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Satoshi Uno - One of the best experts on this subject based on the ideXlab platform.
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real world evidence for long term safety and effectiveness of Ipragliflozin in treatment naive versus non naive japanese patients with type 2 diabetes mellitus subgroup analysis of a 3 year post marketing surveillance study stella long term
Diabetology international, 2021Co-Authors: Hiroshi Maegawa, Ichiro Nakamura, Kazuyuki Tobe, Satoshi UnoAbstract:STELLA-LONG TERM was a 3-year post-marketing surveillance study that evaluated the long-term safety and effectiveness of Ipragliflozin in Japanese patients with type 2 diabetes mellitus (T2DM). This subgroup analysis examined the safety and effectiveness of Ipragliflozin in treatment-naive and non-naive patients. Patients were stratified into two subgroups: treatment-naive (patients who had not received any antidiabetic drugs before starting Ipragliflozin monotherapy) and non-naive (all other patients). Patients who had added or switched antidiabetic drugs during follow-up were excluded from the analysis from that point. The incidence of adverse drug reactions (ADRs) and changes from baseline in glycosylated hemoglobin (HbA1c), body weight, fasting plasma glucose (FPG) and laboratory parameters were assessed. Of the 11,051 patients in the safety analysis set, 1980 patients (17.92%) were treatment-naive and 9071 (82.08%) were non-naive. In the safety analysis set, treatment-naive patients reported significantly lower incidences of ADRs (10.81% vs 20.87%; p < 0.001) and serious ADRs (0.86% vs 2.09%; p < 0.001) compared with non-naive patients, as well as significantly lower incidences of polyuria/pollakiuria, volume depletion-related events, skin complications and renal disorders. In the effectiveness analysis, sustained and significant reductions from baseline to 36 months were observed in HbA1c, FPG and body weight in both treatment-naive and non-naive patients (all p < 0.001 vs baseline). Over 3 years, Ipragliflozin was better tolerated in treatment-naive than in non-naive Japanese patients with T2DM and had similar efficacy in these populations. Therefore, Ipragliflozin is a useful first-line treatment option for patients with T2DM. ClinicalTrials.gov: NCT02479399.
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real world evidence for long term safety and effectiveness of Ipragliflozin in japanese patients with type 2 diabetes mellitus final results of a 3 year post marketing surveillance study stella long term
Expert Opinion on Pharmacotherapy, 2021Co-Authors: Ichiro Nakamura, Kazuyuki Tobe, Hiroshi Maegawa, Satoshi UnoAbstract:To evaluate the long-term safety and effectiveness of Ipragliflozin in real-world clinical practice in Japanese patients with type 2 diabetes mellitus (T2DM). This post-marketing surveillance study...
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impact of body mass index on the efficacy and safety of Ipragliflozin in japanese patients with type 2 diabetes mellitus a subgroup analysis of 3 month interim results from the specified drug use results survey of Ipragliflozin treatment in type 2 di
Journal of Diabetes Investigation, 2019Co-Authors: Kazuyuki Tobe, Ichiro Nakamura, Hiroshi Maegawa, Hiromi Tabuchi, Satoshi UnoAbstract:AIMS/INTRODUCTION Specified Drug Use Results Survey of Ipragliflozin Treatment in Type 2 Diabetic Patients: Long-term Use is an ongoing postmarketing study of Ipragliflozin for long-term use in Japanese patients with type 2 diabetes mellitus. A subgroup analysis of data from the study was carried out to investigate the impact of obesity on the efficacy and safety of Ipragliflozin in this population. MATERIALS AND METHODS Patients were divided into the following subgroups according to their body mass index (BMI): <22.0, 22.0 to <25.0, 25.0 to <30.0 and ≥30.0 kg/m2 . Changes in bodyweight and glycemic parameters up to 3 months were evaluated, as well as adverse drug reactions (ADRs) that occurred during Ipragliflozin treatment. RESULTS In the efficacy analysis set (8,633 patients), glycemic control and bodyweight statistically significantly improved from baseline to 3 months in all BMI subgroups (all P < 0.05). No strong correlations were identified between changes in bodyweight and changes in hemoglobin A1c, waist circumference or BMI in any of the subgroups. The incidence of adverse drug reactions was 6.29, 8.44, 11.18 and 11.74% in the <22.0, 22.0 to <25.0, 25.0 to <30.0 and ≥30.0 kg/m2 groups, respectively (P = 0.001), in the safety analysis set (n = 11,053 patients). CONCLUSIONS In Japanese patients with type 2 diabetes mellitus, Ipragliflozin improved glycemic control and reduced bodyweight, regardless of BMI. Adverse drug reactions were more common in patients with higher BMI than in those with lower BMI.
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safety and effectiveness of Ipragliflozin in elderly versus non elderly japanese type 2 diabetes mellitus patients 12 month interim results of the stella long term study
Current Medical Research and Opinion, 2019Co-Authors: Hiroshi Maegawa, Ichiro Nakamura, Kazuyuki Tobe, Satoshi UnoAbstract:Objective: STELLA-LONG TERM is an ongoing post-marketing surveillance study examining the safety and effectiveness of Ipragliflozin in real-world clinical practice in Japan. This interim report of ...
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safety and effectiveness of Ipragliflozin for type 2 diabetes in japan 12 month interim results of the stella long term post marketing surveillance study
Advances in Therapy, 2019Co-Authors: Ichiro Nakamura, Kazuyuki Tobe, Hiroshi Maegawa, Satoshi UnoAbstract:The present interim report of the STELLA-LONG TERM study aimed to examine the safety and effectiveness of Ipragliflozin in real-word clinical practice in Japan using data up to 12 months. We also evaluated the effect of Ipragliflozin on aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in patients with normal vs. abnormal liver function. This is an ongoing 3-year post-marketing surveillance study. We analyzed data from Japanese type 2 diabetes mellitus (T2DM) patients who were first prescribed Ipragliflozin between 17 July 2014 and 16 October 2015 at participating centers in Japan, and whose data were locked by 16 January 2018. The incidence of adverse drug reactions (ADRs) was evaluated for safety. Changes in glycemic control and body weight were evaluated for effectiveness. The effect on liver function was evaluated by changes in the fatty liver index, and changes in AST and ALT were evaluated in patients with normal and abnormal liver function. The safety analysis set comprised 11,051 patients and the efficacy analysis set comprised 8788 patients. The incidence rates of ADRs and serious ADRs were 14.6% (1616/11,051) and 0.97% (107/11,051), respectively. Significant reductions (all P < 0.001 vs. baseline, paired t test) in glycated hemoglobin (− 0.8%), fasting plasma glucose (− 31.9 mg/dL), body weight (− 2.9 kg), and fatty liver index (− 8.7) were observed. In patients with normal liver function at baseline, no clinically significant changes in AST and ALT were observed. In patients with abnormal liver function at baseline, clinically and statistically significant decreases (P < 0.05 vs. baseline, two-sample t test) in AST (− 9.0 U/L) and ALT (− 14.7 U/L) levels were observed. Ipragliflozin was effective and well tolerated in Japanese patients with T2DM over 12 months in the real-world clinical setting. Improvements in liver function parameters (AST and ALT) were observed in T2DM patients with abnormal liver function. ClinicalTrials.gov identifier, NCT02479399. Astellas Pharma Inc., Japan.
Ichiro Nakamura - One of the best experts on this subject based on the ideXlab platform.
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real world evidence for long term safety and effectiveness of Ipragliflozin in treatment naive versus non naive japanese patients with type 2 diabetes mellitus subgroup analysis of a 3 year post marketing surveillance study stella long term
Diabetology international, 2021Co-Authors: Hiroshi Maegawa, Ichiro Nakamura, Kazuyuki Tobe, Satoshi UnoAbstract:STELLA-LONG TERM was a 3-year post-marketing surveillance study that evaluated the long-term safety and effectiveness of Ipragliflozin in Japanese patients with type 2 diabetes mellitus (T2DM). This subgroup analysis examined the safety and effectiveness of Ipragliflozin in treatment-naive and non-naive patients. Patients were stratified into two subgroups: treatment-naive (patients who had not received any antidiabetic drugs before starting Ipragliflozin monotherapy) and non-naive (all other patients). Patients who had added or switched antidiabetic drugs during follow-up were excluded from the analysis from that point. The incidence of adverse drug reactions (ADRs) and changes from baseline in glycosylated hemoglobin (HbA1c), body weight, fasting plasma glucose (FPG) and laboratory parameters were assessed. Of the 11,051 patients in the safety analysis set, 1980 patients (17.92%) were treatment-naive and 9071 (82.08%) were non-naive. In the safety analysis set, treatment-naive patients reported significantly lower incidences of ADRs (10.81% vs 20.87%; p < 0.001) and serious ADRs (0.86% vs 2.09%; p < 0.001) compared with non-naive patients, as well as significantly lower incidences of polyuria/pollakiuria, volume depletion-related events, skin complications and renal disorders. In the effectiveness analysis, sustained and significant reductions from baseline to 36 months were observed in HbA1c, FPG and body weight in both treatment-naive and non-naive patients (all p < 0.001 vs baseline). Over 3 years, Ipragliflozin was better tolerated in treatment-naive than in non-naive Japanese patients with T2DM and had similar efficacy in these populations. Therefore, Ipragliflozin is a useful first-line treatment option for patients with T2DM. ClinicalTrials.gov: NCT02479399.
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real world evidence for long term safety and effectiveness of Ipragliflozin in japanese patients with type 2 diabetes mellitus final results of a 3 year post marketing surveillance study stella long term
Expert Opinion on Pharmacotherapy, 2021Co-Authors: Ichiro Nakamura, Kazuyuki Tobe, Hiroshi Maegawa, Satoshi UnoAbstract:To evaluate the long-term safety and effectiveness of Ipragliflozin in real-world clinical practice in Japanese patients with type 2 diabetes mellitus (T2DM). This post-marketing surveillance study...
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impact of body mass index on the efficacy and safety of Ipragliflozin in japanese patients with type 2 diabetes mellitus a subgroup analysis of 3 month interim results from the specified drug use results survey of Ipragliflozin treatment in type 2 di
Journal of Diabetes Investigation, 2019Co-Authors: Kazuyuki Tobe, Ichiro Nakamura, Hiroshi Maegawa, Hiromi Tabuchi, Satoshi UnoAbstract:AIMS/INTRODUCTION Specified Drug Use Results Survey of Ipragliflozin Treatment in Type 2 Diabetic Patients: Long-term Use is an ongoing postmarketing study of Ipragliflozin for long-term use in Japanese patients with type 2 diabetes mellitus. A subgroup analysis of data from the study was carried out to investigate the impact of obesity on the efficacy and safety of Ipragliflozin in this population. MATERIALS AND METHODS Patients were divided into the following subgroups according to their body mass index (BMI): <22.0, 22.0 to <25.0, 25.0 to <30.0 and ≥30.0 kg/m2 . Changes in bodyweight and glycemic parameters up to 3 months were evaluated, as well as adverse drug reactions (ADRs) that occurred during Ipragliflozin treatment. RESULTS In the efficacy analysis set (8,633 patients), glycemic control and bodyweight statistically significantly improved from baseline to 3 months in all BMI subgroups (all P < 0.05). No strong correlations were identified between changes in bodyweight and changes in hemoglobin A1c, waist circumference or BMI in any of the subgroups. The incidence of adverse drug reactions was 6.29, 8.44, 11.18 and 11.74% in the <22.0, 22.0 to <25.0, 25.0 to <30.0 and ≥30.0 kg/m2 groups, respectively (P = 0.001), in the safety analysis set (n = 11,053 patients). CONCLUSIONS In Japanese patients with type 2 diabetes mellitus, Ipragliflozin improved glycemic control and reduced bodyweight, regardless of BMI. Adverse drug reactions were more common in patients with higher BMI than in those with lower BMI.
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safety and effectiveness of Ipragliflozin in elderly versus non elderly japanese type 2 diabetes mellitus patients 12 month interim results of the stella long term study
Current Medical Research and Opinion, 2019Co-Authors: Hiroshi Maegawa, Ichiro Nakamura, Kazuyuki Tobe, Satoshi UnoAbstract:Objective: STELLA-LONG TERM is an ongoing post-marketing surveillance study examining the safety and effectiveness of Ipragliflozin in real-world clinical practice in Japan. This interim report of ...
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safety and effectiveness of Ipragliflozin for type 2 diabetes in japan 12 month interim results of the stella long term post marketing surveillance study
Advances in Therapy, 2019Co-Authors: Ichiro Nakamura, Kazuyuki Tobe, Hiroshi Maegawa, Satoshi UnoAbstract:The present interim report of the STELLA-LONG TERM study aimed to examine the safety and effectiveness of Ipragliflozin in real-word clinical practice in Japan using data up to 12 months. We also evaluated the effect of Ipragliflozin on aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in patients with normal vs. abnormal liver function. This is an ongoing 3-year post-marketing surveillance study. We analyzed data from Japanese type 2 diabetes mellitus (T2DM) patients who were first prescribed Ipragliflozin between 17 July 2014 and 16 October 2015 at participating centers in Japan, and whose data were locked by 16 January 2018. The incidence of adverse drug reactions (ADRs) was evaluated for safety. Changes in glycemic control and body weight were evaluated for effectiveness. The effect on liver function was evaluated by changes in the fatty liver index, and changes in AST and ALT were evaluated in patients with normal and abnormal liver function. The safety analysis set comprised 11,051 patients and the efficacy analysis set comprised 8788 patients. The incidence rates of ADRs and serious ADRs were 14.6% (1616/11,051) and 0.97% (107/11,051), respectively. Significant reductions (all P < 0.001 vs. baseline, paired t test) in glycated hemoglobin (− 0.8%), fasting plasma glucose (− 31.9 mg/dL), body weight (− 2.9 kg), and fatty liver index (− 8.7) were observed. In patients with normal liver function at baseline, no clinically significant changes in AST and ALT were observed. In patients with abnormal liver function at baseline, clinically and statistically significant decreases (P < 0.05 vs. baseline, two-sample t test) in AST (− 9.0 U/L) and ALT (− 14.7 U/L) levels were observed. Ipragliflozin was effective and well tolerated in Japanese patients with T2DM over 12 months in the real-world clinical setting. Improvements in liver function parameters (AST and ALT) were observed in T2DM patients with abnormal liver function. ClinicalTrials.gov identifier, NCT02479399. Astellas Pharma Inc., Japan.
Toshiyuki Takasu - One of the best experts on this subject based on the ideXlab platform.
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therapeutic effects of sglt2 inhibitor Ipragliflozin and metformin on nash in type 2 diabetic mice
Endocrine Research, 2020Co-Authors: Atsuo Tahara, Toshiyuki TakasuAbstract:Background and aim: Sodium-glucose cotransporter (SGLT) 2 is responsible for most of the glucose reabsorption in the kidneys and has been proposed as a novel therapeutic target for the treatment of type 2 diabetes. In recent years, nonalcoholic steatohepatitis (NASH), the pathogenesis of which is strongly associated with insulin resistance, obesity, and type 2 diabetes, has become a considerable healthcare burden worldwide. However, there is currently no established pharmacotherapy for NASH. Here, we investigated the therapeutic effects of the SGLT2 selective inhibitor Ipragliflozin alone and in combination with metformin on NASH in high fat and cholesterol diet-fed KK/Ay type 2 diabetic mice.Results: This diabetic model had hyperglycemia, insulin resistance, and obesity, and also exhibited steatosis, inflammation, and fibrosis in the liver, pathological features resembling those in human NASH. Four-week repeated administration of Ipragliflozin significantly improved not only hyperglycemia, insulin resistance, and obesity but also hyperlipidemia and NASH-associated symptoms including hepatic steatosis and fibrosis. In addition, Ipragliflozin attenuated inflammation and oxidative stress in the liver. Repeated administration of metformin also significantly improved symptoms of type 2 diabetes with NASH to a comparable degree to that by Ipragliflozin. In addition, combination treatment with Ipragliflozin and metformin additively improved these symptoms.Conclusions: These results demonstrate that the SGLT2 selective inhibitor Ipragliflozin improves not only hyperglycemia but also NASH in type 2 diabetic mice, suggesting that treatment with Ipragliflozin alone and in combination with metformin may be effective for treating type 2 diabetes with NASH.
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effect of Ipragliflozin an sglt2 inhibitor on cardiac histopathological changes in a non diabetic rat model of cardiomyopathy
Life Sciences, 2019Co-Authors: Toshiyuki Takasu, Shoji TakakuraAbstract:Abstract Aims We investigated the effect of the selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor Ipragliflozin on cardiac dysfunction and histopathology in a non-diabetic rat model of cardiomyopathy. Main methods Ipragliflozin was mixed with chow (0.01%, w/w) and administered to male DahlS.Z-Leprfa/Leprfa (DS/obese) rats for 8 weeks. Male DahlS.Z-Lepr+/Lepr+ (DS/lean) rats of the same age were used as controls. Systolic blood pressure (SBP) and heart rate (HR) were measured every 4 weeks. After 8 weeks of treatment, echocardiography and histopathological examinations were performed. Further, the effect of Ipragliflozin on blood and urine parameters were investigated. Key findings In the DS/obese rats, Ipragliflozin delayed the age-related increase in SBP without affecting HR, reduced left ventricular (LV) mass and intraventricular septal thickness in echocardiography, and ameliorated hypertrophy of cardiomyocytes and LV fibrosis in histopathological examination. Although Ipragliflozin significantly increased both urine volume and urinary glucose excretion in DS/obese rats, it did not alter plasma glucose levels. Significance Ipragliflozin prevented LV hypertrophy and fibrosis in non-diabetic DS/obese rats without affecting plasma glucose levels. These findings suggest that SGLT2 inhibitors have a cardio-protective effect in non-diabetic patients with cardiomyopathy.
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in vitro pharmacological profile of Ipragliflozin a sodium glucose co transporter 2 inhibitor
Biological & Pharmaceutical Bulletin, 2019Co-Authors: Toshiyuki Takasu, Masanori Yokono, Atsuo Tahara, Shoji TakakuraAbstract:Ipragliflozin, a selective sodium glucose cotransporter 2 (SGLT2) inhibitor, is used for the treatment of type 2 diabetes mellitus. To date, the only known in vitro pharmacological characteristic of Ipragliflozin is its selectivity for SGLT2 over SGLT1, which was previously reported by our group. Therefore, in this study, we investigated other in vitro pharmacological characteristics of Ipragliflozin and compared them with those of phlorizin, a naturally occurring SGLT inhibitor. Selectivity of Ipragliflozin and phlorizin for human (h) SGLT2 over hSGLT3, hSGLT4, hSGLT5, hSGLT6 and hSodium/myo-inositol (MI) cotransporter 1 (hSMIT1) was examined in Chinese hamster ovary (CHO) cells overexpressing each transporter using specific radio-ligands. Ipragliflozin had higher selectivity for hSGLT2 than other hSGLTs. Phlorizin showed lower selectivity for hSGLT2 compared to Ipragliflozin. Studies using CHO cells overexpressing hSGLT2 demonstrated that both Ipragliflozin and phlorizin competitively inhibited SGLT2-mediated methyl-α-D-glucopyranoside (AMG) uptake with an inhibitory constant (Ki) of 2.28 and 20.2 nM, respectively. Ipragliflozin, but not phlorizin, inhibited hSGLT2 in a wash-resistant manner, suggesting that binding of Ipragliflozin to hSGLT2 was persistent. These data demonstrate that Ipragliflozin is a competitive inhibitor of SGLT2, has high selectivity for SGLT2 over not only SGLT1 but also other SGLT family members, and binds persistently to hSGLT2.
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effects of the sglt2 inhibitor Ipragliflozin on food intake appetite regulating hormones and arteriovenous differences in postprandial glucose levels in type 2 diabetic rats
Biomedicine & Pharmacotherapy, 2018Co-Authors: Atsuo Tahara, Toshiyuki Takasu, Yoshinori Kondo, Hiroshi TomiyamaAbstract:Abstract Aims The sodium-glucose cotransporter (SGLT) 2 inhibitor, Ipragliflozin, improves not only hyperglycemia but also obesity in type 2 diabetic animals and patients; however, there have been concerns that it may also cause an increase in compensatory food intake. Appetite is regulated by complex mechanisms involving the central nervous system, part of which involves appetite-related hormones and arteriovenous differences in postprandial glucose levels. We evaluated the effect of Ipragliflozin in type 2 diabetic rats on food intake, appetite-related hormones and arteriovenous differences in postprandial glucose levels, and their correlation with food intake. Main methods Ipragliflozin and several antidiabetic drugs were administered to type 2 diabetic rats and various parameters concerning food intake were measured. Key findings Ipragliflozin significantly increased urinary glucose excretion and reduced postprandial hyperglycemia. Compared to normal rats, diabetic rats exhibited hyperphagia and elevated plasma levels of the appetite-stimulating hormones neuropeptide Y and ghrelin. Ipragliflozin induced significant weight loss and reduced plasma levels of appetite-stimulating hormones without affecting food intake. Diabetic rats exhibited a significantly reduced arteriovenous difference in postprandial glucose levels due to insulin insufficiency; this was improved by Ipragliflozin, which increased renal arteriovenous differences in glucose levels by increasing urinary glucose excretion. Significance: These results indicate that the SGLT2 inhibitor, Ipragliflozin, exerts antihyperglycemic actions by increasing urinary glucose excretion, and induces weight loss without a compensatory increase in food intake in type 2 diabetic mice. The mechanisms underlying these effects can be attributed, in part, to an increased arteriovenous difference in postprandial glucose levels and improved regulation of appetite-related hormones in the diabetic animal model. While this study was conducted in rodents and the results may be distinct from those in humans, it is possible that some of the pharmacological mechanisms, including the regulation of appetite-related hormones, can be extrapolated to clinical settings and may be valuable for further studies including clinical investigations.
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Ipragliflozin improves mitochondrial abnormalities in renal tubules induced by a high fat diet
Journal of Diabetes Investigation, 2018Co-Authors: Susumu Takagi, Toshiyuki Takasu, Yuta Takagaki, Munehiro Kitada, Kyoko Nitta, Keizo Kanasaki, Daisuke KoyaAbstract:AIMS/INTRODUCTION Complete mechanisms of renoprotective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors have not been elucidated yet. Mitochondrial biogenesis is regulated by membrane GTPases, such as optic atrophy factor 1 and mitofusion 2. Here, we investigated whether SGLT2 inhibition in mice fed with a high-fat diet (HFD) improved mitochondrial morphology and restored mitochondrial biogenesis-related molecules. MATERIALS AND METHODS Mice were fed a control diet or HFD with or without Ipragliflozin treatment. After 16 weeks, the kidneys were taken out and utilized for the analysis. RESULTS HFD-fed mice treated with Ipragliflozin showed increased caloric intake and ate more food than the control HFD-fed mice. Body and kidney weights, and blood glucose levels were not altered by Ipragliflozin treatment in HFD-fed mice. Histological analysis showed that, compared with control mice, HFD-fed mice displayed tubular vacuolation, dilatation and epithelial cell detachment; Ipragliflozin ameliorated these alterations. Furthermore, ultrastructural analysis showed that the tubule mitochondria of HFD-fed mice exhibited significant damage. Again, Ipragliflozin reversed the damage to a normal state, and restored optic atrophy factor 1 and mitofusion 2 levels in HFD-fed mice. Increased urine 8-hydroxydeoxyguanosine levels in HFD-fed mice were suppressed by Ipragliflozin as well. In vitro experiments using HK-2 cells revealed that either high glucose or high palmitate suppressed optic atrophy factor 1 and mitofusion 2 levels. Suppression of SGLT2 by a specific small interfering ribonucleic acid or Ipragliflozin restored these GTPase levels to their normal values. CONCLUSIONS SGLT2 inhibition might act directly on tubular cells and protect kidney tubular cells from mitochondrial damage by metabolic insults regardless of blood glucose levels or improvement in bodyweight reduction.
Atsuo Tahara - One of the best experts on this subject based on the ideXlab platform.
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therapeutic effects of sglt2 inhibitor Ipragliflozin and metformin on nash in type 2 diabetic mice
Endocrine Research, 2020Co-Authors: Atsuo Tahara, Toshiyuki TakasuAbstract:Background and aim: Sodium-glucose cotransporter (SGLT) 2 is responsible for most of the glucose reabsorption in the kidneys and has been proposed as a novel therapeutic target for the treatment of type 2 diabetes. In recent years, nonalcoholic steatohepatitis (NASH), the pathogenesis of which is strongly associated with insulin resistance, obesity, and type 2 diabetes, has become a considerable healthcare burden worldwide. However, there is currently no established pharmacotherapy for NASH. Here, we investigated the therapeutic effects of the SGLT2 selective inhibitor Ipragliflozin alone and in combination with metformin on NASH in high fat and cholesterol diet-fed KK/Ay type 2 diabetic mice.Results: This diabetic model had hyperglycemia, insulin resistance, and obesity, and also exhibited steatosis, inflammation, and fibrosis in the liver, pathological features resembling those in human NASH. Four-week repeated administration of Ipragliflozin significantly improved not only hyperglycemia, insulin resistance, and obesity but also hyperlipidemia and NASH-associated symptoms including hepatic steatosis and fibrosis. In addition, Ipragliflozin attenuated inflammation and oxidative stress in the liver. Repeated administration of metformin also significantly improved symptoms of type 2 diabetes with NASH to a comparable degree to that by Ipragliflozin. In addition, combination treatment with Ipragliflozin and metformin additively improved these symptoms.Conclusions: These results demonstrate that the SGLT2 selective inhibitor Ipragliflozin improves not only hyperglycemia but also NASH in type 2 diabetic mice, suggesting that treatment with Ipragliflozin alone and in combination with metformin may be effective for treating type 2 diabetes with NASH.
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in vitro pharmacological profile of Ipragliflozin a sodium glucose co transporter 2 inhibitor
Biological & Pharmaceutical Bulletin, 2019Co-Authors: Toshiyuki Takasu, Masanori Yokono, Atsuo Tahara, Shoji TakakuraAbstract:Ipragliflozin, a selective sodium glucose cotransporter 2 (SGLT2) inhibitor, is used for the treatment of type 2 diabetes mellitus. To date, the only known in vitro pharmacological characteristic of Ipragliflozin is its selectivity for SGLT2 over SGLT1, which was previously reported by our group. Therefore, in this study, we investigated other in vitro pharmacological characteristics of Ipragliflozin and compared them with those of phlorizin, a naturally occurring SGLT inhibitor. Selectivity of Ipragliflozin and phlorizin for human (h) SGLT2 over hSGLT3, hSGLT4, hSGLT5, hSGLT6 and hSodium/myo-inositol (MI) cotransporter 1 (hSMIT1) was examined in Chinese hamster ovary (CHO) cells overexpressing each transporter using specific radio-ligands. Ipragliflozin had higher selectivity for hSGLT2 than other hSGLTs. Phlorizin showed lower selectivity for hSGLT2 compared to Ipragliflozin. Studies using CHO cells overexpressing hSGLT2 demonstrated that both Ipragliflozin and phlorizin competitively inhibited SGLT2-mediated methyl-α-D-glucopyranoside (AMG) uptake with an inhibitory constant (Ki) of 2.28 and 20.2 nM, respectively. Ipragliflozin, but not phlorizin, inhibited hSGLT2 in a wash-resistant manner, suggesting that binding of Ipragliflozin to hSGLT2 was persistent. These data demonstrate that Ipragliflozin is a competitive inhibitor of SGLT2, has high selectivity for SGLT2 over not only SGLT1 but also other SGLT family members, and binds persistently to hSGLT2.
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effects of the sglt2 inhibitor Ipragliflozin on food intake appetite regulating hormones and arteriovenous differences in postprandial glucose levels in type 2 diabetic rats
Biomedicine & Pharmacotherapy, 2018Co-Authors: Atsuo Tahara, Toshiyuki Takasu, Yoshinori Kondo, Hiroshi TomiyamaAbstract:Abstract Aims The sodium-glucose cotransporter (SGLT) 2 inhibitor, Ipragliflozin, improves not only hyperglycemia but also obesity in type 2 diabetic animals and patients; however, there have been concerns that it may also cause an increase in compensatory food intake. Appetite is regulated by complex mechanisms involving the central nervous system, part of which involves appetite-related hormones and arteriovenous differences in postprandial glucose levels. We evaluated the effect of Ipragliflozin in type 2 diabetic rats on food intake, appetite-related hormones and arteriovenous differences in postprandial glucose levels, and their correlation with food intake. Main methods Ipragliflozin and several antidiabetic drugs were administered to type 2 diabetic rats and various parameters concerning food intake were measured. Key findings Ipragliflozin significantly increased urinary glucose excretion and reduced postprandial hyperglycemia. Compared to normal rats, diabetic rats exhibited hyperphagia and elevated plasma levels of the appetite-stimulating hormones neuropeptide Y and ghrelin. Ipragliflozin induced significant weight loss and reduced plasma levels of appetite-stimulating hormones without affecting food intake. Diabetic rats exhibited a significantly reduced arteriovenous difference in postprandial glucose levels due to insulin insufficiency; this was improved by Ipragliflozin, which increased renal arteriovenous differences in glucose levels by increasing urinary glucose excretion. Significance: These results indicate that the SGLT2 inhibitor, Ipragliflozin, exerts antihyperglycemic actions by increasing urinary glucose excretion, and induces weight loss without a compensatory increase in food intake in type 2 diabetic mice. The mechanisms underlying these effects can be attributed, in part, to an increased arteriovenous difference in postprandial glucose levels and improved regulation of appetite-related hormones in the diabetic animal model. While this study was conducted in rodents and the results may be distinct from those in humans, it is possible that some of the pharmacological mechanisms, including the regulation of appetite-related hormones, can be extrapolated to clinical settings and may be valuable for further studies including clinical investigations.
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prevention of progression of diabetic nephropathy by the sglt2 inhibitor Ipragliflozin in uninephrectomized type 2 diabetic mice
European Journal of Pharmacology, 2018Co-Authors: Atsuo Tahara, Toshiyuki TakasuAbstract:Abstract Diabetic nephropathy is the leading cause of end-stage renal disease in the world. Although recent development of sodium-glucose cotransporter (SGLT) 2 inhibitors offers a new antidiabetic therapeutic strategy, it remains unclear whether such treatments are beneficial for limiting the progression of type 2 diabetic overt nephropathy. This study examined the effect of the SGLT2 inhibitor Ipragliflozin on the progression of nephropathy in uninephrectomized KK/Ay type 2 diabetic mice, which exhibit not only typical diabetic symptoms such as hyperglycemia, hyperinsuemia, glucose intolerance, insulin resistance, hyperlipidemia, inflammation, and obesity, but also moderate hypertension and overt nephropathy with decline in renal function. Four-week repeated administration of Ipragliflozin improved various diabetic symptoms, including hyperglycemia, insulin resistance, and inflammation by increasing urinary glucose excretion. In addition, Ipragliflozin ameliorated albuminuria/proteinuria; decline in renal function, as measured by creatinine clearance; hypertension; and renal injury, including glomerulosclerosis and interstitial fibrosis. These effects were significant at doses of 1 mg/kg or higher and were similar to those observed following administration of losartan (30 mg/kg). These results suggest that the SGLT2 inhibitor Ipragliflozin prevents progression to diabetic overt nephropathy in uninephrectomized type 2 diabetic mice. SGLT2 inhibitors may therefore represent a promising therapeutic option for the management of type 2 diabetes to slow the progression of diabetic nephropathy.
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antidiabetic and antiobesity effects of sglt2 inhibitor Ipragliflozin in type 2 diabetic mice fed sugar solution
European Journal of Pharmacology, 2018Co-Authors: Atsuo Tahara, Masanori Yokono, Toshiyuki Takasu, Masakazu Imamura, Eiji KurosakiAbstract:Obesity due to excessive calorie intake is a known aggravating factor contributing to the development and progression of type 2 diabetes. Recently, excessive intake of sugar-sweetened beverages has presented challenges in stemming the tide of obesity. Here, we investigated the possible effects of sugar solution intake on the antidiabetic effects of sodium-glucose cotransporter 2 (SGLT2) inhibitor Ipragliflozin in type 2 diabetic mice that were fed ordinary drinking water, water + glucose solution, or water + sucrose solution. Under all feeding conditions, all mice exhibited type 2 diabetic symptoms, including hyperglycemia, hyperinsulinemia, and obesity; Ipragliflozin subsequently improved these symptoms through increases in urinary glucose excretion. Effective dose of and response to Ipragliflozin for diabetes improvement did not significantly differ by feeding condition. Further, under all feeding conditions, Ipragliflozin administration resulted in significantly increased intake of both water and sugar solutions in association with increased urine volume resulting from increased urinary glucose excretion. In sugar solution-fed diabetic mice, Ipragliflozin administration tended to slightly increase the proportion of sugar solution intake in total drinking volume, although not significantly so. In addition, Ipragliflozin significantly decreased calorie balance, as calculated using calorie intake from food and sugar solution and calorie excretion via urinary glucose excretion. Our observation that the antidiabetic and antiobesity effects of the SGLT2 inhibitor Ipragliflozin were not greatly affected by sugar solution intake in type 2 diabetic mice suggests that, in a clinical setting, Ipragliflozin will remain an effective treatment for type 2 diabetic patients with excessive intake of carbohydrates.
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real world evidence for long term safety and effectiveness of Ipragliflozin in treatment naive versus non naive japanese patients with type 2 diabetes mellitus subgroup analysis of a 3 year post marketing surveillance study stella long term
Diabetology international, 2021Co-Authors: Hiroshi Maegawa, Ichiro Nakamura, Kazuyuki Tobe, Satoshi UnoAbstract:STELLA-LONG TERM was a 3-year post-marketing surveillance study that evaluated the long-term safety and effectiveness of Ipragliflozin in Japanese patients with type 2 diabetes mellitus (T2DM). This subgroup analysis examined the safety and effectiveness of Ipragliflozin in treatment-naive and non-naive patients. Patients were stratified into two subgroups: treatment-naive (patients who had not received any antidiabetic drugs before starting Ipragliflozin monotherapy) and non-naive (all other patients). Patients who had added or switched antidiabetic drugs during follow-up were excluded from the analysis from that point. The incidence of adverse drug reactions (ADRs) and changes from baseline in glycosylated hemoglobin (HbA1c), body weight, fasting plasma glucose (FPG) and laboratory parameters were assessed. Of the 11,051 patients in the safety analysis set, 1980 patients (17.92%) were treatment-naive and 9071 (82.08%) were non-naive. In the safety analysis set, treatment-naive patients reported significantly lower incidences of ADRs (10.81% vs 20.87%; p < 0.001) and serious ADRs (0.86% vs 2.09%; p < 0.001) compared with non-naive patients, as well as significantly lower incidences of polyuria/pollakiuria, volume depletion-related events, skin complications and renal disorders. In the effectiveness analysis, sustained and significant reductions from baseline to 36 months were observed in HbA1c, FPG and body weight in both treatment-naive and non-naive patients (all p < 0.001 vs baseline). Over 3 years, Ipragliflozin was better tolerated in treatment-naive than in non-naive Japanese patients with T2DM and had similar efficacy in these populations. Therefore, Ipragliflozin is a useful first-line treatment option for patients with T2DM. ClinicalTrials.gov: NCT02479399.
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real world evidence for long term safety and effectiveness of Ipragliflozin in japanese patients with type 2 diabetes mellitus final results of a 3 year post marketing surveillance study stella long term
Expert Opinion on Pharmacotherapy, 2021Co-Authors: Ichiro Nakamura, Kazuyuki Tobe, Hiroshi Maegawa, Satoshi UnoAbstract:To evaluate the long-term safety and effectiveness of Ipragliflozin in real-world clinical practice in Japanese patients with type 2 diabetes mellitus (T2DM). This post-marketing surveillance study...
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impact of body mass index on the efficacy and safety of Ipragliflozin in japanese patients with type 2 diabetes mellitus a subgroup analysis of 3 month interim results from the specified drug use results survey of Ipragliflozin treatment in type 2 di
Journal of Diabetes Investigation, 2019Co-Authors: Kazuyuki Tobe, Ichiro Nakamura, Hiroshi Maegawa, Hiromi Tabuchi, Satoshi UnoAbstract:AIMS/INTRODUCTION Specified Drug Use Results Survey of Ipragliflozin Treatment in Type 2 Diabetic Patients: Long-term Use is an ongoing postmarketing study of Ipragliflozin for long-term use in Japanese patients with type 2 diabetes mellitus. A subgroup analysis of data from the study was carried out to investigate the impact of obesity on the efficacy and safety of Ipragliflozin in this population. MATERIALS AND METHODS Patients were divided into the following subgroups according to their body mass index (BMI): <22.0, 22.0 to <25.0, 25.0 to <30.0 and ≥30.0 kg/m2 . Changes in bodyweight and glycemic parameters up to 3 months were evaluated, as well as adverse drug reactions (ADRs) that occurred during Ipragliflozin treatment. RESULTS In the efficacy analysis set (8,633 patients), glycemic control and bodyweight statistically significantly improved from baseline to 3 months in all BMI subgroups (all P < 0.05). No strong correlations were identified between changes in bodyweight and changes in hemoglobin A1c, waist circumference or BMI in any of the subgroups. The incidence of adverse drug reactions was 6.29, 8.44, 11.18 and 11.74% in the <22.0, 22.0 to <25.0, 25.0 to <30.0 and ≥30.0 kg/m2 groups, respectively (P = 0.001), in the safety analysis set (n = 11,053 patients). CONCLUSIONS In Japanese patients with type 2 diabetes mellitus, Ipragliflozin improved glycemic control and reduced bodyweight, regardless of BMI. Adverse drug reactions were more common in patients with higher BMI than in those with lower BMI.
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safety and effectiveness of Ipragliflozin in elderly versus non elderly japanese type 2 diabetes mellitus patients 12 month interim results of the stella long term study
Current Medical Research and Opinion, 2019Co-Authors: Hiroshi Maegawa, Ichiro Nakamura, Kazuyuki Tobe, Satoshi UnoAbstract:Objective: STELLA-LONG TERM is an ongoing post-marketing surveillance study examining the safety and effectiveness of Ipragliflozin in real-world clinical practice in Japan. This interim report of ...
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safety and effectiveness of Ipragliflozin for type 2 diabetes in japan 12 month interim results of the stella long term post marketing surveillance study
Advances in Therapy, 2019Co-Authors: Ichiro Nakamura, Kazuyuki Tobe, Hiroshi Maegawa, Satoshi UnoAbstract:The present interim report of the STELLA-LONG TERM study aimed to examine the safety and effectiveness of Ipragliflozin in real-word clinical practice in Japan using data up to 12 months. We also evaluated the effect of Ipragliflozin on aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in patients with normal vs. abnormal liver function. This is an ongoing 3-year post-marketing surveillance study. We analyzed data from Japanese type 2 diabetes mellitus (T2DM) patients who were first prescribed Ipragliflozin between 17 July 2014 and 16 October 2015 at participating centers in Japan, and whose data were locked by 16 January 2018. The incidence of adverse drug reactions (ADRs) was evaluated for safety. Changes in glycemic control and body weight were evaluated for effectiveness. The effect on liver function was evaluated by changes in the fatty liver index, and changes in AST and ALT were evaluated in patients with normal and abnormal liver function. The safety analysis set comprised 11,051 patients and the efficacy analysis set comprised 8788 patients. The incidence rates of ADRs and serious ADRs were 14.6% (1616/11,051) and 0.97% (107/11,051), respectively. Significant reductions (all P < 0.001 vs. baseline, paired t test) in glycated hemoglobin (− 0.8%), fasting plasma glucose (− 31.9 mg/dL), body weight (− 2.9 kg), and fatty liver index (− 8.7) were observed. In patients with normal liver function at baseline, no clinically significant changes in AST and ALT were observed. In patients with abnormal liver function at baseline, clinically and statistically significant decreases (P < 0.05 vs. baseline, two-sample t test) in AST (− 9.0 U/L) and ALT (− 14.7 U/L) levels were observed. Ipragliflozin was effective and well tolerated in Japanese patients with T2DM over 12 months in the real-world clinical setting. Improvements in liver function parameters (AST and ALT) were observed in T2DM patients with abnormal liver function. ClinicalTrials.gov identifier, NCT02479399. Astellas Pharma Inc., Japan.