Journal Club OrbanT, Bundy B, Becker DJ, Dimeglio LA, Gitelman SE, Goland R, Gottlieb PA, Greenbaum CJ, Marks JB, Monzavi R, Moran A, Raskin P, Rodriguez H, Russell WE, Schatz D, Wherrett D, Wilson DM, Krischer JP, Skyler JS; the Type 1 Diabetes TrialNetAbatacept Study Group. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet. 2011 Jun 28. [Epub ahead of print] Avanzini F, Marelli G, Donzelli W, Busi G, Carbone S, Bellato L, Colombo EL, Foschi R, Riva E, Roncaglioni MC, De Martini M; on behalf of the Desio Diabetes Diagram Study Group. Transition From Intravenous to Subcutaneous Insulin: Effectiveness and safety of a standardized protocol and predictors of outcome in patients with acute coronary syndrome. Diabetes Care. 2011 Jul;34(7):1445-1450. Epub 2011 May 18. 埼玉医科大学 総合医療センター 内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田 昌文 Matsuda, Masafumi 2011年7月21日8:30-8:55 ８階 医局
Figure: Role of co-stimulation in immunopathogenesis and immune intervention in type 1 diabetes β-cell proteins are taken up by antigen-presenting cells (APC) and presented by HLA molecules to the immune system. Naive autoreactive T cells (Tn) recognise that these proteins could be primed to become proinflammatoryeffector T cells (Th1) through co-stimulation by CD28 on T cells with CD80 or CD86 on APC. Effector Th1 cells orchestrate cascade of autoimmune responses that include activation of B cells to produce islet autoantibodies and cytotoxic T cells to lyse β cells expressing islet autoantigen. Once T cells have become activated, they become less dependent on co-stimulation. Regulatory T cells (Tregs) engage co-stimulatory molecule CTLA4 endorsing negative immune regulation to inhibit immune effector T cells. Modulation of co-stimulation via CTLA4 by abatacept interferes with priming of naive T cells through competition with CD28. This could prevent priming of naive T cells and avoid spreading of autoimmune response and progression of disease. Conversely, blockade of CTLA4 with antibody represses regulatory T cells and promotes proinflammatory T-cell responses. abatacept (CTLA4 immunoglobulin fusion protein), believed to interfere with priming and activation of T cells,
Joslin Diabetes Center, Boston, MA, USA (T Orban MD); University of South Florida, Tampa, FL, USA (B Bundy PhD, Prof J P Krischer PhD); University of Pittsburgh, Pittsburgh, PA, USA (Prof D J Becker MD); Indiana University School of Medicine, Indianapolis, IN, USA (L A DiMeglio MD, Prof H Rodriguez MD); University of California San Francisco, San Francisco, CA, USA (Prof S E Gitelman MD); Columbia University, New York, NY, USA (Prof R Goland MD); University of Colorado Barbara Davis Center for Childhood Diabetes, Aurora, CO, USA (Prof P A Gottlieb MD); Benaroya Research Institute, Seattle, WA, USA (C J Greenbaum MD); University of Miami Diabetes Research Institute, Miami, FL, USA (Prof J B Marks MD, Prof J S Skyler MD); Children’s Hospital Los Angeles, Los Angeles, CA, USA (R Monzavi MD); University of Minnesota, Minneapolis, MN, USA (Prof A Moran MD); University of Texas Southwestern Medical School, Dallas, TX, USA (Prof P Raskin MD); Vanderbilt University, Nashville, TN, USA (Prof W E Russell MD); University of Florida, Gainesville, FL, USA (Prof D Schatz MD); Hospital for Sick Children, University of Toronto, Toronto, ON, Canada (D Wherrett MD); and Stanford University, Stanford, CA, USA (Prof D M Wilson MD) doi:10.1016/S0140-6736(11)60886-6 www.thelancet.com Published online June 28, 2011
Background The immunopathogenesis of type 1 diabetes mellitus is associated with T-cell autoimmunity. To be fully active, immune T cells need a co-stimulatory signal in addition to the main antigen-driven signal. Abatacept modulates co-stimulation and prevents full T-cell activation. We evaluated the effect of abatacept in recent-onset type 1 diabetes.
Methods In this multicentre, double-blind, randomised controlled trial, patients aged 6–45 years recently diagnosed with type 1 diabetes were randomly assigned (2:1) to receive abatacept (10 mg/kg, maximum 1000 mg per dose) or placebo infusions intravenously on days 1, 14, 28, and monthly for a total of 27 infusions over 2 years. Computergenerated permuted block randomisation was used, with a block size of 3 and stratified by participating site. Neither patients nor research personnel were aware of treatment assignments. The primary outcome was baseline-adjusted geometric mean 2-h area-under-the-curve (AUC) serum C-peptide concentration after a mixed-meal tolerance test at 2 years’ follow-up. Analysis was by intention to treat for all patients for whom data were available. This trial is registered at ClinicalTrials.gov, NCT00505375.
We screened patients (aged 6–45 years) diagnosed with type 1 diabetes within the past 100 days. Patients were eligible to participate in the study if they had at least one diabetes-related autoantibody (microassayed insulin antibodies [if duration of insulin therapy was less than 7 days]; glutamic acid decarboxylase-65 [GAD-65] antibodies; islet-cell antigen-512 [ICA-512] antibodies; or islet-cell autoantibodies) and had stimulated C-peptide concentrations of 0・2 nmol/L or higher measured during a mixed-meal tolerance test (MMTT) done at least 21 days after diagnosis of diabetes and within 37 days of randomisation.
β-cell function was assessed by stimulated C-peptide secretion. The prespecifiedprimary outcome of this trial was a comparison of the area under the curve (AUC) of stimulated C-peptide response over the first 2 h of a 4-h MMTT, done at the 24-month visit. 4-h MMTTs were done at baseline and at 24 months; 2-h MMTTs were obtained at 3, 6, 12, and 18 months.
Figure 5: The population mean of (A) HbA1c and (B) insulin use over time for each treatment group Estimates are from the ANCOVA model adjusting for age, sex, baseline value of HbA1c, and treatment assignment. Insulin use is per kg of bodyweight, at 3-month intervals. Error bars show 95% CIs. HbA1c=glycatedhaemoglobin A1c.
Example • Grade 1, Mild: Transient or mild discomfort; no limitation in activity; no medical intervention/therapy required • Grade 2, Moderate: Mild to moderate limitation in activity –some assistance may be needed; no or minimal medical intervention/therapy required • Grade 3, Severe: Marked limitation in activity, some assistance usually required; medical intervention/therapy required and hospitalization possible • Grade 4, Life-Threatening: Extreme limitation in activity, significant assistance required; significant medical intervention/therapy required; hospitalization or hospice care probable • Grade 5, death
Findings 112 patients were assigned to treatment groups (77 abatacept, 35 placebo). Adjusted C-peptide AUC was 59% (95% CI 6・1–112) higher at 2 years with abatacept (n=73, 0・378 nmol/L) than with placebo (n=30, 0・238 nmol/L; p=0・0029). The difference between groups was present throughout the trial, with an estimated 9・6 months’ delay (95% CI 3・47–15・6) in C-peptide reduction with abatacept. There were few infusion-related adverse events (36 reactions occurred in 17 [22%] patients on abatacept and 11 reactions in six [17%] on placebo). There was no increase in infections (32 [42%] patients on abataceptvs15 [43%] on placebo) or neutropenia (seven [9%] vsfi ve [14%]).
Interpretation Co-stimulation modulation with abatacept slowed reduction in β-cell function over 2 years. The beneficial effect suggests that T-cell activation still occurs around the time of clinical diagnosis of type 1 diabetes. Yet, despite continued administration of abatacept over 24 months, the decrease in β-cell function with abatacept was parallel to that with placebo after 6 months of treatment, causing us to speculate that T-cell activation lessens with time. Further observation will establish whether the beneficial effect continues after cessation of abatacept infusions. Funding US National Institutes of Health.
the 1Division of Cardiology and Intensive Cardiac Care Unit, Ospedale di Desio, Desio, Italy; the 2Istituto di RicercheFarmacologiche “Mario Negri,” Milan, Italy; and the 3Diabetes and Metabolic Diseases Unit, Ospedale di Desio, Desio, Italy Diabetes Care 34:1445–1450, 2011
OBJECTIVE—The study objectives were 1) to assess the effectiveness and safety of a standardized protocol for the transition to subcutaneous insulin and oral feeding in diabetic or hyperglycemic patients with acute coronary syndrome (ACS) who were receiving intravenous insulin and glucose at the time of the transfer from the intensive cardiac care unit to a general ward and 2) to identify predictors of transition outcome.
RESEARCH DESIGN AND METHODS—This was a prospective observational study. The protocol specifies that patients receive a 100% of their daily subcutaneous insulin requirement from the first day of oral feeding, calculated from the intravenous insulin rate during the final 12 h divided into two: 50% basal and 50% prandial.
Safety of the protocol Pre- or postprandial hypoglycemia (BG ,70 mg/dL) was observed in 11 patients (7.7%) on the first day after transition from intravenous to subcutaneous insulin, in 21 patients (14.8%) on the second day, and in 20 patients (14.1%) on the third day. Overall, 38 patients (26.8%) presented at least one episode of hypoglycemia in the first 3 days after transition. BG was ,70 mg/dL 13 times on the first day (2.8% of BG measured before meals and 0.2% of BG measured after meals), 25 times on the second day (3.7% of pre- and 2.6% of postprandial BG measurements), and 23 times on the third day (3.7% of pre- and 2.4% of postprandial BG measurements). Of all the 61 hypoglycemic episodes in the first 3 days after transition, 2 (3.3%) were ,40 mg/dL, 3 (4.9%) were 40–49 mg/dL, 11 (18.0%) were 50–59 mg/dL, and the majority (45, 73.8%) were 60– 69 mg/dL. All hypoglycemic episodes were asymptomatic, with no manifest clinical consequences. Among the 38 patients with hypoglycemic episodes during the first 3 days after transition to subcutaneous insulin, there was one death (2.6%) and six major nonlethal cardiovascular complications (15.8%). The corresponding figures for 104 patients without hypoglycemic events were 2 (1.9%) and 9 (7.7%).
Predictors of outcomes of the transition from intravenous to subcutaneous insulin The transition to subcutaneous insulin was successful (half or more of all firstday BG values in the strict ranges of 100– 140 mg/dL before meals and 100–180 after meals) in 75 patients (52.8%) and unsuccessful in 67 patients (47.2%). Variables associated with unsuccessful transition by multivariate analysis were old age (≧72 years, OR 2.292, 95% CI 1.082–4.856), high mean dose of intravenous insulin infused in the 24 h preceding the transition (≧1.6 units/h, OR 2.202, 95% CI 1.045–4.640), and wide BG coefficient of variation in the 24 h preceding the transition (≧11.9%, OR 1.751, 95% CI 0.841–3.646).
RESULTS—In 142 patients (93 male, 49 female, age range 47–88 years, 135 with known diabetes) the first day after transition, 44.8% of blood glucose (BG) measurements were within the strict range of 100–140 mg/dLbefore meals and 100–180mg/dLafter meals, and 70.8%were within the broader ranges of 80–160 mg/dL and 80–200 mg/dL, respectively. Pre- or postprandial hypoglycemia (BG ,70 mg/dL) occurred in 11 patients (7.7%) on the first day and in 38 patients (26.8%) on the first 3 days after transition. Old age, high doses of intravenous insulin, and wide BG variations in the 24 h before insulin infusion was stopped were predictive of poor BG control after transition.
CONCLUSIONS—This study shows the effectiveness and safety of a standardized protocol for the transition from intravenous to subcutaneous insulin in patients with ACS when regular oral feeding was resumed.
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