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Long-term (52-week) efficacy and safety of ipragliflozin add-on therapy to insulin in Japanese patients with type 1 diabetes mellitus: An uncontrolled, open-label extension of a phase III study.
Kaku, K, Isaka, H, Sakatani, T, Toyoshima, J
Journal of diabetes investigation. 2020;(3):662-671
Abstract
INTRODUCTION The aim of the present study was to assess the long-term (52-week) efficacy and safety of ipragliflozin in insulin-treated Japanese patients with type 1 diabetes mellitus and inadequate glycemic control. MATERIALS AND METHODS In this 28-week, open-label extension of a multicenter, randomized, placebo-controlled, 24-week phase III study, ipragliflozin recipients continued treatment (50 mg, once daily), and placebo recipients were switched to once-daily 50 mg ipragliflozin at the start of the extension period. The ipragliflozin dose could be increased to 100 mg if warranted. The primary end-point was change in glycated hemoglobin; secondary end-points were change in insulin dose and bodyweight. Safety outcomes were monitored as treatment-emergent adverse events. RESULTS A total of 53 (placebo switched to ipragliflozin) and 108 (ipragliflozin) patients completed the open-label extension (treatment period 2), with 24 and 44 patients, respectively, receiving dose increases. From baseline to end of treatment, the overall mean change (standard deviation [SD]) in glycated hemoglobin was -0.33% (0.72; -3.7 mmol/mol [7.9]), with changes in basal, bolus and total insulin doses of -3.76 IU (SD 3.85 IU), -2.51 IU (SD 7.08 IU) and -6.27 IU (SD 8.16 IU), respectively. No serious drug-related treatment-emergent adverse events or deaths were reported. Treatment-emergent adverse events leading to study discontinuation occurred in zero and three (2.6%) patients in the placebo switched to ipragliflozin and ipragliflozin groups, respectively; all were considered drug-related. There were no cases of severe hypoglycemia or diabetic ketoacidosis, and no safety concerns related to dose increase. CONCLUSIONS The efficacy and safety of 50 mg, once-daily ipragliflozin in insulin-treated type 1 diabetes mellitus patients were confirmed in this long-term, open-label extension study. No safety concerns were attributed to a dose increase to 100 mg.
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Dilatation of Retinal Arterioles Induced by Topical Dorzolamide for One Week Is Impaired in Patients with Type 1 Diabetes and Mild Retinopathy.
Tilma, KK, Bek, T
Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde. 2020;(3):236-242
Abstract
BACKGROUND Diabetic retinopathy is characterised by morphological lesions in the retina secondary to disturbances in retinal blood flow. Previous studies have shown that the carbonic anhydrase inhibitor (CAI) dorzolamide can induce immediate dilatation of retinal arterioles and a sustained increase in retinal blood flow in primary open-angle glaucoma. However, the effect of sustained treatment with CAI on retinal arterioles in normal persons and in patients with diabetic retinopathy is unknown. METHODS The Dynamic Vessel Analyzer was used to assess the baseline diameter and the diameter response of retinal arterioles during an increase in arterial blood pressure induced by isometric exercise and during flicker stimulation before and 2 h, 24 h and 1 week after onset of topical treatment with dorzolamide. At each examination the diameter responses were studied before and during breathing in of a hypercapnic gas mixture. RESULTS Treatment with dorzolamide for 1 week significantly increased the diameter of retinal arterioles in normal persons, and breathing in of a hypercapnic gas mixture reduced this response. The pathological vasodilatation and reduced retinal autoregulation in patients with diabetic retinopathy were unaffected by dorzolamide and hypercapnia. CONCLUSIONS The study suggests a lack of relevance of CAI for the treatment of pathological vasodilatation in early diabetic retinopathy.
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Combination of Intravitreal Bevacizumab and Topical Dorzolamide versus Intravitreal Bevacizumab Alone for Diabetic Macular Edema: A Randomized Contralateral Clinical Trial.
Fazel, F, Nikpour, H, Pourazizi, M
BioMed research international. 2020;:6794391
Abstract
PURPOSE To evaluate the efficacy of three intravitreal bevacizumab (IVB) injections versus the same combined with 2% of topical dorzolamide in the treatment of diabetic macular edema (DME). METHODS In this randomized double-masked clinical trial, 32 eyes of 16 treatment-naive patients with bilateral DME were enrolled. The eyes were randomly assigned to receive three monthly injections of IVB (1.25 mg) plus topical dorzolamide 2% twice daily or IVB (1.25 mg) plus topical artificial tear twice daily. Best-corrected visual acuity (BCVA) was the primary outcome of the study followed by the central macular thickness (CMT) and central macular volume (CMV) as the secondary outcomes. RESULTS Mean BCVA changes were insignificant in both groups. It changed from 0.21 ± 0.08 logMAR at baseline to 0.23 ± 0.09 (P=0.24) in the combination group and from 0.18 ± 0.09 logMAR to 0.21 ± 0.09 (P=0.11) in the IVB alone group, at 3 months, respectively. Changes in mean CMT and CMV were significant in both groups. However, the difference between the groups was not significant at all the visits. In the study, no major ocular complication or systemic side effects were noted regarding IVB or topical dorzolamide. CONCLUSION This randomized contralateral clinical trial demonstrated that adjuvant topical dorzolamide with IVB injection had no additional effects on IVB in the treatment of DME over a three-month course. This trial is registered with the Iranian Registry of Clinical Trials under the registration code IRCT20131229015975N5.
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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.
Tanaka, M, Yamakage, H, Inoue, T, Odori, S, Kusakabe, T, Shimatsu, A, Satoh-Asahara, N
Internal medicine (Tokyo, Japan). 2020;(5):601-609
Abstract
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.
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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.
Inoue, H, Morino, K, Ugi, S, Tanaka-Mizuno, S, Fuse, K, Miyazawa, I, Kondo, K, Sato, D, Ohashi, N, Ida, S, et al
Journal of diabetes investigation. 2019;(4):1012-1021
Abstract
AIMS/INTRODUCTION Sodium-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 METHODS In 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. RESULTS BW 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. CONCLUSIONS Ipragliflozin 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.
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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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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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Inhibition Mechanisms of Rhodococcus Erythropolis 2'-Hydroxybiphenyl-2-sulfinate Desulfinase (DszB).
Yu, Y, Mills, LC, Englert, DL, Payne, CM
The journal of physical chemistry. B. 2019;(43):9054-9065
Abstract
Naturally occurring enzymatic pathways enable highly specific, rapid thiophenic sulfur cleavage occurring at ambient temperature and pressure, which may be harnessed for the desulfurization of petroleum-based fuel. One pathway found in bacteria is a four-step catabolic pathway (the 4S pathway) converting dibenzothiophene (DBT), a common crude oil contaminant, into 2-hydroxybiphenyl (HBP) without disrupting the carbon-carbon bonds. 2'-Hydroxybiphenyl-2-sulfinate desulfinase (DszB), the rate-limiting enzyme in the enzyme cascade, is capable of selectively cleaving carbon-sulfur bonds. Accordingly, understanding the molecular mechanisms of DszB activity may enable development of the cascade as industrial biotechnology. Based on crystallographic evidence, we hypothesized that DszB undergoes an active site conformational change associated with the catalytic mechanism. Moreover, we anticipated this conformational change is responsible, in part, for enhancing product inhibition. Rhodococcus erythropolis IGTS8 DszB was recombinantly produced and purified via Escherichia coli BL21 to test these hypotheses. Activity and the resulting conformational change of DszB in the presence of HBP were evaluated. The activity of recombinant DszB was comparable to the natively expressed enzyme and was inhibited via competitive binding of the product, HBP. Using circular dichroism, global changes in DszB conformation were monitored in response to HBP concentration, which indicated that both product and substrate produced similar structural changes. Molecular dynamics (MD) simulations and free energy perturbation with Hamiltonian replica exchange molecular dynamics (FEP/λ-REMD) calculations were used to investigate the molecular-level phenomena underlying the connection between conformation change and kinetic inhibition. In addition to the HBP, MD simulations of DszB bound to common, yet structurally diverse, crude oil contaminants 2',2-biphenol (BIPH), 1,8-naphthosultam (NTAM), 2-biphenyl carboxylic acid (BCA), and 1,8-naphthosultone (NAPO) were performed. Analysis of the simulation trajectories, including root-mean-square fluctuation (RMSF), center of mass (COM) distances, and strength of nonbonded interactions, when compared with FEP/λ-REMD calculations of ligand binding free energy, showed excellent agreement with experimentally determined inhibition constants. Together, the results show that the combination of a molecule's hydrophobicity and nonspecific interactions with nearby functional groups contributes to a competitive inhibition mechanism that locks DszB in a closed conformation and precludes substrate access to the active site.
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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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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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Factors with remission of fatty liver in patients with type 2 diabetes treated with ipragliflozin.
Yamauchi, Y, Nakamura, A, Takahashi, K, Takase, T, Yamamoto, C, Yokota, I, Atsumi, T, Miyoshi, H
Endocrine journal. 2019;(11):995-1000
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We investigated the factors associated with fatty liver remission via treatment with ipragliflozin. The analysis was obtained from our multi-center prospective observational study, including 200 Japanese patients with type 2 diabetes treated with ipragliflozin (50 mg/day) for 24 weeks. The extent of fatty liver was estimated using a fatty liver index (FLI). Based on the FLI after the treatment with ipragliflozin, patients were classified into remission group (FLI < 30) and non-remission group (FLI ≥ 30). After treatment with ipragliflozin for 24 weeks, FLI significantly improved from 64.5 ± 21.6 to 51.9 ± 26.5 (p < 0.01). Body weight, body mass index, waist circumference, aspartate aminotransferase, alanine aminotransferase, and FLI in the remission group were significantly lower compared with those of the non-remission group. Stepwise analysis showed that the baseline FLI (Odds ratio 0.86; 95% confidence interval 0.81-0.90, p < 0.01) was an independent factor associated with FLI remission. Using a receiver operating characteristic (ROC) analysis, the adequate cut-off value for the remission was 50. The area under the ROC curve was 0.93 with the sensitivity and specificity 84.6% and 90.1% respectively. In conclusion, ipragliflozin ameliorated fatty liver. These results suggest that patients with fatty liver with a lower FLI are more likely to attain remission by the treatment with ipragliflozin.