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Ipragliflozin Improves the Hepatic Outcomes of Patients With Diabetes with NAFLD.
Takahashi, H, Kessoku, T, Kawanaka, M, Nonaka, M, Hyogo, H, Fujii, H, Nakajima, T, Imajo, K, Tanaka, K, Kubotsu, Y, et al
Hepatology communications. 2022;(1):120-132
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Abstract
Sodium glucose cotransporter-2 inhibitors (SGLT2is) are now widely used to treat diabetes, but their effects on nonalcoholic fatty liver disease (NAFLD) remain to be determined. We aimed to evaluate the effects of SGLT2is on the pathogenesis of NAFLD. A multicenter, randomized, controlled trial was conducted in patients with type 2 diabetes with NAFLD. The changes in glycemic control, obesity, and liver pathology were compared between participants taking ipragliflozin (50 mg/day for 72 weeks; IPR group) and participants being managed without SGLT2is, pioglitazone, glucagon-like peptide-1 analogs, or insulin (CTR group). In the IPR group (n = 25), there were significant decreases in hemoglobin A1c (HbA1c) and body mass index (BMI) during the study (HbA1c, -0.41%, P < 0.01; BMI, -1.06 kg/m2 , P < 0.01), whereas these did not change in the CTR group (n = 26). Liver pathology was evaluated in 21/25 participants in the IPR/CTR groups, and hepatic fibrosis was found in 17 (81%) and 18 (72%) participants in the IPR and CTR groups at baseline. This was ameliorated in 70.6% (12 of 17) of participants in the IPR group and 22.2 % (4 of 18) of those in the CTR group (P < 0.01). Nonalcoholic steatohepatitis (NASH) resolved in 66.7% of IPR-treated participants and 27.3% of CTR participants. None of the participants in the IPR group developed NASH, whereas 33.3% of the CTR group developed NASH. Conclusion: Long-term ipragliflozin treatment ameliorates hepatic fibrosis in patients with NAFLD. Thus, ipragliflozin might be effective for the treatment and prevention of NASH in patients with diabetes, as well as improving glycemic control and obesity. Therefore, SGLT2is may represent a therapeutic choice for patients with diabetes with NAFLD, but further larger studies are required to confirm these effects.
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Should sulfonylurea be discontinued or maintained at the lowest dose when starting ipragliflozin? A multicenter observational study in Japanese patients with type 2 diabetes.
Takahashi, K, Cho, KY, Nakamura, A, Miya, A, Miyoshi, A, Yamamoto, C, Nomoto, H, Niwa, H, Takahashi, K, Manda, N, et al
Journal of diabetes investigation. 2019;(2):429-438
Abstract
AIMS/INTRODUCTION We investigated the difference in efficacy and safety between discontinuation and maintaining of sulfonylurea when adding a sodium-glucose cotransporter 2 inhibitor. MATERIALS AND METHODS In the present multicenter, prospective observational study, 200 patients with type 2 diabetes treated with sulfonylurea and with a need to add ipragliflozin were enrolled and divided into two groups: discontinued sulfonylurea (Discontinuation group) or maintained sulfonylurea, but at the lowest dose (Low-dose group) when adding ipragliflozin. We compared the two groups after 24 weeks using propensity score matching to adjust for differences between the groups. RESULTS In the matched cohort (58 patients in each group), baseline characteristics of both groups were balanced. The primary outcome of the proportion of patients with non-exacerbation in glycated hemoglobin after 24 weeks was 91.4% in the Low-dose group and 75.9% in the Discontinuation group, a significant difference (P = 0.024). However, bodyweight was significantly decreased in the Discontinuation group compared with the Low-dose group (-4.4 ± 2.1 kg vs -2.9 ± 1.9 kg, P < 0.01). Similarly, liver enzyme improvement was more predominant in the Discontinuation group. A logistic regression analysis showed that high-density lipoprotein cholesterol, age and sulfonylurea dose were independent factors associated with non-exacerbation of glycated hemoglobin in the Discontinuation group. CONCLUSIONS The purpose of using ipragliflozin should be considered when making the decision to discontinue or maintain sulfonylurea at the lowest dose. Furthermore, low high-density lipoprotein cholesterol level, low dose of sulfonylurea and younger age were possible markers to not show worsening of glycemic control by discontinuing sulfonylurea.
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Safety and efficacy of tofogliflozin in Japanese patients with type 2 diabetes mellitus in real-world clinical practice: Results of 3-month interim analysis of a long-term post-marketing surveillance study (J-STEP/LT).
Utsunomiya, K, Senda, M, Kakiuchi, S, Kameda, H, Tamura, M, Kurihara, Y, Gunji, R, Fujii, S, Fujiwara, H, Kaku, K
Journal of diabetes investigation. 2019;(5):1272-1283
Abstract
AIMS/INTRODUCTION The present study analysis was carried out to evaluate the safety and efficacy of tofogliflozin, a sodium-glucose cotransporter 2 inhibitor, in Japanese patients with type 2 diabetes mellitus in real-world clinical practice. MATERIALS AND METHODS This was a 3-year non-interventional observational study of patients with type 2 diabetes mellitus newly administered tofogliflozin who were uncontrolled on current therapy. We carried out a 12-week interim analysis of tofogliflozin as part of 3-year post-marketing surveillance study. The incidence of adverse drug reactions was evaluated as a safety end-point. As efficacy end-points, glycated hemoglobin and bodyweight were evaluated. RESULTS A total of 6,897 patients were enrolled. Tofogliflozin significantly reduced mean changes from baseline glycated hemoglobin (-0.63%, P < 0.0001) and bodyweight (-2.02 kg, P < 0.0001). The change in glycated hemoglobin and bodyweight reductions in response to tofogliflozin was consistently observed in all body mass index subgroups. Adverse drug reactions occurred in 345 of 6,712 patients (5.14%). There was a low incidence of adverse drug reactions known to be associated with sodium-glucose cotransporter 2 inhibitors, and they were reported as non-serious. The incidences of polyuria/pollakiuria were higher in patients aged ≥65 years than <65 years, and were significantly different among estimated glomerular filtration rate subgroups. Urinary tract and genital infections occurred more frequently in women than in men. CONCLUSIONS Tofogliflozin was well tolerated, and no emerging new safety concerns were observed. Tofogliflozin significantly improved glycemic control with no impact on bodyweight gain. The short-term administration of tofogliflozin is considered to have a favorable benefit-risk profile in Japanese patients with type 2 diabetes mellitus.
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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).
Koshizaka, M, Ishikawa, K, Ishibashi, R, Maezawa, Y, Sakamoto, K, Uchida, D, Nakamura, S, Yamaga, M, Yokoh, H, Kobayashi, A, et al
Diabetes, obesity & metabolism. 2019;(8):1990-1995
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Abstract
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.
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Novel Approach to Estimate Osteoarthritis Progression: Use of the Reliable Change Index in the Evaluation of Joint Space Loss.
Parsons, CM, Judge, A, Leyland, K, Bruyère, O, Petit Dop, F, Chapurlat, R, Reginster, JY, Edwards, MH, Dennison, EM, Cooper, C, et al
Arthritis care & research. 2019;(2):300-307
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Abstract
OBJECTIVE Osteoarthritis-related changes in joint space measurements over time are small and sensitive to measurement error. The Reliable Change Index (RCI) determines whether the magnitude of change observed in an individual can be attributed to true change. This study aimed to examine the RCI as a novel approach to estimating osteoarthritis progression. METHODS Data were from 167 men and 392 women with knee osteoarthritis (diagnosed using the American College of Rheumatology criteria) randomized to the placebo arm of the 3-year Strontium Ranelate Efficacy in Knee Osteoarthritis trial (SEKOIA) and assessed annually. The RCI was used to determine whether the magnitude of change in joint space width (JSW) on radiographs between study years was likely to be true or due to measurement error. RESULTS Between consecutive years, 57-69% of participants had an apparent decrease (change <0) in JSW, while 31-43% of participants had annual changes indicating improvement in JSW. The RCI identified JSW decreases in only 6.0% of patients between baseline and year 1, and in 4.5% of patients between the remaining study years. The apparent increases in JSW were almost eliminated between baseline and year 1, and between years 1 and 2 only 1.3% of patients had a significant increase, dropping to 0.9% between years 2 and 3. CONCLUSION The RCI provides a method to identify change in JSW, removing many apparent changes that are likely to be due to measurement error. This method appears to be useful for assessing change in JSW from radiographs in clinical and research settings.
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Comparative study of the effects of ipragliflozin and sitagliptin on multiple metabolic variables in Japanese patients with type 2 diabetes: A multicentre, randomized, prospective, open-label, active-controlled study.
Tsurutani, Y, Nakai, K, Inoue, K, Azuma, K, Mukai, S, Maruyama, S, Iizuka, T, Matsuzawa, Y, Saito, J, Omura, M, et al
Diabetes, obesity & metabolism. 2018;(11):2675-2679
Abstract
In the present randomized study, we assessed the efficacy of ipragliflozin compared with sitagliptin in 124 Japanese patients with type 2 diabetes. Sodium-glucose co-transporter-2 inhibitor-naïve and incretin-related agent-naïve patients were randomly assigned to receive additional 50 mg ipragliflozin or sitagliptin. The primary endpoint was the proportion of participants with >0.5% decrease in glycated haemoglobin (HbA1c) without body weight gain at 12 weeks. For secondary endpoints, we measured several biomarkers related to metabolic changes. After 12 weeks, 53.9% of participants in the ipragliflozin and 42.9% in the sitagliptin group reached the primary endpoint (P = 0.32). Decreases in homeostatic model assessment of insulin resistance, body fat percentage and skeletal muscle mass index, and increases in free fatty acids, ketone body concentration and HDL cholesterol levels were greater in the ipragliflozin group. Increases in homeostatic model assessment of β-cell function and decreases in proinsulin-to-insulin ratio were greater in the sitagliptin group. No serious adverse events occurred in either group. In conclusion, ipragliflozin had beneficial effects on fat reduction, insulin resistance and lipid metabolism, while sitagliptin had beneficial effects on β-cell function.
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Efficacy and safety of ipragliflozin and metformin for visceral fat reduction in patients with type 2 diabetes receiving treatment with dipeptidyl peptidase-4 inhibitors in Japan: a study protocol for a prospective, multicentre, blinded-endpoint phase IV randomised controlled trial (PRIME-V study).
Koshizaka, M, Ishikawa, K, Ishikawa, T, Kobayashi, K, Takemoto, M, Horikoshi, T, Shimofusa, R, Takahashi, S, Nagashima, K, Sato, Y, et al
BMJ open. 2017;(5):e015766
Abstract
INTRODUCTION In Japan, dipeptidyl peptidase-4 (DPP-4) inhibitors are frequently used as the treatment of choice for patients with type 2 diabetes. In some cases, however, poor glycaemic and body weight control issues persist despite treatment with DPP-4 inhibitors. Previous researchers have revealed that sodium-dependent glucose transporter-2 (SGLT-2) inhibitors reduce both plasma glucose levels and body weight in patients with type 2 diabetes. However, further investigation regarding the effects of SGLT-2 inhibitors on body composition, especially in the Asian population who tends to have relatively low-to-moderate body mass indices, is required. Therefore, we aim to determine the effects of treatment with SGLT-2 inhibitors or metformin for reducing visceral fat in 106 Asian patients with type 2 diabetes who were undergoing treatment with the DPP-4 inhibitor sitagliptin (50 mg daily) for poor glycaemic control. METHODS AND ANALYSIS A prospective, multicentre, blinded-endpoint phase IV randomised controlled study will be conducted to evaluate the safety and efficacy of a 24-week treatment with either an SGLT-2 inhibitor (ipragliflozin) or metformin for reducing visceral fat and plasma glucose levels in patients with type 2 diabetes. Patients who satisfy the eligibility criteria will be randomised (1:1) to receive ipragliflozin (50 mg daily) or metformin (1000 mg daily). The primary outcome is the rate of change in the total area of visceral fat for patients in both treatment groups, measured using CT, after 24 weeks of therapy. Two radiologists, blinded to the clinical information, will perform centralised analysis of the images in a unified measurement condition. ETHICS AND DISSEMINATION The protocol was approved by the institutional review board of each hospital. This study is ongoing and due to finish in April 2017. The findings of this study will be disseminated via peer-reviewed publications and conference presentations, and will also be disseminated to participants. TRIAL REGISTRATION NUMBER UMIN000015170, R000016861 (https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000016861); Pre-results.
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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.
Ishihara, H, Yamaguchi, S, Nakao, I, Okitsu, A, Asahina, S
Diabetes, obesity & metabolism. 2016;(12):1207-1216
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AIMS: To examine the efficacy and safety of add-on ipragliflozin in Japanese patients with type 2 diabetes in the early stage of insulin therapy. METHODS Patients 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. RESULTS The 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. CONCLUSION Ipragliflozin was well tolerated and effective in insulin-treated patients, especially when used with a DPP-4 inhibitor.
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An open-label, randomized, controlled, multicenter study exploring two treatment strategies of rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment strategy in subjects with atrial fibrillation who undergo percutaneous coronary intervention (PIONEER AF-PCI).
Gibson, CM, Mehran, R, Bode, C, Halperin, J, Verheugt, F, Wildgoose, P, van Eickels, M, Lip, GY, Cohen, M, Husted, S, et al
American heart journal. 2015;(4):472-8.e5
Abstract
BACKGROUND Guidelines recommendations regarding anticoagulant therapy after percutaneous coronary intervention (PCI) among patients with atrial fibrillation (AF) rely on retrospective, nonrandomized observational data. Currently, patients are treated with triple-therapy (dual antiplatelet therapy [DAPT] + oral anticoagulation therapy), but neither the duration of DAPT nor the level of anticoagulation has been studied in a randomized fashion. Recent studies also suggest dual pathway therapy with clopidogrel plus oral anticoagulation therapy may be superior, and other studies suggest that novel oral anticoagulants such as rivaroxaban may further improve patient outcomes. DESIGN PIONEER AF-PCI (ClinicalTrials.gov NCT01830543) is an exploratory, open-label, randomized, multicenter clinical study assessing the safety of 2 rivaroxaban treatment strategies and 1 vitamin K antagonist (VKA) treatment strategy in subjects who have paroxysmal, persistent, or permanent nonvalvular AF and have undergone PCI with stent placement. Approximately 2,100 subjects will be randomized in a 1:1:1 ratio to receive either rivaroxaban 15 mg once daily plus clopidogrel 75 mg daily for 12 months (a WOEST trial-like strategy), or rivaroxaban 2.5 mg twice daily (with stratification to a prespecified duration of DAPT 1, 6, or 12 months, an ATLAS trial-like strategy), or dose-adjusted VKA once daily (with stratification to a prespecified duration of DAPT 1, 6, or 12 months, traditional triple therapy). All patients will be followed up for 12 months for the primary composite end point of Thrombolysis in Myocardial Infarction major bleeding, bleeding requiring medical attention, and minor bleeding (collectively, clinically significant bleeding). CONCLUSION The PIONEER AF-PCI study is the first randomized comparison of VKA vs novel oral anticoagulant therapy in patients with NVAF receiving antiplatelet therapy after PCI to assess the relative risks of bleeding complications.
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Ipragliflozin in combination with metformin for the treatment of Japanese patients with type 2 diabetes: ILLUMINATE, a randomized, double-blind, placebo-controlled study.
Kashiwagi, A, Kazuta, K, Goto, K, Yoshida, S, Ueyama, E, Utsuno, A
Diabetes, obesity & metabolism. 2015;(3):304-8
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This multicenter, double-blind, placebo-controlled study examined the efficacy and safety of ipragliflozin, a sodium-glucose co-transporter 2 inhibitor, in combination with metformin in Japanese patients with type 2 diabetes mellitus (T2DM). Patients were randomized in a 2 : 1 ratio to 50 mg ipragliflozin (n = 112) or placebo (n = 56) once daily for 24 weeks, followed by a 28-week open-label extension in which all patients received 50 or 100 mg ipragliflozin, while continuing metformin. The primary outcome was the change in glycated haemoglobin (HbA1c) from baseline to week 24. HbA1c decreased significantly in the ipragliflozin group (-0.87%; adjusted mean difference from placebo: -1.30%; p < 0.001). The overall incidence of treatment-emergent adverse events was similar in both groups, although pollakiuria and constipation were more common in the ipragliflozin group; thus, ipragliflozin significantly improved glycaemic control and reduced body weight without major safety issues in Japanese patients with T2DM.