown that dapagliflozin (and ipragliflozin) may be categorized as longacting SGLT-2i, in contrast to empagliflozin and canagliflozin (besides tofogliflozin and luseogliflozin), as they have an intermediate action [43]. Long-acting SGLT-2i may be more potent, with better glucose control throughout the day and a lower plasma insulin variability, also improving glucose tolerance in T2DM mice and demonstrating a trend towards superiority regarding diabetesrelated complications [44,45]. Regarding selectivity for SGLT-2, empagliflozin is the most selective of the 3, followed by dapagliflozin, with canagliflozin being the least selective [46][47][48].…”

Section: Benefits Of Sglt-2i: a Class Effect?mentioning

confidence: 99%

SGLT-2 Inhibitors in Heart Failure and Type-2 Diabetes: Hitting Two Birds with One Stone?

2019

View full text Add to dashboard Cite

Type 2 diabetes mellitus (T2DM) and heart failure (HF) have a tremendous impact worldwide, markedly reducing life-expectancy and quality of life. It is now known that each disease represents a risk factor for the other. Moreover, when they are combined, the prognosis is significantly worse. Until recently, these pathologies have been managed independently. However, their treatment paradigm is rapidly changing, with recent cardiovascular outcome trials showing that sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are effective in the management of both diseases. This article explores the interactions between T2DM and HF and the concept of diabetic cardiomyopathy and summarizes recent data regarding the effects of SGLT-2i on HF hospitalization and the proposed pathophysiological mechanisms involved. sively "glucocentric approach," T2DM management should rather contemplate the use of strategies that can reduce the risk of cardiovascular (and renal) events, including these new drugs and integrated control of all cardiovascular risk factors.This article aims to review the interaction between T2DM and HF and the concept of diabetic cardiomyopathy and to summarize recent data regarding the effects of SGLT-2i on HF hospitalization (HHF) and the proposed pathophysiological mechanisms involved.

show abstract

Characterization and comparison of SGLT2 inhibitors: Part 3. Effects on diabetic complications in type 2 diabetic mice

Cited by 43 publications

References 31 publications

Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease

Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease

SGLT2 inhibitor ipragliflozin alone and combined with pioglitazone prevents progression of nonalcoholic steatohepatitis in a type 2 diabetes rodent model

SGLT-2 Inhibitors in Heart Failure and Type-2 Diabetes: Hitting Two Birds with One Stone?

Contact Info

Product

Resources

About