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iGlarLixi reduces residual hyperglycemia in Japanese patients with type 2 diabetes uncontrolled on basal insulin: A post-hoc analysis of the LixiLan JP-L trial.
Yabe, D, Iizuka, K, Baxter, M, Watanabe, D, Kaneto, H
Journal of diabetes investigation. 2021;(11):1992-2001
Abstract
INTRODUCTION Treatments for type 2 diabetes targeting baseline glucose levels but not postprandial glucose can result in normalized fasting blood glucose but suboptimal overall glycemic control (high glycated hemoglobin): residual hyperglycemia. In Japanese patients with type 2 diabetes the predominant pathophysiology is a lower insulin secretory capacity, and residual hyperglycemia is common with basal insulin treatment. Single-injection, fixed-ratio combinations of glucagon-like peptide-1 receptor agonists and basal insulin have been developed. iGlarLixi (insulin glargine 100 units/mL [iGlar]: lixisenatide ratio of 1 unit:1 µg) is for specific use in Japan. Post-hoc analysis of the LixiLan JP-L trial (NCT02752412) compared the effect of iGlarLixi with iGlar on this specific subpopulation with residual hyperglycemia. MATERIALS AND METHODS Outcomes at week 26 (based on the last observation carried forward) were assessed in patients in the modified intent-to-treat population with baseline residual hyperglycemia. RESULTS Overall, 83 (32.5%) patients in the iGlarLixi group and 79 (30.7%) patients in the iGlar group had baseline residual hyperglycemia. The proportion of patients with residual hyperglycemia at week 26 decreased to 15.7% in the iGlarLixi group, and increased to 36.9% in the iGlar group. Patients in the iGlarLixi group had significantly greater reductions in glycated hemoglobin compared with the iGlar group (-0.72% difference between groups; P < 0.0001). CONCLUSIONS New data from this post-hoc analysis of the JP-L trial show that treatment with the fixed-ratio combination iGlarLixi reduced the proportion of Japanese patients with residual hyperglycemia from baseline to week 26 and significantly reduced glycated hemoglobin vs similar doses of iGlar alone.
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Poor Sensitivity of Fecal Gluten Immunogenic Peptides and Serum Antibodies to Detect Duodenal Mucosal Damage in Celiac Disease Monitoring.
Laserna-Mendieta, EJ, Casanova, MJ, Arias, Á, Arias-González, L, Majano, P, Mate, LA, Gordillo-Vélez, CH, Jiménez, M, Angueira, T, Tébar-Romero, E, et al
Nutrients. 2020;(1)
Abstract
A lifelong gluten-free diet (GFD) is the only current treatment for celiac disease (CD), but strict compliance is complicated. Duodenal biopsies are the "gold standard" method for diagnosing CD, but they are not generally recommended for disease monitoring. We evaluated the sensitivity and specificity of fecal gluten immunogenic peptides (GIPs) to detect duodenal lesions in CD patients on a GFD and compared them with serum anti-tissue transglutaminase (tTG) IgA antibodies. A prospective study was conducted at two tertiary centers in Spain on a consecutive series of adolescents and adults with CD who maintained a long-lasting GFD. Adherence to a GFD and health-related quality of life were scored with validated questionnaires. Mucosal damage graded according to the Marsh-Oberhüber classification (Marsh 1/2/3) was used as the reference standard. Of the 97 patients included, 27 presented duodenal mucosal damage and 70 had normal biopsies (Marsh 0). The sensitivity (33%) and specificity (81%) of GIPs were similar to those provided by the two assays used to measure anti-tTG antibodies. Scores in questionnaires showed no association with GIP, but an association between GIPs and patients' self-reported gluten consumption was found (p = 0.003). GIP displayed low sensitivity but acceptable specificity for the detection of mucosal damage in CD.
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Impact of Teduglutide on Quality of Life Among Patients With Short Bowel Syndrome and Intestinal Failure.
Chen, K, Mu, F, Xie, J, Kelkar, SS, Olivier, C, Signorovitch, J, Jeppesen, PB
JPEN. Journal of parenteral and enteral nutrition. 2020;(1):119-128
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BACKGROUND Teduglutide reduces or eliminates parenteral support (PS) dependency in patients with short bowel syndrome (SBS). Recent post hoc analyses demonstrated that effects are correlated with baseline PS volume. We assessed the SBS-related quality-of-life (QoL) impact of teduglutide, particularly whether improvements are greater among subgroups achieving more PS volume reduction. METHODS Using phase 3 trial data of teduglutide in patients with SBS (NCT00798967), change in Short Bowel Syndrome-Quality of Life (SBS-QoL) scores from baseline were compared between teduglutide vs placebo in the overall population and subgroups classified by baseline PS volume requirement, disease etiology, and bowel anatomy. Generalized estimating equation models were fitted to assess impact of teduglutide on SBS-related QoL using data from all visits, adjusted for baseline characteristics. RESULTS Of 86 patients, 43 each were randomized to teduglutide or placebo (mean age: 51 vs 50 years, respectively). In adjusted analyses, teduglutide had a nonsignificant reduction (improvement) of -8.6 points (95% CI: 2.6 to -19.8) in SBS-QoL sum score from baseline to Week-24 vs placebo. The impact of teduglutide varied by subgroup. Patients treated with teduglutide experienced significantly greater reductions in SBS-QoL sum score at Week-24 vs placebo in 2 subgroups, ie, the third (highest) tertile baseline PS volume (-27.3, 95% CI: -50.8 to -3.7) and inflammatory bowel disease (IBD; -29.6, 95% CI: -46.3 to -12.9). Results were similar for SBS-QoL subscale and item scores. CONCLUSIONS The impact of teduglutide treatment on SBS-related QoL vs placebo varied among subgroups and was significant and most pronounced among patients with highest baseline PS volume requirement or IBD.
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Citrulline correlations in short bowel syndrome-intestinal failure by patient stratification: Analysis of 24 weeks of teduglutide treatment from a randomized controlled study.
Jeppesen, PB, Gabe, SM, Seidner, DL, Lee, HM, Olivier, C
Clinical nutrition (Edinburgh, Scotland). 2020;(8):2479-2486
Abstract
BACKGROUND & AIMS Disease-associated factors influence parenteral support (PS) reduction in response to teduglutide in patients with intestinal failure associated-short bowel syndrome (SBS-IF). We sought to determine correlative relationships between plasma citrulline levels, small bowel length, and PS volume. METHODS A post hoc analysis of plasma citrulline levels from patients in the STEPS 24-week study of teduglutide in patients with SBS-IF. Plasma citrulline was assessed in all patients; patients were stratified 3 times into subgroups based on bowel anatomy, cause of SBS-IF, and baseline PS volumes. Correlation analyses used simple linear regression models. Statistical comparisons between study groups were conducted using 2-sided t tests for 2 independent mean differences. RESULTS Baseline plasma citrulline correlated with remnant small bowel length (r = 0.355, P = 0.002), but not with baseline PS volume (r = -0.167, P = 0.14), in the overall population. There was a robust correlation between the baseline and Week 24 citrulline (r = 0.705, P < 0.0001), and an inverse correlation between change from baseline in citrulline and PS volume from baseline to Week 24 (r = -0.359, P = 0.001). In all subgroups, patients treated with teduglutide showed numerically greater increases in plasma citrulline at Week 24 compared with placebo. CONCLUSION Baseline plasma citrulline showed significant correlations with small bowel length in patients with ≥50% colon remaining/no stoma/colon-in-continuity, and patients with SBS-IF causes other than IBD/vascular disease. Citrulline levels may correlate with PS changes in response to teduglutide and more research may reveal a relationship between citrulline levels within the heterogeneous population of patients with SBS-IF. ClinicalTrials.gov NCT00798967, ClinicalTrialsRegister.eu 2008-006193-15.
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Interferon Gamma-1b Does Not Increase Markers of Bone Resorption in Autosomal Dominant Osteopetrosis.
Imel, EA, Liu, Z, Acton, D, Coffman, M, Gebregziabher, N, Tong, Y, Econs, MJ
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2019;(8):1436-1445
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In autosomal dominant osteopetrosis type 2 (ADO2) CLCN7 mutations cause impaired osteoclast function. Severe consequences include skeletal fragility despite high bone mass, osteomyelitis, osteonecrosis, bone marrow failure, and severe cranial nerve impingement. There is no effective medical treatment for ADO2. We recruited subjects with ADO2 into a 14-week, open-label, pilot clinical trial of interferon gamma-1b. Doses were titrated based on tolerability and if fasting serum C-telopeptide (CTX) was <25% above baseline at week 8, targeting doses of 100 µg/m2 three times a week. The primary outcomes were change from baseline in CTX and N-telopeptide/creatinine ratio (NTX/Cr) at week 14. Secondary outcomes included changes in urine calcium/creatinine ratio, bone formation markers and tolerability. Nine adults and three children were recruited. Severe manifestations of ADO2 included histories of fractures (100%), osteomyelitis (16.7%), vision loss (50%), and anemia (58.3%). Baseline CTX and NTX/Cr were generally low-normal. Procollagen type I N-terminal propeptide was elevated or in the upper-normal range in 11 of 12 (91.6%) subjects. Elevations of aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were common. One subject withdrew due to rash. Five subjects achieved doses of 50 µg/m2 3 days a week, while six reached the full dose of 100 µg/m2 3 days a week. Only 3 of 11 (27.3%) completing subjects achieved the primary outcome of increasing CTX ≥25% above baseline at week 14. The mean ± SD change from baseline in CTX at week 14 was +2.2% ± 43.2%, p = 0.86). Likewise, there was no significant change in NTX/Cr (mean change -2.1%, p = 0.81). Interferon gamma-1b was poorly tolerated. Most subjects had adverse events, and the Mental Health and Mental Component Scales of the SF-36v2 health survey declined slightly (p < 0.05). Over 14 weeks, interferon gamma-1b failed to significantly increase bone turnover markers in ADO2 and was poorly tolerated. Consequently, interferon gamma-1b is unlikely to be effective for decreasing bone mass in ADO2. © 2019 American Society for Bone and Mineral Research.
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Phase I/II trial testing safety and immunogenicity of the multipeptide IMA950/poly-ICLC vaccine in newly diagnosed adult malignant astrocytoma patients.
Migliorini, D, Dutoit, V, Allard, M, Grandjean Hallez, N, Marinari, E, Widmer, V, Philippin, G, Corlazzoli, F, Gustave, R, Kreutzfeldt, M, et al
Neuro-oncology. 2019;(7):923-933
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BACKGROUND Peptide vaccines offer the opportunity to elicit glioma-specific T cells with tumor killing ability. Using antigens eluted from the surface of glioblastoma samples, we designed a phase I/II study to test safety and immunogenicity of the IMA950 multipeptide vaccine adjuvanted with poly-ICLC (polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose) in human leukocyte antigen A2+ glioma patients. METHODS Adult patients with newly diagnosed glioblastoma (n = 16) and grade III astrocytoma (n = 3) were treated with radiochemotherapy followed by IMA950/poly-ICLC vaccination. The first 6 patients received IMA950 (9 major histocompatibility complex [MHC] class I and 2 MHC class II peptides) intradermally and poly-ICLC intramuscularly (i.m.). After protocol amendment, IMA950 and poly-ICLC were mixed and injected subcutaneously (n = 7) or i.m. (n = 6). Primary endpoints were safety and immunogenicity. Secondary endpoints were overall survival, progression-free survival at 6 and 9 months, and vaccine-specific peripheral cluster of differentiation (CD)4 and CD8 T-cell responses. RESULTS The IMA950/poly-ICLC vaccine was safe and well tolerated. Four patients presented cerebral edema with rapid recovery. For the first 6 patients, vaccine-induced CD8 T-cell responses were restricted to a single peptide and CD4 responses were absent. After optimization of vaccine formulation, we observed multipeptide CD8 and sustained T helper 1 CD4 T-cell responses. For the entire cohort, CD8 T-cell responses to a single or multiple peptides were observed in 63.2% and 36.8% of patients, respectively. Median overall survival was 19 months for glioblastoma patients. CONCLUSION We provide, in a clinical trial, using cell surface-presented antigens, insights into optimization of vaccines generating effector T cells for glioma patients. TRIAL REGISTRATION Clinicaltrials.gov NCT01920191.
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Patients With Short Bowel on Narcotics During 2 Randomized Trials Have Abdominal Complaints Independent of Teduglutide.
Fujioka, K, Jeejeebhoy, K, Pape, UF, Li, B, Youssef, NN, Schneider, SM
JPEN. Journal of parenteral and enteral nutrition. 2017;(8):1419-1422
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BACKGROUND Narcotic agents are frequently administered to manage increased intestinal motility in patients with short bowel syndrome, but long-term use is associated with gastrointestinal (GI) complaints. This analysis evaluated the incidence of narcotic use and abdominal adverse events among patients with short bowel syndrome receiving teduglutide. MATERIALS AND METHODS Pooled data from patients who received ≥1 dose of teduglutide 0.05 mg/kg/d (n = 77) or placebo (n = 59) in either of 2 randomized, double-blind, phase III studies were analyzed. RESULTS Of 136 patients, 52 (38%) received narcotics. GI adverse events occurred more often among patients who received narcotics than among those who did not (abdominal pain, 51% vs 21%; nausea, 42% vs 11%; abdominal distension, 17% vs 8%; vomiting, 19% vs 6%). Logistic regression analysis indicated that the probability of GI adverse events was significantly increased in patients with narcotic use ( P = .0009). In contrast, teduglutide treatment, as well as the interaction between teduglutide and narcotic use, did not affect the probability of GI adverse events. CONCLUSIONS These results suggest that patients with short bowel syndrome receiving narcotics have chronic GI complaints independent of teduglutide treatment. Data included in this analysis were derived from ClinicalTrials.gov NCT00081458 and NCT00798967 (EudraCT 2004-000438-35 and 2008-006193-15).
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Clinical Effectiveness of Intravenous Exenatide Infusion in Perioperative Glycemic Control after Coronary Artery Bypass Graft Surgery: A Phase II/III Randomized Trial.
Besch, G, Perrotti, A, Mauny, F, Puyraveau, M, Baltres, M, Flicoteaux, G, Salomon du Mont, L, Barrucand, B, Samain, E, Chocron, S, et al
Anesthesiology. 2017;(5):775-787
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BACKGROUND We aimed to assess the clinical effectiveness of intravenous exenatide compared to insulin in perioperative blood glucose control in coronary artery bypass grafting surgery patients. METHODS Patients more than 18 yr old admitted for elective coronary artery bypass grafting were included in a phase II/III nonblinded randomized superiority trial. Current insulin use and creatinine clearance of less than 60 ml/min were exclusion criteria. Two groups were compared: the exenatide group, receiving exenatide (1-h bolus of 0.05 µg/min followed by a constant infusion of 0.025 µg/min), and the control group, receiving insulin therapy. The blood glucose target range was 100 to 139 mg/dl. The primary outcome was the proportion of patients who spent at least 50% of the study period within the target range. The consumption of insulin (Cinsulin) and the time to start insulin (Tinsulin) were compared between the two groups. RESULTS In total, 53 and 51 patients were included and analyzed in the exenatide and control groups, respectively (age: 70 ± 9 vs. 68 ± 11 yr; diabetes mellitus: 12 [23%] vs. 10 [20%]). The primary outcome was observed in 38 (72%) patients in the exenatide group and in 41 (80%) patients in the control group (odds ratio [95% CI] = 0.85 [0.34 to 2.11]; P = 0.30). Cinsulin was significantly lower (60 [40 to 80] vs. 92 [63 to 121] U, P < 0.001), and Tinsulin was significantly longer (12 [7 to 16] vs. 7 [5 to 10] h, P = 0.02) in the exenatide group. CONCLUSIONS Exenatide alone at the dose used was not enough to achieve adequate blood glucose control in coronary artery bypass grafting patients, but it reduces overall consumption of insulin and increases the time to initiation of insulin.
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A phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, for secondary hyperparathyroidism in Japanese haemodialysis patients.
Fukagawa, M, Yokoyama, K, Shigematsu, T, Akiba, T, Fujii, A, Kuramoto, T, Odani, M, Akizawa, T, ,
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2017;(10):1723-1730
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BACKGROUND Secondary hyperparathyroidism (SHPT) is a major complication associated with chronic kidney disease. We evaluated the efficacy and safety of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, in Japanese haemodialysis patients with SHPT. METHODS In this phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study, etelcalcetide was administered three times per week at an initial dose of 5 mg, and subsequently adjusted to doses between 2.5 and 15 mg at 4-week intervals for 12 weeks. A total of 155 SHPT patients with serum intact parathyroid hormone (iPTH) levels ≥300 pg/mL were assigned to receive etelcalcetide (n = 78) or placebo (n = 77). The primary endpoint was the proportion of patients with decreased serum iPTH to the target range proposed by the Japanese Society for Dialysis Therapy (60-240 pg/mL). The major secondary endpoint was the proportion of patients with ≥30% reductions in serum iPTH from baseline. RESULTS The proportion of patients meeting the primary endpoint was significantly higher for etelcalcetide (59.0%) versus placebo (1.3%). Similarly, the proportion of patients meeting the major secondary endpoint was significantly higher for etelcalcetide (76.9%) versus placebo (5.2%). Serum albumin-corrected calcium, phosphorus and intact fibroblast growth factor-23 levels were decreased in the etelcalcetide group. Nausea, vomiting and symptomatic hypocalcaemia were mild with etelcalcetide. Serious adverse events related to etelcalcetide were not observed. CONCLUSIONS This study demonstrated the efficacy and safety of etelcalcetide. As the only available intravenous calcium-sensing receptor agonist, etelcalcetide is likely to provide a new treatment option for SHPT in haemodialysis patients.
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Association of Bone Metabolic Markers With Diabetic Retinopathy and Diabetic Macular Edema in Elderly Chinese Individuals With Type 2 Diabetes Mellitus.
Zhang, X, Yang, J, Zhong, Y, Xu, L, Wang, O, Huang, P, Li, C, Qu, B, Wang, J, Zheng, C, et al
The American journal of the medical sciences. 2017;(4):355-361
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BACKGROUND Diabetic retinopathy (DR) is a common and specific microvascular complication of diabetes. The association of bone metabolic markers with the risk of DR and diabetic macular edema (DME) is unclear. MATERIALS AND METHODS We investigated the association between bone turnover markers commonly examined in a clinical setting and DR and DME risk in elderly Chinese patients with type 2 diabetes mellitus (T2DM). A total of 408 patients aged 55-70 years with T2DM were included. We first performed univariable logistic regression followed by multivariable logistic regression that included variables selected using purposeful selection. RESULTS Fasting blood glucose (P = 0.007) and duration of diabetes (P < 0.0001) were significantly associated with DME in multivariable logistic regression; however, the association of beta C-terminal telopeptide of collagen type I (β-CTx) with DME risk was not statistically significant (P = 0.053). Sex-stratified analysis showed that β-CTx was significantly associated with DME only in female subjects (P = 0.011). CONCLUSIONS β-CTx had no significant association with DR. It was significantly associated with DME in female patients with T2DM, but not in male patients with T2DM. More prospective studies with larger sample sizes are warranted to validate our findings.