Ipragliflozin Group Research Articles

Long-term effects of ipragliflozin and pioglitazone on metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes: 5 year observational follow-up of a randomized, 24 week, active-controlled trial: Effect of ipragliflozin in MASLD.

We conducted a 5 year post-trial monitoring study of our previous randomized 24 week, open-label, active-controlled trial that showed beneficial effects of ipragliflozin on metabolic dysfunction-associated steatotic liver disease (MASLD), identical to those of pioglitazone. In our previous trial, 66 patients with MASLD and type 2 diabetes were randomly assigned to receive either ipragliflozin (n = 32) or pioglitazone (n = 34). Upon its conclusion, 61 patients were monitored for 5 years for outcome measures of MASLD, glycemic, and metabolic parameters. Differences between the two groups were analyzed at baseline, 24 weeks, and 5 years; changes in outcome measures from baseline were also evaluated. At 5 years, the mean liver-to-spleen attenuation ratio increased by 0.20 (from 0.78 ± 0.24 to 0.98 ± 0.20) in the ipragliflozin group and by 0.26 (from 0.76 ± 0.26 to 1.02 ± 0.20) in the pioglitazone group (P = 0.363). Similarly, ipragliflozin and pioglitazone significantly improved serum aminotransferase, HbA1c, and fasting plasma glucose levels over 5 years. In the ipragliflozin group, significant reductions in body weight and visceral fat area observed at 24 weeks were sustained throughout the 5 years (-4.0%, P = 0.0075 and -7.6%, P = 0.045, respectively). Moreover, ipragliflozin significantly reduced the values of fibrosis markers (serum ferritin and FIB-4 index), was well tolerated, and had a higher continuation rate for 5 years compared with pioglitazone. Ipragliflozin and pioglitazone improved MASLD and glycemic parameters over 5 years. In the ipragliflozin group, significant reductions in body weight and visceral fat mass persisted for 5 years.

Erythropoiesis and estimated fluid volume regulation following initiation of ipragliflozin treatment in patients with type 2 diabetes mellitus and chronic kidney disease: A post-hoc analysis of the PROCEED trial.

To analyse the changes in erythropoietic and estimated fluid volume parameters after the initiation of ipragliflozin, a sodium-glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). This was a post-hoc analysis of the PROCEED trial, which evaluated the effect of 24-week ipragliflozin treatment on endothelial dysfunction in patients with T2DM and CKD. We evaluated the changes in erythropoietic and estimated fluid volume parameters from baseline to 24 weeks post-treatment in 53 patients who received ipragliflozin (ipragliflozin group) and 55 patients with T2DM and CKD without sodium-glucose co-transporter 2 inhibitors (control group), a full analysis set of the PROCEED trial. The increases in haemoglobin [estimated group difference, 0.5 g/dl; 95% confidence interval (CI), 0.3-0.8; p < .001], haematocrit (estimated group difference, 2.2%; 95% CI, 1.3-3.1; p < .001) and erythropoietin (estimated log-transformed group difference, 0.1; 95% CI, 0.01-0.3; p = .036) were significantly greater in the ipragliflozin group than those in the control group. Ipragliflozin treatment was significantly associated with an increase in erythropoietin, independent of the corresponding change in haemoglobin (β = 0.253, p < .001) or haematocrit (β = 0.278, p < .001). Reductions in estimated plasma volume (estimated group difference, -7.94%; 95% CI, -11.6 to -4.26%; p < .001) and estimated extracellular volume (estimated group difference, -181.6 ml; 95% CI, -275.7 to -87.48 ml; p < .001) were significantly greater in the ipragliflozin group than those in the control group. Erythropoiesis was enhanced and estimated fluid volumes were reduced by ipragliflozin in patients with T2DM and CKD. PROCEED trial (registration number: jRCTs071190054).

Metabolomic analysis of serum samples from a clinical study on ipragliflozin and metformin treatment in Japanese patients with type 2 diabetes: Exploring human metabolites associated with visceral fat reduction.

The effects of the sodium-dependent glucose transporter-2 inhibitor ipragliflozin were compared with metformin in a previous study, which revealed that ipragliflozin reduced visceral fat content by 12%; however, the underlying mechanism was unclear. Therefore, this sub-analysis aimed to compare metabolomic changes associated with ipragliflozin and metformin that may contribute to their biological effects. In the previous study, 103 patients with type 2 diabetes were randomly assigned to receive ipragliflozin 50 mg or metformin 1000 mg daily. Of the 103 patients, 15 patients in the ipragliflozin group with the highest reduction in visceral fat areas and 15 patients in the metformin group with matching characteristics, such as age, sex, baseline A1C, baseline visceral fat area, smoking status, and concomitant medication, were selected. The clinical data were reanalyzed, and metabolomic analysis of serum samples collected before and 24 weeks after drug administration was performed using capillary electrophoresis time-of-flight mass spectrometry. The reduction in the mean visceral fat area after 24 weeks of treatment was significantly larger (P=0.002) in the ipragliflozin group (-19.8%) than in the metformin group (-2.5%), as were the subcutaneous fat area and body weight. The A1C and blood glucose levels decreased in both groups. Glutamic pyruvic oxaloacetic transaminase, γ-glutamyl transferase, uric acid, and triglyceride levels decreased in the ipragliflozin group. Low-density lipoprotein cholesterol level decreased in the metformin group. After ipragliflozin administration, N2 -phenylacetylglutamine, inosine, guanosine, and 1-methyladenosine levels increased, whereas galactosamine, glucosamine, 11-aminoundecanoic acid, morpholine, and choline levels decreased. After metformin administration, metformin, hypotaurine, methionine, methyl-2-oxovaleric acid, 3-nitrotyrosine, and cyclohexylamine levels increased, whereas citrulline, octanoic acid, indole-3-acetaldehyde, and hexanoic acid levels decreased. Metabolites that may affect visceral fat reduction were detected in the ipragliflozin group. Studies are required to further elucidate the underlying mechanisms.

Lack of impact of ipragliflozin on endothelial function in patients with type 2 diabetes: sub-analysis of the PROTECT study

BackgroundWe assessed the impact of 24 months of treatment with ipragliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on endothelial function in patients with type 2 diabetes as a sub-analysis of the PROTECT study.MethodsIn the PROTECT study, patients were randomized to receive either standard antihyperglycemic treatment (control group, n = 241 ) or add-on ipragliflozin treatment (ipragliflozin group, n = 241) in a 1:1 ratio. Among the 482 patients in the PROTECT study, flow-mediated vasodilation (FMD) was assessed in 32 patients in the control group and 26 patients in the ipragliflozin group before and after 24 months of treatment.ResultsHbA1c levels significantly decreased after 24 months of treatment compared to the baseline value in the ipragliflozin group, but not in the control group. However, there was no significant difference between the changes in HbA1c levels in the two groups (7.4 ± 0.8% vs. 7.0 ± 0.9% in the ipragliflozin group and 7.4 ± 0.7% vs. 7.3 ± 0.7% in the control group; P = 0.08). There was no significant difference between FMD values at baseline and after 24 months in both groups (5.2 ± 2.6% vs. 5.2 ± 2.6%, P = 0.98 in the ipragliflozin group; 5.4 ± 2.9% vs. 5.0 ± 3.2%, P = 0.34 in the control group). There was no significant difference in the estimated percentage change in FMD between the two groups (P = 0.77).ConclusionsOver a 24-month period, the addition of ipragliflozin to standard therapy in patients with type 2 diabetes did not change endothelial function assessed by FMD in the brachial artery.Trial registrationRegistration Number for Clinical Trial: jRCT1071220089 (https://jrct.niph.go.jp/en-latest-detail/jRCT1071220089).

Vascular and metabolic effects of ipragliflozin versus sitagliptin (IVS) in type 2 diabetes treated with sulphonylurea and metformin: IVS study.

In patients with type 2 diabetes who were inadequately controlled with metformin and sulphonylurea, we compared the glucose-lowering efficacy, cardiometabolic parameters and safety of two drugs, ipragliflozin, a sodium-glucose cotransporter-2 inhibitor, and sitagliptin, a dipeptidyl peptidase-4 inhibitor. MATERIALSANDMETHODS: Patients with 7.5%-9.0% glycated haemoglobin treated with metformin and sulphonylurea were randomly assigned to ipragliflozin (50 mg, n = 70) or sitagliptin (100 mg, n = 70) therapy for 24 weeks. Measures of glycaemic control, fatty liver indices, other metabolic parameters and subclinical atherosclerosis were compared by a paired t-test before and after 24 weeks of treatment. Mean glycated haemoglobin levels decreased from 8.5% to 7.5% in the ipragliflozin group and from 8.5% to 7.8% in the sitagliptin group, resulting in a 0.34% between-group difference (95% confidence interval, 0.10%-0.43%, p = .088). Fasting and postprandial 2-h glucose levels also showed a similar trend, with a greater reduction with ipragliflozin therapy. An increase of over 70% in ketone levels and a decrease in whole body and abdominal fat masses were observed with ipragliflozin treatment. Fatty liver indices also improved with ipragliflozin treatment. Despite no difference in carotid intima-media thickness and ankle-brachial index, ipragliflozin therapy improved flow-mediated vasodilation, reflecting endothelial function, while sitagliptin did not. The safety profile did not differ between the two groups. Ipragliflozin add-on therapy can be a viable option for better glycaemic control with multiple vascular and metabolic benefits in patients with type 2 diabetes who are inadequately controlled with metformin and sulphonylurea.

Effects of ipragliflozin on left ventricular diastolic function in patients with type 2 diabetes and heart failure with preserved ejection fraction: The EXCEED randomized controlled multicenter study.

AimWe carried out a randomized controlled trial using ipragliflozin. We analyzed changes in diastolic function using echocardiography in patients with type 2 diabetes and heart failure with preserved ejection fraction.MethodsWe carried out an open‐label, multicenter, randomized, two‐arm interventional trial. A total of eligible 68 participants were randomly assigned into two groups (ipragliflozin group n = 36; conventional treatment group n = 32). Primary end‐points were the change in E/e' and e'. Secondary end‐points were other parameters of echocardiography, plasma NT‐proBNP level, New York Heart Association class, hemoglobin A1c and blood pressure.ResultsAfter 24 weeks of follow up, E/e' decreased in both groups (ipragliflozin: 11.0 vs 10.4; conventional treatment 10.5 vs 10.1; multivariate‐adjusted P = 0.95). There were no significant differences in the amount of change in E/e', e', echocardiography parameters, plasma NT‐proBNP level, New York Heart Association class, hemoglobin A1c and blood pressure between the two groups. In the subgroup analysis, ipragliflozin treatment decreased in left ventricular mass index in patients aged ≥70 years and also decreased in NT‐proBNP levels in patients with baseline NT‐proBNP ≥400 pg/mL.ConclusionsIn this randomized controlled study carried out in patients with type 2 diabetes and heart failure with preserved ejection fraction, 24‐week ipragliflozin treatment did not improve left ventricular diastolic function compared with conventional treatment. As the subgroup, ipragliflozin treatment decreased in left ventricular mass index in participants aged ≥70 years. Geriatr Gerontol Int 2022; 22: 298–304.

A Prospective, Open-Label Short-Term Pilot Study on Modification of the Skin Hydration Status During Treatment With a Sodium-Glucose Cotransporter-2 Inhibitor.

IntroductionVarious types of skin lesions with pruritus have been reported in participants of Asian clinical trials on sodium-glucose cotransporter-2 (SGLT2) inhibitors. The aim of this study was to determine whether the diuretic effect of a SGLT2 inhibitor could modify skin hydration status in patients with type 2 diabetes mellitus.MethodsA prospective, short-term, open-label, two-parallel-arm, pilot study was conducted. Eligible patients were assigned to either a SGLT2 inhibitor (50 mg ipragliflozin once daily) group or to a dipeptidyl peptidase-4 inhibitor (50 mg sitagliptin once daily) group (control). The biophysical characteristics of the skin were measured and blood chemistry tests were run in all participants 1 day prior to medication initiation (pre-treatment values) and 14 days thereafter (post-treatment values).ResultsFourteen patients were enrolled in the study, of whom eight were in the ipragliflozin group and six in the sitagliptin group. Compared to the pre-treatment values, the glycated hemoglobin (HbA1c) levels were slightly but significantly reduced in the ipragliflozin group (p = 0.02), but the changes in HbA1c from the pre-treatment to post-treatment time points did not significantly differ between the two treatment groups. Serum 3-hydroxy butyrate levels were significantly higher in the ipragliflozin group than in the sitagliptin group (p < 0.02). Neither electrical capacitance nor electrical conductance of the stratum corneum (SC), parameters that reflect skin water content, was reduced by 14 days of ipragliflozin treatment; similarly, no changes in these parameters were found in the sitagliptin control group. There was also no difference in the changes in water barrier function of the SC between the two treatment groups. There was a significant linear correlation (p < 0.01) in skin water content at pre-treatment and that 14 days after treatment with each drug, respectively.ConclusionIpragliflozin treatment for 14 days did not significantly affect the skin hydration status in patients with well-controlled type 2 diabetes mellitus.

Comparison of Visceral Fat Reduction by Ipragliflozin and Metformin in Elderly Type 2 Diabetes Patients: Sub-Analysis of a Randomized-Controlled Study.

IntroductionTo compare the effects of ipragliflozin, a sodium-glucose transporter 2 inhibitor, with those of metformin on visceral fat (as well as muscles and bones) in Japanese elderly patients with type 2 diabetes (T2D), we conducted a sub-analysis of a prospective, multicenter, blinded-endpoint randomized-controlled study.MethodsIn total, 103 patients with T2D (body mass index ≥ 22 kg/m2; glycated hemoglobin, 7–10%) and being treated with sitagliptin (a dipeptidyl peptidase-4 inhibitor) were included and randomized to receive ipragliflozin or metformin. The primary outcome was the change in visceral fat area measured using computed tomography 24 weeks following treatment. The secondary outcomes included changes in subcutaneous and total fat area, muscle volume, bone density measured using computed tomography, handgrip strength, bone markers, plasma glucose, insulin, homeostasis model assessment (HOMA)2-beta, HOMA2-R, glycated hemoglobin, lipid panel, uric acid, blood pressure, adiponectin, and high-sensitivity C-reactive protein. All patients aged 65–74 years were selected for sub-analysis.ResultsThe sub-analysis included 15 and 14 patients in the ipragliflozin and metformin groups, respectively. The patients’ backgrounds were well balanced. Visceral fat area reduction was greater in the ipragliflozin group than in the metformin group (− 10.58% vs. − 6.93%; P = 0.034). There were significant differences in the changes in bone absorption markers, uric acid, and total cholesterol levels between the groups.ConclusionIpragliflozin significantly reduced the visceral fat area compared with metformin when added to sitagliptin in elderly patients with T2D. Long-term and large-scale studies are required to elucidate whether ipragliflozin is suitable for elderly patients.Trial RegistrationThe study was registered at https://www.umin.ac.jp/ctr/ (UMIN-ID: UMIN 000015170).Electronic supplementary materialThe online version of this article (10.1007/s13300-020-00949-0) contains supplementary material, which is available to authorized users.

Adverse Drug Events Observed with the Novel Sodium/Glucose Co-Transporter 2 Inhibitor Ipragliflozin for the Treatment of Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis of Randomized Studies.

Type 2 diabetes mellitus (T2DM) is becoming a major issue worldwide. To effectively control the blood sugar of patients with T2DM, several novel oral hypoglycemic agents (OHAs) are being developed. Sodium/glucose co-transporter 2 (SGLT 2) inhibitors have recently shown beneficial outcomes in patients with T2DM. In this analysis, we aimed to systematically compare the adverse drug events observed with ipragliflozin versus placebo for the treatment of patients with T2DM. http://www.ClinicalTrials.gov , the bibliographic database of life science and biomedical information MEDLINE, EMBASE and the Cochrane Central were searched for English publications satisfying the inclusion and exclusion criteria of this study. Adverse drug events were the end points in this analysis. The latest version (5.4) of the RevMan software was used to analyze the data, and risk ratios (RR) with 95% confidence intervals (CI) were used to represent the data post analysis. Eight randomized studies with a total of 1519 participants with T2DM were included in this analysis whereby total treatment-emergent adverse events (RR: 1.06, 95% CI: 0.96-1.16; P = 0.26), including mild (RR: 0.95, 95% CI: 0.79-1.13; P = 0.54), moderate (RR: 1.04, 95% CI: 0.72-1.51; P = 0.83) and severe treatment-emergent adverse events (RR: 0.72, 95% CI: 0.26-1.96; P = 0.52), were not significantly different in those patients who were assigned to ipragliflozin versus placebo for the treatment of T2DM. Moreover, drug-related adverse events (RR: 1.04, 95% CI: 0.69-1.58; P = 0.85), adverse events leading to drug discontinuation (RR: 1.09, 95% CI: 0.57-2.10; P = 0.79), urinary tract infection (RR: 1.03, 95% CI: 0.60-1.77; P = 0.91), naso-pharyngitis (RR: 0.54, 95% CI: 0.19-1.52; P = 0.25), constipation (RR: 1.94, 95% CI: 0.90-4.20; P = 0.09), dizziness (RR: 0.81, 95% CI: 0.20-3.23; P = 0.76), gastrointestinal disorders (RR: 0.96, 95% CI: 0.68-1.36; P = 0.82) and dehydration (RR: 2.26, 95% CI: 0.38-13.43; P = 0.37) were also not significantly different. However, genital infection (RR: 4.53, 95% CI: 1.48-13.85; P = 0.008) and hypoglycemia (RR: 1.68, 95% CI: 1.03-2.74; P = 0.04) rates were significantly higher in the ipragliflozin group. The current analysis showed ipragliflozin to be associated with significantly higher genital infection rates compared to placebo, whereas no significant difference was observed compared to the other adverse drug events in these patients with T2DM. In addition, hypoglycemia was also not significantly different following sensitivity analysis.

31-OR: Ipragliflozin Ameliorated Overweight and Pathological Liver Fibrosis in Diabetic Patients with Nonalcoholic Fatty Liver Disease in a Multicenter Randomized Controlled Trial

Background: Ipragliflozin (IPR) is a sodium-glucose cotransporter 2 inhibitor (SGLT2i) used to treat diabetes. Given the global increase in diabetes and nonalcoholic fatty liver disease (NAFLD), the effects of SGLT2i on hepatic outcomes and glycemic control are of interest. Methods: The current study was a multicenter randomized controlled trial, and all patients included were diabetics with liver biopsy-proven NAFLD. They were divided into an IPR group (n = 24) administered IPR orally (50 mg/day), and a control group (CTR; n = 26) who undertook enhanced lifestyle modifications including diet and exercise therapy and/or antidiabetic drugs other than SGLT2i, pioglitazone, or GLP-1 analogs. After 72 weeks, a second liver biopsy was performed and clinical parameters including pathological indicators were compared in the two groups. All liver biopsies were evaluated by two expert pathologists. Results: There were no significant differences in basal bodyweight, hemoglobin A1c, or pathological NAFLD findings between the groups. Mean bodyweight reduction from baseline at 72 weeks was significantly greater in the IPR group (-3.2 vs. -0.4, p &amp;lt; 0.01). Compared to the CTR group, hemoglobin A1c was significantly lower at 48 weeks (-0.46 vs. -0.09, p &amp;lt; 0.05). The mean decrease in visceral fat area determined with CT scan was significantly greater in the IPR group. Neither AST nor ALT differed significantly between the groups. Liver fibrosis improved in 57.1% of patients in the IPR group and 16% in the CTR group (p &amp;lt; 0.01). Liver steatosis improved in 19.0% of patients in the IPR group and 28% in the CTR group (p &amp;gt; 0.05; not significant). Low-grade adverse events were observed in both groups. Conclusion: IPR reduces bodyweight and hemoglobin A1c in diabetics with NAFLD, and ameliorates liver fibrosis. Long-term IPR administration improves hepatic outcomes of NAFLD, and obesity and glycemic control. Disclosure H. Takahashi: Research Support; Self; Astellas Pharma Inc. T. Kessoku: None. M. Kawanaka: None. M. Nonaka: None. H. Hyogo: None. H. Fujii: None. T. Nakajima: None. K. Imajo: None. K. Tanaka: None. Y. Kubotsu: None. H. Isoda: None. S. Oeda: None. O. Kurai: None. M. Yoneda: None. M. Ono: None. A. Takamori: None. R. Tajiri: None. A. Kawaguchi: None. S. Aishima: None. M. Kage: None. A. Nakajima: Consultant; Self; Kowa Company, Ltd. Speaker’s Bureau; Self; Astellas Pharma Inc., Mylan. Y. Eguchi: None. K. Anzai: Research Support; Self; Astellas Pharma Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc. Speaker’s Bureau; Self; Daiichi Sankyo, Kyowa Hakko Kirin Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Astellas Pharma Inc.

Beneficial Effects of Ipragliflozin on the Renal Function and Serum Uric Acid Levels in Japanese Patients with Type 2 Diabetes: A Randomized, 12-week, Open-label, Active-controlled Trial.

Objective To examine the add-on effects, compared to the existing antidiabetes treatment, of the sodium-glucose cotransporter 2 inhibitor ipragliflozin on glycemic control and the risk factors of cardiovascular disease (CVD) and chronic kidney disease (CKD) in patients with inadequately controlled type 2 diabetes. Methods This 12-week, randomized, open-label, active-controlled trial included 30 patients with type 2 diabetes who were randomized 1:1 to ipragliflozin and control groups (n=15 each). The ipragliflozin group received 50 mg of ipragliflozin once daily in addition to conventional therapy. The primary outcome was the change in hemoglobin A1c (HbA1c) from the baseline. Secondary outcomes were changes from the baseline in indices of glycemic control, uric acid (UA), renal function, and arterial stiffness. Results The patients' diminished estimated glomerular filtration rate (eGFR) was alleviated in the ipragliflozin group compared to the control group [difference between groups (Δ)=4.6 (95% confidence interval (CI): 1.5-7.7) mL/min/1.73 m2, p=0.006] prior to significant improvements in HbA1c and other parameters, including anthropometric indices and arterial stiffness. Furthermore, ipragliflozin add-on therapy resulted in a greater reduction in serum UA levels than control therapy [Δ=-52.3 (95% CI: -85.5-19.1) μmol/L, p=0.003]. The changes in the eGFR with ipragliflozin treatment were associated with ipragliflozin-mediated changes in the UA, even after adjusting for the age, sex, baseline HbA1c, baseline UA, and baseline eGFR (standardized regression coefficient=-0.535, p=0.010). Conclusion Ipragliflozin add-on therapy was associated with beneficial renal effects in parallel with reducing serum UA levels.

Comparing the effects of ipragliflozin versus metformin on visceral fat reduction and metabolic dysfunction in Japanese patients with type 2 diabetes treated with sitagliptin: A prospective, multicentre, open-label, blinded-endpoint, randomized controlled study (PRIME-V study).

A prospective, multicentre, open‐label, blinded‐endpoint, randomized controlled study was conducted to evaluate the efficacy of treatment with ipragliflozin (sodium‐dependent glucose transporter‐2 inhibitor) versus metformin for visceral fat reduction and glycaemic control among Japanese patients with type 2 diabetes treated with sitagliptin, HbA1c levels of 7%‐10%, and body mass index (BMI) ≥ 22 kg/m2. Patients were randomly assigned (1:1) to receive ipragliflozin 50 mg or metformin 1000‐1500 mg daily. The primary outcome was change in visceral fat area as measured by computed tomography after 24 weeks of therapy. The secondary outcomes were effects on glucose metabolism and lipid metabolism. Mean percentage reduction in visceral fat area was significantly greater in the ipragliflozin group than in the metformin group (−12.06% vs. −3.65%, P = 0.040). Ipragliflozin also significantly reduced BMI, subcutaneous fat area, waist circumference, fasting insulin, and homeostatic model assessment (HOMA)‐resistance, and increased HDL‐cholesterol levels. Metformin significantly reduced HbA1c and LDL‐cholesterol levels and increased HOMA‐beta. There were no severe adverse events. The use of ipragliflozin or metformin in combination with dipeptidyl peptidase‐4 inhibitors, widely used in Japan, may have beneficial effects in ameliorating multiple cardiovascular risk factors.

Ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, reduces bodyweight and fat mass, but not muscle mass, in Japanese type 2 diabetes patients treated with insulin: A randomized clinical trial.

Aims/IntroductionSodium–glucose cotransporter 2 inhibitors reduce bodyweight (BW) by creating a negative energy balance. Previous reports have suggested that this BW reduction is mainly loss of body fat and that ~20% of the reduction is lean mass. However, the effects of sodium–glucose cotransporter 2 inhibitors on BW and body composition remain unclear. We examined these effects in Japanese patients with type 2 diabetes mellitus treated with insulin.Materials and MethodsIn this open‐label, randomized controlled trial, 49 overweight patients (body mass index ≥23 kg/m2) with inadequate glycemic control (hemoglobin A1c >7.0%) receiving insulin treatment were randomly assigned to receive add‐on ipragliflozin or no additional treatment (control group). Patients were followed for 24 weeks. The goal for all patients was to achieve glycated hemoglobin <7.0% without hypoglycemia. The primary end‐point was a change in BW from baseline to week 24. Body composition was assessed with dual‐energy X‐ray absorptiometry and bioelectrical impedance analysis.ResultsBW change was significantly larger in the ipragliflozin group than in the control group (−2.78 vs −0.22 kg, P < 0.0001). Total fat mass was reduced evenly in the arms, lower limbs and trunk in the ipragliflozin group. Total muscle mass and bone mineral content were maintained, but muscle mass in the arms might have been affected by ipragliflozin treatment.ConclusionsIpragliflozin treatment for 24 weeks resulted in reduced BW, mainly from fat mass loss. Muscle mass and bone mineral content were maintained. Further study is necessary to elucidate the long‐term effects of ipragliflozin.

Protective Effects of Ipragliflozin, a Sodium-glucose Cotransporter 2 Inhibitor, on a Non-alcoholic Steatohepatitis Mouse Model

The options for the treatment of nonalcoholic steatohepatitis (NASH) are limited. We examined the effects of ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, on the fatty liver Shionogi (FLS)-ob/ob mice, a non-alcoholic steatohepatitis mouse model. FLS-ob/ob male mice were treated with vehicle (n = 10) and ipragliflozin (n = 8). Serum metabolic markers, histopathology of the liver, hepatic cholesterol and triglyceride levels and hepatic mRNA levels related to fibrosis, lipid metabolism and endoplasmic reticulum (ER) stress were compared between the two groups. The body weight and hepatic cholesterol and triglyceride levels were significantly decreased in the ipragliflozin group compared with the control group. Hepatic steatosis and fibrosis were significantly ameliorated by the treatment with ipragliflozin. Hepatic infiltration of macrophage, expression levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) and hepatic mRNA levels of ER stress markers were not significantly modulated by the treatment with ipragliflozin. Ipragliflozin can be a therapeutic option for patients with NASH. The precise mechanisms of action need to be clarified in future studies.

Comparing the Effects of Ipragliflozin versus Metformin Added to Sitagliptin on Visceral Fat Reduction in Asian Patients with Type 2 Diabetes: A Prospective, Multicenter, Blinded-Endpoint Randomized Controlled Study (PRIME-V Study)

Background: Visceral fat accumulation is associated with insulin resistance and various metabolic complications. We aimed to determine the effect of ipragliflozin (sodium-dependent glucose transporter-2 inhibitor) versus metformin with a dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin) in reducing visceral fat in Asian patients with insufficiently controlled type 2 diabetes. Methods: A prospective, multicenter, blinded-endpoint, randomized controlled study was conducted to evaluate the efficacy of treatment with either ipragliflozin or metformin combined with sitagliptin on visceral fat reduction and glycemic control among Japanese patients with type 2 diabetes, HbA1c 7-10%, and BMI ≥22 kg/m2. Patients who met the eligibility criteria were randomly assigned (1:1) to receive ipragliflozin 50 mg (n=51) or metformin 1000-1500 mg daily (n=52). The primary outcome was rate change in visceral fat area measured by computed tomography at 24 weeks of therapy. Two radiologists, blinded to patients' clinical information and randomized treatment assignment, analyzed the images. Secondary outcomes included effects on blood glucose, fasting insulin level, and lipids. The full analysis set was used for analysis. Findings: Mean percent reduction in visceral fat area was significantly greater in the ipragliflozin group than in the metformin group (-12·06% vs. -3·65%, group difference [95% CI] -8·40%; [-16·4 to -3·38], P=0·040). The ipragliflozin group also showed significant lowering of fasting insulin (-20·73% vs. 0·85%, group difference [95% CI] -21·58%, [2·80 to 34·20], P=0·018), while HbA1c decreased in the metformin group compared with ipragliflozin group. Interpretation: Ipragliflozin significantly reduced the visceral fat area compared with metformin, as the secondary agent used in combination with DPP-4 inhibitor. Since the fasting insulin level decreased, the reduction in visceral fat associated with ipragliflozin administration might have contributed to the improvement in insulin resistance. Trial Registration Number: Trial registration: UMIN 000015170. Funding Statement: To conduct this study, an agreement was signed between Chiba University and Astellas Pharma Inc. (Tokyo, Japan). Astellas Pharma Inc. funded this work. Declaration of Interests: KY received research grants from Astellas Pharma Inc. and MSD K.K. (Tokyo, Japan), and received a lecture fee from Astellas Pharma Inc. and Sumitomo Dainippon Pharma (Tokyo, Japan). No conflicts of interest are declared for other authors. Ethics Approval Statement: The study protocol was approved by the Institutional Review Boards (IRBs), Ethics Review Committees, or Ethics Committees of the following institutions: Chiba University Hospital (ID number: G26009), Asahi General Hospital (ID number: 2014091602), National Hospital Organization Chiba Medical Center, Seirei Sakura Citizen Hospital, Chiba Rosai Hospital (ID number: 26-21), Toho University Sakura Medical Center (ID number: 2014-077), Tokyo Women’s Medical University Yachiyo Medical Center (ID number: 150303), Chiba Aoba Municipal Hospital, Kimitsu Chuo Hospital, Funabashi Central Hospital (ID number: H27-1), and Chiba Kaihin Municipal Hospital. In other facilities, approval was provided at Chiba University Hospital (which had the centralized IRB).

Improved cardiometabolic risk factors in Japanese patients with type 2 diabetes treated with ipragliflozin: a pooled analysis of six randomized, placebo-controlled trials.

To examine differential improvements among cardiovascular risk factors in response to treatment with ipragliflozin in Japanese type 2 diabetes mellitus (T2DM) patients, we conducted a pooled analysis of six randomized, double-blind trials of Japanese T2DM patients who received ipragliflozin 50 mg/day or placebo and had patient-level data for cardiometabolic risk parameters. Risk factors included glycated hemoglobin (HbA1c), body weight, homeostatic model assessment for insulin resistance and beta-cell function (HOMA-R and HOMA-beta, respectively), systolic blood pressure, fasting serum insulin concentrations, and the concentration of uric acid, lipids, and liver enzymes from baseline to end of treatment (EOT; 12-24 weeks). The primary endpoint of each trial was the change in HbA1c from baseline to EOT. Changes in risk factors from baseline to EOT were compared between ipragliflozin-treated and placebo groups, and between two subgroups (high- and low-risk groups for each parameter). All parameters, except low-density lipoprotein cholesterol (LDL-C) and non high-density lipoprotein cholesterol (non HDL-C), improved significantly in the ipragliflozin group. Subgroup analysis revealed a significantly greater improvement in the high-risk group versus low-risk group in HbA1c, HOMA-R, HOMA-beta, aspartate transaminase, alanine transaminase, and gamma-glutamyltransferase, but not in any of the lipid parameters or blood pressure. Liver function improvement in the ipragliflozin group was significantly correlated with changes in body weight, HbA1c, HOMA-beta, and HOMA-R. This analysis demonstrated that, in Japanese T2DM patients, ipragliflozin 50 mg/day was associated with improvements in cardiometabolic risk factors, except for LDL-C and non HDL-C.

The effects of ipragliflozin on the liver-to-spleen attenuation ratio as assessed by computed tomography and on alanine transaminase levels in Japanese patients with type 2 diabetes mellitus.

We assessed the effects of a 12-week ipragliflozin treatment on the liver-to-spleen attenuation ratio (L/S ratio) using computed tomography and on alanine transaminase (ALT) levels in Japanese patients with type 2 diabetes mellitus (T2DM). Sixty-two patients with T2DM [age, 56±8years; hemoglobin A1c (HbA1c) levels, 8.1±0.9%; body mass index (BMI), 27.5±3.3kg/m2] were randomly assigned in a 2:1 ratio to receive ipragliflozin (50mg/day; ipragliflozin group; n=40) or continued treatment (control group; n=22) for 12weeks. The primary endpoints were changes in ALT levels; the secondary endpoints included changes in the L/S ratio and in the visceral fat area (VFA) and subcutaneous fat area (SFA) before and after 12weeks of the treatment as assessed by computed tomography. ALT levels (-12.45 vs. +5.82IU/l, P<0.001), L/S ratio (+0.07 vs. -0.08, P<0.001), SFA (-5.8 vs. +13.3cm2, P<0.05), and VFA (+1.4 vs. +20.4cm2, P<0.05) significantly changed from baseline in the ipragliflozin group compared with the values in the control group. Multiple regression analysis among all subjects revealed that the independent factor contributing to the %ΔALT and %ΔL/C ratio was treatment group alone (ipragliflozin group=1; control group=0; β coefficient=-32.08, P<0.001 and β coefficient=19.98, P<0.05, respectively). Thus, ipragliflozin may lower ALT levels associated with increased L/S ratios, indicating its potential therapeutic efficacy in T2DM-associated hepatic steatosis.

Addition of Ipragliflozin to Metformin Treatment in Korean Patients with Type 2 Diabetes Mellitus: Subgroup Analysis of a Phase 3 Trial.

BackgroundThis is a subgroup analysis of Korean patients from a phase 3 clinical trial investigating the efficacy and safety of ipragliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin.MethodsThis multicenter, placebo-controlled, double-blind, parallel-group study was carried out between November 2011 and January 2013. Patients entered a 2-week placebo pretreatment period, followed by a 24-week treatment period with either ipragliflozin (50 mg/day) or placebo, while continuing metformin. Efficacy outcomes (glycosylated hemoglobin [HbA1c], fasting plasma glucose [FPG], and body weight) and safety outcomes (treatment-emergent adverse events [TEAEs]) were measured and compared between the two treatment groups for patients enrolled in all 18 study sites in Korea.ResultsEighty-two Korean patients received ipragliflozin (n=43) or placebo (n=39) during the study period. Mean changes in HbA1c levels from baseline to the end of treatment were –0.97% in the ipragliflozin group and –0.31% in the placebo group, with an adjusted between-group difference of –0.60% (P<0.001). Compared to placebo, FPG and body weight also decreased significantly (both P<0.001) from baseline after treatment in the ipragliflozin group, with between-group differences of –21.4 mg/dL and –1.53 kg, respectively. Decreased weight was the most common TEAE in the ipragliflozin group (7.0%); there were no reports of genital and urinary tract infection.ConclusionIpragliflozin treatment in addition to metformin led to significant improvement in glycemic outcomes and reduction in body weight in Korean patients with type 2 diabetes mellitus, compared with metformin treatment alone; the safety profile was comparable in both groups.

Efficacy and safety of ipragliflozin as add-on therapy to insulin in Japanese patients with type 2 diabetes mellitus (IOLITE): a multi-centre, randomized, placebo-controlled, double-blind study.

AimsTo examine the efficacy and safety of add‐on ipragliflozin in Japanese patients with type 2 diabetes in the early stage of insulin therapy.MethodsPatients treated with insulin (bolus component <30% of total daily dose) with/without a dipeptidyl peptidase‐4 (DPP‐4) inhibitor were randomized to receive placebo (n = 87) or ipragliflozin (n = 175) for 16 weeks. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline. Secondary endpoints included changes in fasting plasma glucose (FPG) and metabolic hormones. Safety endpoints were also examined.ResultsThe changes in HbA1c were 0.27% and −0.79% (2.9 and −8.7 mmol/mol) in the placebo and ipragliflozin groups, respectively (baseline: 8.62% vs 8.67% [70.8 vs 71.2 mmol/mol]), corresponding to an adjusted mean difference of −1.07% (95% confidence interval −1.24, −0.91) or −11.7 mmol/mol (−13.5, −9.9), p < .001. Ipragliflozin reduced FPG and serum C‐peptide levels and body weight (all p < .001), and increased serum adiponectin levels (p = .022). There was a statistically significant interaction for use/non‐use of a DPP‐4 inhibitor × treatment group for the change in HbA1c (p = .042). Hypoglycaemia was the only treatment‐related adverse event reported in >5% of patients (14.9% vs 29.1%). Events consistent with urinary tract infection (placebo 1.1% vs ipragliflozin 2.3%) or genital infection (0.0% and 4.0%, respectively) occurred in <5% of patients.ConclusionIpragliflozin was well tolerated and effective in insulin‐treated patients, especially when used with a DPP‐4 inhibitor.

Rationale and design of a multicenter randomized controlled study to evaluate the preventive effect of ipragliflozin on carotid atherosclerosis: the PROTECT study.

BackgroundType 2 diabetes mellitus is associated strongly with an increased risk of micro- and macro-vascular complications, leading to impaired quality of life and shortened life expectancy. In addition to appropriate glycemic control, multi-factorial intervention for a wide range of risk factors, such as hypertension and dyslipidemia, is crucial for management of diabetes. A recent cardiovascular outcome trial in diabetes patients with higher cardiovascular risk demonstrated that a SGLT2 inhibitor markedly reduced mortality, but not macro-vascular events. However, to date there is no clinical evidence regarding the therapeutic effects of SGLT2 inhibitors on arteriosclerosis. The ongoing PROTECT trial was designed to assess whether the SGLT2 inhibitors, ipragliflozin, prevented progression of carotid intima-media thickness in Japanese patients with type 2 diabetes mellitus.MethodsA total of 480 participants with type 2 diabetes mellitus with a HbA1c between 6 and 10 % despite receiving diet/exercise therapy and/or standard anti-diabetic agents for at least 3 months, will be randomized systematically (1:1) into either ipragliflozin or control (continuation of conventional therapy) groups. After randomization, ipragliflozin (50–100 mg once daily) will be added on to the background therapy in participants assigned to the ipragliflozin group. The primary endpoint of the study is the change in mean intima-media thickness of the common carotid artery from baseline to 24 months. Images of carotid intima-media thickness will be analyzed at a central core laboratory in a blinded manner. The key secondary endpoints include the change from baseline in other parameters of carotid intima-media thickness, various metabolic parameters, and renal function. Other cardiovascular functional tests are also planned for several sub-studies.DiscussionThe PROTECT study is the first to assess the preventive effect of ipragliflozin on progression of carotid atherosclerosis using carotid intima-media thickness as a surrogate marker. The study has potential to clarify the protective effects of ipragliflozin on atherosclerosis.Trial registration Unique Trial Number, UMIN000018440 (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021348)Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0449-7) contains supplementary material, which is available to authorized users.