Effects Of Ipragliflozin Research Articles

923-P: Effects of Ipragliflozin and Metformin on Hepatic Steatosis and Liver Fibrosis

923-P: Effects of Ipragliflozin and Metformin on Hepatic Steatosis and Liver Fibrosis

Effects of ipragliflozin on left ventricular diastolic function in patients with type 2 diabetes: A sub-analysis of the PROTECT trial

BackgroundWe hypothesized that the beneficial effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on diastolic function might depend on baseline left ventricular (LV) systolic function. MethodsTo investigate the effects of SGLT2 inhibitors on LV diastolic function in patients with type 2 diabetes mellitus (T2DM), we conducted a post-hoc sub-study of the PROTECT trial, stratifying the data according to LV ejection fraction (LVEF) at baseline. After excluding patients without echocardiographic data at baseline or 24 months into the PROTECT trial, 31 and 38 patients with T2DM from the full analysis dataset of the PROTECT trial who received ipragliflozin or no SGLT2 inhibitor (control), respectively, were included. The primary endpoint was a comparison of the changes in echocardiographic parameters and N-terminal pro-brain natriuretic peptide levels from baseline to 24 months between the two groups stratified according to baseline LVEF. ResultsDifferences in diastolic functional parameters (e' and E/e') were noted between the two groups. Among the subgroups defined according to median LVEF values, those with higher LVEF (≥60 %) who received ipragliflozin appeared to have a higher e' and lower E/e' than did those who received the standard of care with no SGLT2 inhibitor, indicating longitudinal improvements between baseline and follow up (p = 0.001 and 0.016, respectively). ConclusionsIpragliflozin generally improved LV diastolic function in patients with type 2 diabetes, the extent of this improvement might appear to vary with LV systolic function.

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.

Safety and effectiveness of ipragliflozin in Japanese patients with type 2 diabetes mellitus and impaired renal function: subgroup analysis of a 3-year post-marketing surveillance study (STELLA-LONG TERM)

STELLA-LONG TERM, a 3-year post-marketing surveillance study, evaluated the safety and effectiveness of the sodiumglucose cotransporter 2 inhibitor ipragliflozin in Japanese type 2 diabetes mellitus (T2DM) patients. Final results in the safety (n = 6697) and effectiveness populations (n = 5625) were analyzed by stratifying patients by baseline estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) into four subgroups (≥90, 60 to <90, 45 to <60, and <45) and two subgroups (≥60 and <60). Adverse drug reaction (ADR) incidence, and changes from baseline in glycosylated hemoglobin (HbA1c), bodyweight, and eGFR were assessed. The percentage of patients experiencing ADRs and serious ADRs was similar across most eGFR subgroups. Polyuria/pollakiuria was the most common ADR. Renal disorders and volume depletion ADRs were more frequent in the subgroups with more severe renal impairment at baseline than in those with an eGFR of 60 to <90 or ≥90 mL/min/1.73 m2. Bodyweight and HbA1c decreased in all subgroups, the latter by − 0.91% to − 0.40% (P <0.05 vs. baseline). eGFR increased in the 45 to <60 mL/min/1.73 m2 subgroup (+ 1.42 ± 8.77 mL/min/1.73 m2; P = 0.006). It decreased in the ≥90 and 60 to <90 mL/min/1.73 m2 subgroups (− 8.27 ± 13.73 and − 1.22 ± 10.34 mL/min/1.73 m2; P <0.001), but not to <60 mL/min/1.73 m2. In conclusion, there were no new or unexpected safety findings in Japanese patients treated with ipragliflozin for T2DM, and long-term sustained improvements in HbA1c and bodyweight were observed regardless of the presence of renal impairment.

Real-world evidence for long-term safety and effectiveness of ipragliflozin in treatment-naïve versus non-naïve Japanese patients with type 2 diabetes mellitus: subgroup analysis of a 3-year post-marketing surveillance study (STELLA-LONG TERM).

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-naïve and non-naïve patients. Patients were stratified into two subgroups: treatment-naïve (patients who had not received any antidiabetic drugs before starting ipragliflozin monotherapy) and non-naïve (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-naïve and 9071 (82.08%) were non-naïve. In the safety analysis set, treatment-naïve 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-naïve 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 36months were observed in HbA1c, FPG and body weight in both treatment-naïve and non-naïve patients (all p < 0.001 vs baseline). Over 3years, 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. The online version contains supplementary material available at 10.1007/s13340-021-00501-w.

Safety and Effectiveness of Ipragliflozin in Elderly Versus Non-elderly Japanese Patients with Type2 Diabetes: Subgroup Analysis of STELLA-LONGTERM.

IntroductionSTELLA-LONG TERM is a post-marketing surveillance study evaluating the safety and effectiveness of ipragliflozin in Japanese patients with type 2 diabetes mellitus.MethodsPatients were classified by age at ipragliflozin initiation (< 65 and ≥ 65 years), and elderly patients were subclassified by baseline body mass index (BMI) < 25.0 or ≥ 25.0 kg/m2. Incidence of adverse drug reactions (ADRs) and effectiveness were evaluated over 3 years.ResultsAmong 11,051 patients, 7894 (71.4%) were aged < 65 years and 3157 (28.6%) ≥ 65 years. The 3-year ADR incidence was similar in patients aged ≥ 65 (19.04%) and < 65 years (19.36%; P = 0.701). Serious ADRs were more frequent in the subgroup ≥ 65 years (2.79% vs 1.55%; P < 0.001). In terms of ADRs of special interest, a significantly greater proportion of elderly patients had skin complications (2.22% vs 1.62%, P = 0.033), renal disorders (2.28% vs 1.51%, P = 0.005), hypoglycemia (0.73% vs 0.43%, P = 0.048), or malignant tumors (1.01% vs 0.24%, P < 0.001), while the incidence of polyuria/pollakiuria (5.97% vs 4.47%, P = 0.002) and hepatic disorders (1.39% vs 0.73%, P = 0.004) was significantly higher in non-elderly than elderly patients. In patients aged ≥ 65 years, the incidence of ADRs was higher when baseline BMI was ≥ 25 kg/m2 versus < 25 kg/m2 (24.40% vs 17.68%; P < 0.001). Glycosylated hemoglobin, fasting blood glucose, and body weight significantly decreased from baseline in both age groups at each evaluation up to 3 years (all P < 0.001).ConclusionsIpragliflozin was well tolerated and effective for 3 years in routine clinical use in elderly and non-elderly patients, although elderly patients had a higher rate of serious ADRs. No new safety concerns were identified.Clinical Trial RegistrationClinicalTrials.gov identifier NCT02479399.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-021-01042-w.

Comprehensive efficacy of ipragliflozin on various conditioned type 2 diabetes compared with dipeptidyl peptidase-4 inhibitors and with both agents, based on a real-world multicenter trial

The effects of ipragliflozin, the first sodium-glucose co-transporter 2 inhibitors (SGLT2i) launched in Japan in 2014, and with dipeptidyl peptidase-4 inhibitors (DPP-4i) on glycemic control and metabolic changes were investigated comprehensively on various conditioned type 2 diabetes (T2DM) by evaluating various clinical parameters in a real-world setting. A total of 101 patients with T2DM aged 20-80years with 7.0% ≤ HbA1c < 10.0% were followed in this 52-week, open-label, prospective, real-world, multicenter study. HbA1c decreased significantly in all groups. In ipragliflozin using groups, body weight, waist circumference, blood pressure, HOMA-IR, AST, ALT, γ-GTP, uric acid and leptin levels decreased, in contrast, HDL-cholesterol, total ketone bodies, blood urea nitrogen, creatinine, RBC, hemoglobin and hematocrit levels increased, however, in DPP-4i sole group, no significant trends were observed in these parameters. Change in leptin positively correlated with insulin, while change in total ketone bodies inversely correlated with ALT in ipragliflozin using groups. Fasting active gastric inhibitory polypeptide levels decreased in ipragliflozin sole group. Glucagon showed no changes. No significant safety concerns were observed in this study. Ipragliflozin is useful and safe, showing some contrastive effects on several clinical parameters which are not shown with DPP-4i, resulting several clinical benefits. The co-administration of ipragliflozin and a DPP-4i has a better clinical outcome than either single-agent therapy.

Effect of ipragliflozin on liver function in Japanese type 2 diabetes mellitus patients: subgroup analysis of a 3-year post-marketing surveillance study (STELLA-LONG TERM).

The STELLA-LONG TERM prospective post-marketing surveillance study assessed ipragliflozin in Japanese patients with type 2 diabetes mellitus (T2DM). This subgroup analysis of patients with liver impairment used the final 3-year results. Data on patients, adverse drug reactions (ADRs), and changes in glycemic parameters and liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transpeptidase [γ-GTP] and alkaline phosphatase [ALP]) were collected, and the fatty liver index (FLI) was calculated. In the effectiveness analysis (n = 8,763), baseline liver function was normal in 2,605 patients (ALT <31/<21 U/L [men/women]) and abnormal in 3,277 (ALT ≥31/≥21 U/L). The abnormal liver function group had higher mean body weight and BMI than the normal liver function group (p < 0.001). In the safety analysis (n = 11,051), urinary tract infections, genital infections and hepatic disorders were more common in the abnormal than normal liver function group (2.25% vs. 1.07%; 1.78% vs. 1.14% and 1.85% vs. 1.01%). In the abnormal liver function group, there were significant (p < 0.001) decreases from baseline at 36 months in AST and ALT (from 38.8 and 53.7 U/L to 29.3 and 37.7 U/L, respectively), γ-GTP (from 75.4 to 51.7 U/L) and ALP (from 254.8 to 234.5 U/L), which were greater than in the normal liver function group. FLI reductions at 36 months were significant (p < 0.001) in subgroups with baseline FLI of ≥30 or ≥60. In conclusion, ipragliflozin improved liver function over 3 years in patients with impaired liver function, although ADRs occurred more frequently than in the normal liver function group.

Safety and effectiveness of ipragliflozin in Japanese patients with type 2 diabetes mellitus and impaired renal function: subgroup analysis of a 3-year post-marketing surveillance study (STELLA-LONG TERM).

STELLA-LONG TERM, a 3-year post-marketing surveillance study, evaluated the safety and effectiveness of the sodium-glucose cotransporter 2 inhibitor ipragliflozin in Japanese type 2 diabetes mellitus (T2DM) patients. Final results in the safety (n = 6697) and effectiveness populations (n = 5625) were analyzed by stratifying patients by baseline estimated glomerular filtration rate (eGFR, mL/min/1.73m2) into four subgroups (≥ 90, 60 to < 90, 45 to < 60, and < 45) and two subgroups (≥ 60 and < 60). Adverse drug reaction (ADR) incidence, and changes from baseline in glycosylated hemoglobin (HbA1c), bodyweight, and eGFR were assessed. The percentage of patients experiencing ADRs and serious ADRs was similar across most eGFR subgroups. Polyuria/pollakiuria was the most common ADR. Renal disorders and volume depletion ADRs were more frequent in the subgroups with more severe renal impairment at baseline than in those with an eGFR of 60 to < 90 or ≥ 90mL/min/1.73m2. Bodyweight and HbA1c decreased in all subgroups, the latter by -0.91% to -0.40% (P < 0.05 vs. baseline). eGFR increased in the 45 to < 60mL/min/1.73m2 subgroup (+ 1.42 ± 8.77mL/min/1.73m2; P = 0.006). It decreased in the ≥ 90 and 60 to < 90mL/min/1.73m2 subgroups (-8.27 ± 13.73 and -1.22 ± 10.34mL/min/1.73m2; P < 0.001), but not to < 60mL/min/1.73m2. In conclusion, there were no new or unexpected safety findings in Japanese patients treated with ipragliflozin for T2DM, and long-term sustained improvements in HbA1c and bodyweight were observed regardless of the presence of renal impairment.

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)

ABSTRACT Objective To evaluate the long-term safety and effectiveness of ipragliflozin in real-world clinical practice in Japanese patients with type 2 diabetes mellitus (T2DM). Research design and methods This post-marketing surveillance study (STELLA-LONG TERM) included Japanese patients newly initiated on ipragliflozin between 17 July 2014 and 16 October 2015 (data lock: 30 September 2019). Survey items included demographics, treatments, adverse drug reactions (ADRs), vital signs, and laboratory variables. Results Of 11,424 registered patients, safety and efficacy analysis sets comprised of 11,051 and 8,763 patients, respectively. ADRs occurred in 2,129 patients (19.27%) and serious ADRs occurred in 210 patients (1.90%). Renal and urinary disorders (n = 739, 6.69%), particularly polyuria/pollakiuria (n = 612, 5.54%) and volume depletion-events, including dehydration (n = 243, 2.20%), comprised the most common ADRs. Mean (SD) change in hemoglobin A1c (─0.66 [1.25] %), fasting plasma glucose (─28.8 [50.1] mg/dL) and body weight (─3.33 [4.32] kg) from baseline to 36 months were statistically significant (P < 0.001). Conclusions The safety profile of long-term ipragliflozin treatment in routine clinical practice is consistent with previously reported interim data at 12 or 24 months and pre-approval clinical trials. Ipragliflozin treatment was also associated with sustained improvements in efficacy parameters for over 3 years.

Effects of ipragliflozin on the development and progression of kidney disease in patients with type2 diabetes: An analysis from a multicenter prospective intervention study.

Aims/IntroductionType 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long‐term treatments are available. MethodsThis was an investigator‐initiated multicenter prospective intervention study in which ipragliflozin (50 mg) was administered once daily, and glycemic control, estimated glomerular filtration rate (eGFR) and adverse events were evaluated until 104 weeks after starting research.ResultsThere were 407 patients analyzed. In the eGFR ≥90 group and eGFR ≥60 to <90 group, eGFR had significantly decreased compared with baseline at all time points from 4 to 104 weeks. There were significant increases in the eGFR ≥45 to <60 groups compared with baseline at 36 weeks (2.3 ± 1.0) and 52 weeks (2.6 ± 1.2). Comparison between the eGFR <60, urine albumin‐to‐creatinine ratio >300 group and the eGFR <60, urine albumin‐to‐creatinine ratio <300 group showed a greater reduction in eGFR in the former (−5.4 ± 2.4 vs 3.3 ± 1.1) at 12 weeks and was maintained to 104 weeks. In any group, eGFR did not significantly decrease until 104 weeks compared with 4 weeks. The urine albumin‐to‐creatinine ratio after 52 weeks and after 104 weeks was significantly decreased compared with baseline in the eGFR ≥90 group.ConclusionsIpragliflozin lowers eGFR and corrects hyperfiltration in patients with high eGFR (eGFR ≥60). In patients with low eGFR (eGFR ≥30 to <60), ipragliflozin has the possibility of increasing eGFR and exerting a renoprotective effect.

SGLT2 inhibitor ipragliflozin attenuates breast cancer cell proliferation.

Cancer is currently one of the major causes of death in patients with type 2 diabetes mellitus. We previously reported the beneficial effects of the glucagon-like peptide-1 receptor agonist exendin-4 against prostate and breast cancer. In the present study, we examined the anti-cancer effect of the sodium-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin using a breast cancer model. In human breast cancer MCF-7 cells, SGLT2 expression was detected using both RT-PCR and immunohistochemistry. Ipragliflozin at 1-50 μM significantly and dose-dependently suppressed the growth of MCF-7 cells. BrdU assay also revealed that ipragliflozin attenuated the proliferation of MCF-7 cells in a dose-dependent manner. Because the effect of ipragliflozin against breast cancer cells was completely canceled by knocking down SGLT2, ipragliflozin could act via inhibiting SGLT2. We next measured membrane potential and whole-cell current using the patch clamp technique. When we treated MCF-7 cells with ipragliflozin or glucose-free medium, membrane hyperpolarization was observed. In addition, glucose-free medium and knockdown of SGLT2 by siRNA suppressed the glucose-induced whole-cell current of MCF-7 cells, suggesting that ipragliflozin inhibits sodium and glucose cotransport through SGLT2. Furthermore, JC-1 green fluorescence was significantly increased by ipragliflozin, suggesting the change of mitochondrial membrane potential. These findings suggest that the SGLT2 inhibitor ipragliflozin attenuates breast cancer cell proliferation via membrane hyperpolarization and mitochondrial membrane instability.

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

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 STELLA-LONG TERM examined the safety and effectiveness of ipragliflozin in non-elderly and elderly Japanese patients with type 2 diabetes mellitus (T2DM) using data up to 12 months.Methods: Data from T2DM patients who were first prescribed ipragliflozin between July 2014 and October 2015 and whose 12 month data were locked by January 2018 were analyzed and compared between non-elderly (<65 years) and elderly patients (≥65 years).Results: The safety and efficacy analysis sets included 11,051 and 8788 patients, respectively. Elderly patients accounted for 28.6% (n = 3157) of the study population. The mean body mass index was 29.9 kg/m2 and 26.8 kg/m2, the percentage of patients with glycated hemoglobin (HbA1c) <8.0% was 50.1% and 59.5%, and the percentage of patients with complications was 83.2% and 87.3% in the non-elderly and elderly groups, respectively. Mean HbA1c and body weight decreased significantly from baseline to 12 months in both age groups, regardless of baseline HbA1c and body weight (all p < .05). The incidence of adverse drug reactions (ADRs) was 14.8% and 14.2% and that of serious ADRs was 0.8% and 1.4% in non-elderly and elderly patients, respectively (p = .002 for serious ADRs).Conclusion: The incidence of serious ADRs was higher in elderly patients than non-elderly patients. Ipragliflozin was effective in both non-elderly and elderly patients with T2DM in the real-world clinical setting.

2344-PUB: Predictors of the Glucose-Lowering or Weight-Loss Effects of Ipragliflozin and Sitagliptin

Sodium-glucose cotransporter 2 inhibitor and dipeptidyl peptidase-4 inhibitor are widely used in Japan, but only a few studies have directly compared the effects of these two drugs. We have reported that ipragliflozin (Ipra) had beneficial effects on fat reduction, insulin resistance, and lipid metabolism, while sitagliptin (Sita) had beneficial effects on β-cell function in a randomized controlled study. In this subanalysis study, we screened for predictors of the glucose-lowering effects of Ipra and Sita, and the weight-loss effects of Ipra. The participants were 119 patients aged 20-75 years with type 2 diabetes, HbA1c ≥ 6.5%, and BMI ≥ 23 kg/m2, and were randomly assigned to 12 weeks of treatment with 50 mg of either Ipra or Sita. We analyzed the correlations between the change in glycated hemoglobin HbA1c (ΔHbA1c) or body weight (ΔBW) and multiple clinical variables at the baseline. In the Ipra group, the mean ΔHbA1c was -1.1% and ΔBW was -2.2 kg. There was no significant correlation between ΔHbA1c and ΔBW (ρ = 0.22, p = 0.095). ΔHbA1c had a significant positive correlation with age (ρ = 0.41, p = 0.001) and negative correlation with the HbA1c level (ρ = -0.68, p &amp;lt; 0.001), HOMA-IR (ρ = -0.36, p = 0.011), and ALT level (ρ = -0.34, p = 0.014), while ΔBW had a significant negative correlation with the total ketone concentration at the baseline (ρ = -0.31, p = 0.041). In the Sita group, the mean ΔHbA1c was -0.81%; no significant change in BW was seen. ΔHbA1c had a significant negative correlation with HbA1c level at the baseline (ρ = -0.42, p = 0.0016), but no significant correlation with other variables at the baseline. In conclusion, our results suggest that the glucose-lowering effects of Ipra were more prominent in younger patients with increased insulin resistance accompanied by fatty liver, while its weight-loss effects were more prominent in patients with high total ketone concentration at the baseline. Meanwhile, the glucose-lowering effects of Sita may be exhibited regardless of the patient pathology. Disclosure Y. Tsurutani: Research Support; Self; Astellas Pharma Inc. K. Nakai: None. J. Saito: None. M. Omura: None. T. Nishikawa: None.

Effect of ipragliflozin, an SGLT2 inhibitor, on cardiac histopathological changes in a non-diabetic rat model of cardiomyopathy

AimsWe 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 methodsIpragliflozin 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 findingsIn 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. SignificanceIpragliflozin 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.

Effects of ipragliflozin on glycemic control, appetite and its related hormones: A prospective, multicenter, open-label study (SOAR-KOBE Study).

Aims/IntroductionSodium–glucose cotransporter 2 (SGLT‐2) inhibitors improve blood glucose control, as well as reducing bodyweight by promoting urinary glucose excretion. The weight loss is less than expected from urinary glucose loss, however, likely because of an increase in food intake. To investigate whether SGLT‐2 inhibitors might increase appetite by affecting related hormones, we examined the effects of the SGLT‐2 inhibitor, ipragliflozin, including those on appetite‐regulating hormones, in individuals with suboptimally controlled type 2 diabetes.Materials and MethodsThe present prospective, multicenter, open‐label study was carried out with 96 patients with a body mass index of ≥22 kg/m2 who were treated with ipragliflozin (50 mg/day) for 16 weeks. Parameters including glycated hemoglobin level, bodyweight, circulating leptin and active ghrelin concentrations, and appetite as assessed with a visual analog scale were measured before and during treatment.ResultsBoth glycated hemoglobin level (from 7.9 ± 0.8 to 7.1 ± 0.7%) and bodyweight (from 75.2 ± 12.6 to 72.6 ± 12.4 kg) were significantly decreased after treatment for 16 weeks. The fasting serum leptin level was significantly decreased after 2 weeks (from 19.5 ± 13.1 to 18.1 ± 12.4 ng/mL) and remained decreased up to 16 weeks, even after adjustment for bodyweight, whereas the plasma active ghrelin level showed no significant change. The visual analog scale score for hunger was significantly increased at 2 and 8 weeks.ConclusionsThe present results suggest that ipragliflozin improved glycemic control and reduced bodyweight, but also reduced serum leptin levels and might thereby have increased appetite.

Safety and Effectiveness of Ipragliflozin for Type 2 Diabetes in Japan: 12-Month Interim Results of the STELLA-LONG TERM Post-Marketing Surveillance Study.

IntroductionThe 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.MethodsThis 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.ResultsThe 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.ConclusionIpragliflozin 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.Trial RegistrationClinicalTrials.gov identifier, NCT02479399.FundingAstellas Pharma Inc., Japan.

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.

Comparing the Effects of Ipragliflozin and Metformin on Visceral Fat Reduction in Patients with Type 2 Diabetes Inadequately Controlled with Sitagliptin–A Prospective, Multicenter, Blinded-Endpoint, Randomized Controlled Study in Japan (PRIME-V Study)

Objective: To determine the effects of SGLT2 inhibitor or metformin on reducing visceral fat in Asian patients with type 2 diabetes inadequately controlled with DPP-4 inhibitor, sitagliptin. Methods: A prospective, multicenter, blinded-endpoint, randomized controlled trial was conducted to evaluate the efficacy of treatment with either SGLT2 inhibitor (ipragliflozin) or metformin added on to sitagliptin for visceral fat reduction and glucose control in patients with type 2 diabetes. Patients who met the eligibility criteria were randomly selected (1:1) to receive ipragliflozin (Ipr; 50 mg daily) or metformin (Met; 1000 mg daily). The primary outcome is the change rate in visceral fat area, measured using computed tomography, after 24 weeks of therapy. Two radiologists, blinded to the information, analyzed the images. Results: A total of 51 patients were in enrolled in the Ipr group and 52 in the Met group. The reduction rate in visceral fat area was significantly greater in the Ipr group (-12.06% vs. -3.65%, group difference of -8.40%; 95% CI of -16.4 to -3.38, P&amp;lt;0.05) than in the Met group. Subcutaneous fat area, total fat area, body weight, BMI, and waist circumference also decreased significantly in the Ipr group. The Ipr group showed a significant decrease in fasting insulin (-20.73% vs. 0.85%, group difference -21.58%, 95% CI 2.80 to 34.20, P&amp;lt;0.05), while HbA1c decreased in the Met group compared with the Ipr group. The difference in the muscle volume and bone mineral density between the two groups was insignificant. Conclusion: Ipr significantly reduced the visceral fat area compared with Met as the secondary agent used in combination with DPP-4 inhibitors. As the fasting insulin level decreased, the reduction in visceral fat associated with Ipr administration may have contributed to the improvement of insulin resistance. Disclosure M. Koshizaka: None. K. Ishikawa: None. R. Ishibashi: None. Y. Maezawa: None. K. Sakamoto: None. D. Uchida: Speaker's Bureau; Self; Takeda Pharmaceuticals Japan, Tanabe Mitsubishi Pharmaceuticals Japan, Sanofi, MSD K.K., Novo Nordisk Inc. S. Nakamura: None. H. Yokoh: None. A. Kobayashi: None. S. Onishi: None. K. Kobayashi: None. J. Ogino: None. H. Tokuyama: None. F. Shimada: None. E. Ohara: None. T. Ishikawa: None. M. Shoji: None. K. Ide: None. S. Ide: None. Y. Baba: None. T. Horikoshi: None. R. Shimofusa: None. S. Takahashi: None. K. Nagashima: None. M. Takemoto: None. K. Yokote: Research Support; Self; Astellas Pharm Ltd, MSD K.K..

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.