Linda A. DiMeglio

Current State of Type 1 Diabetes Treatment in the U.S.: Updated Data From the T1D Exchange Clinic Registry

To examine the overall state of metabolic control and current use of advanced diabetes technologies in the U.S., we report recent data collected on individuals with type 1 diabetes participating in the T1D Exchange clinic registry. Data from 16,061 participants updated between 1 September 2013 and 1 December 2014 were compared with registry enrollment data collected from 1 September 2010 to 1 August 2012. Mean hemoglobin A1c (HbA1c) was assessed by year of age from <4 to >75 years. The overall average HbA1c was 8.2% (66 mmol/mol) at enrollment and 8.4% (68 mmol/mol) at the most recent update. During childhood, mean HbA1c decreased from 8.3% (67 mmol/mol) in 2–4-year-olds to 8.1% (65 mmol/mol) at 7 years of age, followed by an increase to 9.2% (77 mmol/mol) in 19-year-olds. Subsequently, mean HbA1c values decline gradually until ∼30 years of age, plateauing at 7.5–7.8% (58–62 mmol/mol) beyond age 30 until a modest drop in HbA1c below 7.5% (58 mmol/mol) in those 65 years of age. Severe hypoglycemia (SH) and diabetic ketoacidosis (DKA) remain all too common complications of treatment, especially in older (SH) and younger patients (DKA). Insulin pump use increased slightly from enrollment (58–62%), and use of continuous glucose monitoring (CGM) did not change (7%). Although the T1D Exchange registry findings are not population based and could be biased, it is clear that there remains considerable room for improving outcomes of treatment of type 1 diabetes across all age-groups. Barriers to more effective use of current treatments need to be addressed and new therapies are needed to achieve optimal metabolic control in people with type 1 diabetes.

Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial

BACKGROUND Glutamic acid decarboxylase (GAD) is a major target of the autoimmune response that occurs in type 1 diabetes mellitus. In animal models of autoimmunity, treatment with a target antigen can modulate aggressive autoimmunity. We aimed to assess whether immunisation with GAD formulated with aluminum hydroxide (GAD-alum) would preserve insulin production in recent-onset type 1 diabetes. METHODS Patients aged 3-45 years who had been diagnosed with type 1 diabetes for less than 100 days were enrolled from 15 sites in the USA and Canada, and randomly assigned to receive one of three treatments: three injections of 20 μg GAD-alum, two injections of 20 μg GAD-alum and one of alum, or 3 injections of alum. Injections were given subcutaneously at baseline, 4 weeks later, and 8 weeks after the second injection. The randomisation sequence was computer generated at the TrialNet coordinating centre. Patients and study personnel were masked to treatment assignment. The primary outcome was the baseline-adjusted geometric mean area under the curve (AUC) of serum C-peptide during the first 2 h of a 4-h mixed meal tolerance test at 1 year. Secondary outcomes included changes in glycated haemoglobin A(1c) (HbA(1c)) and insulin dose, and safety. Analysis included all randomised patients with known measurements. This trial is registered with ClinicalTrials.gov, number NCT00529399. FINDINGS 145 patients were enrolled and treated with GAD-alum (n=48), GAD-alum plus alum (n=49), or alum (n=48). At 1 year, the 2-h AUC of C-peptide, adjusted for age, sex, and baseline C-peptide value, was 0·412 nmol/L (95% CI 0·349-0·478) in the GAD-alum group, 0·382 nmol/L (0·322-0·446) in the GAD-alum plus alum group, and 0·413 nmol/L (0·351-0·477) in the alum group. The ratio of the population mean of the adjusted geometric mean 2-h AUC of C-peptide was 0·998 (95% CI 0·779-1·22; p=0·98) for GAD-alum versus alum, and 0·926 (0·720-1·13; p=0·50) for GAD-alum plus alum versus alum. HbA(1c), insulin use, and the occurrence and severity of adverse events did not differ between groups. INTERPRETATION Antigen-based immunotherapy therapy with two or three doses of subcutaneous GAD-alum across 4-12 weeks does not alter the course of loss of insulin secretion during 1 year in patients with recently diagnosed type 1 diabetes. Although antigen-based therapy is a highly desirable treatment and is effective in animal models, translation to human autoimmune disease remains a challenge. FUNDING US National Institutes of Health.

Most Youth With Type 1 Diabetes in the T1D Exchange Clinic Registry Do Not Meet American Diabetes Association or International Society for Pediatric and Adolescent Diabetes Clinical Guidelines

OBJECTIVE To assess the proportion of youth with type 1 diabetes under the care of pediatric endocrinologists in the United States meeting targets for HbA1c, blood pressure (BP), BMI, and lipids. RESEARCH DESIGN AND METHODS Data were evaluated for 13,316 participants in the T1D Exchange clinic registry younger than 20 years old with type 1 diabetes for ≥1 year. RESULTS American Diabetes Association HbA1c targets of <8.5% for those younger than 6 years, <8.0% for those 6 to younger than 13 years old, and <7.5% for those 13 to younger than 20 years old were met by 64, 43, and 21% of participants, respectively. The majority met targets for BP and lipids, and two-thirds met the BMI goal of <85th percentile. CONCLUSIONS Most children with type 1 diabetes have HbA1c values above target levels. Achieving American Diabetes Association goals remains a significant challenge for the majority of youth in the T1D Exchange registry.

Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials

BACKGROUND Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes. METHODS We did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0·2 nM. Patients in the canakinumab trial were aged 6-45 years and those in the anakinra trial were aged 18-35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00947427 and NCT00711503, and EudraCT number 2007-007146-34. FINDINGS Patients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0·01 nmol/L (95% CI -0·11 to 0·14; p=0·86), and between the anakinra and the placebo groups at 9 months was 0·02 nmol/L (-0·09 to 0·15; p=0·71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0·018), which was mainly because of a higher number of injection site reactions in the anakinra group. INTERPRETATION Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes. Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders. FUNDING National Institutes of Health and Juvenile Diabetes Research Foundation.

Fracture prediction and the definition of osteoporosis in children and adolescents: the ISCD 2007 Pediatric Official Positions.

Osteoporosis in adults has been defined on the basis of densitometric criteria, but at present the term osteoporosis does not have a widely recognized definition in pediatrics. Consequently, the International Society for Clinical Densitometry (ISCD) 2007 Position Development Conference reviewed the literature describing the relationship between bone densitometric studies and fractures in apparently healthy children and adolescents, and prepared Official Positions regarding the definition of osteoporosis in children and adolescents. The ISCD Official Positions with respect to the above issues, as well as the rationale and evidence used to derive these positions, are presented here.

Consensus Statement: Global Consensus Recommendations on Prevention and Management of Nutritional Rickets

BACKGROUND Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. EVIDENCE A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describe the strength of the recommendation and the quality of supporting evidence. PROCESS Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. RESULTS This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. CONCLUSION Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.

Global Consensus Recommendations on Prevention and Management of Nutritional Rickets

Background: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. Evidence: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describes the strength of the recommendation and the quality of supporting evidence. Process: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. Results: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. Conclusion: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.

In Vitro Hyperglycemia or a Diabetic Intrauterine Environment Reduces Neonatal Endothelial Colony-Forming Cell Numbers and Function

OBJECTIVE—Emerging data demonstrate that maternal diabetes has long-term health consequences for offspring, including the development of hypertension. In adults, circulating endothelial progenitor cells (EPCs) participate in vascular repair, and EPC numbers and function inversely correlate with the risk of developing vascular disease. Therefore, our objectives were to determine whether hyperglycemia or exposure to a diabetic intrauterine environment alters EPC function. RESEARCH DESIGN AND METHODS—We used well-established clonogenic endothelial colony-forming cell (ECFC) assays and murine transplantation experiments to examine human vasculogenesis. RESULTS—Both in vitro hyperglycemia and a diabetic intrauterine environment reduced ECFC colony formation, self-renewal capacity, and capillary-like tube formation in matrigel. This cellular phenotype was linked to premature senescence and reduced proliferation. Further, cord blood ECFCs from diabetic pregnancies formed fewer chimeric vessels de novo after transplantation into immunodeficient mice compared with neonatal ECFCs harvested from uncomplicated pregnancies. CONCLUSIONS—Collectively, these data demonstrate that hyperglycemia or exposure to a diabetic intrauterine environment diminishes neonatal ECFC function both in vitro and in vivo, providing potential mechanistic insights into the long-term cardiovascular complications observed in newborns of diabetic pregnancies.

Two-year clinical trial of oral alendronate versus intravenous pamidronate in children with osteogenesis imperfecta

A 2‐year prospective, partially randomized open‐label trial comparing oral alendronate with intravenous pamidronate therapy in children with OI showed equivalence in increasing total body BMD, spine BMD, and linear growth, and decreasing bone turnover and fracture incidence. Children with mild OI had greater responses than severe OI in BMD and growth.

Safety of tenofovir use during pregnancy: Early growth outcomes in HIV-exposed uninfected infants

Objective:To evaluate the association of tenofovir disoproxil fumarate (TDF) use during pregnancy with early growth parameters in HIV-exposed, uninfected (HEU) infants. Design:US-based prospective cohort study of HEU children to examine potential adverse effects of prenatal TDF exposure. Methods:We evaluated the association of maternal TDF use during pregnancy with small for gestational age (SGA); low birth weight (LBW, <2.5 kg); weight-for-age z-scores (WAZ), length-for-age z-scores (LAZ), and head circumference-for-age (HCAZ) z-scores at newborn visit; and LAZ, HCAZ, and WAZ at age 1 year. Logistic regression models for LBW and SGA were fit, adjusting for maternal and sociodemographic factors. Adjusted linear regression models were used to evaluate LAZ, WAZ, and HCAZ by TDF exposure. Results:Of 2029 enrolled children with maternal antiretroviral information, TDF was used by 449 (21%) HIV-infected mothers, increasing from 14% in 2003 to 43% in 2010. There was no difference between those exposed to combination regimens with vs. without TDF for SGA, LBW, and newborn LAZ and HCAZ. However, at age 1 year, infants exposed to combination regimens with TDF had significantly lower adjusted mean LAZ and HCAZ than those without TDF (LAZ: −0.17 vs. −0.03, P = 0.04; HCAZ: 0.17 vs. 0.42, P = 0.02). Conclusion:TDF use during pregnancy was not associated with increased risk for LBW or SGA. The slightly lower mean LAZ and HCAZ observed at age 1 year in TDF-exposed infants are of uncertain significance but underscore the need for additional studies of growth outcomes after TDF use during pregnancy.